Acute lymphoblastic leukemias: clinical guidelines

List of Abbreviations

allo-HSCT – allogeneic hematopoietic stem cell transplantation

ALT – alanine aminotransferase

AST – aspartate aminotransferase

auto-HSCT – autologous hematopoietic stem cell transplantation

aPTT – activated partial thromboplastin time

RFS – relapse-free survival

WHO classification – World Health Organization classification

G-CSF – granulocyte colony-stimulating factor (L03AA Colony-stimulating factors)

HSC – Hematopoietic Stem Cells

IT – induction therapy

TKI – tyrosine kinase inhibitor (Bruton's tyrosine kinase (BTK) inhibitors, BCR-ABL tyrosine kinase inhibitors, protein kinase inhibitors)

CT – clinical trials

BM – bone marrow

CT – computed tomography

BL – Burkitt lymphoma

LBL – lymphoblastic lymphoma

LDH – lactate dehydrogenase

MRD – minimal residual disease

NHL – non-Hodgkin lymphomas

CBC – complete blood count

OS – overall survival

AL – acute leukemia

ALL – acute lymphoblastic leukemia

AML – acute myeloid leukemia

ARDS – acute respiratory distress syndrome

RT-PCR – reverse transcription polymerase chain reaction

CR – complete remission

PCR – polymerase chain reaction

PET/CT – positron emission tomography/computed tomography

HSCT – hematopoietic stem cell transplantation

LCE – level of confidence of evidence

US – ultrasound examination

GRS – grade of recommendation strength

CT – chemotherapy

CML – chronic myeloid leukemia

CMV — cytomegalovirus

CNS – central nervous system

ECG – electrocardiography

EchoCG – echocardiography

CD – cluster of differentiation

ECOG (Eastern Cooperative Oncology Group status) – Eastern Cooperative Oncology Group performance status scale

EWALL – European Working Group on Adult Acute Lymphoblastic Leukemia

FISH study – fluorescence in situ hybridization assay

GMALL – German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia

GRAALL – Group for Research on Adult Acute Lymphoblastic Leukemia

MD Anderson CRC – MD Anderson Cancer Center Research Group

Ph+ ALL or Ph-positive ALL – acute lymphoblastic leukemia characterized by the t(9;22) translocation

Ph– ALL or Ph-negative ALL – acute lymphoblastic leukemia without detectable t(9;22) translocation

RALL – Russian Adult Acute Lymphoblastic Leukemia Study Group

TdT – terminal deoxynucleotidyl transferase

** – vital and essential drugs

# – drug used off-label (not in accordance with the indications, contraindications, routes of administration, or dosages specified in the drug's package insert)

Terms and Definitions

Acute lymphoblastic leukemias are a heterogeneous group of clonal hematopoietic disorders resulting from mutations in precursor T or B cells.

Ph-negative acute lymphoblastic leukemias are a group combining several acute lymphoblastic leukemia subtypes in which the Philadelphia chromosome (t(9;22)(q34;q11)) is not detected. This includes all B-cell and T-cell acute lymphoblastic leukemias and lymphoblastic lymphomas.

Ph-positive acute lymphoblastic leukemia is a variant of acute lymphoblastic leukemia in which the t(9;22)(q34;q11) translocation is detected by standard cytogenetic analysis (G-banding) or FISH. The diagnosis of Ph-positive acute lymphoblastic leukemia cannot be based solely on molecular detection of the chimeric transcript. Cytogenetic or FISH (in situ hybridization) assays are mandatory. Polymerase chain reaction determines the chimeric transcript variant, which is subsequently used for minimal residual disease monitoring.

Complete remission is a state of hematopoietic tissue characterized by 5% or fewer blast cells in the bone marrow aspirate with normal ratios of all hematopoietic lineages, a peripheral blood neutrophil count >1.0×10⁹/L, a platelet count ≥100×10⁹/L, and no extramedullary sites of leukemic involvement. Morphologic complete remission (and consequently, resistance) is evaluated after either the first or second phase of induction therapy. If complete remission is not achieved after completing two induction phases, refractory acute lymphoblastic leukemia is diagnosed. In this regard, it should be emphasized that in some patients, following the second induction phase and early bone marrow recovery after cytotoxic therapy, an increased percentage of blast cells (up to 10-12%) may be observed. In such cases (especially if complete remission was documented after the first induction phase), it is advisable to perform a repeat sternal puncture (obtaining a bone marrow cytologic specimen by aspiration) one week later against the background of recovered hematopoiesis.

Complete remission may also be characterized as: 1) cytogenetic, 2) molecular, 3) with incomplete recovery of peripheral blood counts, where the neutrophil count is <1×10⁹/L and the platelet count is <100×10⁹/L. The latter category is specified separately because, according to several studies, the prognosis for such patients is somewhat worse. At the same time, experts do not recommend declaring complete remission in such patients. Nevertheless, outside of clinical trials, this response terminology is rarely used.

Partial remission (partial response) – this term is recommended for use only in phase I-II clinical trials evaluating anti-tumor efficacy, toxicity, and tolerability of new drugs and determining their optimal doses.

Refractory form – a form of the disease diagnosed when complete remission is not achieved after the completion of two induction phases.

Early death – patient death during the period of induction therapy (two induction phases for acute lymphoblastic leukemias). It should be emphasized that this criterion is a generalized concept for patient mortality during induction therapy. The term "death during induction" is more commonly used as it more accurately reflects the situation, since in some cases patient death occurs during the second phase of induction therapy despite having achieved complete remission after the first phase. In such instances, the death is considered as death during consolidation or death after achieving complete remission.

Relapse – this state is diagnosed when bone marrow aspirate reveals >5% blast cells. Disease relapse is not diagnosed when a routine follow-up bone marrow aspirate shows >5% but <10% blasts if the bone marrow puncture is performed shortly after a course of chemotherapy, or if hematopoietic growth factors were used to shorten the period of neutropenia, provided that peripheral blood analysis is normal and there are no extramedullary lesions. A second diagnostic aspiration is performed 7-10 days after the first. If the blast percentage remains above 5% or shows an increase (e.g., from 7% to 13%), relapse is diagnosed.

Early relapse – a relapse is designated as early if it is diagnosed less than six months after the end of maintenance therapy or during post-remission therapy. Late relapse is defined as one occurring six months or more after the completion of maintenance therapy. Extramedullary involvement (neuroleukemia, testicular involvement, splenomegaly, etc.) is also considered a relapse, even in the absence of blood and bone marrow changes. Extramedullary relapses (especially central nervous system involvement) occur in approximately 4-8% of cases with modern treatment protocols. If an isolated extramedullary relapse is diagnosed, in addition to local therapy (treatment of neuroleukemia, testicular irradiation/orchiectomy, excision of a leukemic focus in the ovary, etc.), systemic induction therapy according to protocols designated for such relapses is mandatory.

Minimal residual disease, or minimal resistant disease, is a small population of tumor cells that cannot be detected by light microscopy but is identified by more sensitive assays detecting 1 leukemic cell per 10^4-6 cells tested. The main methods for detecting minimal residual disease are flow cytometry and polymerase chain reaction. Standard cytogenetic analysis and FISH are not used to assess minimal residual disease.

Cytogenetic remission is complete clinical and hematologic remission in which standard cytogenetic techniques fail to detect the original karyotypic abnormalities; the karyotype must be normal, and the number of analyzed metaphases must be at least 20. Cytogenetic remission is a new concept that emerged with the regular use of cytogenetic methods for bone marrow aspirates during complete remission.

Cytogenetic relapse is a relapse diagnosed when mitoses with chromosomal aberrations identified at baseline are present in the bone marrow aspirate against the background of ongoing clinical and hematologic remission.

Molecular remission is a complete clinico-hematologic remission in the absence of initial acute leukemia molecular markers in the bone marrow, as determined by polymerase chain reaction with a method sensitivity of 10^–4. This is also a new concept that has currently become pivotal. It should be noted that cytogenetic remission can be achieved while molecular markers may still be detectable.

Molecular relapse is the reappearance of initially detected molecular markers of acute leukemias in two repeated assays (performed at a short time interval) against the background of persisting clinico-hematologic remission.

An important and one of the most accurate methods for evaluating the efficacy of acute leukemia therapy is the application of statistical methods and the construction of survival curves for patients who received a particular treatment. Overall survival, relapse-free survival, event-free survival, and the probability of maintaining complete remission (or its inverse, the probability of relapse) are most frequently evaluated.

Overall survival. To evaluate overall survival, the time parameters of all patients included in the study are analyzed. The starting point is the day therapy begins. The only event considered is the death of the patient from any cause (early mortality, death during remission from any cause, death during relapse). An event on the survival curve is graphically represented by a downward step. Patients alive at the time of analysis are treated as cases and marked on the curve with a tick, i.e., censored. Patients whose fate is unknown are censored at the time they were last known to be alive. Patients who refused treatment are censored on the day of treatment refusal.

Relapse-free survival. When evaluating relapse-free survival, data are considered only for patients who achieved complete remission. The starting point is the date complete remission was achieved. Events are defined as relapse or death from any cause (during consolidation or maintenance therapy, from relapse, during remission from another cause, e.g., suicide). Only patients who were alive and in complete remission at the time of analysis are censored. Patients whose fate is unknown are censored at the time they were last known to be alive in complete remission. Patients who achieved complete remission but refused treatment during remission are censored on the day of treatment refusal.

Probability of maintaining complete remission (inverse of the probability of relapse). When evaluating the probability of maintaining complete remission, data are considered only for patients who achieved complete remission. The starting point is the date complete remission was achieved. The only event considered is disease relapse. All patients who are alive in complete remission at the time of analysis are censored. Patients who died during complete remission from treatment-related complications or other causes are censored on the day of death as patients in complete remission. Patients whose fate is unknown are censored at the time they were last known to be alive in complete remission. Patients who achieved complete remission and refused treatment during remission are censored on the day of treatment refusal.

The probability of maintaining complete remission is the metric that allows for the evaluation of the true anti-tumor efficacy of a given therapy, independent of subjective factors such as nursing patients through treatment-related complications.

Event-free survival. This metric evaluates the survival of all patients included in the analysis from the start of therapy. Events are defined as early mortality, failure to achieve complete remission within two months of treatment initiation, death during remission from chemotherapy complications or other causes, and disease relapse. Only patients who achieved complete remission within the first two cycles of chemotherapy and remain alive in complete remission at the time of analysis are censored.

Induction – the period of initial treatment aimed at the fastest and most substantial reduction of tumor mass and the achievement of complete remission is called the induction period (usually 1–2 cycles). It is during this period, against the background of anti-tumor drugs, that the number of leukemic cells in the bone marrow decreases by approximately 100-fold, i.e., at the time complete remission is established, less than 5% of tumor cells are morphologically detected in the bone marrow.

Consolidation. The second stage of acute leukemia therapy is the consolidation of the achieved anti-tumor effect (a variable number of cycles depending on the protocol). The objective of this period is, if possible, a further reduction in the number of leukemic cells remaining after induction.

Maintenance therapy – the continuation of cytostatic action at lower doses than during the remission induction period, targeting any potentially remaining tumor clone.

Burkitt lymphoma/leukemia is a highly aggressive lymphoproliferative disorder originating from immunologically mature B cells with a predominantly extranodal localization. Clinically, 3 variants of Burkitt lymphoma are distinguished: endemic, sporadic, and HIV-associated.

Endemic variant of Burkitt lymphoma is a variant of Burkitt lymphoma typical of indigenous black children in equatorial Africa and African migrants to New Guinea. The clinical presentation frequently features involvement of the facial skeleton: upper and lower jaws, orbit, as well as kidneys, testes, ovaries, salivary glands, mammary glands, and the central nervous system.

Sporadic variant of Burkitt lymphoma is a typical Burkitt lymphoma by morphological, immunophenotypic, and cytogenetic criteria, occurring outside the endemic zone.

Immunodeficiency-associated variant of Burkitt lymphoma is a Burkitt lymphoma occurring against the background of immunodeficiency states (in HIV-infected patients, post-organ transplantation, and in patients with primary immunodeficiencies). It is most frequently encountered in HIV-infected patients, specifically in the early stages of development (prior to the depletion of CD⁴⁺ cells).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Acute lymphoblastic leukemias (hereinafter – ALL) / acute lymphoblastic lymphomas (LBL) are a heterogeneous group of malignant clonal blood system disorders originating from hematopoietic precursor cells of predominantly lymphoid differentiation lineage and characterized most frequently by primary bone marrow (hereinafter – BM) involvement, suppression of normal hematopoiesis, and involvement of various organs and body systems (central nervous system (hereinafter – CNS), testes, lymphatic tissue of any localization), as well as the possibility of primary involvement of lymphatic tissue organs without BM involvement [1–5].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology is not precisely established. The etiology and pathogenesis are explained by the accepted clonal theory: all leukemic cells are progeny of a single progenitor cell that ceased its differentiation at one of the early maturation stages. Due to the uncontrolled proliferation of tumor cells, normal hematopoiesis is suppressed, and metastases (leukemic infiltrates) form outside hematopoietic organs [1–5].

1.3 Epidemiology of the Disease or Condition

ALL can occur in individuals of any age, ranging from infancy to elderly, however, peak incidence rates occur in childhood (60% of ALL patients are younger than 20 years) [1, 2, 6].

ALL is the most common hematopoietic malignancy in children, accounting for 30% of all childhood malignancies. In patients younger than 15 years, ALL is diagnosed in 75% of all acute leukemias (hereinafter – AL). The peak incidence of ALL occurs at ages 3–4 years, after which its frequency declines, and a second peak, albeit less substantial, is observed at ages 50–60 years [1–5, 7].

In Russia in 2014, the diagnosis of ALL was established in 1,731 patients, half of whom were individuals under 18 years of age [8].

The incidence of ALL in elderly patients is steadily increasing. According to registry data, the annual frequency of ALL increases from 0.39 cases per 100,000 population at ages 35–39 years to 2.1 cases per 100,000 population at ages ≥85 years. Furthermore, approximately 30% of ALL cases are diagnosed at age ≥60 years. The Philadelphia chromosome (Ph) is detected in 20–30% of adult B-ALL patients. While Ph+ ALL accounts for less than 5% of all cases in children, its frequency rises to 40% in adults aged 40 years, and then by 10% during each subsequent decade of life [9].

1.4 Features of Coding the Disease or Condition

Lymphoid leukemia (C91):

• C91.0 Acute lymphoblastic leukemia

• C91.5 Adult T-cell leukemia/lymphoma

• C91.7 Other specified lymphoid leukemia

• C91.9 Lymphoid leukemia, unspecified

• C83.5 Lymphoblastic (diffuse) lymphoma

1.5 Classification of the disease or condition

In the World Health Organization (hereinafter – WHO) classification, ALL is discussed in the section on precursor T- and B-cell neoplasms [3]:

• B-cell lymphoblastic leukemia/lymphoma (synonym: precursor B-cell ALL);

• T-cell lymphoblastic leukemia/lymphoma (synonym: precursor T-cell ALL).

Equal use of the described definitions is possible, and the authors of the classification merely suggest that with 25% or more blast cells in the bone marrow, it is appropriate to speak of AL, and with less than 25%, of LBL. However, most often these terminological complexities have no practical significance, since their therapy is identical.

B-lymphoblastic leukemia/lymphoma

• B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).

• B-lymphoblastic leukemia/lymphoma defined by recurrent (non-random, repeating) genetic abnormalities:

– B-lymphoblastic leukemia/lymphoma with t(9;22)(q34;q11.2)/BCR::ABL1; Ph+-ALL;

– B-lymphoblastic leukemia/lymphoma with t(v;11q23)/KMT2A (formerly MLL);

– B-lymphoblastic leukemia/lymphoma with t(12;21)(p13;q22)/ETV6::RUNX1 (formerly TEL::AML1));

– B-lymphoblastic leukemia/lymphoma with hyperdiploidy;

– B-lymphoblastic leukemia/lymphoma with hypodiploidy;

– B-lymphoblastic leukemia/lymphoma with t(5;14)(q31;q32)/IL3::IGH;

– B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3)/TCF3::PBX1;

– B-lymphoblastic leukemia/lymphoma with intrachromosomal amplification of chromosome 21 (iAMP21);

– B-lymphoblastic leukemia/lymphoma with various genetic alterations (cytogenetic abnormalities and gene mutations) that activate cytokine receptor and kinase signaling pathways (BCR::ABL1-like);

T-lymphoblastic leukemia/lymphoma

– Early T-cell precursor lymphoblastic leukemia;

– NK-cell lymphoblastic leukemia/lymphoma.

According to the 2017 WHO classification, LBL with and without bone marrow involvement are combined into a single group of "precursor B- or T-cell lymphoblastic leukemias/lymphomas." Despite the widespread view that ALL and LBL are characterized by different clinical manifestations of the same disease, gene expression analysis [5] demonstrated a clear separation between T-cell ALL and T-cell LBL due to differences in the expression of individual genes. A number of these differences may be due to specific mechanisms related to stromal cells. At the same time, there is evidence that important signaling pathways regulating cell growth in T-cell ALL and T-cell LBL may differ, which partially explains the differences in the clinical manifestations of both diseases [5].

In 2022, an article dedicated to the 5th WHO revision of the classification of acute lymphoblastic leukemias was published, but the approved WHO classification at the time of the revision of these clinical guidelines has not yet been published [236].

1.6 Clinical presentation of the disease or condition

The duration of the disease anamnesis from the moment of the first clinical signs to morphological verification of the diagnosis ranges from several weeks to several months. The clinical picture is determined by the degree of bone marrow dysfunction in the form of anemia, hemorrhagic syndrome, and the development of infections of varying severity; the presence of tumor mass in the form of organomegaly, a large number of tumor cells in the peripheral blood, lymphadenopathy, and mediastinal masses; in some cases, with the development of pain syndrome associated with bone lesions, the appearance of clinical signs of CNS involvement, and skin lesions [1, 2, 4, 5, 10, 11].

Clinical manifestations in patients with ALL are very non-specific and are associated with the development of symptoms caused by the displacement of normal hematopoiesis by tumor cells. The main symptoms of the disease are weakness, non-infectious fever, bone and joint pain, and hemorrhagic syndrome. Infectious complications are infrequent, mainly occurring when the neutrophil count does not exceed 0.2×10⁹/L. In 1% of patients, headaches, nausea, and vomiting are observed, most commonly when the CNS is involved [12].

LBL is more common in males (61-75%). In the majority (58–95%) of patients at the time of diagnosis, the disease is at stage III-IV. A significant proportion of patients exhibit fever, night sweats, and weight loss (16-48%), as well as elevated lactate dehydrogenase (hereinafter referred to as LDH) activity (48-84%). The frequency of primary CNS involvement is similar to that in ALL (0-10%). Patients with T-cell LBL are younger compared to patients with B-cell LBL [13], have a higher frequency of mediastinal lymph node and bone marrow involvement, as well as stage IV disease, whereas extranodal involvement is more common in B-cell LBL [14]. In contrast to ALL, peripheral blood parameters in LBL, particularly hemoglobin concentration and platelet count, are generally closer to normal values, indicating a potentially higher bone marrow reserve and better tolerance to chemotherapy (hereinafter referred to as CT).

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have a limited evidence base (in accordance with the scales for evaluating the level of certainty of evidence (hereinafter referred to as LCE) and the level of recommendation consensus (hereinafter referred to as LRC)) due to the lack of clinical trials dedicated to them. Despite this, they are necessary elements of patient examination to establish a diagnosis and choose treatment tactics, since more effective and proven methods have not yet been developed.

Artificial intelligence technologies may be used to interpret diagnostic studies (if available and adapted for the diagnosis of acute lymphoblastic leukemias).

2.1 Complaints and Anamnesis

2.2 Physical Examination

Comments: physical examination may reveal varying degrees of skin pallor, petechial rashes, bruises, gum bleeding, fever, lymphadenopathy including enlarged palatine tonsils, splenomegaly, hepatomegaly, kidney enlargement, and tenderness upon bone percussion. Skin involvement in ALL is rare, and when diagnosed, is associated with a pre-B immunophenotype [11].

2.3 Laboratory Diagnostics

Comments: in the diagnosis of ALL, blood counts may be normal in some patients. The leukocyte count can vary from 0.5×10⁹/L to 700×10⁹/L; an increase in leukocyte count above 10.0×10⁹/L is noted in 60% of patients, above 100.0×10⁹/L in 10%; thrombocytopenia less than 50.0×10⁹/L is determined in 60% of patients.

Comments: additionally, if indicated, at any stage of ALL diagnosis and treatment, other blood parameters may be tested: blood serum iron test, blood serum transferrin test, blood erythropoietin test, blood serum folic acid test, blood immunoglobulins test; determination of protein fraction ratios by electrophoresis; nephron function test by creatinine clearance (Rehberg's test) and others.

Comments: if changes are detected in screening test results and clinical indications are present, additional coagulation parameters are tested (e.g., blood tests for soluble fibrin monomer complexes, protein C in the blood, determination of protein S activity in the blood, antithrombin III, and others).

Comments: if indicated, additional urine tests are performed, for example, to rule out infection and identify the pathogen type—Nechyporenko urine test, Zimnitskiy urine test, various microbiological (culture) urine tests, and urine microscopy. Also, when indicated, at any stage of ALL diagnosis and treatment, urine hemosiderin testing, urinary free cortisol testing, urinary alpha-amylase activity determination, and others are performed.

Comments: The ordering of necessary tests and assays, as well as the selection of a specific type of blood component for transfusion (type of red blood cell-containing component, platelet concentrate type, plasma product type), is carried out by the attending physician or transfusiologist in accordance with the clinical situation and based on Order of the Russian Ministry of Health No. 1170n dated October 28, 2020 "On Approval of the Rules of Medical Care Delivery to the Population in Transfusiology", Order of the Russian Ministry of Health No. 1134n dated October 20, 2020 "On the Procedure for Medical Examination of the Recipient, Performing Individual Compatibility Tests, Including Biological Test, During Transfusion of Donor Blood and (or) its Components", the guidelines "Clinical Use of Red Blood Cell-Containing Blood Components" (2018), Government Resolution No. 797 dated June 22, 2019 "On Approval of the Rules for Procurement, Storage, Transportation and Clinical Use of Donor Blood and its Components and on Invalidation of Certain Acts of the Government of the Russian Federation", and other regulatory acts (see Appendix A3.9).

Comments: acute leukemia (AL) is diagnosed when 20% or more blast cells are detected in the bone marrow. However, for precursor lymphoid acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) from the same precursor cells, there is another universally accepted definition: the diagnosis of ALL (B-cell or T-cell) is established when 25% or more blast cells are detected in the bone marrow. If the percentage of blast cells in the bone marrow is less than 25% or blast cells are absent in the bone marrow but present in other sites of involvement (lymph nodes of any location, thymus, skin, etc.), a diagnosis of T- or B-LBL is established [1, 2, 4, 5].

Comments: during cytochemical examination, blast cells are assessed as undifferentiated because myeloperoxidase activity in them is negative, and PAS-positive granules frequently contained within them are not specific markers determining commitment to the lymphoid lineage. Therefore, immunophenotyping is one of the key diagnostic methods for ALL. Nevertheless, performing cytochemical reactions for myeloperoxidase, non-specific esterase, and glycogen is mandatory, since the determination of the blast cell lineage is carried out through a comprehensive analysis of cytochemical and immunophenotypic data, thereby ruling out/verifying mixed-phenotype acute leukemia variants. [1, 2, 236].

Comments: immunophenotypic characteristics approximately 80% of LBLs are characterized by the expression of T-cell markers, unlike ALL, in which >70% are B-cell lineage. The T-cell subtype predominates among all LBLs. The immunophenotypic characteristics of tumor cells in T-LBL are positive for the following markers: TdT, CD7, and cytoplasmic CD3; CD1a, CD2, CD4, CD5, and CD8 are variable; co-expression of CD4 and CD8, CD10 +/– may occur; co-expression of myeloid markers CD13, CD33, and CD117 is rarely detected. In one-third of T-LBL cases, translocations involving T-cell receptor genes (α, ß, γ, δ) and various partner genes, including MYC, TAL1, HOX11, etc., have been identified.

The immunophenotypic characteristics of tumor cells in B-LBL are positive for: TdT (nuclear staining), HLA-DR, CD19, and cytoplasmic (cyt)CD79a; CD20 and CD22 are variable. Immunoglobulin light chains (cyt-µ) are occasionally detected in the cytoplasm. Surface immunoglobulins are usually absent, though their detection does not rule out a diagnosis of B-LBL; CD45 may be negative. Molecular genetic features are poorly characterized and have no prognostic significance.

Comments: immunophenotyping is performed using multiparameter flow cytometry (typically at least 6-color). It is used to more clearly determine the lineage affiliation of blast cells following the establishment of a morphological diagnosis of ALL. The immunophenotypic characteristics of blast cells in ALL are presented in Appendix G2. B-cell precursor ALL (70–80% of cases) can be classified into four groups according to the stages of early B-cell development. T-cell precursor ALL (20–30% of cases) can also be divided into 4 groups, according to the stages of early T-cell development. In some cases, blast cells exhibit features of both lymphoid and myeloid differentiation simultaneously. These cases of acute leukemia can be defined as mixed-phenotype acute leukemia (MPAL) (B/myeloid, T/myeloid) if they meet the necessary WHO classification criteria (2017) [3]. Other cases of acute leukemia may be characterized by the absence of the required combination or sufficient number of markers to determine their lineage direction. In such cases, acute undifferentiated leukemia or acute leukemia of ambiguous lineage may be diagnosed, without further specification, in accordance with the definitions provided in the WHO classification.

The 2017 WHO classification separately identifies early T-cell precursor lymphoblastic leukemia (ETP-ALL). Blast cells in ETP exhibit features of myeloid and stem cells, and the immunophenotype must meet specific criteria:

• T-lineage commitment (presence of cyCD3+CD7+ expression)

• Absence of CD1a and CD8 expression (<5% positive blast cells)

• Absent or weak expression of CD5 (<75% positive blast cells)

• at least one of the following markers is positive: CD34, CD117, HLA-DR, CD13, CD33, CD11b, CD65 (≥25% positive blast cells).

In cases of bright and more monomorphic expression of CD5 (≥75%), while meeting all other criteria for early T-cell precursor lymphoblastic leukemia, a diagnosis of near-ETP-ALL is established.

Approximately 80% of LBLs are characterized by the expression of T-cell markers, unlike ALL, in which >70% are B-cell lineage. Therefore, the T-cell subtype predominates among all LBLs.

Immunomorphological characteristics of tumor cells in T-LBL: positive for terminal deoxynucleotidyl transferase (hereinafter referred to as TdT), CD7, and cytoplasmic CD3; variable for CD1a, CD2, CD4, CD5, CD8; co-expression of CD4 and CD8, CD10 +/– may be present; co-expression of myeloid markers CD13, CD33, CD117 is rarely detected. In one-third of T-LBL cases, translocations involving T-cell receptor genes (α, ß, γ, δ) and various partner genes, including MYC, TAL1, HOX11, etc., are identified.

Immunomorphological characteristics of tumor cells in B-LBL: positive for TdT (nuclear staining), HLA-DR, CD19, and cytoplasmic (cyt)CD79a; CD20 and CD22 are variable. Surface immunoglobulins are usually absent, but their detection does not rule out a diagnosis of B-LBL; CD45 may be negative.

1. hepatitis B virus surface antigen (HBsAg) in the blood;

2. antibodies to hepatitis B virus surface antigen (HBsAg) in the blood;

3. antibodies to hepatitis B virus core antigen (HBcAg) in the blood;

Comments: The cytogenetic study of bone marrow aspirate cells must include karyotyping and fluorescence in situ hybridization (FISH) to detect characteristic cytogenetic abnormalities. In case of technical difficulties in obtaining a bone marrow aspirate, chromosomal abnormalities can be established based on the study of peripheral blood cells if there are more than 10% circulating tumor cells. In the absence of BM involvement, which occurs in patients with LBL, the cytogenetic study should be performed on the biopsy specimen of the tumor mass.

The most significant genetic diagnostic and prognostic factors for adult B-ALL are t(9;22)(q34;q11)/BCR::ABL1; t(11q23)/KMT2A (MLL); and t(1;19)(q23;p13)/TCF3::PBX1. The B-ALL variant with t(12;21)(р12;q22)/ETV6::RUNX1 is characteristic of children, while the B-ALL variant with iAMP21 is also rarely found in young adults. During karyotyping, 20 metaphases are analyzed whenever possible to detect chromosomal aberrations in both the main clone and potential subclones. The absence of detected abnormalities when analyzing fewer than 20 metaphases cannot reliably rule out their presence in the tumor clone. All patients with B-cell ALL and mixed-phenotype acute leukemia undergo FISH testing for t(9;22)(q34;q11)/BCR::ABL1 and t(v;11q23)/KMT2A if they were not identified by karyotyping. The detection of these cytogenetic abnormalities during the pre-phase determines the entire subsequent therapeutic strategy.

Translocations involving the KMT2A gene locus (formerly MLL) can involve more than 100 chromosomal partners. When a rearrangement in the KMT2A gene locus is detected by FISH, testing for the most frequent translocations—such as t(4;11)(q21;q23)/KMT2A::AFF1, t(9;11)(p21;q23)/KMT2A::MLLT3, t(11;19)(q23;p13)/KMT2A::MLLT1, t(6;11)(q27;q23)/KMT2A::AFDN, t(10;11)(p12;q23)/MLLT10::KMT2A, and t(11;19)(q23;p13.1)/KMT2A::ELL—should be performed, if possible, to monitor the dynamics of the tumor clone during therapy using PCR.

Given the classification of BCR::ABL1-like B-ALL as a distinct subgroup requiring specific therapeutic options in some cases, it is highly desirable at diagnosis or during refractory disease to determine, using FISH, rearrangements involving the gene loci CRLF2 (IGH::CRLF2, P2RY8::CRLF2), ABL1, ABL2, JAK2, EPOR, PDGFRB (CSF1R).

Patients with early T-cell precursor ALL (ETP ALL) should ideally undergo FISH testing to detect rearrangements in the BCL11B/14q32 T-cell transcription factor gene locus. The BCL11B/14q32 translocation occurs in 30% of ETP ALL cases and determines a more favorable prognosis compared to ETP ALL without the translocation [236].

Comments: Patients with B-ALL harboring MYC and/or BCL2 and BCL6 translocations are classified into the high-risk group [236].

Comments: detection of molecular transcripts in ALL with BCR::ABL1, MYC::IgH, MLL::AF4 is necessary to monitor anti-tumor response and make therapeutic decisions. Molecular testing for numerous other aberrations is currently one of the key methods used internationally to stratify patients into risk groups. The detection of chimeric transcripts, gene mutations, rearrangements, and gene duplications is available only in large research centers. At the molecular genetic level, the BCR::ABL1 gene transcript can be detected using reverse transcription polymerase chain reaction (RT-PCR). The location of the breakpoint in the BCR gene results in the p190^BCR-ABL protein being detected in 66.3% of Ph+ ALL cases, and the p210^BCR-ABL protein (31.2%) is also frequently detected in these patients. In remaining cases, transcripts of both types or atypical transcripts are identified. Determination of BCR::ABL1 gene point mutations can help identify resistance to tyrosine kinase inhibitor therapy and assist in selecting a targeted drug that is effective in the presence of mutations.

Comments: from a molecular perspective, all cases of ALL develop from B- or T-lymphocyte precursor cells, and therefore all of them demonstrate clonal rearrangements of Ig heavy chain genes and/or TCR genes. This phenomenon makes it possible to identify patient-specific rearrangements and use them as molecular disease markers when monitoring MRD. In addition to patient-specific markers, ALL exhibits a wide range of genetic and molecular rearrangements and mutations involving various genes. A list of the main molecular and genetic anomalies identified in adult and pediatric ALL and currently used in molecular diagnostics is provided in Appendix G2. This list is not exhaustive and represents a compromise between the modern and most appropriate molecular method for detecting or ruling out an anomaly and the most frequently used technique.

Comments: there is a high probability of leptomeningeal involvement in all variants of ALL. Therefore, all patients are indicated for a diagnostic lumbar puncture with morphological examination of the cerebrospinal fluid. If the platelet count cannot be raised to 30×10⁹/L or higher, the puncture may be deferred until platelet counts recover post-course. If patients present with leukocytosis exceeding 30×10⁹/L, the first lumbar puncture should be postponed until the leukocyte count drops below 10×10⁹/L. Performing an immunophenotypic study of the cerebrospinal fluid in some cases makes it possible to verify the etiology of the lesion in the presence of pleocytosis, especially in diagnostically challenging cases requiring the verification of specific, infectious, or toxic involvement.

Comments: as part of the overall chemotherapy program, all patients with ALL require therapy for CNS involvement. In the absence of meningeal prophylaxis, CNS relapses occur within several months of achieving complete remission in approximately one-third of patients. CNS relapse in adult ALL is characterized by an unfavorable prognosis, as it is usually followed by a hematologic relapse. At the same time, approaches to the treatment of CNS involvement and its prophylaxis vary, taking into account patient characteristics, age, and other prognostic factors.

Comments: preservation of primary biological material (DNA extracted from bone marrow cells or frozen cells) for future molecular studies to clearly define risk groups.

Comments: pleural cavity puncture with cytological examination of pleural fluid, bronchoalveolar lavage with cytological examination of lavage fluid, and lumbar puncture with cytological examination of cerebrospinal fluid cells are performed most frequently; however, based on indications, puncture of any accessible organ and tissue followed by cytological examination may be performed, including – oral cavity tissue microprinters, peritoneal fluid, skin microprinters, lymph node tissue specimens, tumor punctates, bone-like tumor formations, liver tissue, large intestine tissue, uterine cavity aspirate, vaginal tissue, uterine tissue, prostate tissue, testicular tissue, kidney tissue, urinary bladder tissue, and punctates and imprint biopsies of retroperitoneal tumors. Biological material obtained after aspiration/puncture, upon confirmation of its diagnostic adequacy (presence of tumor cells), may be sent for cytogenetic and molecular studies to verify the disease variant

Comments: the most commonly performed biopsies are of skin lesions, bone marrow (trephine biopsy), and lymph nodes. However, depending on indications, a biopsy of any organ and tissue may be performed, including the oral mucosa, nasal mucosa, lung tissue, mediastinal tumor, spleen, liver, esophagus, stomach, colon, breast, bone, female genital organs, prostate gland, male genital organs, urinary bladder, kidney, and retroperitoneal tissues.

2.4 Instrumental Diagnostics

Comments: electrocardiography is routinely performed; in the presence of clinical indications, assessment of the electrical activity of the cardiac conduction system, Holter heart rate monitoring, electrocardiographic data monitoring, and fetal cardiotocography are also performed.

Comments: the most frequently performed studies include MRI of bone tissue, contrast-enhanced brain MRI, contrast-enhanced spinal cord MRI, pelvic MRI, contrast-enhanced spinal MRI; and CT of the facial skull, spine, paranasal sinuses, larynx, upper respiratory tract and neck, CT angiography of a single anatomical area, female pelvic organs, male pelvic organs, brain, abdominal organs, abdominal organs with intravenous bolus contrast enhancement, and retroperitoneal space. PET in patients with mediastinal involvement and other extramedullary sites of involvement is recommended prior to therapy initiation and at response evaluation time points—after completion of induction and consolidation, upon suspicion of disease relapse, and at other follow-up intervals.

Comments: also, in the presence of clinical indications at any stage of ALL diagnosis and treatment, ultrasound of other anatomical areas is performed (most commonly ultrasound of soft tissues, joints, lymph nodes, pleural cavity, mediastinum, Doppler ultrasound of upper extremity vessels (arteries and veins), lower extremity vessels (arteries and veins), colon, transabdominal uterus and appendages, transvaginal uterus and appendages, mammary glands, thyroid and parathyroid glands, parathyroid glands, kidneys and adrenal glands, urinary tract, retroperitoneal space)

Comments: in many LBL patients with massive mediastinal lymph node involvement initially, residual masses persist on radiography or CT after completion of chemotherapy. The purpose of additional diagnostic procedures is to answer whether these formations represent areas of necrotic or scar tissue, or contain viable tumor cells. Imaging methods, in particular PET/CT, are likely useful in disease staging. It has been shown that positive PET/CT results make it possible to predict residual disease or relapse involvement in non-Hodgkin lymphoma with high probability [95].

2.5 Other Procedures

Comments: failure to perform these specified procedures and diagnostic methods is acceptable only in extreme cases where the patient is in a terminal state upon admission to a specialized institution, or their somatic status is such that no specific treatment will be administered—only palliative care—or if the patient refuses examination and treatment, which must be documented in the medical record.

Comments: for diagnostic purposes during pregnancy, it is advisable to use magnetic resonance imaging and ultrasound, including of the lung tissue [1, 2].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: infections are among the leading complications in the treatment of ALL/LBL, especially during the induction and consolidation of remission, and during neutropenia. Infectious complications become more frequent with the resistant variant of the tumor, high-dose chemotherapy, concomitant hypogammaglobulinemia, and during periods of forced physical inactivity and strict bed rest. Infectious complications in patients with hematological disorders are characterized by diversity in both etiology and localization of the infectious process, and require a combination of laboratory tests for diagnosing infectious complications and special approaches to their therapy that differ from the management of infectious manifestations in patients without oncohematological diseases. The main factor determining the development of infectious complications is neutropenia (neutrophils <0.5×10⁹/L) or leukopenia (leukocytes ≤1.000×10⁹/L), as well as the rate of neutrophil count decline and the duration of neutropenia. The risk of infections increases with damage to the mucous membranes of the gastrointestinal tract (especially grade III–IV mucositis) and the presence of a central venous catheter (CVC).

In ALL/LBL, various viral, bacterial, and fungal infectious complications can develop, including opportunistic infections, the timely diagnosis and treatment of which is a crucial component of successful patient management. Diagnostic evaluations include necessary imaging studies (CT and magnetic resonance imaging of involved areas, including brain CT scan when indicated); endoscopic, puncture, and biopsy procedures (including bronchoalveolar lavage, pleural puncture, and lumbar puncture when indicated); laboratory tests (including blood gas and acid-base balance analysis, and blood procalcitonin level when indicated); cultures and other microbiological (culture), molecular biological, microscopic, and other bacteriological tests for aerobic and facultatively anaerobic microorganisms (including aerobic and facultatively anaerobic opportunistic microorganisms), Pneumocystis, Mycoplasma, Legionella, Mycobacterium tuberculosis, fungi (yeast and mold), Clostridioides, and others.

• For all patients with ALL/LBL at any stage of diagnosis, monitoring, or treatment, electroencephalography is recommended when indicated to rule out a focus of brain lesions with abnormal electrical activity [1, 2].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• For all patients with ALL/LBL at any stage of diagnosis, monitoring, or treatment, radiography of the affected area is recommended when indicated to rule out a lesion focus or the development of complications [1, 2].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: radiography of the entire skull in one or more projections, paranasal sinuses (including paranasal sinuses with contrast), spine, pelvis, femur, pericardium, mediastinum, kidneys and urinary tract, plain abdominal and pelvic radiographs, and fluoroscopy of the lungs are most frequently used.

Dynamic assessment of treatment efficacy

Comments: standardized time points for BM sampling are necessary for MRD monitoring. MRD monitoring is a key study in all modern ALL treatment protocols. In Russia, where clinical trials include a minimal number of patients, recommending standardized MRD monitoring and making therapeutic decisions based on the obtained values seems premature. This is due to the fact that in most cases ALL treatment regimens are modified, the principles of "dose-intensity" and intervals are not observed, and in some cases, the drugs stipulated by the specific protocol are missing. MRD determination is necessary to address the feasibility of allogeneic hematopoietic stem cell transplantation (hereinafter referred to as allo-HSCT). Therefore, it seems reasonable to consider all ALL patients who are not included in controlled clinical trials as candidates for allo-HSCT, especially in the case of a fully matched related transplantation.

Contrary to the recommendation, which is questionable in the Russian healthcare setting, to monitor MRD in patients with Ph-negative ALL, MRD monitoring in patients with Ph-positive ALL is a key treatment condition for ALL (!) patients even within the Russian Federation, as this is directly linked to the requirement of guidelines to change the Bruton's tyrosine kinase (BTK) inhibitor (hereinafter referred to as TKI) in case of failure to achieve a molecular response [1, 2, 52].

MRD

Currently, the monitoring of the residual tumor cell population (MRD) using flow cytometry and/or molecular biological methods has become the standard for assessing the efficacy of ALL treatment. These methods have high sensitivity (detecting 1 leukemic cell per 10^4–6 normal hematopoietic cells) and can be used to track the persistence of the leukemic clone over time. The detection of MRD after cytotoxic therapy, especially after the completion of induction, is the most powerful prognostic factor in patients with ALL, indicating the need to change therapeutic tactics and employ allo-HSCT in the treatment program.

Methods for MRD assessment

Several methods for assessing MRD in ALL have been developed. These methods differ in labor intensity, time consumption, applicability in specific situations, sensitivity, cost, and certain other aspects. The most important thing in MRD testing is repeated examination and dynamic assessment over time.

As noted previously, methods for MRD detection and monitoring make it possible to evaluate the effectiveness of ongoing treatment at the molecular level. MRD assessment is performed ONLY in patients who have achieved complete clinico-hematological remission.

Comments: it is not recommended to perform MRD monitoring by FISH or standard cytogenetic analysis. When evaluating MRD in a patient, only one method must be used for therapeutic decision-making, and monitoring should be performed from the first days of therapy and carried out in a single laboratory. MRD analysis is performed in BM samples. The first portion of the BM aspirate with a volume of no more than 1 ml is used as the material for MRD testing. If the volume of the BM aspirate significantly exceeds 1 ml or if a non-first portion of BM is sent to the laboratory for MRD testing, a significant blood contamination of the sample can be expected. It is strongly recommended to send a sample of the patient's bone marrow at disease onset to search for a leukemia-associated immunophenotype (LAIP) by flow cytometry using the same antibody panel that will subsequently be used for MRD detection. The MRD test result is considered positive if flow cytometric analysis reveals a population of leukemic cells consisting of at least 10–50 cells with aberrant homogeneous expression of specific antigens. The number of cells forming the minimum population may vary across different laboratories. If 10–50 leukemic cells are not detected among the collected cells, it is concluded that MRD was not detected at the achieved assay sensitivity. The required sensitivity of the method is 0.01%. To achieve such sensitivity, it is necessary to analyze 200,000 cells or more (if a population consisting of 20 cells was taken as the minimum). If such sensitivity is not achieved, for example, due to low BM cellularity or significant dilution of the BM sample with peripheral blood, a repeated BM puncture and repeated MRD testing must be performed.

Timing of monitoring

In different clinical trials, the key MRD assessment time points that determine prognosis and, accordingly, changes in therapy strategy, differ somewhat. In general, researchers evaluate the residual tumor cell population at the end of the 1st induction phase (week 6 from the start of therapy) and at the consolidation stage (weeks 12–16 from the start of therapy). It seems appropriate to use MRD assessment time points in patients in accordance with the treatment protocol used and only provided it is adequately implemented (German group: weeks 10 and 16; French group: weeks 6 and 12 [week 6 for determining treatment tactics]; UK: weeks 10 and 15; Italy: weeks 10–16–22 [week 22 for determining treatment tactics]).

When using the protocols of the Russian research group "ALL-2009" and "ALL-2016", BM samples are analyzed at weeks 10, 16, and 28 of therapy and before/after allo-HSCT. In situations where a patient exhibited MRD persistence or a relapse is suspected, additional MRD monitoring time points may be considered, including during maintenance therapy and before drug withdrawal.

Recommendations for MRD monitoring

Comments: when monitoring MRD in B-ALL, analysis of at least 7 antigens is mandatory. Testing of at least the following is required: CD19, CD10, CD34, CD38, CD20, CD45, CD58. Other markers may also be analyzed additionally, for example, CD11a, CD13, CD33, CD9, CD22, CD81.

When monitoring MRD in T-ALL, testing of 9 or more markers is recommended, primarily: CD7, CD5, CD2, CD3 (surface and intracellular), CD4, CD5, CD1a, CD16/CD56, CD45, CD99, TdT, CD48.

A particular challenge is the analysis of BM samples from patients receiving therapy with targeted drugs against CD19 (blinatumomab**), against CD22 (inotuzumab ozogamicin), and T-cell therapy (Chimeric Antigen Receptor T-cell — CAR-T). Immunotherapy can lead to changes in the immunophenotype of blast cells and requires revision of the monoclonal antibody panel standardly used in the laboratory; therefore, upon receipt of a BM sample for MRD analysis, information on the use of targeted drugs must be reflected in the accompanying documents.

• Evaluation of MRD in patients can be carried out by various methods, but it is strictly recommended [53, 54]:

  • determination of leukemia-specific markers, patient-specific clonal rearrangements, and aberrant immunophenotype before the start of therapy;

  • carrying out monitoring using either a single method or simultaneously two methods (without alternating or replacing one with another);

  • performing the test in a single laboratory according to recommended standardized approaches within the precise timeframes stipulated by the protocols upon their adequate implementation.

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. Main principles of ALL/LBL chemotherapy

Regardless of the chemotherapy approach used in the treatment of ALL/LBL, there are several main stages of therapy: remission induction, remission consolidation, maintenance therapy, and prophylaxis (treatment) of neuroleukemia.

The period of initial treatment aimed at a substantial reduction of tumor mass and achievement of CR is called the period of remission induction. ALL therapy uses two induction phases lasting 4 weeks each. It is during this period, against the background of antitumor drug administration, that the number of leukemic cells in the BM decreases approximately 100-fold, i.e., at the time CR is established, morphological determination shows less than 5% tumor cells in the BM. When using a pulsed approach (Hyper-CVAD regimen), the induction stage is considered to consist of two courses: the actual 2-week Hyper-CVAD course and the subsequent course of high-dose cytarabine** and methotrexate** following a break. In most cases, CR is achieved already after the 1st induction phase (or after the 1st Hyper-CVAD course), and only in a fraction of patients (10–30%) after the 2nd induction phase (or the 2nd course of high-dose cytarabine** and methotrexate**) [56–60].

The second stage of ALL therapy is remission consolidation (consolidation of the achieved antitumor effect). Currently, in most cases, consolidation is the most aggressive and high-dose stage in ALL treatment. The objective of this period is to achieve an even greater reduction, if possible, in the number of leukemic cells remaining after induction. Most often, 1–2 such courses are provided, and then, before maintenance treatment, re-induction programs (longer ones, similar to IT) may be used. In the Russian research group protocol, the consolidation period is designated as five prolonged consecutive (3–4 week) stages, between which no breaks are provided (!), but only the set of drugs used during this period changes and the dosages of a number of antitumor drugs are modified. It should be emphasized that rotation of the consolidation stages stipulated by the protocol is possible, depending on cytopenic syndrome and complication variants [56–60].

After completion of the consolidation stage, the period of maintenance treatment follows, i.e., continuation of cytostatic action at lower doses than during the remission induction period, targeting any potentially remaining tumor clone [56–60].

Currently, the basis of all programmed therapy for ALL/LBL is a differentiated approach: 1) for immunologically mature B-ALL, the efficacy of potent pulse short-term therapy combined with CD20 (cluster of differentiation 20) inhibitors has been proven (90% 5-year RFS) [61]; 2) for Ph-positive ALL, the key factor for efficacy is the use of BCR-ABL tyrosine kinase inhibitors (80% 3-year survival) [52]; 3) for patients with persistent minimal residual disease of tumor cells, therapy aims to reduce the minimal residual clone and allo-HSCT [55, 62].

It is fundamentally necessary to distinguish three key groups of ALL requiring different treatments: 1) B-mature ALL, including those with MYC translocation; 2) Ph-positive ALL; 3) Ph-negative ALL [1, 2, 4, 5, 52, 55, 61, 62].

Comments: usually, after completing 4–6 blocks, patients are taken off therapy, do not receive maintenance treatment, and do not require auto- or allo-HSCT.

Comments: this intervention must be continuous. The volume of chemotherapy in Ph-positive ALL remains a subject of debate. Both minimal cytostatic therapy (either glucocorticoids alone or glucocorticoids combined with vincristine**) and more intensive approaches (classical chemotherapy protocols for ALL, high-dose pulse protocols) are used.

Comments: the results of major research groups on the treatment of Ph-negative ALL in adults, depending on the chemotherapy approach, are presented in Appendix A3.2. Summarizing the table data, it can be noted that overall 5-year overall survival (hereinafter – OS) of adult patients with ALL, varying by risk group and age, is 45–55%. The results of the Russian study are fully comparable and even exceed those of foreign studies despite the low proportion of allo-HSCT, with a 5-year OS of 65% [66].

Comments: Previously in Russia, auto-HSCT was performed as late high-dose consolidation, most commonly in the treatment of T-cell ALL/LBL; however, the randomized "ALL-2016" study showed no improvement in treatment outcomes in the auto-HSCT group compared to chemotherapy. In foreign studies, auto-HSCT is recommended for patients in molecular remission of Ph-positive ALL in the absence of a potential allogeneic hematopoietic stem cell donor. Allo-HSCT is a mandatory stage of therapy for high-risk ALL patients, and its efficacy is associated with establishing permanent immunological control over the residual tumor clone remaining after cytostatic treatment (graft-versus-tumor effect).

Comments: this stage spans all periods of programmed treatment – remission induction, consolidation, and maintenance therapy. Prophylaxis of neuroleukemia (the main period comprising 5–6 intrathecal drug administrations) is usually performed during chemotherapy, followed by prophylactic lumbar punctures with varying frequencies across consolidation and maintenance stages (on average, the number of prophylactic spinal punctures should be 15–20). Neuroleukemia treatment follows different principles. First, intrathecal administration of antineoplastic agents is performed every 2–3 days until cerebrospinal fluid parameters normalize and at least 3 normal cerebrospinal fluid analysis results are obtained. Then, for six months, punctures are performed every 2–3 weeks, followed by a transition to a prophylactic administration schedule. In most cases, cranial irradiation at a dose of 2400 rad is not required. This approach may be used only in patients in whom, due to various reasons (anatomical features, extremely poor tolerance to spinal puncture), neuroleukemia prophylaxis via intrathecal antineoplastic drug administration cannot be performed. Cranial irradiation is also considered in cases of refractory neuroleukemia (absence of a complete response after 5–6 drug administrations).

Comments: unless otherwise prescribed (according to the applicable protocol), the recommended dosing regimen for adults aged 18 to 21 years is up to 2500 IU/m² of pegaspargase** every 14 days, and for adults over 21 years – 2000 IU/m²; however, according to various protocols, the dose for adults may range from 500 to 1000 IU/m² (in the Russian ALL-2009 protocol for patients over 55 years old – 500 IU/m², and in the ALL-2016 protocol the dose is 1000 IU/m²). The total dose per single administration must not exceed 3750 IU and should not be given more frequently than once every 14 days. Contraindications for native asparaginase** and pegaspargase** include: anaphylactic shock during prior use of native asparaginase** or pegaspargase**; severe hepatic impairment (bilirubin > 3 times the upper limit of normal; transaminases > 10 times the ULN); history of severe thrombosis following asparaginase** therapy; history of pancreatitis, including pancreatitis associated with prior asparaginase** therapy; history of severe hemorrhagic complications following asparaginase** therapy. Certain protocols and regimens, particularly pediatric ones, specifically require pegaspargase**, and these doses cannot be applied or recalculated for native asparaginase**. Premedication is administered to patients 30–60 minutes prior to pegaspargase** infusion in accordance with the product labeling to reduce the risk and severity of infusion-related and hypersensitivity reactions. Treatment can be monitored by serum asparaginase activity measured before the next pegaspargase** dose. If asparaginase activity does not reach the target value, transitioning to another asparaginase preparation may be considered**. Many foreign adult ALL treatment protocols, as well as Russian pediatric ALL therapy protocols, incorporate frontline pegaspargase** rather than reserving it only for hypersensitivity reactions. This tactic is applicable, and many protocols provide an equivalent dose of native asparaginase** and pegaspargase** within the same protocol (e.g., the ALL-2016 protocol, relapse therapy protocols containing #bortezomib**, dexamethasone**, vincristine**, #mitoxantrone**, and asparaginase**/pegaspargase**).

3.2. Prognostic factors of treatment efficacy

Comments: the concept of prognostic factors in acute leukemia emerged with the advent of adequate chemotherapy, as only the use of standard regimens makes it possible to identify patients with specific clinical, morphological, immunophenotypic, cytogenetic, and molecular genetic characteristics of the disease in whom treatment is successful or unsuccessful. A detailed study of the causes of treatment failure under standard protocols leads to the formation of risk groups and, accordingly, the creation of new differentiated approaches to the treatment of these patients. It should be emphasized that the presence of an unfavorable prognostic factor in a patient is by no means a basis for switching to palliative care. All prognostic factors are used and studied solely in the context of modifying therapy to improve its efficacy in such patients.

For at least two decades, the so-called treatment-efficacy-associated risk factors for adult ALL patients have remained unchanged. The exceptions are Ph-positive ALL and B-ALL with a mature immunophenotype, which have been classified into entirely separate groups requiring specific therapeutic interventions (TKIs and block immunochemotherapy, respectively), and whose prognosis has consequently changed significantly.

In Ph-negative ALL, despite therapy intensification and a significant number of allo-HSCT procedures performed across various protocols by different research groups, certain clinical and laboratory parameters continue to determine the prognosis of the disease, just as they did several decades ago. For Ph-negative B-cell ALL, recognized risk factors by most researchers include: older age (30 years and older), initial leukocyte count (30×10⁹/L and higher), early phenotype (early pre-B or BI according to the EGIL classification), a 2-fold or greater increase in LDH activity, late attainment of complete remission (later than day 35), and detection of t(4;11). For T-cell ALL, risk factors include early and mature immunophenotypes (TI/II and TIV according to the EGIL classification), initial leukocyte count (100×10⁹/L and higher), and late attainment of complete remission. Additionally, early precursor T-ALL (ETP variant) is distinguished as a separate category, and patients in this group should be considered as a very high-risk group. Furthermore, over the past decade, the measurable residual disease (MRD) assessment has become a key prognostic factor for all ALL types: if detected with a method sensitivity of 10^–4 within 6 months of treatment, the prognosis is defined as negative. For ALL patients, determination of the risk group, which dictates the therapeutic strategy, must be performed exclusively within the framework of the protocol being used in the specific patient [1, 2, 4, 5, 11].

Failure to follow the treatment protocol, unprescribed dose reductions, and prolonged treatment intervals not stipulated by the protocol must be considered major violations of the chemotherapy protocol, and such patients should be evaluated as having extremely unfavorable treatment outcomes [1, 2].

3.3. Prognostic significance of MRD

It is known that the persistence of MRD after induction/consolidation therapy is associated with an unfavorable prognosis and a high relapse rate despite continued chemotherapy in both Ph-positive and Ph-negative ALL [55, 67–72].

A molecular (MRD) relapse is also an extremely unfavorable factor. The median time from the detection of MRD in the bone marrow to the development of a fully manifested hematological relapse is about 1–4 months.

Comment: in molecular relapse of Ph+ ALL, it is necessary to switch TKIs (protein kinase inhibitors); in this case, testing the mutational status of the BCR::ABL1 gene is recommended to prescribe an effective TKI (protein kinase inhibitor). In addition, blinatumomab** [73] and inotuzumab ozogamicin have demonstrated high efficacy in both Ph- and Ph+ ALL, including with the inclusion of TKIs (protein kinase inhibitors), in cases of molecular relapse or MRD persistence. The presence of a molecular relapse may serve as an inclusion criterion for clinical trials involving investigational drugs.

A negative prognostic factor regarding relapse-free survival is the detection of MRD both before and after HSCT. The probability of relapse is significantly higher in patients who test positive for MRD.

3.4. Treatment of patients with Ph-negative ALL

Selection of chemotherapy regimen in patients under 55 years of age

Different research groups apply different treatment regimens (Appendix A3.1); there is no single unified ALL treatment protocol. The general principle of therapy consists of a pre-phase, remission induction, remission consolidation, and maintenance therapy.

Comments: the Russian research group conducted prospective multicenter studies and demonstrated treatment outcomes for Ph-negative ALL/LBL in adults comparable to other research chemotherapy protocols.

Comments: regardless of the chosen treatment protocol, patients with ALL harboring 11q23/KMT2A rearrangements (t(4;11) and others), t(9;22), t(1;19), ETP variants, as well as Nijmegen breakage syndrome, must be classified as a very high-risk group, and allo-HSCT should be considered for all of them from the very beginning.

Prephase

The pre-phase must be initiated immediately after all diagnostic procedures are completed.

Comments: glucocorticoid monotherapy is the basis of the pre-phase – the initial therapy for ALL. The duration of the pre-phase is 7 days, and it is immediately followed by induction phase I. The pre-phase makes it possible to stabilize the condition of patients who are admitted to the hematology department with severe infectious complications, metabolic disorders, and/or major bleeding (with systemic antibacterial and antifungal drugs, transfusion therapy, replacement therapy, blood clotting factors, #allopurinol**)[23, 240], and to start induction phase 1 without delay or with minimal deviations. During the pre-phase, cytogenetic diagnostics are performed, which makes it possible to identify patients with Ph-positive ALL and promptly initiate induction phase 1 for them using a less toxic protocol for Ph+ ALL. There is a small proportion of adult patients with ALL who exhibit very high sensitivity of tumor cells to prednisolone**, and complete remission (hereinafter referred to as CR) can be achieved after 7 days of glucocorticoid monotherapy. Despite the fact that in a number of protocols the pre-phase is not a mandatory component, for example, in the MDACRC program (Hyper-CVAD/HMA), Russian experts believe that performing the pre-phase is highly advisable.

Remission induction

Comments: Phase I of induction is the most critical, lasting 4 weeks (or 2 weeks in the Hyper-CVAD protocol). It is during this stage of chemotherapy that the highest number of complications, both toxic and infectious, is recorded, with an expected early mortality rate of approximately ≥5%. In a Russian multicenter clinical trial including data on 300 patients with ALL aged 15 to 55 years, the early mortality rate was 9%.

During this period, it is necessary to perform the full range of supportive care, including monitoring and correction of plasma hemostasis, thrombocytopenia, anemia, treatment of infectious complications, metabolic disorders (diabetes mellitus), psychiatric disorders, neurological symptoms, acute hepatitis, pancreatitis, etc. In the event of extremely severe complications and/or profound cytopenia (leukocytes less than 500 cells/µL), cytostatic therapy must be interrupted (except for prednisolone**) and resumed once complications are corrected and blood counts recover.

All treatment regimens include vincristine**, prednisolone**, and anthracyclines and related compounds (daunorubicin**).

Asparaginase** is frequently used in induction phase I and may subsequently be used throughout the entire ALL treatment program. This drug is believed to increase the duration of CR (but not the probability of achieving it). However, early discontinuation of asparaginase** due to toxic reactions does not affect long-term outcomes, whereas coagulation hemostasis disorders occur frequently (in more than 60%) and require monitoring of coagulation parameters, and when necessary, replacement with antithrombin III and/or fibrinogen.

Failure to achieve CR after this induction phase is considered refractory, and patients are transferred to treatment regimens for refractory forms of ALL, which differ significantly depending on the immunophenotypic variant. Chemotherapy protocols are provided in Appendix A3.1.

Consolidation

Comments: therapy administered after achieving CR—consolidation—differs significantly in intensity across various treatment protocols. Most European research groups use high-dose protocols incorporating several courses of high-dose cytarabine** and methotrexate**, which have a significant myelosuppressive effect and are accompanied by prolonged periods of myelotoxic agranulocytosis and treatment-free intervals. The widely used American Hyper-CVAD/HMA protocol defines consolidation as 4 consecutive alternating courses similar to induction, two of which are high-dose [56]. A fundamentally different approach is the consolidation phase in the Russian "ALL-2009" protocol, which represents continuous low-dose cytostatic exposure. The interval between the end of induction phase II and the start of the consolidation phase is 7 days; all other consolidation phases (phases 1–3) are carried out without interruptions. Consolidation 4 in the ALL-2009 protocol (see Appendix A3.1) consists of a single high-dose administration of methotrexate** (1.5 g/m²) administered with a 3-day course of dexamethasone** and a single dose of asparaginase**; consolidation 5 consists of a 1-day administration of cytarabine** at a dose of 2 g/m² twice daily with a 3-day course of dexamethasone** and a single dose of asparaginase** [66].

It should be noted that Russian hematology centers virtually lack the ability to monitor methotrexate** concentrations, which is strictly required when administering high-dose therapy. Consequently, even a single use of high-dose methotrexate** is associated with drug toxicity-related mortality. Therefore, we would like to draw the attention of hematologists choosing alternative foreign treatment regimens to the fact that high-dose methotrexate** is used repeatedly in these protocols, and administering methotrexate** at the prescribed doses without adequate monitoring is highly likely to result in a fatal outcome.

The "ALL-2016" protocol fully complies with the therapeutic principles of the "ALL-2009" protocol; however, it avoids the use of high doses of methotrexate** and cytarabine** in consolidation phases 4 and 5, replacing them with 4-week courses using mercaptopurine**, methotrexate**, and cytarabine** at standard doses for ALL. The results of a multicenter study demonstrated that the long-term efficacy of both protocols is comparable.

Prophylaxis and treatment of CNS leukemia

Initiation of CNS prophylaxis, as a key component of ALL therapy, is performed concurrently with the start of systemic chemotherapy [1, 2, 4, 5].

Comments: intrathecal administration of antineoplastic agents is recommended for all patients at the time of the first, so-called diagnostic lumbar puncture for therapeutic and prophylactic purposes.

Comments: within the Russian protocol, prophylactic CNS RT is not recommended [66]. If anatomical features prevent the performance of lumbar punctures, an Ommaya reservoir (a subcutaneous device implanted on the scalp for drug delivery into the cerebral ventricles) may be placed.

Comments: The diagnosis of neuroleukemia is established upon the detection of blast cells in the cerebrospinal fluid (in any number) or so-called pleocytosis greater than 15/3 (or 5 cells per microliter). Microscopic examination of the cerebrospinal fluid must be performed for all patients with pleocytosis ≥5/µL. To improve the accuracy of the analysis, it is recommended to use a cytocentrifuge for preparing cerebrospinal fluid cytological specimens.

Comments: Currently, no highly effective treatment approach has been developed for patients with ETP-ALL, and even allo-HSCT does not always achieve long-term favorable treatment outcomes. Therefore, some research groups use #venetoclax in ETP-ALL starting from the induction phase and/or for refractory neuroleukemia during intrathecal therapy. In suspected Ph-like ALL (confirmed specific translocations and aberrations), targeted drugs such as dasatinib** [237], #ruxolitinib**, #venetoclax**, and #sorafenib** may be used in case of persistent MRD, depending on the detected genetic lesion, to rapidly reduce the chemo-refractory tumor clone [237].

Comments: The introduction of immunotherapy with blinatumomab** has demonstrated high efficacy, and current clinical studies are investigating the necessary duration of this therapy, as publications are already emerging on the feasibility of short 14-day courses with equal efficacy in a subset of patients, which reduces treatment toxicity and increases cost-effectiveness [245]. Furthermore, the FDA has already approved an indication for blinatumomab** in first-line consolidation therapy regardless of MRD status [246].

Maintenance therapy

Maintenance therapy is an integral and necessary part of standard ALL treatment in adults, except for mature B-cell ALL. Its average duration is 2 years.

• For patients with Ph- ALL (excluding mature B-ALL variant), it is recommended to administer maintenance therapy consisting of daily mercaptopurine**, methotrexate** (dosage according to the patient's treatment protocol, see Appendix A3.1) once a week, and glucocorticoid and vincristine** pulses once a month or according to the POMP regimen for 2 years [1, 2, 4, 5, 56].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: this stage of treatment may be complicated by the development of myelotoxic agranulocytosis; therefore, recommendations for dose adjustments of antineoplastic agents must be strictly followed.

• It is recommended to administer maintenance therapy taking into account the dose reduction recommendations specified in the patient's treatment protocol to minimize infectious complications associated with cytopenia (see Appendix A3.1) [1, 2, 4, 5].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: in ALL patients who achieve CR only after targeted therapy, the corresponding targeted therapy may be continued after allo-HSCT (for example, if CR is achieved in Ph-like ALL with a dasatinib**-containing regimen, maintenance therapy with dasatinib** can be administered after allo-HSCT; or in ETP-ALL, if MRD-negativity is achieved or relapse is treated exclusively with #venetoclax**, therapy with #venetoclax** may be continued).

• All patients are recommended to take #cotrimoxazole [sulfamethoxazole + trimethoprim]** (480 mg once daily) throughout maintenance therapy for the prevention of Pneumocystis jirovecii pneumonia [1, 2].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Treatment of lymphoblastic lymphoma

Comments: in ALL, involvement of the lymph nodes, liver, spleen, mediastinal lymph nodes, and thymus is not classified as extramedullary, since these organs are part of the body's lymphatic system and their involvement in ALL is a common manifestation of the disease. Extramedullary involvement includes neuroleukemia (see above), skin involvement (leukemia cutis), soft tissue, bone, testes, ovaries, etc.

3.5. Ph-negative ALL in elderly patients

3.6. Treatment of patients with Ph-positive ALL

• For patients aged <55 years or candidates for allo-HSCT, it is recommended to administer therapy with imatinib** (600 mg/day) in combination with a 4–5-drug chemotherapy regimen (ALL-2012m, ALL-2012 protocol – see treatment regimen in Appendix A3.1) [52, 249].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: the detection of the t(9;22)(q34;q11) translocation in ~30% of ALL patients and, consequently, the chimeric BCR-ABL transcript allows the use of imatinib** – a 1st-generation TKI (Protein kinase inhibitors) that inhibits BCR::ABL1 tyrosine kinase activity, achieving a hematological response as monotherapy in 70% of patients, with a CR rate of only 19–20%. Therefore, various combination regimens utilizing antineoplastic drugs are currently being developed to achieve CR in 90–95% of patients and improve the quality of response prior to HSCT.

Comments: therapeutic approaches for patients older than 55 years are primarily aimed at reducing treatment intensity by using imatinib** (at a fixed dose of 600 mg/day) as base therapy in combination with oral prednisolone** (at a dose of 40 mg/m²/day) and low-intensity chemotherapy regimens (vincristine** and dexamethasone**).

Comments: imatinib** penetrates the blood-brain barrier poorly, and its concentration in the cerebrospinal fluid reaches only 1–2% of that in blood serum. Therefore, active neuroprophylaxis is necessary for all Ph+ ALL patients.

Post-induction therapy

Comments: Modern studies demonstrate that performing allo-HSCT significantly improves the prognosis in young patients under 40 years of age, whereas for the group over 40 years old, allo-HSCT can be performed in the second complete remission, taking transplant-related risks into account, and the decision must be made based on the risk assessment of these complications.

Comments: MRD negativity in Ph+ ALL is defined as the complete absence of the transcript (p190 and/or p210) determined by a quantitative method.

Maintenance therapy

Therapy of Ph-positive ALL in elderly patients

Comments: treatment outcomes in elderly patients are significantly worse than in children and younger adults. This is due to the limited opportunities for intensive therapy caused by the patients' performance status and concomitant diseases in older age, as well as unfavorable prognostic factors inherent in patients of this age group. Elderly ALL patients are currently defined as a separate patient group requiring age-specific protocols. In most ALL studies, the older age group includes patients aged 55 years and older. Moreover, among patients older than 55 years, 30-50% have Ph+ ALL.

Comments: the choice of drug should be based on the analysis of the BCR::ABL mutational status.

Recurrence

Comments: blast cells in Ph+ ALL are characterized by acquired genetic anomalies, which significantly affect its prognosis and contribute to disease progression. Approximately 80% of Ph+ ALL patients who relapse during imatinib** therapy have bcr-abl mutations, among which T315I dominates.

Dasatinib** is a more active drug compared to imatinib** and is effective against imatinib**-resistant kinase domain conformations. It is capable of inhibiting the proliferation and activity of the wild-type kinase, as well as 14 of the 15 mutant variants of BCR-ABL1, with the exception of the T315I mutation. Phase II clinical trials confirmed the efficacy of dasatinib** in imatinib**-resistant Ph+ ALL patients, as well as in patients intolerant to imatinib**.

Currently, #nilotinib**, #bosutinib** and ponatinib, #asciminib can be considered as alternatives to imatinib** and dasatinib**. At the same time, they are still not formally registered for the treatment of ALL. The prescription of a particular TKI should be carried out after determining the mutational status.

3.7. Special conditions in the treatment of acute lymphoblastic leukemia

Hyperleukocytosis

Comments: a leukocyte count in the hemogram >100×10⁹/L at the onset of ALL is observed in 10-30% of ALL cases and is, as in other variants of acute leukemia, an unfavorable prognostic factor. Leukocytosis in ALL more frequently develops at a young age, in men, in the T-cell variant (in 38% of cases, the leukocyte count is >100×10⁹/L), in the presence of mediastinal involvement, massive hepatosplenomegaly, neuroleukemia, as well as in Ph+ ALL and MLL leukemia. Clinical manifestations of hyperleukocytosis in ALL are caused by manifestations of leukostasis. However, their severity is significantly less than in acute myeloid leukemia (hereinafter referred to as AML), and, accordingly, early mortality is lower (2-6%). Less common is the clinical presentation of leukostasis manifested by signs of tissue hypoxia, DIC syndrome, organ dysfunction, hemorrhagic complications, including those involving the central nervous system (2-3%), as well as lung tissue damage with the development of acute respiratory distress syndrome (hereinafter referred to as ARDS) (6%) and renal failure. Therapy for this condition in ALL is primarily aimed at preventing tumor lysis syndrome and DIC syndrome during the initiation of chemotherapy. Leukapheresis is used for this purpose, but its efficacy in ALL is significantly lower than in AML.

• In all patients with a rapid decrease in leukocyte count during the prednisolone** pre-phase, it is recommended to perform plasmapheresis to remove toxic tumor cell breakdown products [84].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

ALL in pregnancy

The incidence of pregnancy-associated malignancies is relatively low, accounting for 0.02-0.1% of all pregnancies. Leukemias during pregnancy are rare (approximately 1 case per 75,000-100,000 pregnancies). Most of them are acute leukemias, a third of which are ALL. The relative rarity of these pathological conditions is the main limiting factor that complicates conducting large prospective studies, evaluating treatment principles and outcomes; as a result, only small retrospective studies and individual case reports are described. Furthermore, pregnancy is an exclusion criterion in most clinical trials, which also limits the possibility of developing unified approaches to the management of these patients and evaluating their treatment results. Within the framework of a multicenter clinical trial (ALL-2009) (ClinicalTrials.gov: NCT01193933), it was decided to include women in the study who were diagnosed with ALL at various stages of pregnancy.

In total, from 1990 to 2016, physicians of the Russian Leukemia Study Group investigated 28 pregnant women with ALL. The distribution of immunological variants of ALL corresponds to that in the general population of ALL patients: B-ALL was diagnosed in 68% of cases and T-ALL in 32%. A higher incidence of negative prognostic factors was noted in patients during pregnancy. Thus, MLL leukemia (t(4;11)) was detected almost 10 times more frequently during pregnancy compared to the general population of examined ALL patients (27.3% and 3.2%, respectively). Moreover, based on the combination of prognostic factors and response to the prednisolone** pre-phase, almost all patients were classified into the high-risk group. When administering therapy according to the ALL-2009 protocol in pregnant women, it was noted that compared to the general patient population, no statistically significant differences were revealed either in the frequency of infectious and toxic complications or in the duration of treatment intervals according to the protocol.

The treatment of ALL during pregnancy is carried out by a multidisciplinary team of physicians, including a hematologist, an obstetrician-gynecologist, an anesthesiologist-intensivist, in a hospital equipped to provide obstetric care and emergency delivery [85, 86].

Comments: if the woman and her family insist on continuing the pregnancy, treatment can also be initiated in the first trimester of pregnancy.

• If ALL is diagnosed between 13 and 36 weeks of gestation (after the completion of the first trimester), it is recommended to initiate chemotherapy, provided that the full range of diagnostic and therapeutic measures for both ALL and pregnancy can be performed in a timely manner [86].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• If ALL is diagnosed after 36 weeks of gestation, it is recommended to perform delivery during the prednisolone** pre-phase followed by chemotherapy [87].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: adherence to antineoplastic drug doses in accordance with the selected treatment regimen (without dose reduction), calculated based on the patient's body surface area with weight adjustment during treatment.

In the event of life-threatening complications (e.g., Pneumocystis pneumonia, CMV infection), the use of prescribed medications (e.g., co-trimoxazole [sulfamethoxazole+trimethoprim]**, ganciclovir**, and others) is acceptable [253].

• or according to the ALL-2012m protocol [253] (Appendix A3.1) [253].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comments: the choice of delivery method is determined by the condition of the fetus, the somatic status of the patient, hematological parameters, and strictly in accordance with obstetric indications. Vaginal delivery may be chosen as the method of delivery only if the patient has ALL remission, satisfactory hemogram parameters, and a good somatic status of the patient and condition of the fetus. In other situations, it is preferable to perform delivery by Caesarean section.

3.8. Lymphoblastic lymphomas

Early publications on the use of standard chemotherapy protocols designed for the treatment of non-Hodgkin lymphomas (hereinafter referred to as NHL), in particular CHOP-like regimens, led to extremely low complete response (CR) rates (53-71%) and disease-free survival (0-53%). Since the mid-1970s, ALL-oriented chemotherapy programs have been used in the treatment of lymphoblastic NHL in adults.

Comments: since treatment regimens developed for NHL were not successful in LBL, it appears that treatment regimens used in the treatment of ALL will provide more favorable outcomes.

Comments: cranial irradiation for the prophylaxis of CNS involvement has been abandoned in most protocols; it is used only in patients with initial CNS involvement (cranial irradiation 12–18 Gy on a linear γ-accelerator).

Comments: in most cases, mediastinal lymph node involvement in LBL is characterized by a very good response to primary chemotherapy. There is no clear definition of a residual mediastinal tumor mass; a residual tumor size of >3 cm according to CT and/or a positive PET result (greater than 3 scores) may be considered as such. Radiation therapy for residual mediastinal tumor masses appears to be the best treatment option. The question of the optimal dose in this case (24 or 36 Gy) remains open.

Treatment of relapse

The prognosis for LBL relapse is extremely unfavorable. LBL relapses typically develop within the first 2 years after achieving remission and are more frequently local. Relapse therapy is determined by the relapse characteristics (localization and timing) and the treatment tactics of the first acute period. ALL relapse treatment protocols, high-dose therapy, and drugs not previously used in the first acute period are utilized (ICE courses, nelarabine**, #gemcitabine**, etc. – see Appendix A3.1); allo-HSCT is recommended upon achieving a second remission. The efficacy of relapse therapy remains extremely low for T-cell LBL and somewhat better for B-LBL.

Comments: experience with allo-HSCT in LBL in the first CR is limited [13].

3.9. Relapses of Ph-negative ALL

Relapse of leukemia in adult patients with Ph- ALL remains an unresolved therapeutic problem. Treatment outcomes for this phase of the disease are modest, and ALL relapse is still regarded as a generally incurable pathological condition. Although some patients may achieve a second complete remission (hereinafter referred to as CR2), the CR2 rate remains low, and the post-relapse median survival is short. It is widely accepted that patients who experience a disease relapse cannot be cured by chemotherapy alone. The only radical treatment option is allo-HSCT. Overall, this requires achieving a relatively stable CR2 with salvage therapy, which should be associated with minimal toxicity. In this context, relapses occurring after allo-HSCT present an even greater therapeutic problem. Due to unfavorable overall outcomes in these patients, there remains a significant need to develop and investigate new medicinal products. A potential treatment option for this patient group is inclusion in clinical trials, including trials of novel drugs. Thus, one of the main clinical decisions in patients with relapsed Ph- ALL is the choice between standard salvage chemotherapy and experimental therapy, followed by allo-HSCT whenever possible; treatment of these patients is conducted within clinical trials.

Comments: The introduction of blinatumomab** immunotherapy demonstrates high efficacy, and current clinical trials are currently investigating, among other things, the required duration of this therapy, as publications are already emerging on the possibility of short 14-day courses with the same efficacy in some patients, which can not only reduce therapy toxicity but also increase cost-effectiveness [245].

Comments: Inotuzumab ozogamicin has shown high efficacy in extramedullary ALL relapses compared to standard chemotherapy.

Comments: The introduction of chimeric antigen receptor T-cell (CAR-T) therapy into clinical practice opens up new prospects for the treatment of this group of patients. CAR-T cells are genetically engineered modified T lymphocytes capable of expressing a chimeric antigen receptor (CAR) on their surface that recognizes a specific tumor antigen. CAR consists of an antigen-recognizing domain, which is essentially the variable fragment of a tumor-specific monoclonal antibody with the required amino acid sequence for targeted action, linked to a part of the T-cell receptor consisting of a transmembrane domain, a signaling domain, and costimulatory molecules that mediate T-cell activation. As a result of this fusion, a CAR-bearing cell is able to recognize a tumor antigen, become activated, and destroy the tumor cell, thus combining the advantages of a monoclonal antibody with high affinity and specificity and a lymphocyte with the capacity for proliferation and cytotoxic action [221]. Following the results demonstrating the efficacy of CD19 CAR-T cells in the ELIANA trial in 2017 [222], the US Food and Drug Administration (FDA) first approved CTL019 (tisagenlecleucel) for the treatment of children and young adults up to 25 years of age with R/R B-ALL. Tisagenlecleucel is approved in Russia for the indication of relapsed B-ALL in children and young adults up to 25 years of age inclusive. Furthermore, the introduction of CAR-T cell therapy into clinical practice within clinical trials at academic centers, specifically manufactured for an individual patient directly at the medical institution where this biomedical cell product is used, has demonstrated efficacy [238, 239].

3.10. Hematopoietic stem cell transplantation

Allogeneic HSCT

Indications for allo-HSCT are determined according to the specific treatment protocol selected by the hematology center (ALL-2009, ALL-2016, GMALL, MB2008, Hyper-CVAD/HMA) (see Appendices A3.1 and A3.3) [55, 56, 62, 66, 98].

• For ALL patients under the age of 55 treated according to the ALL 2009 protocol (Appendix A3.1) from the very high-risk group identified at disease onset (cytogenetic abnormalities with 11q23 rearrangement, t(4;11) or t(1;19), as well as Ph+ ALL (t(9;22/BCR::ABL1) and the ETP variant of T-ALL, as well as congenital syndromes associated with tumor predisposition—such as Nijmegen breakage syndrome), allo-HSCT from a matched related or unrelated donor is recommended due to the high risk of disease relapse [66, 99].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

Comment: performing HSCT in the presence of detectable MRD has a significantly lower long-term efficacy compared to patients who received HSCT in an MRD-negative status.

Comments: allo-HSCT in advanced disease relapse and chemotherapy-refractory settings is inappropriate.

Auto-HSCT

3.11. Supportive therapy

General management

ALL treatment protocols provide for intensive induction and consolidation chemotherapy. At the same time, the use of antitumor drugs and immunosuppressants, alongside the underlying disease, can lead to a predictable wide range of severe complications, notably infections, hemorrhages, mucositis, organ-specific toxicity, vomiting, etc., requiring correction directly during ALL treatment. For this reason, patients with ALL require careful monitoring as well as appropriate prophylactic and supportive care.

Antiemetic prophylaxis and therapy

Comments: serotonin receptor antagonists and glucocorticoids are used for antiemetic purposes. These drugs are recommended for combination use when employing CT regimens characterized by moderate and high emetogenicity. In certain situations, in particular during high-dose combination CT, the choice of drug should be determined by the most emetogenic component (see Appendix A3.5) [102].

Transfusion therapy

Successful treatment of AL, in particular ALL, is impossible without blood component replacement therapy and supportive care.

Red blood cell and platelet transfusions

Prophylaxis of hemorrhagic and thrombotic complications

Comments: therapy with glucocorticoids, anthracyclines and related compounds, and especially asparaginase**, can lead to severe acquired deficiency of serpin class proteins (serine protease inhibitors), predominantly antithrombins and alpha-1-antitrypsin. The prevalence of these complications ranges from 2.1% to 15%.

Antithrombin is the main physiological inhibitor of thrombin and coagulation factors IXa, Xa, and XIa. It is also an antagonist of coagulation factor VII, accelerating the dissociation of complexes formed by factor VIIa and tissue factor. Antithrombin forms irreversible bonds with active enzymes, depriving them of proteolytic activity. In addition, when using asparaginase**, a change in the conformation of the antithrombin molecule has been reported, leading to loss of stability and resulting in the formation of protein aggregates that accumulate in the cisternae of the endoplasmic reticulum. Thus, patients administered asparaginase** are characterized by an increased risk of thrombosis. Although a decrease in antithrombin concentration is often accompanied by hypofibrinogenemia, it has been shown that a low fibrinogen concentration predisposes to thrombosis rather than bleeding.

• In the presence of massive extramedullary lesions (most commonly mediastinal organs in ALL/LBL), thrombotic complications during therapy, or a history of thrombosis, it is recommended to administer anticoagulant therapy according to existing treatment protocols for venous thromboembolic complications (see relevant clinical guidelines for the diagnosis, treatment, and prevention of venous thromboembolic complications, section 7.5) [1, 2, 4, 5, 106].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Immunoglobulin replacement therapy

Comments: hypogammaglobulinemia is frequently detected in patients with ALL, but to date, no evidence of the efficacy of prophylactic immunoglobulin infusions has been obtained. Patients receiving blinatumomab** or #rituximab** therapy need to have their immunoglobulin levels monitored every 2-4 weeks, depending on the clinical situation, and, if necessary, undergo immunoglobulin replacement therapy [1, 2].

Other supportive therapy

Growth factors

Comments: in most European national protocols, G-CSF is used prophylactically during remission induction and consolidation. The use of G-CSF is possible in ALL patients who develop life-threatening septic complications.

Medical nutrition therapy

Therapeutic clinical nutrition for patients with acute lymphoblastic leukemia during inpatient treatment in medical organizations is prescribed in accordance with the current orders of the Russian Ministry of Health, taking into account the patient's somatic status and comorbidity, as well as dietary restrictions associated with the presence and severity of cytopenia.

Suppression of menstruation, fertility preservation, and management of abnormal uterine bleeding

• In all premenopausal women with ALL, it is recommended to suppress menstruation to minimize bleeding risks associated with thrombocytopenia [108]

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: Tranexamic acid** is used as an antifibrinolytic agent at 1000–1500 mg orally 2–3 times/day or intravenously 1000–1500 mg 2–3 times a day, with a course of treatment of 5–7 days. Hormonal hemostasis can be performed with systemic hormonal contraceptives (combined oral contraceptives [COCs]) or progestogen medications. Hormonal hemostasis with COCs is advisable for women of early and active reproductive age who are not at risk for endometrial proliferative processes; for patients whose diagnostic curettage was performed no more than 3 months ago and revealed no pathological endometrial changes. In severe menorrhagia, it is advisable to "suppress" menstruation with gonadotropin-releasing hormone (GnRH) agonists – #goserelin** 3.6 mg s.c. once every 28 days [253], with a treatment course of up to 6 months. For prolonged abnormal uterine bleeding, uterotonic therapy with #oxytocin** 10 IU i.v. drip [253] in 100 ml of 0.9% sodium chloride physiological solution** until bleeding stops is also performed; this therapy is used after ruling out organic uterine pathology.

Comments: Cabergoline** 0.5 mg, 1 mg (2 tablets) single dose on the first day after childbirth, or 0.25 mg (1/2 tablet) 2 times/day every 12 h for 2 days (total dose 1 mg) is used as therapy aimed at suppressing established lactation.

Comments: Surgical methods for arresting abnormal uterine bleeding include: hysteroscopy and fractional diagnostic curettage of the uterine cavity walls, resectoscopy in the presence of intrauterine pathology. This surgery has both a diagnostic goal (to rule out organic pathology of the uterine cavity) and a therapeutic goal of stopping abnormal uterine bleeding. Also, in case of inefficacy and/or according to indications, hysterectomy, embolization or sclerotherapy of uterine vessels — in case of their anomalies, or endometrial ablation may be performed.

Analgesic therapy

• In the event of acute or chronic pain syndrome, it is recommended that the patient receive analgesic therapy in accordance with existing pain management protocols (see relevant clinical guidelines for chronic pain, clinical guidelines for anesthesiology) [1, 2, 4, 5, 109].

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: It should be noted that the patient may present with atypical disease manifestations or a combination of the specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for choosing the optimal diagnostic and treatment tactics.

Gastroprotective therapy and prophylaxis

Administration of antidotes during chemotherapy

Comments:Nephrotoxicity of methotrexate** depends on the drug dose and elimination rate. When administered in high doses (1 g/m²) under conditions of acidic urine, precipitation of metabolite crystals occurs inside the renal tubules, and within 1-2 days, crystal-induced non-oliguric and non-proteinuric renal failure develops. The drug causes hypokalemic acidosis and hypocalciuria, as well as hepatotoxicity and myelosuppression. Extrarenal complications can be observed for an average of 7 days after methotrexate** administration. Risk factors that increase methotrexate-mediated nephrotoxicity include advanced age, male sex, high doses of the drug, low creatinine clearance, and concurrent therapy with certain systemic antibacterial drugs and proton pump inhibitors. To reduce the risk of methotrexate nephrotoxicity**, hyperhydration with electrolyte- and osmolarity-balanced solutions at a dose of 40-60 mL/kg/day and urine alkalinization by administration of sodium bicarbonate** (the reaction should be alkaline on the day of administration and the following 2-3 days) are recommended. For this purpose, a mixture of 40 mL of 4.2% sodium bicarbonate** solution (NaHCO₃) and 400-800 mL of isotonic sodium chloride** solution is administered IV drip on the eve, on the day of treatment, and for the subsequent 2-3 days. Treatment with methotrexate** at high and very high doses (2-15 g/m²) is combined with forced hydration (up to 2 L of fluid per day). If acidosis is detected, correction of base deficit with sodium bicarbonate** is required based on the formula (BE × body weight) / 2 = X mL of 5% sodium bicarbonate** solution under the control of blood acid-base status (BE – buffer base concentration deviation from normal). If necessary, prescribe loop diuretics. When prescribing high doses of methotrexate** (2-15 g/m²), IV administration of calcium folinate** at a dose of 25 to 100 mg/m is required.² every 3 and 6 h after methotrexate administration**. If a high methotrexate concentration** persists in the blood, regardless of the azotemia level, high-flow hemodialysis or hemo(dia)filtration is indicated, calculating individual clearance based on the serum methotrexate level**. During the aforementioned extracorporeal hemocorrection, the methotrexate** level decreases by an average of 75% (ranging from 42 to 94%). It is necessary to monitor the creatinine level and blood methotrexate** concentration during the first 24–48 h after administration, which allows for the timely organization of necessary emergency measures, including the administration of calcium folinate**, thereby significantly reducing systemic toxicity and nephrotoxicity.

Comments: The #ifosfamide** metabolite acrolein damages the urinary tract epithelium and causes hemorrhagic cystitis. The cumulative toxic dose of #ifosfamide** is 60-72 g/m² over the treatment period. The risk of #ifosfamide** nephrotoxicity significantly increases with age and in the presence of concomitant renal disease. Combining #ifosfamide** with #allopurinol** [23] increases the blood concentration of uric acid, which increases the risk of nephropathy and enhances the myelotoxic effect of the drug. To prevent drug nephrotoxicity and the development of hemorrhagic cystitis, it is necessary to administer normal saline (sodium chloride**) at a rate of 25-30 ml/kg/day before #ifosfamide** administration; during #ifosfamide** administration, mesna** must be prescribed as an antidote to acrolein and oxazaphosphorine metabolites (cyclophosphamide** and #ifosfamide**). The single dose of mesna** for adults is 20% of the antineoplastic drug dose; the first administration is performed simultaneously with the first #ifosfamide** administration, the second and third 4 and 8 hours after the first administration. With continuous infusion (24 h) of #ifosfamide** or cyclophosphamide**, mesna** should be administered at a dose of 20% of the antineoplastic drug dose at the start of the infusion, then at a dose of 100% of the antineoplastic drug dose as a 24-hour infusion; upon completion of the antineoplastic drug administration, mesna** administration is continued for another 6-12 hours at the same dose. If symptoms of toxic renal damage appear, drug administration should be discontinued.

Antimicrobial therapy and prophylaxis

Comments: Prophylaxis of bacterial infections in allogeneic HSCT recipients is permissible only after prior investigation of intestinal mucosal colonization by microorganisms in these patients. Prophylaxis of bacterial infections in other categories of patients is excluded due to ineffectiveness caused by the high frequency of detection of multidrug-resistant bacteria.

Comments: Prophylaxis of fungal infections in ALL patients is carried out depending on the type of fungal complication: for candidemia – fluconazole** 400 mg i.v. or orally per day, or #caspofungin** 50 mg i.v. per day, or #micafungin** 100 mg i.v. per day, or #anidulafungin** 100 mg i.v. per day [240]; invasive aspergillosis – voriconazole** 200 mg i.v. or orally twice a day, or posaconazole** 200 mg 3 times a day or 300 mg twice a day orally, isavuconazole 200 mg 3 times a day on days 1-2 and then 200 mg once a day; mucormycosis – posaconazole** 200 mg 3 times a day or 300 mg twice a day orally, isavuconazole 200 mg 3 times a day on days 1-2 and then 200 mg once a day

Comment: Cefepime** 2 g twice a day i.v. remains the drug of choice only for pregnant women with ALL and febrile neutropenia.

Comment: Indications for prescribing antipseudomonal carbapenems (Imipenem+[Cilastatin]**, meropenem**) in the 1st line of febrile neutropenia in ALL are septic shock and pneumonia with respiratory failure.

Comment: The drug of choice is caspofungin** 70 mg i.v. on day 1, then 50 mg/day, or #micafungin** 100 mg i.v. per day, or #anidulafungin** 200 mg on day 1, then 100 mg per day i.v.; alternatives include #voriconazole** 6 mg/kg intravenously twice a day on day 1, then 4 mg/kg twice a day, #amphotericin B** 0.8-1 mg/kg i.v. per day [240].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no special rehabilitation methods for ALL/LBL.

Comments: after completion of treatment, it is recommended to maintain a healthy lifestyle and avoid sun exposure and physiotherapeutic procedures.

5. Prevention and Dispensary Observation

There is no primary prevention for ALL.

Comments: unscheduled bone marrow examination is indicated if any blood count abnormalities are detected. Most relapses occur within 1-5 years after treatment completion.

6. Organization of Medical Care

Medical care, except for medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the fundamentals of protecting the health of citizens in the Russian Federation", is organized and provided:

– in accordance with the regulations on organizing medical care by types of medical care, approved by the authorized federal executive body;

– in accordance with the procedure for providing care in the profile "hematology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

– based on these clinical guidelines;

– taking into account the standards of medical care approved by the authorized federal executive body.

Primary specialized health care is provided by a hematologist and other medical specialists at an ambulatory hematology/oncology care center, a primary hematology/oncology office, a primary hematology department, or an outpatient department of an oncological dispensary.

If acute lymphoblastic leukemia (hereinafter – ALL) is detected or suspected in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for consultation to an outpatient hematological/oncological care center, a primary hematology office, or a primary hematology department of a medical organization for the provision of primary specialized health care.

An outpatient or inpatient hematologist organizes the diagnostic tests necessary to establish the diagnosis, including disease extent and stage.

If it is impossible to perform diagnostic tests, the attending physician refers the patient to a medical organization providing medical care to patients with hematological diseases to establish a diagnosis and provide specialized, including high-tech, medical care.

If ALL is detected or suspected during the provision of emergency medical care, the patient shall be transferred or referred to medical organizations providing medical care to patients with hematological diseases to determine management tactics and the need for additional specialized anti-tumor treatment methods.

Specialized, including high-tech, medical care is provided by hematologists in medical organizations providing care to ALL patients, possessing a license, the necessary material and technical base, certified specialists, in inpatient and day-care settings, and includes the prevention, diagnosis, and treatment of hematological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with ALL, the tactics of medical examination and treatment are established by hematologists, involving other medical specialists if necessary, and holding a medical board (consilium) when required. The decision of the medical board is formalized in a protocol, signed by the members of the board, and entered into the patient's medical records.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the profile "hematology" are determined by a hematologist/medical board with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

1. Suspension/establishment of ALL diagnosis.

2. Diagnosis of ALL relapse.

3. Administration of a routine course of chemotherapy in an inpatient or day-care setting.

4. Performance of planned HSCT.

5. Performance of elective surgical interventions.

6. Performance of elective extracorporeal blood purification methods and renal replacement therapy.

7. Administration of blood component replacement therapy.

Indications for emergency hospitalization:

Emergency conditions in patients with ALL and suspected ALL:

– leukocytosis >100×10⁹/L

– febrile neutropenia and infectious complications during chemotherapy;

– hemorrhagic syndrome;

– thrombotic complications;

– need for emergency blood component replacement therapy;

– other systemic disorders caused by the underlying disease or resulting from the treatment administered.

Indications for patient discharge from the hospital:

1. Recovery of peripheral blood counts (leukocytes >1×10⁹/L, granulocytes >0.5×10⁹/L, platelets >50×10⁹/L, hemoglobin >80 g/L) after a regular course of chemotherapy.

2. Normothermia for 3–5 days and the absence of uncontrolled infectious complications in the post-course period.

3. Relief of hemorrhagic complications.

4. Relief of thrombotic complications.

5. Relief of systemic disorders caused by the underlying disease or resulting from the treatment administered.

The conclusion regarding the feasibility of transferring the patient to a specialized medical organization is made after a preliminary consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the organization to which the transfer is planned.

Before starting therapy, it is recommended to inform all patients about the risk of infertility following therapy and potential fertility preservation methods, as well as the need to use effective contraception methods for at least one year after completing therapy.

7. Additional Information

7.1. Full compliance with treatment protocols (therapy regimens) for acute lymphoblastic leukemia/lymphoma

The ability to complete a full course of induction-consolidation therapy within the specified time frame and subsequently adhere strictly to maintenance therapy is a clear prognostic factor, repeatedly demonstrated in Russian studies. Foreign researchers also agree with this concept. Adequate chemotherapy remains the foundation of successful treatment. Unfortunately, inadequate adherence to treatment protocols remains one of the main reasons for significantly lower treatment efficacy in patients with acute leukemias across many hematology centers.

7.2. Prevention, diagnosis, and treatment of hemorrhagic complications in patients with acute lymphoblastic leukemia/lymphoma

Hemorrhagic manifestations in patients with ALL/ALL are diverse and may be caused by the disease itself or its complications, including those resulting from specific therapy, as well as appear as a result of antithrombotic therapy. Prevention, diagnosis, and treatment of hemorrhagic complications in patients with ALL/ALL are carried out in accordance with current guidelines [103, 104, 240].

7.3. Prophylaxis and treatment of menorrhagia in patients with acute lymphoblastic leukemia

Abnormal uterine bleeding (AUB) is a common pathology in women with acute lymphoblastic leukemias, which includes menstrual cycle disorders related to frequency, regularity, duration, and volume of blood loss in patients. The prevalence of AUB in the general female population ranges from 14% to 30%; the prevalence in patients with acute lymphoblastic leukemias is unknown. Prevention, diagnosis, and treatment of menorrhagia in patients with ALL/ALL are carried out in accordance with current guidelines [112, 113, 240].

7.4. Intracranial hemorrhages in patients with acute lymphoblastic leukemias.

Intracranial hemorrhages (ICH) are a frequent (expected) complication of the underlying disease and/or specific (including chemotherapeutic) treatment in patients with acute lymphoblastic leukemias, often associated with plasma and/or platelet hemostasis disorders [114]. Without emergency neurosurgical care, massive ICHs in ALL patients inevitably lead to a fatal outcome.

Diagnosis and treatment of ICH occurring in patients with acute lymphoblastic leukemias are carried out directly during the course of anti-tumor chemotherapy for acute leukemia. Prevention, diagnosis, and treatment of intracranial hemorrhages in patients with ALL/ALL are carried out in accordance with current guidelines [114, 240].

7.5 Prevention, diagnosis, and treatment of thrombotic complications

In ALL, both initially and during chemotherapy and other treatments, thrombotic complications frequently occur, requiring prevention and therapy. The incidence of thrombotic disorders in blood system malignancies varies; chemotherapy increases the incidence of thrombotic complications almost twofold, from 2.21% to 4.24% relative to baseline [109, 110]. Prevention, diagnosis, and treatment of thrombotic complications in patients with ALL/ALL are carried out in accordance with current guidelines [109, 110, 111, 240].

Diagnosis and treatment of thrombotic complications that naturally arise in ALL patients are carried out directly during the period of anti-tumor chemotherapy [240].

To assess the risk of thrombotic disorders and their relapses in ALL, a thorough medical history is necessary, including clarifying the presence of thrombosis in the patient and first-degree relatives, as well as assessing the patient's general condition and identifying comorbid conditions.

Laboratory evaluation of the blood coagulation system is carried out during the initial examination of the patient, prior to specific therapy, including before each course of chemotherapy (as indicated), and in the event of thrombotic disorders at any stage of diagnosis, monitoring, or treatment.

7.6. Diagnosis and treatment of neurological manifestations in acute lymphoblastic leukemia

Involvement of the central nervous system (CNS) and peripheral nervous system may be detected in ALL. Neurological manifestations can be either a manifestation of specific nervous system involvement (tumor involvement of the CNS) or a manifestation of complications of ALL and its treatment (hemorrhagic, thrombotic, toxic lesions of the nervous system). For the diagnosis and treatment of neurological manifestations and complications of ALL, a set of neurological examinations and therapy appropriate to the type of disorder, taking into account the nature of the underlying disease, are used [240]. Specific tumor involvement of the CNS involving the brain, spinal cord, and meninges can be a manifestation of acute lymphoblastic leukemia. Most often, tumor involvement of the CNS is localized in the frontal lobe (50%), less commonly in the corpus callosum and deep brain structures (40%), multifocal involvement (35%), leptomeningeal involvement (16%), and isolated spinal cord involvement (1%). In addition, specific CNS involvement may develop as leukemic infiltration of the meninges and cerebrospinal fluid involvement (neuroleukemia).

Prevention, diagnosis, and treatment of neurological manifestations in patients with ALL/LBL are carried out in accordance with current clinical guidelines [240].

7.7. Prevention of gastric and duodenal ulcers during glucocorticoid therapy in ALL

The vast majority of anti-tumor treatment protocols for ALL include high doses of glucocorticoids (GCs). Gastric or duodenal ulcer is one of the serious adverse effects of GC therapy. The mechanism of the ulcerogenic action of GCs involves increased secretion of hydrochloric acid in the stomach, changes in the qualitative composition of mucus, and inhibition of surface epithelial regeneration. When GCs are combined with nonsteroidal anti-inflammatory and antirheumatic drugs or antithrombotic agents, the risk of steroid ulcers increases. Due to their ulcerogenic potential, antisecretory therapy must be administered when using GCs to prevent steroid ulcers [115, 116, 118, 119, 240]. Prevention of gastric and duodenal ulcers in patients with ALL/LBL is carried out in accordance with current clinical guidelines [115, 116, 240].

7.8. Prevention, diagnosis, and treatment of aseptic osteonecrosis in patients with acute lymphoblastic leukemia.

Aseptic osteonecrosis (AON) in patients with acute lymphoblastic leukemia belongs to the group of secondary osteonecroses. Its development is associated with impaired blood supply and death of bone cells in a specific area of bone tissue resulting from chemotherapy or glucocorticoid exposure. Most frequently, AON is triggered by acute lymphoblastic leukemia therapy (glucocorticoids and other agents) and allogeneic bone marrow transplantation.

AON in patients with acute leukemias predominantly localizes in long tubular bones. Based on their location within the tubular bone, lesions can be identified either independently of the epiphyses, representing medullary osteonecroses, or involving the epiphyses and articular regions of the tubular bones. In these cases, osteonecrosis is defined as aseptic necrosis, followed by the name of the epiphysis, for example, aseptic necrosis of the femoral head. Avascular necrosis (AVN) of the femoral head or other localizations of epiphyseal osteonecrosis in long bones is frequently used as a synonym, although the term “aseptic necrosis” more accurately reflects the pathological process (avascular bone necrosis often accompanies infectious bone and joint diseases, which does not apply to the condition under consideration). Prevention, diagnosis, and treatment of aseptic necroses in patients with ALL/LBL are carried out in accordance with current clinical guidelines [240].

7.9. Diagnosis and treatment of infectious complications in acute lymphoblastic leukemia

Infections are the leading complications in the management of hematological malignancies. The highest incidence is observed in patients with acute leukemias and recipients of allogeneic hematopoietic stem cell transplantation (HSCT), ranging from 30% to 90%. Thus, in patients with acute lymphoblastic leukemias, infections develop predominantly during the remission induction phase (55%), less frequently during remission consolidation (10%), while in allogeneic HSCT recipients, they occur during the granulocytopenic period at the stage of hematopoietic cell engraftment (40-70%) and upon the development of graft-versus-host disease (10-70%) [49, 122]. The incidence of infectious complications is higher during remission induction, in refractory tumor variants, during high-dose chemotherapy, in the presence of concomitant hypogammaglobulinemia, and during periods of forced hypodynamia and strict bed rest.

The primary factor determining the development of infectious complications in patients with ALL is neutropenia (neutrophils <0.5×10⁹/L) or leukopenia (leukocytes ≤1,000×10⁹/L), as well as the duration of neutropenia—the incidence of infections increases significantly when neutropenia lasts longer than 10 days. The risk of infections rises with impaired neutrophil phagocytic function, defects in cellular and humoral immunity, damage to the gastrointestinal mucosa (especially grade III-IV mucositis), and the presence of a central venous catheter (CVC). The source of infection is typically the gastrointestinal tract, driven by active translocation of microorganisms from the mucosa damaged by chemotherapy. Another primary portal of entry for infection during neutropenia is the CVC. Diagnosis and treatment of infectious complications inherently occurring in patients with ALL are performed directly during the course of anti-tumor chemotherapy [240]. Prevention, diagnosis, and treatment of infectious complications in patients with ALL/LBL are carried out in accordance with current clinical guidelines [122-124, 240].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Savchenko V.G., Academician of the Russian Academy of Sciences, MD, Professor

2. Parovichnikova E.N., MD, General Director of the National Research Center for Hematology of the Russian Ministry of Health

3. Troitskaya V.V., MD, First Deputy General Director of the National Research Center for Hematology of the Russian Ministry of Health

4. Aleshina O.A., PhD, Head of the Department of Cellular and Immune Therapy, National Research Center for Hematology of the Russian Ministry of Health

5. Sokolov A.N., PhD, Senior Researcher at the Scientific and Clinical Department of Chemotherapy for Hemoblastoses and Hematopoiesis Depressions, National Research Center for Hematology of the Russian Ministry of Health

6. Kuzmina L.A., PhD, Head of the Scientific and Clinical Department of Bone Marrow Transplantation, National Research Center for Hematology of the Russian Ministry of Health

7. Klyasova G.A., MD, PhD, Professor, Head of the Research and Clinical Laboratory of Microbiology, National Research Center for Hematology, Russian Ministry of Health

8. Dvirnyk V.N., Candidate of Medical Sciences, Head of the Centralized Clinical Diagnostic Laboratory National Research Center for Hematology, Russian Ministry of Health

9. Galtseva I.V., MD, PhD, Head of the Laboratory of Blood and Bone Marrow Cell Immunophenotyping National Research Center for Hematology, Russian Ministry of Health

10. Bondarenko S.N., Candidate of Medical Sciences, RM Gorbacheva Research Institute of Children's Oncology, Hematology and Transplantology, Pavlov University

11. Baranova O.Yu., Candidate of Medical Sciences, Senior Researcher, Department of Antitumor Drug Therapy and Hematology, National Medical Research Center of Oncology named after N.N. Blokhin

12. Konstantinova T.S., Candidate of Medical Sciences, Head of the Hematology Department, Sverdlovsk Regional Clinical Hospital No. 1

13. Samoylova O.S., Candidate of Medical Sciences, Head of the Hematology Department, Nizhny Novgorod Regional Clinical Hospital named after N.A. Semashko

14. Kaporskaya T.S., Candidate of Medical Sciences, Head of the Hematology Department, Irkutsk Order of the Badge of Honor Regional Clinical Hospital

15. Lapin V.A., Candidate of Medical Sciences, Head of the Hematology Department, Yaroslavl Regional Clinical Hospital

16. Ptushkin V.V., MD, PhD, Professor, Deputy Chief Physician for Hematology, Botkin City Clinical Hospital

17. Kaplanov K.D., MD, PhD, Head of Hematology Department No. 11, Botkin City Clinical Hospital

18. Obukhova T.N., Candidate of Medical Sciences, Head of the Karyology Laboratory, National Research Center for Hematology, Russian Ministry of Health

Healthcare Organization Section:

19. Lazareva O.V., Candidate of Medical Sciences, Head of the Department of Regional and Interdepartmental Cooperation in Hematology, National Research Center for Hematology, Russian Ministry of Health

Allogeneic Hematopoietic Stem Cell Transplantation Section

20. Drokov M.Yu., Candidate of Medical Sciences, Head of the Sector for the Study of Immune Effects and Complications after HSCT, National Research Center for Hematology, Russian Ministry of Health

21. Vasilieva V.A., Candidate of Medical Sciences, Head of the Department of Immunochemotherapy with a Day Hospital for Patients after HSCT, National Research Center for Hematology, Russian Ministry of Health

22. Vlasova Yu.Yu., Candidate of Medical Sciences, Head of the Adult Bone Marrow Transplantation Department, Research Institute of Pediatric Oncology, Hematology and Transplantology, First Pavlov State Medical University of St. Petersburg of the Ministry of Health of the Russian Federation

23. Gaponova T.V., MD, PhD, Chief External Expert Transfusiologist of the Ministry of Health of the Russian Federation, Deputy General Director of the National Research Center for Hematology, Russian Ministry of Health, Head of the Blood Cell Processing and Cryopreservation Department

24. Gritsaev S.V., MD, PhD, Head of the Republican HSCT Center, Russian Research Institute of Hematology and Transfusiology of the Federal Medical-Biological Agency

25. Zyuzgin I.S., Head of the Department of Hematology and Bone Marrow Transplantation, National Medical Research Center of Oncology named after N.N. Petrov, Russian Ministry of Health

26. Klimko N.N., MD, PhD, Professor, Head of the Department of Clinical Mycology, Allergology and Immunology, North-Western State Medical University named after I.I. Mechnikov

27. Kulagin A.D., MD, PhD, Acting Director of the Research Institute of Pediatric Oncology, Hematology and Transplantology, First Pavlov State Medical University of St. Petersburg of the Ministry of Health of the Russian Federation,

28. Minaeva N.V., Deputy Director for Clinical Work, Kirov Research Institute of Hematology and Blood Transfusion of the Federal Medical-Biological Agency

29. Moiseev I.S., MD, PhD, Deputy Director for Science, Research Institute of Pediatric Oncology, Hematology and Transplantology, First Pavlov State Medical University of St. Petersburg of the Ministry of Health of the Russian Federation

30. Morozova E.V., MD, PhD, Head of the Department of Adult Hematology, Oncology and Transplantation, Research Institute of Pediatric Oncology, Hematology and Transplantology, First Pavlov State Medical University of St. Petersburg of the Ministry of Health of the Russian Federation

31. Petrova G.D., Candidate of Medical Sciences, Head of the Department of Bone Marrow and Hematopoietic Stem Cell Transplantation, Department of Hematology and Bone Marrow Transplantation, National Medical Research Center of Oncology named after N.N. Blokhin, Russian Ministry of Health,

32. Popova M.O., Candidate of Medical Sciences, Associate Professor, Department of Hematology, Transfusiology and Transplantology, Faculty of Postgraduate Education, First Pavlov State Medical University of St. Petersburg

33. Estrina M.A., Candidate of Medical Sciences, Head of the Clinical Transfusiology Department, Research Institute of Pediatric Oncology, Hematology and Transplantology, First Pavlov State Medical University of St. Petersburg of the Ministry of Health of the Russian Federation

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of the clinical guidelines:

• hematologists;

• oncologists;

• general practitioners (internal medicine);

• obstetricians-gynecologists;

• anesthesiologists-intensivists;

• clinical pharmacologists.

Since 1995, the Russian Acute Leukemia Study Group has conducted 3 multicenter clinical trials on the treatment of patients with ALL aged 15 to 55 years, involving hematology centers from more than 30 cities in Russia. The results of these studies have been repeatedly published and discussed at annual working meetings of the study group. In addition, the creation of national guidelines drew upon the experience of individual federal hematology centers that concentrate patients with this disease.

The Russian Adult ALL Study Group (hereinafter referred to as RALL) participates in pan-European cooperation in this field of hematology, is a member of the European Working Group on Adult ALL, and unites 14 research groups from various European countries. The development of the guidelines also took into account the experience of American research groups and NCCN recommendations.

Since ALL is a rare and highly heterogeneous disease, there is currently no universal treatment program for ALL. ALL therapy is strictly differentiated. The Russian guidelines are based on the results of our own research, European guidelines for the treatment of ALL, and American NCCN guidelines.

Table 2. Levels of reliability of evidence (LRE) scale for diagnostic methods (diagnostic interventions)

Table 3. Levels of reliability of evidence (LRE) scale for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Table 4. Levels of bibliographic consensus (LBC) scale for prevention, diagnostics, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines

The clinical guideline update mechanism provides for their systematic updating—at least once every 3 years or upon the appearance of new information on the management tactics of patients with this disease. The decision to update is made by the Ministry of Health of the Russian Federation based on proposals submitted by medical non-profit professional organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicines and medical devices, as well as the results of clinical approbation.

Appendix A3. Reference Materials

Appendix A3.1. ALL treatment protocols

Protocol of the Russian Study Group for Ph-negative ALL in patients under 55 years of age – "ALL-2009" [1, 66]

Protocol of the Russian Study Group for Ph-negative ALL in patients under 55 years of age – "ALL-2016" [1]

Protocol of the German Study Group GMALL (06/99 and 07/03) [5, 254]

M.D. Anderson CRC Protocol R±Hyper-CVAD/HMA [56, 61]

"ALL-2009" protocol adapted for the treatment of older patients with ALL (55 years and older) [1]

Protocol of the European Group for the treatment of patients over 55 years of age with ALL [5]

Prephase: dexamethasone** (oral, 10 mg/m², on days 1–5), methotrexate** (intratechally 12 mg, on day 1).

Induction, phase I: dexamethasone** (oral, 10 mg/m² on days 6–7*, 13–16); vincristine** (intravenous, 1 mg on days 6, 13); #idarubicin** (intravenous, 10 mg, on days 6–7, 13–14); methotrexate** (intrathecally, 12 mg) + #dexamethasone** (intrathecally, 4 mg) + cytarabine** (intrathecally, 40 mg) on days 12, 20, 27, 34; filgrastim** (subcutaneous, 5 mcg/kg, on day 6, until neutrophil count recovery >1.0×10⁹/L).

Induction, phase II: cyclophosphamide** (intravenous, 300 mg/m² on days 20–22)^[1]; cytarabine** (intravenous, 60 mg/m² on days 21–24, 28–31).

Consolidation (every 4–6 weeks): cycles 1, 3, 5 – methotrexate** (1000 mg/m²; in patients >70 years – 500 mg/m², intravenously, on day 1); asparaginase** (10,000 IU/m²; in patients >70 years – 5000 IU/m², intramuscularly, on day 2); cycles 2, 4, 6 – cytarabine** (1000 mg/m²; in patients >70 years – 500 mg/m², intravenously, on days 1, 3, 5).

Maintenance therapy (duration up to 2 years): dexamethasone** (orally, 40 mg on days 1–2); vincristine** (intravenously, 1 mg on day 1); mercaptopurine** (orally, 60 mg/m² on days 1–90); methotrexate** (intravenously, 25 mg/m², once a week).

POMP regimen therapy (maintenance therapy and regimen for patients over 55 years) [56, 241] – 1 cycle is 28 days:

• Prednisolone** 60 mg/m² orally on days 1–5

• Vincristine** 1.4 mg/m² (maximum 2 mg) IV on day 1

• Mercaptopurine** 60 mg/m² orally on days 1–28

• #Methotrexate** 20 mg/m² orally on days 1, 8, 15, 22

Burkitt leukemia/lymphoma treatment protocols LB-M-04 [63, 1]

Treatment regimen: prephase – 4–6 blocks (-A-C-)

Pre-phase:

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• Dexamethasone** 20 mg orally, days 1–5

Block A:

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 1.5 g/m² IV (over 12 h), day 1

• Vincristine** 2 mg IV, day 1

• Doxorubicin** 50 mg/m² IV, day 3

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 100 mg/m² IV, days 4–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

Block C:

• Methotrexate** 1.5 g/m² IV (over 12 h), day 1

• #Vinblastine** 5 mg/m² IV, day 1

• Cytarabine** 2 g/m² IV every 12 h, days 2–3 (4 administrations in total)

• #Etoposide** 150 mg/m² IV, days 3–5

• #Dexamethasone** 10 mg/m² IV, days 1–5

Neuroleukemia prophylaxis is performed on day 1 of the prephase and on day 1 of each block as intrathecal chemotherapy: cytarabine** 30 mg, #methotrexate** 15 mg, #prednisolone** 30 mg.

Prophylaxis during #ifosfamide** therapy – mesna** at 20% of the #ifosfamide** dose during drug administration and at 4 and 8 hours; during methotrexate** therapy – calcium folinate** 25 mg/m² IV and orally every 3–6 hours starting 24 hours after and for 2–7 days.

#Rituximab** 375 mg/m² is administered on day 0 of each block (4 administrations in total)

Hyper-CVAD/HMA [56]

Cycles 1, 3, 5, 7 (Hyper-CVAD):

• Cyclophosphamide** 300 mg/m² IV every 12 h, days 1–3 (6 administrations in total)

• #Dexamethasone** 40 mg IV or orally, days 1–4, 11–14

• Doxorubicin** 50 mg/m² via continuous 24-hour IV infusion into a central catheter, day 4

• Vincristine** 2 mg IV, days 4 and 11

Cycles 2, 4, 6, 8 (HMA):

• Methotrexate** 1000 mg via continuous 24-hour IV infusion, day 1

• Cytarabine** 3 g/m² (in patients over 60 years – 1 g/m²) IV every 12 h, days 2–3 (4 administrations in total)

• Methylprednisolone** 50 mg IV every 12 h, days 1–3 (6 administrations in total)

• #Rituximab** 375 mg/m² IV, days 1 and 11 (cycles 1, 3) and days 2 and 8 (cycles 2, 4) – 8 administrations in total

• CNS prophylaxis is performed during each course, totaling 16 intrathecal administrations: methotrexate** 12 mg intrathecally on day 2, cytarabine** 100 mg intrathecally on day 7

• Maintenance therapy according to the POMP regimen for 2 years

R-DA-EPOCH [241]

• #Rituximab** 375 mg/m² IV, day 0

• #Etoposide** 50 mg/m² IV over 24 h, days 1–4¹

• Doxorubicin** 10 mg/m² IV over 24 h, days 1–4¹

• #Vincristine** 0.5 mg IV over 24 h, days 1–4

• Prednisolone** 60 mg/m² orally, days 1–5

• Cyclophosphamide** 750 mg/m² IV, day 5^[2]

NHL-BFM 90 (B-NHL 2004 mab.) [63]

Treatment regimen:

• Low-risk group: V – A – B

• Intermediate-risk or high-risk group: V – AA – BB, followed by restaging:

  • if CR, then AA – BB (– AA – BB – in high-risk patients);

  • if partial response, then CC, followed by restaging;

    • if second CR or absence of tumor tissue is achieved according to repeat biopsy, then AA – BB – CC

    • if tumor tissue is present according to repeat biopsy, then auto-HSCT

Prophase (V):

• #Prednisolone** 30 mg/m² orally or IV, days 1–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• Methotrexate** 12 mg intrathecally, day 1

• Cytarabine** 30 mg intrathecally, day 1

• #Prednisolone** 10 mg intrathecally, day 1

Block A:

• #Dexamethasone** 10 mg/m² IV or orally, days 1–5

• #Ifosfamide** 800 mg/m² IV, days 1–5

• Methotrexate** 500 mg/m² IV, day 1 (24-hour infusion)

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 100 mg/m² IV, days 4–5

• Methotrexate** 12 mg intrathecally, day 1

• Cytarabine** 30 mg intrathecally, day 1

• #Prednisolone** 10 mg intrathecally, day 1

Block B:

• #Dexamethasone** 10 mg/m² IV or orally, days 1–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• Methotrexate** 500 mg/m² IV, day 1 (24-hour infusion)

• Doxorubicin** 25 mg/m² IV, days 4–5

• Methotrexate** 12 mg intrathecally, day 1

• Cytarabine** 30 mg intrathecally, day 1

• #Prednisolone** 10 mg intrathecally, day 1

Block AA:

• #Dexamethasone** 10 mg/m² IV or orally, days 1–5

• #Ifosfamide** 800 mg/m² IV, days 1–5

• #Methotrexate** 5 g/m² IV, day 1 (24-hour infusion) (when treated per the B-NHL 2004 mab. protocol – 1 g/m²)

• Vincristine** 1.4 mg/m² (no more than 2 mg) IV, day 1

• Cytarabine** 150 mg/m² IV every 12 h, days 4–5 (4 administrations in total)

• #Etoposide** 100 mg/m² IV, days 4–5

• Methotrexate** 12 mg intrathecally, days 1, 5

• Cytarabine** 15 mg intrathecally, days 1, 5

• #Prednisolone** 5 mg intrathecally, days 1, 5

Block BB:

• #Dexamethasone** 10 mg/m² IV or orally, days 1–5

• Cyclophosphamide** 200 mg/m² IV, days 1–5

• #Methotrexate** 5 g/m² IV, day 1 (24-hour infusion) (when treated per the B-NHL 2004 mab. protocol – 1 g/m²)

• Vincristine** 1.4 mg/m² (no more than 2 mg) IV, day 1

• Doxorubicin** 25 mg/m² IV, days 4–5

• #Methotrexate** 6 mg intrathecally, days 1, 5

• Cytarabine** 15 mg intrathecally, days 1 and 5

• #Prednisolone** 5 mg intrathecally, days 1 and 5

SS Block:

• #Dexamethasone** 20 mg/m² IV or orally, days 1–5

• Vincristine** 1 mg/m² (not exceeding 2 mg) IV, day 1

• Cytarabine** 2 g/m² IV every 12 h, days 1–2 (4 infusions in total)

• #Etoposide** 150 mg/m² IV, days 3–5

• Methotrexate** 12 mg intrathecally, day 5

• Cytarabine** 30 mg intrathecally, day 5

• #Prednisolone** 10 mg intrathecally, day 5

• #Rituximab** 375 mg/m² IV over 6–8 hours, day 0 of each block (per the B-NHL 2004 protocol, mabs are given on day 0 of the first 4 blocks)

Treatment regimens for relapsed and refractory ALL

Flag-Ida [241]:

• #Fludarabine** 25 mg/m² IV over 30 min, every 12 h, days 1, 2, 8, and 9

• Cytarabine** 100 mg/m² IV over 45 min every 3 hours (8 infusions), days 1, 2, 8, and 9

• #Idarubicin** 10 mg/m² IV over 15 min, days 1 and 3

• Filgrastim** 5 mcg/kg subcutaneously starting from day 7 until recovery from cytopenia

FLAM [241]:

• #Fludarabine** 15 mg/m² IV over 30 min, days 1–5

• Cytarabine** 2 g/m² IV over 4 h, administered 4 h after #fludarabine**, days 1–5

• #Mitoxantrone** 10 mg/m² IV over 15 min, days 3 and 10

#Bortezomib** + dexamethasone** + #mitoxantrone** + vincristine** + asparaginase**[1]

• #Bortezomib** 1.3 mg/m² IV infusion, days 1, 4, 8, and 11

• Dexamethasone** 10 mg/m², divided into 2 oral doses, days 1–14

• #Mitoxantrone** 10 mg/m² IV infusion over 15–30 min, days 1 and 2

• Vincristine** 2 mg IV bolus, days 1, 8, and 15

• Asparaginase** 5,000 IU/m² IV infusion, days 15–21

  All patients undergo intrathecal therapy: cytarabine** 30 mg on day 1.

If there is CNS involvement: intrathecal #methotrexate** 15 mg, cytarabine** 30 mg, #dexamethasone** 4 mg on days 8, 15, and 22. In patients who develop polyneuropathy, the vincristine** dose is reduced to 1 mg and administered on days 1 and 8.

Bortezomib + dexamethasone** + #mitoxantrone** + vincristine** + asparaginase**[1]

• #Bortezomib** 1.3 mg/m² subcutaneously, days 1, 4, 8, and 11

• Dexamethasone** 10 mg/m², divided into 2 oral doses, days 1–14

• #Mitoxantrone** 10 mg/m² IV infusion over 15–30 min, days 1 and 2

• Vincristine** 2 mg IV bolus, days 1, 8, and 15

• Asparaginase** 10,000 IU/m² IV infusion, day 21, or pegaspargase** 1,000 IU/m² IV infusion

  All patients undergo intrathecal therapy: cytarabine** 30 mg on day 1.

If there is CNS involvement: intrathecal #methotrexate** 15 mg, cytarabine** 30 mg, #dexamethasone** 4 mg on days 8, 15, and 22. In patients who develop polyneuropathy, the vincristine** dose is reduced to 1 mg and administered on days 1 and 8. For patients over 55 years of age, the asparaginase** dose is 6,000 IU/m2 or pegaspargase** 500 IU/m2.

#Nelarabine** + cyclophosphamide** + #etoposide**[1, 96]

Regimen: Block N and Block CE are administered with a 2-day interval between them in any sequence.

Block N:

• #Nelarabine** 650 mg/m² IV infusion over 1 h, days 1–5 (or days 8–12)

Block CE:

• Cyclophosphamide** 440 mg/m² IV infusion, days 8–12 (or days 1–5)

  #Etoposide** 100 mg/m² IV infusion over 1 h, days 8–12 (or days 1–5)

ALL-2012m protocol regimen for the treatment of Ph-positive ALL [1, 158]

Tyrosine kinase inhibitor (TKI) monotherapy regimens in Ph-positive ALL (maintenance therapy) or in combination with chemotherapy (e.g., ALL-2012m) [241]

- #dasatinib** 140 mg once daily orally

- #nilotinib** 400 mg orally twice daily or once daily (if toxicity develops)

- #bosutinib** 500 mg or 400 mg (if toxicity develops) once daily

- ponatinib 45 mg or 30 mg (if toxicity develops) once daily

- #asciminib 200 mg or 40 mg (if toxicity develops) twice daily

Blinatumomab therapy regimen** [1, 73]

Pre-phase: blinatumomab** 9 mcg/day, days 1–7, continuous 24-hour infusion.

Course: blinatumomab** 28 mcg/day, days 8–28, continuous 24-hour infusion.

NB! Drug doses for patients weighing more than 45 kg.

Interval between courses is 14 days.

For MRD persistence therapy, treatment can be initiated without the pre-phase.

Inotuzumab ozogamicin therapy regimen [243]

Cycle 1 (21–28 days): inotuzumab ozogamicin 0.8 mg/m² on day 1, and 0.5 mg/m² on days 8 and 15.

Cycle 2 and subsequent cycles: inotuzumab ozogamicin 0.5 mg/m² on days 1, 8, and 15.

#Venetoclax** + #decitabine** therapy regimen [158, 229, 233]

Cycle 1 (28 days): #decitabine** 20 mg/m², days 1–5 + #venetoclax** 400 mg once daily, 28 days.

Attention should be paid to the need for dose adjustment of #venetoclax** when used concomitantly with CYP3A inhibitors. The dose of #venetoclax** is reduced by 50% when used concomitantly with moderate CYP3A inhibitors (e.g., fluconazole**, voriconazole**) and reduced by 75% when used concomitantly with strong CYP3A inhibitors (e.g., carbamazepine**, phenytoin**).

#Venetoclax** + #azacitidine** therapy regimen [244, 158]

Cycle 1 (28 days): #azacitidine** 75 mg/m², days 1–7 + #venetoclax** 400 mg once daily, 28 days.

Attention should be paid to the need for dose adjustment of #venetoclax** when used concomitantly with CYP3A inhibitors. The dose of #venetoclax** is reduced by 50% when used concomitantly with moderate CYP3A inhibitors (e.g., fluconazole**, voriconazole**) and reduced by 75% when used concomitantly with strong CYP3A inhibitors (e.g., carbamazepine**, phenytoin**).

Targeted therapy regimens as monotherapy or in combination with chemotherapy/immunotherapy [226, 228]

- #dasatinib** 140 mg/day orally daily ± #blinatumomab** 9 mcg/day days 1-7, 28 mcg/day, days 8-28, continuous 24-hour infusion.

- #sorafenib** 400 mg (200 mg in case of toxicity or cytopenia development) twice daily, daily ± #blinatumomab** 9 mcg/day days 1-7, 28 mcg/day, days 8-28, continuous 24-hour infusion.

- #dasatinib** 140 mg orally + #tretinoin** 45 mg/m² orally in 2 divided doses daily ± #blinatumomab** 9 mcg/day days 1-7, 28 mcg/day, days 8-28, continuous 24-hour infusion.

- #venetoclax** 400 mg orally daily (days 7-21 depending on tolerability and development of cytopenia) ± #blinatumomab** 9 mcg/day days 1-7, 28 mcg/day, days 8-28, continuous 24-hour infusion.

- #trametinib** 2 mg/day orally, daily ± #blinatumomab** 9 mcg/day days 1-7, 28 mcg/day, days 8-28, continuous 24-hour infusion.

- #ruxolitinib** 15 mg twice daily, daily ± #blinatumomab** 9 mcg/day days 1-7, 28 mcg/day, days 8–28, continuous 24-hour infusion.

Therapy for MRD persistence or relapse of T-cell ALL [224, 225]

#Daratumumab** 16 mg/kg IV once weekly for 8 weeks

CAR-T cell therapy regimen with #tisagenlecleucel [222, 256]

Lymphodepleting therapy: #fludarabine** 25 mg/m² on days -6, -5, -4, -3, -2, IV infusion over 30 min, cyclophosphamide** 60 mg/kg IV over 60 min on days -3, -2; on day 0 after #tocilizumab** 8 mg/kg administration over 30 min, #tisagenlecleucel is administered

Appendix A3.2. Long-term outcomes of therapy for Ph-negative adult ALL depending on the chemotherapy principle

Table 5. Long-term outcomes of therapy for Ph-negative adult ALL depending on the chemotherapy principle

Appendix A3.3. Recommendations for prophylactic antiemetic therapy [240]

Table 1. Recommendations for prophylactic antiemetic therapy

^[1] Days are relative to the start of the pre-phase of therapy.

^[2] Depending on the tolerability of the previous course, drug doses are increased or decreased by 20%.

Appendix B. Physician Action Algorithms

Fig. 1. Decision-making algorithm at the time of ALL diagnosis

Fig. 2. Decision-making algorithm upon confirmation of resistance and development of ALL relapse using non-Russian study group protocols

Fig. 3. Decision-making algorithm upon confirmation of resistance and development of ALL relapse using the Russian study group protocol

Fig. 4. Decision-making algorithm for confirming resistance and managing relapse in Ph-positive ALL

Appendix C. Patient Information

ALL, or acute lymphoblastic leukemia, is a malignant disease of the hematopoietic system. The bone marrow, where blood cells are produced, generates an excessive number of immature white blood cells. Normally, all human blood cells grow and renew at a relatively steady rate through a complex maturation process. However, in ALL, this process gets out of control. Instead of growing and maturing into fully functional cells, white blood cells begin to divide rapidly and uncontrollably. Constantly multiplying, they crowd out healthy white blood cells (leukocytes), red blood cells (erythrocytes), and blood platelets (thrombocytes). As a result, a deficiency of essential healthy cells develops. Anemia, infections, and bleeding are not only consequences of ALL but also its initial symptoms. Initially, leukemias are not confined to any specific part of the body. Spreading from the bone marrow into the blood, they affect lymphatic tissue (the lymphatic system), other organs, and consequently, the entire organ system. Therefore, like other leukemias, ALL is classified as a systemic malignant disease. The course of ALL is acute. Without treatment, leukemic cells proliferate and damage human organs. The disease takes a severe form, leading to death within a few months.

ALL is the most common form of leukemia in children and adolescents, accounting for approximately one-third of all malignancies in the pediatric and adolescent age groups. ALL can develop at any age, including in adults. However, it most commonly affects children aged 1 to 5 years, and boys much more frequently than girls.

In ALL, a malignant alteration (mutation) occurs in immature lymphocyte precursor cells. The mutation can happen at various stages of cell development. This means that not only various lymphocyte subpopulations are affected, but also their progenitors. Therefore, there are numerous forms of the disease in ALL. For example, B-cell ALL is named after B-lymphocyte precursor cells, while T-cell leukemias indicate origin from T-lymphocyte precursor cells. It is important to know that there are different forms or subvariants of ALL. They can differ significantly from each other both in disease progression and cure rates (prognosis). These differences are taken into account when choosing a therapeutic strategy.

The initial symptoms of ALL typically develop over several weeks. Malignant cells spread throughout the bone marrow and other organs. Multiplying unhindered in the bone marrow, leukemia cells prevent normal blood cells from growing. Therefore, patients with ALL initially present with general malaise: lethargy, weakness, and pallor (anemia). These symptoms are explained by a shortage of red blood cells, which are responsible for delivering oxygen to other cells in the body. A deficiency of fully functional white blood cells (such as lymphocytes and granulocytes) leads to weakened immunity, resulting in frequent infections with high fever. Due to a lack of platelets, which are responsible for rapid blood clotting, pinpoint hemorrhages on the skin and mucosal bleeding may occur. As leukemic cells spread through the body, they cause more than just blood composition changes. Children experience pain in various organs. Because leukemia cells fill the bone cavities and bone marrow, the bones begin to ache, particularly in the arms and legs. Malignant cells infiltrate the liver, spleen, and lymph nodes. Their enlargement leads to abdominal pain. In principle, no organ is immune to leukemic cells. In ALL patients, malignant cells can also penetrate the leptomeninges, leading to headaches, facial nerve palsy, visual disturbances, and/or vomiting. The symptoms of ALL can vary greatly from person to person. One or even several symptoms do not necessarily indicate that a person has leukemia. Many of them occur in relatively benign diseases unrelated to leukemia. However, if pain appears, we recommend consulting a doctor immediately to determine its cause. And if an ALL diagnosis is indeed confirmed, urgent treatment is required.

If the medical history (anamnesis) or physical examination reveals signs of acute leukemia, the patient is referred for a complete blood count. If specific changes in the hemogram (blood composition record) confirm suspicion of leukemia, obtaining bone marrow cells is necessary for a definitive diagnosis. Therefore, the doctor refers the patient for further evaluation at an inpatient facility specializing in blood diseases and malignancies. Blood and bone marrow tests allow for the precise determination of the presence and type of leukemia in a patient. Furthermore, modern immunological and genetic laboratory analyses not only distinguish ALL from other types of leukemia but also identify the specific subtype of ALL. This is an essential prerequisite for planning precise therapy, because different types of ALL differ from one another at the cellular and molecular levels, have different disease courses, and carry varying prognoses and treatment sensitivities. Once an ALL diagnosis is established, the treatment plan requires determining whether organs other than the bone marrow—such as the brain, liver, spleen, lymph nodes, or bones—are infiltrated by leukemic cells. The diagnosis is determined through imaging from various studies, such as ultrasound, X-ray, magnetic resonance imaging (MRI), computed tomography (CT), and skeletal scintigraphy. To determine if the central nervous system (CNS) is affected, a cerebrospinal fluid sample is collected and analyzed for the presence of leukemic cells. Further preparation for treatment involves assessing cardiac function and brain functional status. Changes that may occur during therapy must be evaluated based on these baseline data. Comprehensive laboratory tests help assess the patient's general condition and determine whether there are metabolic disorders or organ dysfunctions (e.g., of the kidneys or liver) caused by leukemia, which can be particularly important before or during treatment. The patient's blood group should be determined for any potentially required blood transfusions.

Not all examinations are mandatory for every patient. Medical staff will provide you with information on which specific diagnostic procedures are necessary to plan your therapy.

If an ALL diagnosis is confirmed, the patient is urgently referred to a hematology department or center that possesses both the most modern and effective treatment options and hematology subspecialists (physicians, nurses). Physicians in specialized departments work in close daily contact, and patient treatment is carried out according to jointly developed and systematically refined treatment plans.

Chemotherapy (CT) occupies a central place in the treatment of ALL. CT is treatment with medications that inhibit cell growth (cytostatics). Some patients also undergo CNS irradiation (cranial irradiation). In some cases, high-dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT) is used. The goal of treatment is to eradicate leukemic cells throughout the entire body as completely as possible, allowing the bone marrow to resume functioning as a hematopoietic organ. The intensity and duration of CT, the necessity of CNS irradiation or HSCT, and the prognosis of the disease depend primarily on the specific subtype of ALL the patient has, the extent of leukemic cell spread throughout the body, and how the leukemia responds to therapy. Treatment of mature B-cell ALL differs from the treatment of all other ALL subtypes. Patients with this diagnosis receive the same therapy as patients with mature B-cell non-Hodgkin lymphoma. Therefore, the following information regarding the course of treatment does not apply to them.

The treatment of patients diagnosed with ALL (excluding mature B-cell ALL) is divided into 4 major stages. The four phases of therapy differ from each other in duration, the use of certain medications, as well as the intensity and goals of treatment. 1. Induction: a stage of intensive chemotherapy, its goal is to destroy the maximum number of leukemic cells in a short time and achieve remission. Treatment lasts approximately 5 to 8 weeks. 2. Consolidation and intensive therapy: treatment is carried out for several months (approximately 2 to 5), its goal is to continue the destruction of leukemic cells using new drug combinations and consolidate remission. An important element is the prophylaxis of CNS involvement (preventive treatment). For this purpose, medications are injected into the cerebrospinal fluid and, if necessary, additional brain irradiation is prescribed (for example, if there is data on CNS involvement). This stage must prevent leukemic cells from entering the brain and spinal cord or, more commonly, from proliferating there. 3. Reinduction: treatment is carried out similarly to the induction period; its goal is to finally destroy all leukemic cells and thereby minimize the risk of disease relapse. The total duration of reinduction can range from several weeks to months; at this stage, phases of intensive treatment alternate with chemotherapy pauses. 4. Maintenance therapy or prolonged therapy: low doses of chemotherapy are prescribed at this stage. A feature of treatment is that it is carried out for a long time, usually until its total duration reaches 2 years. Treatment is mostly outpatient, and its goal is to destroy all those leukemic cells that managed to survive even after intensive therapy.

Great progress in therapy over the past three decades has significantly increased the chances of being cured of ALL. Thanks to the introduction of modern diagnostic methods and more effective standardized combination chemotherapy protocols, about 70% of patients diagnosed with ALL recover. If a patient survives for 5 years after treatment without relapses, they are considered cured (5-year survival rate). Some patients may experience a return of the disease (relapse). As a rule, relapse occurs in the first 2-3 years after diagnosis and in extremely rare cases after 5 years. In general, the chances of recovery upon relapse are significantly lower than with the primary disease, although some patients achieve a good result with re-treatment. Essential note: the stated percentages of recovered patients are statistical indicators. They accurately and reliably describe only the cohort of patients with ALL. Statistics cannot predict whether a patient will recover or not. Leukemias, even under the most favorable or unfavorable conditions, can behave completely unpredictably.Appendix G. Assessment scales, questionnaires, and other patient condition evaluation tools presented in clinical guidelines.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. ECOG performance status scale

Eastern Cooperative Oncology Group (ECOG) Performance Status

Original title: The ECOG Scale of Performance Status.

Source: Oken M.M. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–65 [16].

Type: rating scale.

Purpose: clinical assessment of the patient's general condition.

Content and interpretation:

Table 1. ECOG Performance Status Scale

Appendix G2. Immunological classification of ALL

The immunological characterization of ALL utilizes the classification of the European Group for the Immunological Characterization of Leukemias (EGIL).

For B-ALL, it distinguishes 4 immunophenotypic variants, conventionally corresponding to the stages of B-cell precursor development (Table 1).

• BI (pro-B-ALL) – blast cells express CD19, cyCD79a, cyCD22, nuclear TdT; CD10, heavy and light immunoglobulin chains are absent.

• BII (“common” B-ALL) – CD10 is positive, heavy and light immunoglobulin chains are negative.

• BIII (pre-B-ALL) – cytoplasmic heavy immunoglobulin chain (IgM) is detected.

• BIV (mature B-ALL; transitional pre-B-ALL) – tumor cells are positive for membrane heavy and/or light IgM chains.

If this variant of B-ALL is detected, additional diagnostic methods (histological, immunohistochemical, cytogenetic, molecular genetic) are often required for differential diagnosis between mature B-lymphoblastic leukemia and mature B-cell lymphoma (follicular lymphoma, Burkitt lymphoma, DLBCL, high-grade B-cell lymphoma).

Table 1. EGIL classification of B-ALL.

Cy – cytoplasmic expression. Surf – surface expression. Nu – nuclear expression.

By analogy with the stages of intrathemic differentiation of T-lymphocytes, 4 variants of T-ALL are distinguished: pro-T, pre-T, cortical T, medullary (mature) T-ALL. In the EGIL classification, these variants are designated as TI, TII, TIII, TIV (Table 2).

• TI – expression of early markers only (cyCD3, CD7, possibly CD10, HLA-DR, CD34) and absence of CD4, CD8, and CD1a.

• TII – CD2 and/or CD5 appear.

• TIII (cortical T-ALL) – mandatory presence of CD1a; membrane CD3 -/+.

• TIV (medullary T-ALL) is characterized by bright membrane CD3 expression and/or T-cell receptor (TCR) expression; CD1a is negative.

Table 2. EGIL classification of T-ALL.

Cy – cytoplasmic expression. Surf – surface expression

The 2016 WHO classification separately distinguishes early T-precursor lymphoblastic leukemia (ETP-ALL). Blast cells in ETP have features of myeloid and stem cells, and the immunophenotype must meet certain criteria:

• T-lineage commitment (cyCD3+CD7+)

• CD1a and CD8 negative (<5%)

• CD5 positive in less than 75% of blasts, weak antigen expression.

• positive for at least one of the following markers: CD34, CD117, HLA-DR, CD13, CD33, CD11b, CD65.

In the case of bright and more monomorphic CD5 expression (≥75%), while meeting all other criteria for early T-precursor lymphoblastic leukemia, the diagnosis of near-ETP-ALL is established.

Appendix G3. Main genetic abnormalities in ALL

Table 1. Main genetic abnormalities in ALL

Appendix G4. Calculation of transplantation risk using the EBMT score

Transplantation risk assessment is performed no later than 10 days before the start of pre-transplant conditioning [218].

Five-year transplantation-related mortality (%) according to the EBMT risk score

Appendix G5. HCT-CI Transplant Risk Assessment

Transplantation risk assessment is performed during the initial evaluation of a patient as a candidate for allo-HSCT and repeated no later than 10 days before the start of pre-transplant conditioning [219,220].

Low risk – 0 points.

Intermediate risk – 1-2 points.

High risk – 3-4 points.

Very high risk – 5 or more points.