Acute Promyelocytic Leukemia: Clinical Guidelines

List of Abbreviations

Allo-HSCT – allogeneic hematopoietic stem cell transplantation (bone marrow transplantation or hematopoietic cell infusion)

Auto-HSCT – autologous hematopoietic stem cell transplantation (bone marrow transplantation or hematopoietic cell infusion)

Anticoagulants – medications of the ATC group Antithrombotic Agents

ALT – alanine aminotransferase

AST – aspartate aminotransferase

aPTT – activated partial thromboplastin time

RFS – relapse-free survival

IV ‒ intravenous

DIC – disseminated intravascular coagulation

DS – differentiation syndrome

Inhibitors of fibrinolysis – medications of the ATC group Antifibrinolytics

RI – remission induction

CT – clinical trial

BM – bone marrow

Cryoprecipitate – a donor blood component containing the cryoglobulin fraction of plasma, obtained by plasma processing

CT – computed tomography

MRD – minimal residual disease

LMWH – low-molecular-weight heparins (heparin group)

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

OS – overall survival

AL – acute leukemia

AML – acute myeloid leukemia

APL – acute promyelocytic leukemia

RT-PCR – reverse transcription polymerase chain reaction

PB – peripheral blood

CR – complete remission

PCR – polymerase chain reaction

Retinoids – medications used for the treatment of acute promyelocytic leukemia of the ATC group L01XF: Other antineoplastic agents, retinoids

FFP – fresh frozen plasma

HSCT – hematopoietic stem cell transplantation

BMT – bone marrow transplantation

LoE ‒ level of evidence

US – ultrasound examination

GoR ‒ grade of recommendation

FAB classification – French-American-British classification

CT – chemotherapy

CNS – central nervous system

ARA-C – cytarabine**

ATO – arsenic trioxide

ATRA – all-trans retinoic acid (tretinoin**)

CD – cluster of differentiation

FISH – fluorescence in situ hybridization

** – vital and essential drugs

# – drug used outside the approved indications, contraindications, routes of administration, or dosing specified in the drug package insert (off-label)

Terms and Definitions

Differentiation syndrome is a life-threatening complication that develops during the treatment of acute promyelocytic leukemia with all-trans retinoic acid (tretinoin**) and arsenic trioxide, diagnosed by the presence of at least 4 symptoms from the following symptom complex: unexplained fever, respiratory distress syndrome, pulmonary infiltration on imaging studies, hypoxemia, edema (including pleural and pericardial effusion), weight gain, acute kidney injury, and arterial hypotension. In diagnosing differentiation syndrome, it is advisable to use the terms "target organs" and "organ damage" instead of "pneumonia," "hepatitis," "pancreatitis," etc.

Complete remission of acute promyelocytic leukemia is defined as a hematopoietic state in which bone marrow aspirate shows ≤ 5% blast cells with a normal ratio of all hematopoietic lineages, an absolute neutrophil count in peripheral blood > 1.0 × 10⁹/L, a platelet count ≥ 100 × 10⁹/L, and the absence of extramedullary leukemic involvement. These parameters must persist for ≥ 1 month.

Resistant acute promyelocytic leukemia can be stated in the absence of complete remission after completing 1 cycle of induction therapy. According to most international and Russian experts, in patients with acute promyelocytic leukemia confirmed by molecular cytogenetic studies, true refractory acute promyelocytic leukemia does not occur when tretinoin** is used in combination with chemotherapy or arsenic trioxide.

Early death – patient death during induction therapy.

Relapse of acute promyelocytic leukemia is established upon detection of > 5% blast cells in the bone marrow aspirate and/or the appearance of extramedullary disease.

Minimal residual disease, or measurable residual disease, refers to a small population of tumor cells that cannot be detected by light microscopy but is identified by more sensitive techniques capable of detecting 1 leukemic cell per 10^4‒6 cells examined.

Cytogenetic remission is complete clinical and hematologic remission in which the PML::RARA fusion gene is not detectable by FISH (fluorescence in situ hybridization).

Cytogenetic relapse – reappearance of the PML::RARA gene detected by FISH in the setting of ongoing clinical and hematologic remission.

Molecular remission is complete clinical and hematologic remission in which the baseline PML/RARA chimeric transcript originally detected by polymerase chain reaction is undetectable at an assay sensitivity of 10^‒4.

Molecular relapse – reappearance of the baseline PML/RARA fusion transcript in two consecutive assays (performed at a short interval of 7–10 days) in the setting of ongoing clinical and hematologic remission.

Hematopoietic stem cell transplantation – an umbrella term that includes the transplantation of hematopoietic stem cells derived from bone marrow, peripheral blood, or umbilical cord (placental) blood.

Overall survival. To evaluate overall survival, time-to-event parameters of all patients enrolled in the study are analyzed using the Kaplan–Meier method. The starting point is the first day of therapy. The event is defined exclusively as death from any cause (early mortality, death in remission from any cause, death during relapse).

Relapse-free survival. This analysis includes only data from patients who achieved complete remission, evaluated using the Kaplan–Meier method. The starting point is the date complete remission was achieved. Events are defined as disease relapse and death from any cause (during consolidation or maintenance therapy, from relapse, or during remission from another cause, such as suicide).

Probability of maintaining complete remission (inverse of cumulative incidence of relapse). The probability of maintaining complete remission is evaluated only in patients who have achieved complete remission, using the Kaplan–Meier method. The starting point is the date complete remission was achieved. The event is defined strictly as disease relapse; death in complete remission is considered a censored event. Patients who are alive in complete remission at the time of analysis are also censored.

Event-free survival. This metric evaluates all events (failure to achieve complete remission after induction, death during induction, death during complete remission, death from any other causes, disease relapse) across all patients included in the analysis from the start of therapy.

Remission induction – the initial treatment phase aimed at the most rapid and substantial reduction of tumor burden and achievement of complete remission (usually 1–2 cycles). It is during this period, under cytotoxic therapy (L01: Antineoplastic agents), that the leukemic cell count in the bone marrow decreases by approximately 100-fold, such that < 5% tumor cells are morphologically identified in the bone marrow when complete remission is achieved.

Remission consolidation – the second phase of acute promyelocytic leukemia therapy, serving to consolidate the achieved antitumor response.

Anti-relapse or maintenance therapy. Continuation of cytotoxic therapy for two years following completion of induction/consolidation. The concept of maintenance therapy does not apply to frontline treatment regimens with arsenic trioxide for patients with newly diagnosed acute promyelocytic leukemia.

Prophylaxis or, when indicated, treatment of central nervous system leukemia is an essential component in the management of high-risk patients with acute promyelocytic leukemia. This component spans all phases of programmed therapy: remission induction, consolidation, and maintenance.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Acute promyelocytic leukemia is a distinct subtype of acute myeloid leukemia characterized by a predominance of abnormal promyelocytes harboring genetic mutations that lead to the fusion of the RARA gene with the PML gene (t(15;17)(q22;q11-12) translocation) or with other partner genes.

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

The etiology of APL is unknown in most cases. In recent years, an increasing number of cases of APL have been described as therapy-related leukemia associated with prior chemotherapy (CT) or radiation therapy. Large multicenter studies indicate that therapy-induced APL most commonly occurs no later than three years after the completion of CT for a primary oncological disease using topoisomerase II inhibitors (L01DB: Anthracyclines and related substances, or mitoxantrone**, less commonly etoposide**). In 57% of patients, the primary tumor was breast cancer, followed by non-Hodgkin lymphomas, and significantly less frequently, Hodgkin lymphoma. The median time from completion of therapy for the primary tumor to the diagnosis of secondary APL is 24 months (ranging from 15 months to 8 years). As the aggressiveness of the chemotherapy increases, the probability of developing secondary APL also increases, while the time interval from the completion of CT to the onset of acute leukemia may correspondingly decrease.

APL is classified as acute myeloid leukemia (AML), which represents a heterogeneous group of hematopoietic tumor diseases arising from a mutation in a hematopoietic stem/progenitor cell, resulting in a differentiation block and the uncontrolled proliferation of undifferentiated tumor blood cells that crowd out normal ones.

It is interesting to note that promyelocytic blastic crises of chronic myeloid leukemia have been described.

1.3 Epidemiology of the Disease or Condition

The true incidence of APL is unknown, as APL is recorded in incidence registries together with other AML variants. It is estimated that APL accounts for 5–15% of all AML cases. While in 2005 the estimated incidence of AML in the USA was evaluated at 11,930 cases per year, the probable incidence of diagnosed APL is 600–800 cases per year [1,3,4].

There are several differences in epidemiological characteristics between AML and APL, particularly regarding the probability of developing APL depending on age. Thus, for AML, the probability of onset gradually increases in proportion to age up to 55 years, followed by a sharp exponential increase in incidence. This pattern is not observed in APL. Although the disease is diagnosed in all age groups, its incidence is extremely low in patients under 10 years of age. In the 0 to 17 age group, the frequency of APL among all AML cases is 3–4%. From 10 to 20 years of age, the probability of developing APL gradually increases, followed by a plateau up to the age of 60, after which the probability of developing the disease declines. Most cases of APL are diagnosed between the ages of 20 and 60. The median age at APL diagnosis is 38 years. According to a Russian registry study conducted by the Russian Acute Leukemia Study Group, APL is diagnosed in 7.25% of all adult acute leukemia cases, and the median age is 47 years (excluding pediatric patients) [2]. There are no real incidence and prevalence figures for APL in Russia.

1.4 Features of Coding the Disease or Condition

C92.4 ‒ acute promyelocytic leukemia

1.5 Classification of the disease or condition

Patients with APL are stratified into risk groups based on laboratory parameters from the complete blood count at disease manifestation [1,2,4]:

• low-risk group: leukocytes < 10 × 10⁹/L

• high-risk group: leukocytes ≥ 10 × 10⁹/L

1.6 Clinical presentation of the disease or condition

Acute promyelocytic leukemia is a well-defined nosological entity with such characteristic clinical and laboratory features (typical morphology of tumor cells, severe hemorrhagic syndrome, hematoma-type bleeding, excessively activated fibrinolysis, disseminated intravascular coagulation [DIC], usually leukopenia) that the diagnosis can sometimes be established based solely on clinical manifestations. At the same time, some cases of APL have a less dramatic course: manifestations of hemorrhagic syndrome are absent, and patients are monitored for several months for leukopenia and moderate thrombocytopenia. Manifestations of hemorrhagic syndrome (gum bleeding, increased skin bruising, ecchymoses, petechiae, frequently nasal and gastrointestinal bleeding) are present at the time of diagnosis in 90% of patients. Hepatosplenomegaly or lymphadenopathy is identified in less than 20% of patients [4].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: APL is diagnosed regardless of the percentage of blast cells in the bone marrow aspirate or peripheral blood (PB) in the presence of the APL-pathognomonic translocation t(15;17)(q22;q11–12) PML::RARA or a variant translocation involving RARA and another partner gene.

2.1 Complaints and Anamnesis

Comments: The clinical manifestation of APL is accompanied by symptoms of anemia, the development of a hemorrhagic syndrome of varying intensity, and infectious complications against the background of neutropenia. These manifestations may develop acutely or progress gradually. Anamnestic data may also reveal a connection with potential toxic or drug agents. A thorough family history is required to rule out congenital anomalies and to check for the presence of siblings [1–3,5].

2.2 Physical Examination

Comments: height and body weight, body temperature (general thermometry) are measured, the musculoskeletal system is assessed, and signs of hemorrhagic syndrome, hepatosplenomegaly, lymphadenopathy, and cardiac, pulmonary, hepatic, and endocrine system dysfunction are evaluated. If papular skin rashes appear, consider a skin biopsy (suspected extramedullary leukemic involvement).

2.3 Laboratory Diagnostics

Comments: In 80% of patients, the disease manifests with leukopenia. If a patient with acute leukemia presents with leukopenia < 1 × 10⁹/L at diagnosis, especially in combination with hypofibrinogenemia, the promyelocytic variant of AML is highly probable. Leukocytosis is detected in 15–20% of patients at onset. The vast majority of patients (80–90%) present with anemia, with hemoglobin concentrations < 100 g/L in half of them. Platelet counts decrease to ≤ 50 × 10⁹/L in 75% of patients. A complete blood count (especially leukocyte and platelet counts) is performed daily during the first days of tretinoin** therapy to assess the risk of differentiation syndrome (DS), and then every 1–2 days until remission is confirmed. Differential count – twice a week.

Comments: In most patients, blast cells in APL are primarily characterized by significant nuclear polymorphism and the presence of coarse purple-brown granules densely filling the cytoplasm, along with a high number of Auer rods (classic hypergranular variant of APL) [6]. In 15–20% of patients, only a few small granules are found in the cytoplasm of tumor cells or they are completely absent, while all other features (clinical, cytochemical, cytogenetic) of APL are present. A classic feature of APL tumor cells is a very prominent cytochemical reaction for myeloperoxidase (MPO), lipids, detected using Sudan Black B (SBB), and chloroacetate esterase.

Comments: immunophenotyping using multicolor flow cytometry can improve the accuracy of APL morphological studies, but it is not a key diagnostic method. Typically, PML::RARA-positive blast cells have an immunophenotype similar to normal promyelocytes (CD34‒/+ heterogeneous, CD117‒/+ dim, HLADR‒/+ dim, CD13+/++, CD11b‒). Nevertheless, unlike normal promyelocytes, PML::RARA-positive promyelocytes exhibit an extremely low level of CD15 (CD15‒/+ dim instead of CD15+++). Blast cells in the hypogranular (variant) form of APL (M3V) frequently co-express T-lineage markers, such as CD2, along with myeloid markers such as CD13 and CD33.

Comments: all cases of APL diagnosed by morphological and cytochemical methods must be confirmed by PCR or FISH at the time of diagnosis, since in 5–10% of cases in the absence of the classic t(15;17), the PML/RARA transcript is detected.

It should also be borne in mind that in less than 2% of APL cases, karyotyping may reveal RARA recombination with a gene other than PML: ZBTB16::RARA, NPM::RARA, NuMA::RARA, STAT5b::RARA, FIP1L12::RARA, etc.

The efficacy of targeted therapy based on retinoids and/or arsenic derivatives (G01AB: Arsenic compounds) strictly depends on the presence of the PML::RARA fusion gene; therefore, genetic confirmation of the diagnosis is mandatory in all cases [8]. Genetic confirmation of the diagnosis should be performed, if possible, on blast cells obtained from the bone marrow. The identification of APL-specific genetic abnormalities in blast cells is carried out using standard karyotyping, fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), or anti-PML monoclonal antibodies.

In clinics where it is not feasible to perform cytogenetic testing (karyotype) or quantitative determination of PML-RARA expression, the diagnosis must be confirmed in a reference laboratory. Bone marrow or peripheral blood samples must be delivered to the laboratory prior to the initiation of therapy.

Comments: in clinics lacking the capability to perform molecular testing, the diagnosis must be confirmed in a reference laboratory. Bone marrow or peripheral blood samples must be delivered to the laboratory prior to therapy initiation. PML/RARA transcript variants (bcr1, bcr2, bcr3) and RARA-PML transcript expression serve as markers for MRD monitoring in APL with t(15;17), but do not determine the prognosis of the disease.

Comments: Laboratory signs of disseminated intravascular coagulation (DIC) and depleted fibrinolysis are detected in 80–90% of patients [4].

In patients showing the slightest signs of coagulopathy during the remission induction phase, all the indicated parameters must be monitored daily. If available, it is advisable to include thrombelastography in the monitoring system.

Comments: if indicated, additional urine tests are performed, for example, to rule out infection and identify the causative agent — Nechyporenko urine test, Zimnitsky test, various microbiological (culture) urine tests, and microscopic urine examination.

Comments: mutations in the gene encoding FMS-like tyrosine kinase-3 (FLT3) are observed more frequently in APL than in other AMLs, occurring in 30–40% of patients. However, although FLT3 mutations are associated with a higher leukocyte count at the time of acute leukemia diagnosis, FLT3 inhibitors (L01E: Protein kinase inhibitors) are not used in the treatment of newly diagnosed APL.

Comments: patients in the low-risk group (baseline leukocyte count < 10 × 10⁹/L) who achieve molecular remission may be monitored exclusively during the first year of treatment.

Comments: the most frequently performed procedures are lumbar puncture with cytological examination of cerebrospinal fluid cells, and bronchoalveolar lavage with cytological examination of the lavage fluid. However, depending on indications, a biopsy of any available organ and tissue with subsequent cytological examination may be performed, including: oral cavity tissue micropreparations, peritoneal fluid, skin micropreparations, lymph node tissue preparations, tumor biopsies, bone tumor-like lesions, liver tissue, large intestine tissue, uterine cavity aspirate, vaginal tissue, uterine tissue, prostate tissue, testicular tissue, kidney tissue, urinary bladder tissue, punctates and touch imprints of retroperitoneal tumors.

2.4 Instrumental Diagnostics

Comments: Brain CT in APL should be performed for all patients in the first days of diagnosis, as asymptomatic intracranial hemorrhages may occur. If headaches, meningism, drowsiness, or lethargy develop during retinoid therapy, a head CT is mandatory, and lumbar puncture is performed after CT (if the platelet count permits).

2.5 Other Procedures

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

The prescription and use of medicinal products specified in the clinical guideline are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and use in a specific clinical situation are determined in accordance with the instructions for use of specific medicinal products, implementing the precautions described in the instructions, and dose adjustments may also be made taking into account the patient's condition.

Treatment regimens with dosing schedules – see Appendix A3.1

3.1. Main principles of APL treatment

Comments: although there is general consensus on the need for molecular genetic confirmation of an APL diagnosis, differentiating (targeted) and supportive therapy must be initiated before receiving the results of genetic testing. Any suspicion of APL must be taken into account: the presence of severe coagulopathy, hemorrhagic syndrome, leukopenia, or a characteristic morphological picture of blast cells. In all such cases, therapy with #tretinoin** should be started immediately and continued until the diagnosis is confirmed or refuted based on genetic testing.

Comments: in all patients, regardless of initial leukocytosis, a course of chemotherapy must be started no later than the 3rd day of #tretinoin** treatment. In patients with a leukocyte count ≥ 10 × 10⁹/L, anti-tumor drug therapy is initiated simultaneously with #tretinoin**. The optimal day to start chemotherapy for patients with a leukocyte count < 10 × 10⁹/L can be considered the 2nd day of #tretinoin** administration, since by this time the diagnosis of APL should already be confirmed and the probability of early retinoic acid syndrome is extremely low.

3.2. Initial actions for supportive therapy when APL diagnosis is suspected

Supportive therapy aimed at correcting hemostasis

Intracerebral hemorrhages, pulmonary and other bleeding events are frequent life-threatening complications of APL due to severe coagulation disorders. These complications are not only the most common cause of death during the early stages of induction therapy, but they also frequently develop before the diagnosis of APL is established and therapy is initiated [21,22].

Comments: therapy should include transfusions of fresh frozen plasma (FFP), cryoprecipitate, and platelet concentrate to maintain a fibrinogen concentration > 2 g/L and a platelet count > 50 × 10⁹/L. Monitoring of these parameters should be performed at least once daily (or more frequently if clinically indicated). Such therapy should be continued throughout the entire induction therapy period until all clinical and laboratory signs of coagulopathy resolve. Attention should be paid to factors increasing the risk of fatal hemorrhages and bleeding. These factors include: ongoing or active bleeding, hypofibrinogenemia (< 1.0 g/L), elevated levels of fibrin degradation products or D-dimers combined with prolonged prothrombin time or activated partial thromboplastin time, as well as hyperleukocytosis, presence of blast cells in the peripheral blood, high creatinine levels, and poor performance status. Central venous catheterization, lumbar punctures, and other invasive procedures (e.g., bronchoscopy) should be avoided prior to the initiation of therapy and during the induction phase due to the high risk of hemorrhagic complications. Intrathecal chemotherapy and invasive diagnostic and therapeutic procedures require maintaining a platelet count ≥ 100 × 10⁹/L. Central venous catheter placement should be performed by experienced physicians only after correction of coagulation disorders. In addition, the procoagulant status in APL may not only increase the risk of hemorrhagic complications but also increase the risk of thrombosis. The benefit of using heparin sodium**, tranexamic acid**, aminocaproic acid**, other anticoagulants (B01A: Antithrombotic agents), or fibrinolysis inhibitors is controversial and unproven, and these drugs should not be used outside of clinical trials. There are also reports on the use of recombinant coagulation factor VII** in cases of severe, life-threatening bleeding [25,26].

3.3. Treatment of patients with newly diagnosed APL

3.3.1. Specific (targeted, goal-directed) remission induction therapy

Comments: the earliest randomized trials on the combined use of #tretinoin** and chemotherapy demonstrated undeniable advantages of this approach over standard chemotherapy: the French group demonstrated in the randomized APL-91 trial that the complete remission rate in the group receiving #tretinoin** combined with chemotherapy was 91% compared to 81% in the chemotherapy-only group. Analysis of long-term treatment efficacy in the same patients showed that the 4-year event-free survival of patients who received chemotherapy combined with #tretinoin** was 62% compared to 15% in patients who received chemotherapy alone (p < 0.0001) [28]. There are no definitive rigid recommendations regarding the choice of the chemotherapy regimen. Most researchers lean toward using the risk-adapted Spanish AIDA protocol, as it shows significantly lower toxicity rates with comparable efficacy. [27].

Comments: the rate of achieving complete remission in these clinical trials evaluating the efficacy of arsenic trioxide therapy ranged from 86 to 95%. However, it should be noted that arsenic trioxide was combined with tretinoin** therapy and/or chemotherapy. [30–34].

Since arsenic trioxide has come to be widely used as both second-line and first-line therapy in patients with APL, constant and significant attention is paid to the adverse effects arising from its use. Serious complications include APL cell differentiation syndrome, development of hyperleukocytosis, QT/QTc interval prolongation, peripheral polyneuropathy, and liver and kidney damage [33,34].

Comments: cases of APL with variant translocations are extremely rare. While slightly more than 30 cases have been reported for APL with the ZBTB16-RARA translocation, the number of descriptions for others can be counted on one hand. Therefore, antineoplastic and supportive care tactics for variant APL are poorly developed. It can be stated that the use of tretinoin and arsenic trioxide is justified only if susceptibility to them is present. In the presence of resistance, therapy based on venetoclax and hypomethylating agents should be considered for patients. For example, cases of effective APL therapy with RARA::HNRNPCP2, RARA::THRAP3, and PLZF-RARA translocations using venetoclax combined with hypomethylating therapy have been described, as well as venetoclax combined with chemotherapy for the STAT5B::RARA translocation. There are also reports of achieving complete remission in APL with the ZBTB16-RARA translocation using venetoclax monotherapy [153-157]. Data on the susceptibility of APL with variant translocations to differentiation therapy are presented in Appendix A 3.5.

3.3.2. Management of coagulopathy

Comments: the use of #tretinoin** did not eliminate the need for aggressive replacement therapy with blood components, but only slightly reduced the volumes of transfusion products used.

3.3.3. Management of hyperleukocytosis

Comments: plasmapheresis is indicated not only as a procedure aimed at preventing and treating tumor lysis syndrome, but also for correcting coagulation complications (disseminated intravascular coagulation syndrome).

3.3.4. Management of side effects of #tretinoin** and arsenic trioxide. Prevention and treatment of tumor cell differentiation syndrome

Comments: in case of clinically significant leukocytosis, cytarabine is prescribed for cytoreduction at 100 mg IV twice a day (no more than 3 administrations). If cytoreduction is ineffective, temporary discontinuation of differentiating therapy is possible.

Comment: administration of #dexamethasone** even at the slightest suspicion of DS is the standard approach to treating DS, despite the lack of direct evidence that prophylactic administration of glucocorticoids reduces mortality associated with this syndrome.

Comment: the use of #tretinoin and arsenic trioxide can cause significant fluid retention, which, combined with massive transfusions of platelet concentrate, fresh frozen plasma, and intravenous infusions necessary for APL, can lead to edema syndrome and, consequently, pulmonary and multi-organ failure, potentially requiring mechanical ventilation and renal replacement therapy. In addition, acute kidney injury associated with tumor lysis syndrome and the administration of nephrotoxic drugs may develop. In such cases, it is important to strictly monitor peripheral edema, free fluid in cavities, fluid intake and output balance, dynamic body weight, and central venous pressure (if a central venous catheter is present). If signs of negative diuresis or edema syndrome appear, loop diuretic therapy should be performed under the control of blood pressure and serum electrolyte concentrations. It is important to differentiate isolated edema syndrome from differentiation syndrome, the symptom complex of which may also include edema, since in the first case, the administration of glucocorticosteroid hormones is unjustified.

3.3.5. Assessment of induction therapy efficacy

Comments: In APL patients after a course of chemotherapy, two waves of recovery from agranulocytosis are observed. The first control cytological examination of a bone marrow smear (myelogram) should be performed no earlier than the end of the second recovery wave, on average on the 30th day after completing the chemotherapy course. Earlier analysis of bone marrow punctate may lead to a miscalculation of the percentage of blast cells and continuing to differentiate tumor cells, which will completely disappear from the bone marrow in 7-10 days. Thus, the first cytological examination of a bone marrow smear (myelogram) is carried out on average on the 30th day after the last administration of idarubicin** (i.e., on the 36-40th day from the start of the course) or upon final recovery of peripheral blood counts.

In patients whose induction treatment is performed with arsenic trioxide in combination with #tretinoin**, the pattern described above is absent.

Comment: a positive PCR result at this stage may reflect delayed maturation of tumor cells rather than true resistance.

3.4. Consolidation therapy

Comment: the use of #tretinoin** at a standard dose (45 mg/m² per day) for 15 days in combination with chemotherapy during the consolidation treatment period reduces the risk of relapse [37]. The Russian Leukemia Group recommends the use of #tretinoin** at all stages of APL therapy [4].

Comment: currently, randomized prospective studies have been conducted that have proven the high efficacy of arsenic trioxide with low toxicity in the treatment of low-risk APL patients. These studies provided for four 4-week cycles of arsenic trioxide consolidation and eight 2-week cycles of #tretinoin** [33,34].

3.5. Maintenance therapy

Comments: maintenance therapy with mercaptopurine** at a dose of 50 mg/m² orally once a day continuously (do not wash down with milk) and #methotrexate** at a dose of 15 mg/m³ subcutaneously or intramuscularly once a week is started 30 days after the last consolidation cycle. #tretinoin** is given for 2 weeks (days 1-15) and applied once every 3 months [4]. Chemotherapy is discontinued 2 years after the completion of consolidation if no molecular relapses have been detected throughout the entire observation period.

Comment: if molecular relapse is confirmed (twice-positive PCR result or a combination of PCR and FISH) during maintenance therapy, the treatment regimen is changed.

3.6. Prevention and treatment of neuroleukemia

Central nervous system (CNS) involvement is the most frequent extramedullary site in APL. Specifically, at least about 10% of hematological relapses are accompanied by CNS involvement. Therefore, the possibility of CNS involvement should be considered in any APL patient presenting with neurological symptoms, and it must be ruled out in all patients with relapse [2].

Comments: It is advisable to maintain a platelet count of 30 × 10⁹/L or higher before performing a lumbar puncture. If the platelet count cannot be increased to 30 × 10⁹/L and higher, in the absence of clinical signs of central nervous system involvement, the puncture may be deferred until the platelet count in the hemogram rises above 30 × 10⁹/L.

If leukocytosis is detected in the patient, the first lumbar puncture should be postponed until the leukocyte count drops below 10 × 10⁹/L.

Comments: Neuroleukemia is diagnosed when any number of blast cells is detected in the cerebrospinal fluid obtained during the first diagnostic lumbar puncture, regardless of the cell count (cytosis), or if cytosis is 15/3 or greater (i.e., more than 5 cells per 1 µL).

Comments: Fractionated head irradiation at a total dose of 24 Gy may be considered for the prevention of neuroleukemia in those patients with relapsed APL who have achieved remission (normalization of CSF cellular composition according to CSF cytology and absence of aberrant immunophenotype cells according to flow cytometry) after systemic and intrathecal therapy.

Comments: The ability of #sorafenib** to cross the blood-brain barrier and achieve therapeutic concentrations has been demonstrated, making it useful in cases of refractory neuroleukemia. A multicenter study showed the efficacy of sorafenib at a dose of 400 mg twice daily for 8 weeks: out of 27 patients with acute leukemias and refractory CNS involvement, CSF clearance was achieved in 21. Three of the 27 were APL patients; all achieved remission of neuroleukemia. The efficacy of sorafenib in this study was not associated with the presence of an FLT3 gene mutation.

Comments: There is a report on the efficacy of venetoclax in an APL relapse patient with refractory CNS involvement who achieved CSF clearance after two weeks of venetoclax therapy combined with intrathecal chemotherapy. Furthermore, it was shown that venetoclax can cross the blood-brain barrier, and its CSF concentration is approximately 1/1000 of its plasma concentration. Additionally, a report by Y. Li et al. showed that combination therapy with venetoclax at 400 mg daily (dose escalation from 100 to 400 mg over 3 days) for 21 days and azacitidine at 75 mg/m² daily for 7 days induced remission in a patient with relapsed APL and CNS involvement.

Level of evidence ‒ C (confidence level of evidence ‒ 4)

Comment: Since the majority of CNS relapses occur in patients with hyperleukocytosis, some researchers include CNS involvement prophylaxis for high-risk patients. For such patients, it is advisable to postpone neuroleukemia prophylaxis until CR is achieved, as the risk of complications associated with lumbar puncture is very high during induction therapy. Patients undergo 5 lumbar punctures (with sequential administration of 3 drugs) during induction/consolidation courses, and then once every 3 months during maintenance therapy [4].

3.7. Special cases of APL

3.7.1. Elderly patients

Comment: Unlike other forms of AML, APL is relatively rare in elderly patients and has a relatively favorable outcome. Treatment efficacy in elderly APL patients is comparable to that in younger patients. In addition, elderly patients are most often classified as low-risk compared to younger patients. However, elderly individuals have significantly higher rates of therapy-related toxicity (a higher incidence of sepsis and increased treatment-related mortality). The Russian Research Group recommends using the AIDA protocol in elderly patients, which provides for reduced dosages of anthracyclines (L01DB: Anthracyclines and related substances) [4].

3.7.2. Patients with severe comorbidities

Comment: several alternative approaches have been developed for the treatment of APL patients, aimed at minimizing the use of chemotherapy. Most of them are based on the use of tretinoin** and arsenic trioxide with minimal or no chemotherapy. These approaches can be used in elderly and young patients with severe comorbidities for whom intensive chemotherapy is contraindicated (e.g., patients with cardiac disease or other major organ pathology). As with tretinoin** therapy combined with anthracyclines (L01DB: Anthracyclines and related substances), the goal of treatment in such patients should be to achieve molecular remission with continuous MRD monitoring to determine the need for additional therapy.

Comment: anthracycline-induced cardiotoxicity is based on subclinical myocardial cell damage progressing to asymptomatic left ventricular ejection fraction reduction and subsequently to heart failure. Clinical manifestations may occur at any time after treatment due to the heart's inability to compensate for initial damage. In rare cases, acute cardiotoxicity may develop at any time during or shortly after anthracycline treatment and is generally reversible upon drug discontinuation.

3.7.3. Management of APL during pregnancy

Comments: #tretinoin** has a high teratogenic effect and is contraindicated for use in the 1st trimester of pregnancy.

Comments: the choice of delivery method is determined by the fetal condition, somatic status of the patient, hematological parameters, and strictly in accordance with obstetric indications. Vaginal delivery may be chosen as the delivery method only if the patient has AML remission, satisfactory complete blood count parameters, and a good somatic status of the patient and fetal condition.

Comments: despite the safety of chemotherapy in the 2nd and 3rd trimesters of pregnancy, its administration is associated with a high risk of spontaneous abortions and preterm labor.

3.8. Treatment of relapsed APL

Comments: although tretinoin** combined with chemotherapy can be used as salvage therapy, arsenic trioxide-based regimens are currently considered the 1st line of treatment for APL relapse after chemotherapy.

Comments: patients who relapse after therapy with tretinoin combined with chemotherapy should be treated using approaches based on arsenic trioxide. In case of relapse after therapy with tretinoin and arsenic trioxide, the use of a combination of tretinoin and chemotherapy is recommended. An exception may be patients with late relapse (duration of the first remission > 2 years). Upon achieving secondary molecular remission, the possibility of performing hematopoietic stem cell transplantation should be considered (see 3.11 Hematopoietic stem cell transplantation in APL).

Comments: Anti-relapse therapy includes induction and consolidation courses. Patients who have achieved molecular remission undergo auto-HSCT with mandatory prophylaxis of neuroleukemia with intrathecal administration of #methotrexate** once a month for 6 months. If auto-HSCT cannot be performed, maintenance therapy is administered. In case of neurotoxicity manifestations during #bortezomib** therapy, it is possible to reduce the #bortezomib** dose to 1 mg/m² or to 0.7 mg/m² per administration. The detailed protocol scheme is presented in the appendix (A 3.1) [58,59].

Comments: according to a report by Y. Li et al., combination therapy with venetoclax at a dose of 400 mg daily (gradual dose escalation from 100 to 400 mg over 3 days) for 21 days and azacitidine at a dose of 75 mg/m² daily for 7 days achieved remission in a patient with relapsed acute promyelocytic leukemia (APL) involving the central nervous system. Furthermore, the relatively low toxicity of venetoclax-containing regimens makes them a viable alternative to bortezomib-containing regimens in elderly patients, those with poor performance status, and patients with severe polyneuropathy.

Comments: tyrosine kinase inhibitors are not used for the treatment of newly diagnosed APL with a FLT3 mutation, as long-term treatment outcomes in patients with a FLT3 mutation receiving tretinoin combined with chemotherapy and, particularly, arsenic trioxide, are comparable to those in patients without the mutation. However, FLT3 inhibitors may be used when other antineoplastic agents are ineffective for treating relapsed APL. There are reports on the efficacy of gilteritinib in the treatment of resistant APL relapse with an extramedullary component [150].

3.9. Treatment of Therapy-Related APL

3.10. Supportive Care

Comments: allopurinol** is prescribed for the management of hyperuricemia at doses according to the manufacturer's instructions. The daily fluid volume administered in APL (sodium chloride solution**, dextrose solution**, FFP, cryoprecipitate, albumin**, and platelets and red blood cells as needed) may exceed 3 L, thus requiring very strict fluid balance monitoring and diuresis stimulation. It should also be borne in mind that hypervolemia in APL can provoke a higher risk of pulmonary complications and heart failure, and mimic differentiation syndrome.

Therapeutic plasma exchange is essential for managing complications during the initiation of chemotherapy in hyperleukocytosis, particularly in the presence of significant volume overload and coagulation disorders.

The prescription of antibacterial agents, systemic antifungal agents, and antiviral drugs in APL is governed by the same rules used in the treatment of AML. The use of colony-stimulating factors is not indicated in APL.

Comment: frequently in patients with APL, severe coagulation disorders and infectious complications require massive blood component transfusions and intravenous infusions, which can lead to edema syndrome and volume overload. In addition, acute kidney injury associated with tumor lysis syndrome and the administration of nephrotoxic drugs may develop. In such cases, it is important to closely monitor for peripheral edema, free fluid in body cavities, intake and output volumes, dynamic changes in body weight, and central venous pressure (if a central venous catheter is in place). If signs of negative diuresis or edema syndrome appear, loop diuretic therapy should be administered under the control of blood pressure and serum electrolyte concentrations. It is important to differentiate isolated edema syndrome from differentiation syndrome, the symptom complex of which may also include edema, since in the former case the administration of glucocorticosteroid hormones is unjustified.

Comments: an analysis of medical documentation of 101 patients with APL treated at MD Anderson demonstrated that it was the administration of filgrastim to APL patients with leukocytopenia, rather than the disease course, that led to an increase in leukocyte counts. However, malignant promyelocytes are characterized by high G-CSF receptor expression; therefore, exposure to filgrastim leads to the stimulation of growth predominantly in the tumor population rather than in normal myeloid precursors. Since a correlation between leukocyte count and coagulation disorders has been proven, the administration of filgrastim may increase the risk of life-threatening bleeding in APL.

Comments: this includes refraining from central venous catheter placement due to the high risk of massive hematoma formation in the neck region. Under conditions of poorly controlled hemostasis, the method of choice for vascular access is PICC lines inserted via the cephalic or basilic veins into the right atrium. PICCs can be safely inserted even in the presence of the most severe hemostatic disorders, and high-flow PICCs allow for adequate volume infusion therapy [145].

Comments: indications for donor blood component transfusions are determined based on laboratory test results and the severity of hemorrhagic and anemia syndromes. Among hemostatic agents, the use of tranexamic acid** is indicated – 250–500 mg orally 3–4 times/day; or intravenously 1000 mg 3–4 times a day; aprotinin, etc. [135].

Comments: when treating according to the AIDA protocol, patients in the low-risk group older than 55 years or with comorbid cardiac pathology receive mitoxantrone for three days. Patients in the high-risk group (initial leukocytosis ≥ 10 × 10⁹/L) receive a 5+2 regimen instead of 7+3 as the second course of remission consolidation.

Comments: antifungal agents (J02 Antifungals for systemic use) are prescribed for prophylaxis to APL patients during induction. Prophylaxis during the consolidation phase of chemotherapy may also be administered during chemotherapy regimens resulting in prolonged neutropenia. The drug of choice for prophylaxis is posaconazole** suspension (200 mg 3 times daily after meals).

Comments: secondary antifungal prophylaxis is indicated during chemotherapy courses accompanied by neutropenia and when using immunosuppressive drugs. For secondary prophylaxis, the agent that achieved cure of the invasive mycosis is prescribed, starting from the 1st day of the post-treatment period or when the granulocyte count is ≤0.5 × 10⁹/L.

3.11. Hematopoietic Stem Cell Transplantation in APL

Comments: harvesting of autologous stem cells is performed in the interval between consolidation courses, provided the patient achieves molecular remission. Auto-HSCT can only be performed if the molecular marker is absent in the harvested autograft. Auto-HSCT is performed after the completion of all consolidation courses and blood count recovery. Transplantation is preceded by myeloablative conditioning including #busulfan** and cyclophosphamide** (see Appendix A3.4. Myeloablative conditioning protocol for auto-HSCT in patients with relapsed APL) [49].

Comments: currently, it is generally accepted that the minimum cell count required for a single autologous transplantation is 2 × 10^6 CD34+ cells/kg of the patient's body weight, with the optimal count being 3-5 × 10^6 CD34+ cells/kg [49].

Comments: maintenance therapy is initiated 30 days after auto-HSCT, provided that blood counts have recovered (platelets > 100 × 10⁹/L, neutrophils > 1 × 10⁹/L). It includes mercaptopurine** at a dose of 50 mg/m² once daily continuously (do not wash down with milk) and #methotrexate** at a dose of 15 mg/m² once weekly, #tretinoin** ‒ 45 mg/m² orally daily after meals (can be divided into 2 doses) for 2 weeks (days 1-15), administered once every 3 months [62]. Chemotherapy is discontinued 2 years after the completion of consolidation, provided no molecular relapses have been detected throughout the entire follow-up period [49].

3.12. Medical Nutrition Therapy for Patients with APL

Comments: the organization of therapeutic dietary nutrition for patients with APL during inpatient treatment in medical organizations is carried out in accordance with the orders of the Russian Ministry of Health No. 330 dated August 5, 2003, "On measures to improve therapeutic nutrition in healthcare institutions of the Russian Federation", No. 395n dated June 21, 2013, "On approval of therapeutic nutrition standards", and No. 1008n dated September 23, 2020, "On approval of the procedure for providing patients with therapeutic nutrition" [146-148].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: There are no special rehabilitation methods for APL.

After completing treatment, it is recommended to maintain a healthy lifestyle and avoid sun exposure and physiotherapy procedures. Chemotherapy may cause cardiotoxicity, hepatotoxicity, neurotoxicity, nephrotoxicity, and other toxic effects, the consequences of which may persist even after its completion.

5. Prevention and Dispensary Observation

Comments: There is no specific prevention for APL. Unscheduled complete blood counts are indicated for any changes in the patient's condition. An unscheduled bone marrow examination (cytological examination of a bone marrow smear (myelogram) and quantitative determination of PML-RAR-a expression) is indicated if any changes in the hemogram are detected. Most relapses occur within 1–3 years after completion of therapy. Standardized bone marrow sampling time points are necessary for MRD monitoring.

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Public Health Protection in the Russian Federation," is organized and provided:

- in accordance with the Regulation on the Organization of 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.

When acute promyelocytic leukemia (APL) is detected or suspected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, 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 to receive primary specialized health care.

An outpatient or inpatient hematologist/oncologist within the hematological care network organizes diagnostic tests necessary to establish the diagnosis, including the extent and stage of the disease. If diagnostic tests cannot be performed, 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.

When APL is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with hematological diseases to determine management tactics and the need for additional specialized antitumor treatment methods.

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

In a medical organization providing medical care to APL patients, the tactics of medical examination and treatment are established by hematologists with the involvement of other medical specialists if necessary, and if required, by holding a medical board. The decision of the medical board is documented in a protocol, signed by its participants, 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 profiles "hematology" and "oncology" are determined by a hematologist/oncologist/medical board with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

• confirmed diagnosis of APL;

• induction therapy;

• consolidation treatment.

Indications for emergency hospitalization:

• suspected diagnosis of APL.

Indications for patient discharge from the hospital:

• achievement of remission during induction treatment;

• performing remission consolidation therapy.

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

Organizational issues. Taking into account the recommendations of the European and international communities, as well as our own experience in treating AML and APL in academic and regional centers, we would like to emphasize that the treatment of patients with acute leukemia (in particular, APL) should be carried out exclusively in medical organizations staffed with physicians across all specialties (multidisciplinary clinical hospitals with their own blood transfusion departments or round-the-clock transfusion support available) and serving a population of at least 500,000. Induction therapy should be performed only in centers treating at least 5 patients with AML per year and providing high-dose chemotherapy among other treatments. In accordance with these recommendations, centers treating 5–10 patients with AML per year will encounter no more than 1 patient with APL every 2 years. Although this limits the experience of smaller centers in treating APL, it is clear that optimal outcomes depend on prompt diagnostic procedures, access to tretinoin**, and blood components. This underscores the need to develop national guidelines and clinical protocols, and to conduct cooperative studies in order to raise clinical awareness and ensure the rapid response required for timely APL diagnosis and adequate supportive care aimed at reducing induction mortality, regardless of the hematology center's size.

7. Additional Information

7.1. Specimen Preparation and Storage for Molecular Genetic Testing

FISH

For FISH testing, 3 to 4 bone marrow smears and 3 to 4 peripheral blood smears obtained at the time of diagnosis are required. Samples can be shipped at room temperature. Smears that are not used immediately must be stored at ‒20°C, covered with aluminum foil.

RT-PCR

RNA extraction and RT-PCR require 1 bone marrow tube (2–3 ml) or 1 peripheral blood tube (20–30 ml, since profound leukopenia is often recorded in APL) containing either sodium citrate or ethylenediaminetetraacetic acid (EDTA). Bone marrow or peripheral blood samples must be processed within 24 hours. Isolated mononuclear cells in guanidine isothiocyanate can be stored at ‒20 °C. Bone marrow is preferred for all tests.

Karyotyping and FISH

For standard karyotyping and FISH testing, bone marrow (volume 1–2 ml) should be placed in a heparinized tube and shipped at room temperature. Samples processed upon receipt in the laboratory as fixed cell pellets using methanol and acetic acid (3:1) can be stored at ‒20°C.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Parovichnikova E.N., MD, PhD, General Director of the National Medical Research Center for Hematology of the Russian Ministry of Health (Moscow), member of the National Hematological Society.

2. Troitskaya V.V., MD, PhD, First Deputy General Director of the National Medical Research Center for Hematology of CSU Ministry of Health (Moscow), member of the National Hematological Society.

3. Sokolov A.N., PhD, Senior Researcher, Department of Chemotherapy of Hemoblastoses, Hematopoiesis Depressions and Bone Marrow Transplantation, National Research Center for Hematology of the Russian Ministry of Health (Moscow), Member of the National Hematological Society.

4. Semyonova A.A., Hematologist, Department of Chemotherapy of Hemoblastoses and Hematopoiesis Depressions with Bone Marrow and Hematopoietic Stem Cell Transplantation Unit, Member of the National Hematological Society.

5. Bondarenko S.N., MD, Head of the Department of Oncology, Hematology and Transplantology for Adolescents and Adults, R.M. Gorbacheva Research Institute of Pediatric Hematology and Transplantology, Pavlov First Saint Petersburg State Medical University of the Russian Ministry of Health (Saint Petersburg), Member of the National Hematological Society.

6. Kuzmina L.A., PhD, Head of the Department of Intensive High-Dose Chemotherapy and Bone Marrow Transplantation with 24-Hour Inpatient Unit, National Research Center for Hematology of the Russian Ministry of Health (Moscow), Member of the National Hematological Society.

7. Klyasova G.A., MD, Professor, Head of the Laboratory of Clinical Bacteriology, Mycology and Antibiotic Therapy, National Research Center for Hematology of the Russian Ministry of Health (Moscow), Member of the National Hematological Society.

8. Gritsaev S.V., MD, Head of the Republican Bone Marrow Transplantation Center, Russian Research Institute of Hematology and Transfusiology of the FMBA (Saint Petersburg), Member of the National Hematological Society.

9. Semochkin S.V., MD, Professor at the Department of Oncology and Hematology, Pirogov Russian National Research Medical University of the Russian Ministry of Health (Moscow), Member of the National Hematological Society.

10. Lapin V.A., PhD, Head of the Hematology Department, Yaroslavl Regional Clinical Hospital (Yaroslavl), Member of the National Hematological Society.

11. Konstantinova T.S., PhD, Regional Hematology Center of the Sverdlovsk Oblast Clinical Hospital No. 1 (Yekaterinburg), Member of the National Hematological Society.

12. Samoilova O.S., PhD, Head of the Hematology Department, Nizhny Novgorod Oblast Clinical Hospital named after N.A. Semashko (Nizhny Novgorod), Member of the National Hematological Society.

13. Kaporskaya T.S., PhD, Head of the Hematology Department, Irkutsk Order of the "Badge of Honour" Oblast Clinical Hospital (Irkutsk), Member of the National Hematological Society.

    Healthcare Organization Section:

14. Tigran G. Gevorkyan, Deputy Director of the Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology, Chief Oncologist of the Moscow Region.

15. Zhanna V. Khaylova, Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

16. Lazareva Olga Veniaminovna, PhD, Head of the Department of Regional and Interagency Cooperation in Hematology, National Research Center for Hematology

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

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience of the clinical guidelines:

1. Hematologists

2. Oncologists

3. Internists

4. Obstetricians-gynecologists

5. Anesthesiologists-intensivists

6. Clinical pharmacologists

Methodology for evidence collection

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the guidelines includes publications from the Cochrane Library, EMBASE, and MEDLINE databases. The search depth was 10 years.

Table A2.1. Scale for assessing the levels of evidence certainty (LEC) for diagnostic methods (diagnostic interventions)

Table A2.2. Levels of Evidence (LoE) grading scale for methods of prevention, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitation interventions)

Table A2.3. Grades of Recommendation (GoR) grading scale for methods of prevention, diagnosis, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, rehabilitation interventions)

Description of the guideline validation method:

• The preliminary version of these guidelines was reviewed by independent experts, who were asked to comment primarily on how accessible the interpretation of the evidence underlying the recommendations is for understanding.

• Comments were obtained from primary care physicians and district general practitioners regarding the clarity of the guidelines and their assessment of the importance of the recommendations as a working tool in daily practice.

• The preliminary version was also sent to a non-medical reviewer for comments from the patients' perspective.

• Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and the resulting changes made to the recommendations were logged. If no changes were made, the reasons for refusing to make changes were logged.

Consultation and peer review:

• The preliminary version was posted on the NHS website for broad discussion aimed at wide discussion and improvement of the guidelines.

• The draft guidelines were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

Appendix A3.1. Treatment Protocols for Acute Promyelocytic Leukemia

AIDA/mAIDA APL treatment protocol [4,37,56]

Induction:

• #Tretinoin** 45 mg/m², daily, after meals (in 2 doses) for at least 30 days.

• #Idarubicin** 12 mg/m² once daily, on days 2, 4, 6, 8 from the start of tretinoin** intake, short infusion.

Consolidation (Course 1)

• #Idarubicin** 5 mg/m² once daily, short infusion, days 1–4.

• #Tretinoin** 45 mg/m² daily, after meals (in 2 doses), days 1–15.

Consolidation (Course 2) (AIDA)

• #Mitoxantrone** 10 mg/m² once daily, short infusion, days 1–5.

• #Tretinoin** 45 mg/m² daily, after meals (in 2 doses), days 1–15.

Consolidation (Course 2) (mAIDA)

• Mitoxantrone** 10 mg/m² once daily, short infusion, days 1–3.

• Cytarabine** 200 mg/m² continuous infusion, days 1–7.

• #Tretinoin** 45 mg/m² daily, after meals (in 2 doses), days 1–15.

Consolidation (Course 3)

• #Idarubicin** 12 mg/m² once daily, short infusion, day 1.

• #Tretinoin** 45 mg/m² daily, after meals (in 2 doses), days 1–15.

Supportive therapy

• Mercaptopurine** 50 mg/m² once daily, continuously for 2 years from the completion of consolidation.

• #Methotrexate** 15 mg/m² IV once a week for 2 years from the completion of consolidation.

• #Tretinoin** 45 mg/m² daily, after meals (in 2 doses), days 1–15 of every 3rd month for 2 years from the completion of consolidation.

7+3 APL treatment protocol

ATO + ATRA APL treatment protocol [62]

Induction

• Arsenic trioxide, 10 mg intravenously once daily (in patients weighing less than 45 kg – 0.15 mg/kg) for 42–60 days (if remission is not achieved by day 42, then 60 days).

• #Tretinoin**, 45 mg/m² daily orally after meals in 2 doses for 42–60 days (if remission is not achieved by day 42, then 60 days).

• #Mitoxantrone**, 10 mg/m² intravenously once daily, days 1–2.

• #Bortezomib**, 1.4 mg/m² subcutaneously once daily, days 2 and 5.

Consolidation

• Arsenic trioxide, 10 mg IV once daily (in patients weighing less than 45 kg – 0.15 mg/kg) for 28 days.

• #Tretinoin**, 45 mg/m² daily orally after meals in 2 divided doses for 28 days.

• #Bortezomib**, 1.4 mg/m² subcutaneously once daily, days 2 and 5.

Supportive therapy

• Arsenic trioxide, 10 mg IV once daily (in patients weighing less than 45 kg – 0.15 mg/kg) on days 1–10 of each month for 6 months.

• #Tretinoin**, 45 mg/m² daily orally after meals in 2 divided doses on days 1–10 of each month for 6 months.

• #Bortezomib**, 1.4 mg/m² subcutaneously once daily, on day 2 of each month for 6 months.

• #Methotrexate**, 12.5 mg intrathecally, on day 1 of each month for 6 months.

Treatment regimen for high-risk APL patients with reduced ejection fraction including #gemtuzumab ozogamicin [3]

Induction

• Arsenic trioxide, 0.15 mg/kg IV once daily for 28–60 days (if remission is not achieved by day 28 according to bone marrow aspiration, continue therapy and repeat the aspiration in 1 week).

• #Tretinoin**, 45 mg/m² daily orally after meals in 2 divided doses for 28–60 days (if remission is not achieved by day 28 according to bone marrow aspiration, continue therapy and repeat the aspiration in 1 week).

• #Gemtuzumab ozogamicin, 9 mg/m² as a single dose on day 1.

Consolidation

• Arsenic trioxide, 0.15 mg/kg IV once daily 5 days a week for 4 weeks every 8 weeks (4 weeks with arsenic trioxide administration, 4 weeks without administration) – 4 cycles in total.

• #Tretinoin**, 45 mg/m² daily orally after meals in 2 divided doses for 2 weeks every 4 weeks – 7 cycles in total.

• If arsenic trioxide and/or #tretinoin are discontinued due to toxicity, administration of #gemtuzumab ozogamicin is possible at a dose of 9 mg/m² once every 4–5 weeks until molecular remission is achieved with a neutrophil count ≥ 1 × 10⁹/L and a platelet count ≥ 100 × 10⁹/L.

Treatment regimen for APL patients with therapy-refractory prolongation of cardiac electrical systole including #gemtuzumab ozogamicin [3]

Induction

• #Tretinoin**, 45 mg/m² daily orally after meals in 2 divided doses for 28–60 days (if remission is not achieved by day 28 according to bone marrow aspiration, continue therapy and repeat the aspiration in 1 week).

• #Gemtuzumab ozogamicin, 9 mg/m² as a single dose on day 1.

Consolidation

• #Tretinoin**, 45 mg/m² daily orally after meals in 2 divided doses for 2 weeks every 4 weeks – 7 cycles in total.

• #Gemtuzumab ozogamicin at a dose of 9 mg/m² once monthly until molecular remission is achieved.

Appendix A3.2. Dosage, route of administration, and adverse events of #tretinoin** [4]

The dose of #tretinoin** is 45 mg/m⁰ per day orally; the dose may be divided into 2 doses – morning and evening after meals (preferably with a certain fat content). The drug is taken daily until CR is achieved (at least 30 days, but not more than 90 days).

#Tretinoin** therapy may be associated with the development of the following adverse effects:

1) headache, somnolence, meningeal signs may be present (nuchal rigidity, Kernig's sign), nystagmus;

2) nausea, vomiting (development of pancreatitis);

3) fever, which can be low-grade or rise up to 40 °C. Upon discontinuation of #tretinoin**, the temperature normalizes on average within 24 hours. In some cases, when there are difficulties in the differential diagnosis of the nature of the fever – infectious or induced by retinoids, #tretinoin** can be discontinued for 1–2 days. Febrile fever is most frequently accompanied by symptoms of differentiation syndrome;

4) pruritus, dry skin and mucous membranes;

5) bone pain;

6) edema;

7) specific infiltrates (like leukemides) in the skin and ocular fundus;

8) appearance of pleocytosis in the cerebrospinal fluid (with initial normal composition);

9) elevated transaminases.

Adverse effects developed during #tretinoin** administration may require modification of therapy.

#Tretinoin can cause severe headaches and, in rare cases, pseudotumor cerebri, which is characterized by increased intracranial pressure without signs of infection, vascular, or structural abnormalities. The cause of this complication is due to increased production and impaired absorption of cerebrospinal fluid by the choroid plexus. In such cases, the addition of #acetazolamide** (125–250 mg two to four times a day), intravenous mannitol** administration at a dose of 1–1.5 g/kg/day, and analgesic therapy are indicated. If severe headaches persist despite analgesic and diuretic therapy, the dose of #tretinoin** can be reduced to 25 mg/m² [171, 62].

In case of persistent headaches (after ruling out their anemia-related nature or connection with #tretinoin** administration), it is advisable to perform: 1) brain CT or brain MRI (to rule out hemorrhage); 2) lumbar puncture after ruling out the risks of brainstem herniation into the foramen magnum according to brain CT or MRI and adequate transfusion support (platelet concentrate transfusion) to rule out neuroleukemia, infectious process (viral meningoencephalitis, cryptococcosis, etc.).

Dry skin and mucous membranes are treated with symptomatic agents (moisturizing cream, gargles), and pruritus is treated with antipruritic agents (including systemic antihistamines and anesthetics).

Elevated transaminase activity, changes in general (clinical) urine tests (except for significant proteinuria – >1 g/l) do not require any therapeutic intervention other than continuous monitoring. Newly emerged significant proteinuria may be a manifestation of DS or a very rare adverse effect. DS is managed with #dexamethasone** 10 mg/m² twice daily IV [62].

Febrile fever without an identified focus of infection (a thorough search for an infection focus is performed – catheter, paraproctitis, labial infiltrate, sinusitis; repeated X-ray (CT) monitoring of lung tissue, blood cultures from a vein and catheter, monitoring of blood galactomannan levels, etc.) in the absence of other adverse events may be the first sign of DS development.

Also, frequently with the transfusion of significant fluid volumes, patients develop pulmonary circulation overload (pulmonary edema), which can mimic the clinical picture of DS; therefore, strict monitoring of diuresis, diuresis stimulation, administration of IV nitrates, potassium-sparing diuretics, and cardiotonics are necessary.

Due to the fact that fully developed DS is a life-threatening condition, at the slightest signs of DS (1) febrile fever without signs of infection, 2) respiratory failure +/- hemoptysis, 3) weight gain (edema +5 kg), 4) radiological pattern with infiltrates resembling acute respiratory distress syndrome, 5) pleural or pericardial effusion, 6) hypotension, 7) acute renal failure) − #dexamethasone** 10 mg/m² twice daily is prescribed immediately until the signs of DS resolve, followed by a fairly rapid taper (total duration of #dexamethasone** administration − optimally 7 days, due to the high risk of infectious complications, especially fungal ones) [35]. This approach is strongly recommended despite the fact that none of the aforementioned signs and symptoms are pathognomonic, and they may inherently be associated with comorbid somatic problems such as bacteremia, sepsis, fungal infections, or congestive heart failure. In the presence of an infectious process or congestive heart failure, the diagnosis of DS is not established, but even in these situations, the administration of #dexamethasone** is justified. The frequency of #dexamethasone** administration across all studies never coincides with the incidence of DS [35].

Development of tumor cell differentiation syndrome can be expected both in the first days of #tretinoin** administration and after the completion of antineoplastic drug administration amidst ongoing tretinoin** intake, during recovery from agranulocytosis, even at low leukocyte counts (e.g., < 2 × 10⁹/L). The diagnostic frequency of DS depends on the treatment program and diagnostic criteria, varying from 2 to 50%, being 25% in the AIDA program.

DS is classified into: moderate − 2/3 symptoms (in an average of 50% of patients) and severe − 4 or more symptoms (in an average of 50%). Early DS (up to 7 days, approximately 54%) and late DS (8–14th day − 5%, 15–30th day − 36%, 31–46th day = 5%) are also distinguished, which differ in mortality rates: 36% and 9%, respectively.

In severe DS (mechanical ventilation, acute renal failure), #tretinoin** therapy must be discontinued; its administration is resumed after the resolution of respiratory, hepatic, and renal failure (can be at half dose).

Temporary discontinuation of #tretinoin** therapy is indicated only in the case of severe manifestations of APL differentiation syndrome (if the patient develops renal failure or respiratory distress syndrome requiring transfer to the intensive care unit). In all other cases, #tretinoin** therapy must be continued.

If DS progression or a lack of response to #dexamethasone** is registered while #dexamethasone** is prescribed and #tretinoin** is continued, #tretinoin** should be discontinued. If a response to #dexamethasone** is subsequently achieved, therapy should be continued until symptoms completely resolve, and then #tretinoin** should be resumed.

Appendix A3.3. Dosage, method of administration, and adverse reactions of arsenic trioxide [62]

The dose of arsenic trioxide (ATO) is 0.15 mg/kg per day; the drug is dissolved in 250 ml of 0.9% sodium chloride or 5% glucose and administered intravenously over 3 hours.

Complications of arsenic trioxide therapy:

• Differentiation syndrome (DS): pathogenesis, clinical presentation, and treatment are similar to those of retinoic acid syndrome.

Arsenic trioxide therapy is discontinued in case of ineffectiveness of #dexamethasone** therapy or development of severe DS (≥ 4 symptoms). After the relief of DS, ATRA+ATO therapy is resumed. For DS prophylaxis, high-risk patients are prescribed #dexamethasone** at a dose of 4 mg/m² bid IV until leukocytosis decreases (no more than 7 days), and cytoreduction is also performed with 1-3 administrations of anthracycline antibiotics (L01DB: Anthracyclines and related substances). If leukocytosis develops during therapy as prophylaxis for DS, #dexamethasone** is also prescribed at a dose of 4 mg/m² bid IV until leukocytosis decreases (no more than 7 days). If leukocytosis is accompanied by severe ossalgia or leukostasis symptoms, administration of cytarabine** at a dose of 100 mg bid IV until symptom relief, but for no more than 3 administrations, is recommended

• Toxic hepatitis is observed in approximately 60% of patients. Monitoring of liver function tests (bilirubin, AST, ALT) is indicated. An increase in liver transaminase activity by 5 times or more requires reducing the dose of arsenic trioxide to 0.1 mg/kg/day, and in the absence of effect, temporary discontinuation (for 5-7 days) of arsenic trioxide and/or ATRA until the aforementioned parameters decrease to less than 2 times the upper limit of normal.

• Prolongation of the corrected QT interval during arsenic trioxide therapy is a consequence of prolonged ventricular repolarization time in the heart. The initial administrations of arsenic trioxide are performed under cardiac monitor control. Monitoring of the corrected QT interval duration is performed once a week or more often if indicated. With the development of cardiotoxicity with a QTc interval prolongation of more than 500 ms [according to Bazett (HR 60-100 bpm) or Fredericia (in tachy- or bradycardia)], the administration of arsenic trioxide may be suspended until this parameter normalizes (QTc < 450 ms). All other QT-prolonging drugs must also be discontinued. It is necessary to monitor serum electrolyte concentrations (K+, Mg2+) and correct their disorders, and use beta-blockers.

• For timely diagnosis of toxic pancreatitis, patients are indicated to monitor serum amylase concentration. In case of acute pancreatitis, the dose of arsenic trioxide is reduced to 0.1 mg/kg/day and supportive care is provided (fasting, antisecretory drugs (A02 Drugs for acid-related disorders)). If these measures are ineffective, arsenic trioxide and/or #tretinoin** are temporarily discontinued (for 5-7 days), and therapy is resumed upon regression of clinical manifestations. For asymptomatic increases in serum amylase concentration, more frequent amylase monitoring is indicated.

Appendix A3.4. Conditioning protocol in myeloablative regimen when performing auto-HSCT in patients with relapsed APL [49,130]

Appendix A3.5. APL with Variant Translocations and Their Drug Sensitivity [49,130]

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Changes in 2 chromosomes lead to a disease called acute promyelocytic leukemia (APL). In almost all cases of APL, a translocation occurs, i.e., the transfer of a part of one chromosome to another. These are chromosomes 15 and 17. In this case, a defect occurs in chromosome 15, which creates a break in the region of the PML gene (promyelocytic leukemia gene) located on it, and a defect in chromosome 17, resulting in a break in the region of the RARA gene (retinoic acid receptor alpha gene). As a result of the transfer of chromosomal parts, these genes fuse, forming the so-called PML fusion gene. This abnormal gene encodes a protein that halts the maturation of blood and bone marrow myeloid cell precursors at the intermediate promyelocyte stage. This translocation is designated as t(15;17).

The identification of the characteristic translocation as the triggering mechanism of APL and the development of so-called targeted therapy have enabled almost all patients who can receive complete initial treatment to achieve a so-called complete remission, i.e., the disappearance of all leukemia symptoms and the restoration of normal hematopoiesis. As a result of targeted therapy, leukemic blast cells can mature and subsequently exhaust their potential for uncontrolled growth and die. Nevertheless, at this stage, there is still a residual population of leukemic cells; therefore, if treatment is stopped at this point, the disease will sooner or later inevitably relapse, making a cure almost impossible. The following important components of APL treatment must also be implemented: consolidation and maintenance therapy. Sequential implementation of all treatment components has resulted in 9 out of 10 patients today having a realistic opportunity to achieve a probability of surviving without signs of disease for more than 5-7 years. Advances in biological technologies have meant that the goal of detecting the residual population of leukemic cells is now to recognize 1 pathological cell per approximately 10–100 thousand normal cells—this has been made possible using polymerase chain reaction technology. Currently, the so-called molecular remission of APL is the treatment goal for patients with APL. Along with achieving molecular remission (or molecular "response"), an important component of patient monitoring is also regular bone marrow testing by polymerase chain reaction at subsequent stages—molecular monitoring of minimal residual disease.

Modern medicine has all the drugs required for the effective treatment of APL in its arsenal.

An integral component of treatment for patients with newly diagnosed APL is also supportive transfusion therapy with donor blood components, primarily fresh frozen plasma and platelet concentrate. These components are essential primarily in the management of so-called APL coagulopathy—a condition characterized by blood clotting disorders with an increased risk of hemorrhage combined with the potential for thrombotic complications.

In conclusion, although APL is often considered within the scope of so-called myeloid leukemias, it is treated according to somewhat different principles than other myeloid leukemias. Bone marrow transplantation is rarely considered a component of treatment for patients with newly diagnosed APL. At the same time, bone marrow transplantation can be an important component of treatment for relapsed APL.

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

Appendix G1. Eastern Cooperative Oncology Group (ECOG) Performance Status Scale

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

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Appendix G2. Khorana Scale for assessing the risk of venous thromboembolism (VTE) in patients receiving chemotherapy

Source: Development and Validation of a predictive model for chemotherapy associated thrombosis. Blood. 2008;111(10):4902-4907

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation: