Waldenström Macroglobulinemia: Clinical Guidelines

List of Abbreviations

IgM — immunoglobulin M

auto-HSCT — autologous hematopoietic stem cell transplantation

ALT - alanine aminotransferase

AST - aspartate aminotransferase

aPTT – activated partial thromboplastin time

PFS — progression-free survival

TTP — time to progression

HDCT — high-dose chemotherapy

HIV – human immunodeficiency virus

HSC — hematopoietic cells

IPT — immunophenotyping by flow cytometry

CT – computed tomography

LDH – lactate dehydrogenase

WM — Waldenström macroglobulinemia

HCV — hepatitis C virus

NHL — non-Hodgkin lymphomas

OS – overall survival

VGPR — very good partial response

PD — progressive disease

CR — complete response

SD — stable disease

US – ultrasound examination

PR — partial response

ECG – electrocardiography

Echo-CG – echocardiography

Terms and Definitions

Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration and secretion of monoclonal IgM (PIgM)

Lymphoplasmacytic lymphoma is a B-cell neoplasm composed of small lymphoid cells, lymphoid cells with plasmacytoid differentiation, and plasma cells.

Immunophenotyping is a method based on the antigen-antibody reaction used to identify specific cell types in samples of blood, bone marrow, lymph nodes, and other tissues. Immunophenotyping is performed using multiparametric flow cytometry (typically at least 4- or 6-color).

Remission is a period of the disease course characterized by a significant attenuation or complete disappearance of symptoms, including data from laboratory and instrumental diagnostic methods.

Relapse – the return of clinical manifestations of the disease, including based on laboratory and instrumental diagnostic methods.

Hyperviscosity syndrome occurs when the level of pathological IgM exceeds 30 g/L. It manifests with fatigue, weakness, somnolence, visual impairment, tinnitus, and nose and gum bleeding.

Autologous hematopoietic stem cell transplantation is the transfusion of the patient's previously harvested stem cells, performed after prior high-dose chemotherapy.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by lymphoplasmacytic bone marrow infiltration and secretion of monoclonal IgM (PIgM). In rare cases (less than 5%), lymphoplasmacytic lymphomas with IgA, IgG secretion or a non-secretory variant of the disease may occur [1].

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

Although the exact etiology of WM remains unclear, it is believed that the malignant WM clone most commonly arises from a post-germinal center B lymphocyte that has encountered antigenic stimulation, undergone somatic hypermutation, and transformed prior to isotype switching.

Literature data indicate the role of genetic predisposition. In a clinical study of 257 WM patients, 19% of patients had at least one first-degree relative suffering from Waldenström macroglobulinemia or another B-cell lymphoproliferative disorder. [2, 3]

Chronic antigenic stimulation is also a risk factor, as there is a correlation between the development of lymphoproliferative disease in patients with a history of autoimmune diseases such as systemic sclerosis, Sjögren's syndrome, autoimmune hemolytic anemia (both warm and cold types), polymyalgia rheumatica, and giant cell arteritis. [2, 3]

A major risk factor for the development of WM is a history of IgM monoclonal gammopathy of undetermined significance (IgM-MGUS). [2, 3]

Somatic mutations in genes encoding the MYD88 protein and chemokine receptor type 4 (CXCR4) have been found in more than 90% and 30–35% of WM patients, respectively, and have been shown to play a key role in the oncogenesis of this disease. [2, 3]

1.3 Epidemiology of the Disease or Condition

WM accounts for 2% of all hemoblastoses and 60% of all IgM-secreting lymphomas. The median age at diagnosis is 71 years. The age-adjusted incidence rate is 0.42 per 100,000 population per year, increasing with age to 3.2 per 100,000 population per year after age 75. The male-to-female ratio is 3.2:1. [1]

1.4 Features of Coding the Disease or Condition

C88.0 – Waldenström macroglobulinemia

1.5 Classification of the disease or condition

No

1.6 Clinical presentation of the disease or condition

The following clinical courses exist:

1. Monoclonal gammopathy of undetermined significance (PIgM-MGUS) is a condition that typically precedes the disease; progression to symptomatic form occurs at a rate of 2% per year. Treatment is not required.

2. Asymptomatic or smoldering WM, does not require specific treatment.

3. Symptomatic WM, requires specific treatment.

The spectrum of clinical manifestations in symptomatic WM is quite diverse and driven by two factors:

1. specific infiltration of the bone marrow (BM) and, in some cases, other organs.

2. presence of PIgM.

Patients may present with non-specific B-symptoms such as fever, weight loss, fatigue, and profuse night sweats. BM involvement typically causes anemia, which is exacerbated by hepcidin secretion from lymphoplasmacytic cells; thrombocytopenia, leukocytosis with lymphocytosis, and sometimes leukopenia are common. Approximately 30% of patients present with lymphadenopathy, splenomegaly, hepatomegaly, less frequently pleural, peritoneal, renal, or skin involvement, and specific central nervous system (CNS) involvement—the so-called Bing-Neel syndrome [4].

PIgM can cause various conditions. First, hyperviscosity syndrome, which occurs when PIgM levels exceed 40 g/L. This complication occurs in 10–15% of patients. It is characterized by hemorrhagic complications—nose and gum bleeding, headaches, dizziness, cardiovascular disturbances, tinnitus, blurred vision, and sometimes vision loss due to retinal hemorrhages or thrombosis. Elevated blood viscosity affecting microcirculation, including in the CNS, can lead to medical emergencies [5].

In 10% of patients, PIgM may exhibit cryoglobulin properties. Type I and II cryoglobulinemia may clinically manifest with skin lesions such as purpura, ulcers, and livedo, particularly on the lower extremities. The presence of cryoglobulinemia may exacerbate hyperviscosity symptoms. In 5% of patients, direct deposition of PIgM in the skin, intestine, or kidneys may occur. AL amyloidosis develops in 10–15% of patients. It is a rare and severe complication in WM. The kidneys, heart, liver, and peripheral nerves are most frequently affected. Thrombocytopenia, autoimmune hemolytic anemia, and cold hemolysin can be associated with the immune activity of PIgM. Some patients may exhibit Schnitzler syndrome, which presents as chronic autoimmune urticaria and other rheumatic manifestations such as recurrent fever, joint and bone pain. [6, 7]

Approximately 20–25% of WM patients develop polyneuropathy due to sensory demyelination associated with IgM paraprotein (IgM-PN) [8]

WM with features of large-cell transformation is a rare, poorly understood variant of the disease course, characterized by an aggressive clinical course and poor prognosis. According to a limited number of publications, features of large-cell transformation are observed in 2–10% of WM patients. [9]

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have limited evidence bases (according to the scales for assessing the levels of certainty of evidence and grades of recommendation) due to the lack of dedicated clinical studies. Despite this, they are necessary elements of patient evaluation for diagnosis and treatment planning, as more effective and proven methods have not yet been developed.

Criteria for establishing the diagnosis of WM:

The following criteria must be met to establish a diagnosis of WM:

1. detection of monoclonal IgM in the blood (regardless of the paraprotein level);

2. bone marrow infiltration by small lymphocytes, plasmacytoid cells, and plasma cells (diffuse, interstitial, or nodular).

3. Detection of the L265P mutation in the MYD88 gene in peripheral blood, bone marrow, lymph node, or other tumor substrate. It should be recalled that, according to research data, the L265P mutation in the MYD88 gene occurs in approximately 90% of patients with WM. MYD88-negative cases also occur. Thus, the absence of the L265P mutation in the MYD88 gene does not rule out the diagnosis of WM in the presence of all other laboratory and clinical criteria for the disease. In cases of IgA and IgG secretion, the disease is diagnosed as lymphoplasmacytic lymphoma.

2.1 Complaints and Anamnesis

• Patients with suspected WM, as well as all patients with verified WM, at each visit are recommended to take a medical history and assess complaints to evaluate the patient's condition and determine factors that may influence the choice of treatment strategy [2, 3].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: complaints are non-specific and caused by lymphoplasmacytic infiltration of organs and tissues and the circulation of macroglobulin, leading to hyperviscosity, cryoglobulinemia, cold hemagglutinin disease, AIHA, immune thrombocytopenia, and amyloidosis:

• Headaches, blurred or loss of vision, episodes of altered consciousness

• Skin and mucosal lesions — bleeding, urticaria, papules, dermatitis

• Progressive sensory loss, tingling, burning, pain in the feet and hands. Unsteady gait, decreased muscle strength

• Raynaud's syndrome, acrocyanosis, leg ulcers

• Diarrhea, abdominal pain

• Asymptomatic enlargement of lymph nodes of any localization may be detected.

• A medical history (including family history) must be taken.

2.2 Physical Examination

• Patients with suspected or confirmed WM at the initial or follow-up visit, during control examinations, and when relapse/disease progression is suspected are recommended to undergo a physical examination, including general inspection, palpation, and auscultation, to determine the extent of the disease and assess the patient's condition across organ systems [2, 3].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: during the patient examination

- measurement of height and body weight, general thermometry; assessment of the condition of the skin and musculoskeletal system; detection of signs of hemorrhagic syndrome; presence of hepatosplenomegaly, lymphadenopathy; presence of signs of dysfunction of the heart, lungs, liver, and endocrine system.

- identification of B-symptoms.

- determination of ECOG performance status (0-4)

2.3 Laboratory Diagnostics

• Patients with WM prior to the first line of antineoplastic therapy are recommended to determine the ratio of protein fractions by serum and urine electrophoresis and to investigate immunoglobulin monoclonality in blood and urine by immunofixation to detect monoclonal immunoglobulin [2, 3].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: detection of monoclonal immunoglobulin M, regardless of its amount, is one of the main diagnostic criteria for Waldenström's macroglobulinemia (WM). In addition, it is necessary to determine the level of normal serum Igs [2, 3].

• Before initiating first-line antineoplastic therapy, it is recommended that patients with WM undergo molecular genetic testing for the p.L265P point mutation in the MYD88 gene using PCR in lymphoplasmacytic cells [10].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: this mutation is detected in 90% of WM patients and significantly less frequently in other lymphoproliferative disorders, making it diagnostically significant in combination with other laboratory and clinical features of WM. However, the absence of this mutation does not exclude a diagnosis of WM if other clinical and laboratory signs of the disease are present. The L265P mutation can be found in any tumor substrate; the bone marrow is most frequently examined, and less commonly blood, lymph nodes, or extramedullary sites.

• Before initiating antineoplastic therapy, it is recommended that patients with WM undergo a complete blood count (CBC) including total hemoglobin, red blood cells, platelets, white blood cells, differential white blood cell count (leukocyte formula), and reticulocyte count to assess the patient's condition, disease activity, and feasibility of antineoplastic treatment [2, 3].

LeR CLoE 5Level of Recommendation C (Level of Evidence — 5)

• Before initiating antineoplastic therapy, it is recommended that patients with WM undergo a general biochemical blood test, which must include the determination of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activity, as well as uric acid, urea, creatinine, total protein, albumin, total bilirubin, unconjugated bilirubin, and conjugated bilirubin, potassium, total calcium, and ionized calcium levels to assess the patient's condition, disease activity, and feasibility of antineoplastic treatment [2, 3, 8, 9, 10].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• Before initiating antineoplastic therapy, it is recommended that patients with WM undergo a routine urinalysis to assess the patient's condition, disease activity, and feasibility of antineoplastic treatment. [44]

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• Before initiating antineoplastic therapy, it is recommended that patients with WM undergo a coagulogram (exploratory hemostasis screening) determining the following parameters: prothrombin (thromboplastin) time, activated partial thromboplastin time (APTT) in blood or plasma, thrombin time, and fibrinogen level to assess the patient's coagulation status and the risk of hemorrhagic complications [44].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• During diagnosis and/or before initiating antineoplastic therapy, it is recommended that patients with WM undergo blood typing and Rh factor determination, testing for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (HCV), and antibodies (IgM, IgG) to human immunodeficiency virus type 1 (HIV-1) to identify comorbidities and determine the potential need for modifying antineoplastic therapy or providing concomitant treatment [44].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• During diagnosis and/or before initiating antineoplastic therapy, for staging according to the IPSSWM/Revised IPSSWM scales, it is recommended that patients with WM undergo beta-2-microglobulin and serum cryoglobulin testing [44].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• During diagnosis and/or before initiating antineoplastic therapy, it is recommended that patients with WM undergo blood viscosity testing to identify potential hyperviscosity syndrome and predict associated complications [3].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

2.4 Instrumental Diagnostics

• During diagnosis and/or before initiating antineoplastic therapy, it is recommended that patients with WM undergo skeletal X-rays or skeletal computed tomography to detect potential specific involvement. [11, 12, 13, 14].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• During diagnosis and/or before initiating antineoplastic therapy, it is recommended that patients with WM undergo chest computed tomography or targeted chest X-ray to detect pulmonary and mediastinal abnormalities [11, 12, 13, 14].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• During diagnosis and/or before initiating antineoplastic therapy, it is recommended that patients with WM undergo abdominal computed tomography or comprehensive abdominal ultrasound, ultrasound examination of all groups of peripheral, intra-abdominal, and retroperitoneal lymph nodes, abdominal and retroperitoneal organs, and measurement of the liver, spleen, and intra-abdominal lymph nodes to evaluate the abdominal organs and assess potential specific involvement. [11, 12, 13, 14].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comment: prior to initiating therapy, patients with WM may undergo positron emission tomography combined with computed tomography (PET-CT) using tumor-tropic radiopharmaceuticals with contrast enhancement, as a method allowing for accurate assessment of the extent of specific involvement, evaluation of additional risks, refinement of indications for treatment initiation, and in some cases, selection of the optimal therapeutic regimen.

2.5 Other Procedures

• During diagnosis and/or before initiating antineoplastic therapy, it is recommended that patients with WM obtain a bone marrow cytologic specimen via puncture and perform a bone marrow smear cytology (myelogram) to detect lymphoplasmacytic infiltration [11, 12, 13, 14].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• For patients with WM during diagnosis and/or prior to antineoplastic therapy, it is recommended to obtain a bone marrow histological specimen (trephine biopsy), perform pathomorphological examination of bone marrow biopsy (surgical) material using immunohistochemical methods and/or immunophenotyping of bone marrow hematopoietic progenitor cells (IPT) and bone marrow aspirate cells [11, 12, 13, 14].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: Tumor substrate cells in WM express pIgM both on their surface (sIgM) and intracellularly (cIgM). The expression of sIgM significantly prevails. There is pronounced expression of such B-cell antigens: CD19, CD20, CD22, CD79a. Cells are weakly positive for CD10 (may be absent), CD21, CD25, CD38, and cCD. Expression of CD5 and CD23 is not typical, although it may occur and is not a factor excluding WM.

• For patients with WM when amyloidosis is suspected with involvement of the skin, gastrointestinal tract, kidneys, bone marrow, or liver, it is recommended to perform a pathomorphological examination of biopsy material (biopsies) from these organs using Congo red staining [6].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For patients with WM when cardiac amyloidosis is suspected, it is recommended to measure the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the blood and perform an echocardiography to rule out cardiac amyloidosis and assess cardiac function [15].

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

• For patients with WM with suspected hyperviscosity syndrome, it is recommended to perform an initial ophthalmological examination (consultation) by an ophthalmologist to diagnose complications of hyperviscosity syndrome [5].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comment: if hyperviscosity syndrome is suspected, an examination of the peripheral fundus using a Goldmann three-mirror lens is necessary. This study should also be performed when the monoclonal IgM level is ≥30 g/L.

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

The prescription and use of medicinal products specified in the clinical guidelines are aimed at providing the patient with clinically effective and safe medical care; therefore, their prescription and application in a specific clinical situation may be determined not only in accordance with the instructions for use, with the implementation of the precautions presented in the instructions, with possible correction of doses and administration regimens taking into account the patient's condition.

It should be taken into account that the patient may have atypical disease manifestations, as well as a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for choosing the optimal diagnostic and treatment tactics.

3.1 Indications for treatment initiation

The treatment strategy is determined at the stage of diagnosis establishment. The choice of treatment program depends on the patient's age, IPSSWM / Revised IPSSWM risk group, features of the WM course—specifically, the presence of cytopenias, extramedullary / extranodal involvement, presence/absence of neuropathy as a symptom of the disease, the need for more rapid tumor reduction, and comorbidities. Patients under 65 years of age with high and intermediate risk according to IPSSWM / Revised IPSSWM represent a special group who may receive combined immunochemotherapy regimens in combination with Bruton's tyrosine kinase inhibitors, and high-dose consolidation with autologous hematopoietic stem cell support in the first line can also be discussed. This approach may be applied within clinical trials in research center settings [16].

- Recurrent fever, night sweats, weight loss, fatigue.

- Hyperviscosity syndrome.

- Lymphadenopathy or massive enlargement of lymph nodes (≥ 5 cm).

- Hepatomegaly and/or splenomegaly.

- Peripheral neuropathy associated with WM.

- Symptomatic cryoglobulinemia.

- Anemia with Hb level ≤10 g/dL.

- Thrombocytopenia with a platelet count of 100 × 10⁹/L or less.

- Hemolytic anemia (caused by cold antibodies).

- Renal failure associated with WM.

- Amyloidosis associated with WM.

- Monoclonal IgM level >50 g/dL, even in the absence of symptoms.

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

3.2 Treatment of patients with newly diagnosed WM

• Plasmapheresis.

Symptomatic hyperviscosity is rarely observed in patients with a pIgM concentration of less than 40 g/L. In the presence of increased viscosity, plasmapheresis should be considered as a temporary measure until systemic therapy reduces the tumor mass and, consequently, the serum paraprotein concentration. A single plasmapheresis session is often sufficient to relieve symptoms and safely initiate systemic therapy [2, 5].

CD20 (cluster of differentiation 20) inhibitors (#rituximab**) [18, 19], alkylating agents (#bendamustine**, #cyclophosphamide**), proteasome inhibitors (#bortezomib** - ATC L01XX Other antineoplastic agents) [20, 21, 22], Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib** ATC L01XE, #zanubrutinib, #acalabrutinib) [23, 24] are safe and effective treatment options for patients with WM. The BCL2 inhibitor (#venetoclax** ATC L01XX other antineoplastic agents) [25], antineoplastic drugs, and immunomodulators [26, 27] can be used in WM therapy. Waldenström macroglobulinemia is characterized by the accumulation of malignant immunoglobulin M-secreting lymphocytes in the bone marrow and other organs. CD38 is a reliable marker of plasmacytic differentiation and is expressed in WM cells. The use of the CD38 (cluster of differentiation 38) inhibitor #daratumumab** in combination with B-cell-targeted agents, such as CD20 (cluster of differentiation 20) inhibitors or Bruton's tyrosine kinase (BTK) inhibitors, offers undeniable clinical benefit [28, 29].

• #Rituximab**

Monotherapy with #rituximab** is inferior to almost all registered combination regimens [30, 31]. The overall response rate is higher with combination therapy than with #rituximab** monotherapy (73% vs. 44%) [31, 32].

Undoubtedly, #rituximab** is the mainstay of treatment, but it should almost always be used in combination with other agents, such as proteasome inhibitors, alkylating agents, purine analogs, antineoplastic drugs and immunomodulators, and Bruton's tyrosine kinase (BTK) inhibitors [34, 35, 36]. #Rituximab** monotherapy is advisable only in patients with isolated peripheral neuropathy associated with IgM anti-myelin-associated glycoprotein activity, without other symptoms of WM [8]. In all other cases where tumor mass reduction is required, multi-agent therapy is used [35, 36].

A feature of #rituximab** therapy is a transient increase in monoclonal IgM levels, which may be accompanied by hyperviscosity syndrome (the so-called paraprotein "flare" phenomenon). Before administering #rituximab** in patients with a monoclonal IgM level ≥50 g/L, it is advisable to perform a plasmapheresis session to prevent the paraprotein "flare" phenomenon and aggravation of hyperviscosity syndrome manifestations [2].

Currently, the therapeutic algorithm boils down to the following: #rituximab** + #bendamustine** (BR) or #rituximab** + #cyclophosphamide** + #dexamethasone** (RCD) regimens are the primary choice for patients with WM-induced cytopenias, moderate to severe organomegaly, or massive lymphadenopathy [4, 30, 35].

For patients with severe symptomatic hyperviscosity, cryoglobulinemia, or cold agglutinin disease, upfront plasmapheresis is required before drug administration, especially for patients with a serum IgM level of at least 4,000 mg/dL, to avoid exacerbation of IgM. Then, a regimen with proteasome inhibitors (weekly subcutaneous administration of #bortezomib**—the #bortezomib** + #rituximab** + #dexamethasone** program) is preferred [4, 5, 38].

The #fludarabine** + #cyclophosphamide** + #rituximab** (FCR) regimen is also effective; however, prolonged therapy with purine analogs is usually accompanied by myelosuppression, immunosuppression, and the development of infectious complications. In addition, there are reports indicating an increased risk of WM transformation into aggressive lymphomas and an increased development of secondary acute myeloid leukemia and myelodysplasia. Therefore, the use of purine analogs should be restricted, especially in young patients who may require autologous hematopoietic stem cell harvesting for subsequent HSCT [39].

For patients with paraprotein-associated neuropathy, plasmapheresis is also necessary, but it should not be used as a permanent method. RCD, CP-R, FCR, or BR regimens are effective for neuropathy. Combination regimens containing neurotoxic agents such as #bortezomib** and #vincristine** should be avoided [8, 32].

In 2015, the results of a phase II study evaluating the efficacy of ibrutinib** (a Bruton's tyrosine kinase (BTK) inhibitor) in patients who had received at least one prior line of therapy were published. Ibrutinib** was administered at a daily dose of 420 mg. The overall response rate was 90.5%, with a major response achieved in 73% of patients. The 2-year PFS and OS rates were 69.1% and 95.2%, respectively [41]. The best results were achieved in patients with the MYD88 mutation. Currently, ibrutinib** at a dose of 420 mg/day is also recommended as a first-line therapy for patients with WM who are ineligible for chemotherapy, or as a relapse therapy [41].

Intensive polychemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is currently recommended by the International Workshop on Waldenström's Macroglobulinemia (IWWM) as a treatment approach for patients under 65 years of age with continuously relapsing or primary refractory WM. For patients under 60 years of age, it is preferable to perform mobilization and collection of autologous peripheral blood stem cells (auto-PBSCs) after therapy to enable subsequent high-dose chemotherapy with stem cell support. [42]

For patients under 65 years of age in the high- and intermediate-risk groups according to IPSSWM\Revised IPSSWM, a combination of immunochemotherapy with ibrutinib may be used, such as the rotating R-EPOCH + ibrutinib** / R-BAC + ibrutinib** regimen followed by high-dose consolidation according to the CEAM program +\- #Daratumumab** with auto-PBSC support in patients under 65 years of age from the high- and intermediate-risk IPSSWM\Revised IPSSWM groups. This protocol consists of four rotating courses of R-EPOCH/R-BAC in combination with ibrutinib**, followed by high-dose consolidation according to the CEAM program or #Daratumumab** + CEAM with auto-HSCT support. The efficacy and safety of this treatment approach were demonstrated in the clinical approbation protocol «Improving the efficacy of induction therapy for patients with Waldenström's Macroglobulinemia — use of a Bruton's tyrosine kinase inhibitor in combination with immunochemotherapy» implemented at the National Research Center for Hematology of the Russian Ministry of Health. The treatment outcomes of 30 patients were analyzed. The overall response rate to therapy was 100%, very good partial responses were 71%, and complete response was 32%. The cumulative incidence of achieving a complete response was higher in patients receiving the Dara-CEAM consolidation regimen compared to those receiving the CEAM program without #daratumumab** (59% and 18%, respectively); the difference was not statistically significant due to the small number of patients in the #daratumumab** subgroup (p = 0.11), but a trend toward greater efficacy of high-dose chemotherapy combined with a CD38 (cluster of differentiation 38) inhibitor was demonstrated. A feature of the method is the alternation of the R-EPOCH and R-BAC programs. Ibrutinib** is administered at 420 mg daily from days 1 to 14 of each course. After the fourth course (the second R-BAC program), mobilization and collection of auto-PBSCs are performed. If auto-PBSC collection is successful, the patient undergoes high-dose therapy according to the CEAM program or #Daratumumab** + CEAM with auto-HSCT support. When choosing the consolidation therapy regimen and deciding whether to add #daratumumab**, the results of flow cytometry should guide the decision. If an aberrant plasma cell population expressing CD38 is present in the bone marrow, the combined regimen of #Daratumumab** + CEAM is preferred. [43, 44]

For patients over 65 years of age in the high- and intermediate-risk groups according to IPSSWM\Revised IPSSWM, a combined program comprising #rituximab**, #bortezomib**, #bendamustine**, and #dexamethasone** — the RBBd regimen — can be used [44, 46]. The RBBd therapy protocol was created by combining two recommended standard therapy programs: #rituximab** + #bendamustine** (RB) and #rituximab** + #bortezomib** + #dexamethasone** (RBd). Based on the experience gained at the National Research Center for Hematology of the Russian Ministry of Health, this program has demonstrated high efficacy. An analysis of treatment outcomes in 20 patients showed an overall response (OR) of 100%, a partial response (PR) achieved in 57% of patients, and deep responses combining very good partial response (VGPR) and complete response (CR) at 43%. Progression-free survival at 36 months was 100%. Compared with the most common standard programs, such as RB and RBd, the RBBd program demonstrated superiority. [44, 46].

In the presence of histological signs of large-cell transformation, the R-EPOCH/R-BAC program can be used in combination with ibrutinib** and the BCL2 inhibitor #venetoclax** — ATC L01XX Other antineoplastic agents, followed by high-dose consolidation with auto-PBSC support. The National Research Center for Hematology of the Russian Ministry of Health analyzed the treatment outcomes of three patients with proven transformation of WM to DLBCL; all achieved a complete response, and with a median follow-up of 12 months post-therapy, there were no signs of progression. See Appendix A3, p. 52 [43, 46]

Management of peripheral neuropathy

Peripheral polyneuropathy in WM occurs with a frequency of 10% to 20%. Given the complex mechanisms of polyneuropathy development, the immune activity of monoclonal IgM directed against myelin-associated glycoprotein (MAG) and other neural tissue antigens is discussed as the primary mechanism. Therefore, peripheral polyneuropathy in WM is considered in most cases to be IgM-associated.

Plasmapheresis procedures are performed to treat IgM-associated peripheral polyneuropathy.

Management of patients with hyperviscosity syndrome

Comments: usually 2-3 plasmapheresis procedures are performed to reduce IgM levels by 30-60%. Specific treatment is initiated shortly after the plasmapheresis sessions, as the paraprotein level can return to baseline within 4-5 weeks.

• Patients with newly diagnosed WM are recommended regimens containing #rituximab**. [4, 11, 32, 35, 36]

Level of Recommendations B (Level of Evidence 2)Level of Evidence 2Level of Recommendations B (Level of Evidence 2).

• Patients with newly diagnosed WM presenting with hyperviscosity syndrome are recommended #bortezomib**-containing courses [4, 5, 38, 47].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: in hyperviscosity syndrome, the #bortezomib**-containing regimen RBD (#rituximab**, #bortezomib**, #dexamethasone**) is used as the regimen of choice. See Appendix A3

• Patients with newly diagnosed WM presenting with hyperviscosity syndrome, massive lymphadenopathy or splenomegaly, or cryoglobulinemia, when rapid tumor reduction is required, are recommended programs incorporating #bendamustine**, #cyclophosphamide**, #bortezomib** — (RB, RBD, RCD) [4, 11, 38]. See Appendix A3

GPR CLoE 5Grade of Recommendation C (Level of Evidence 5). For the RBD therapy regimen, Grade of Recommendation C (Level of Evidence 4).

• Patients with newly diagnosed WM presenting with cytopenias (especially thrombocytopenia) are recommended treatment with programs incorporating #bendamustine**, #cyclophosphamide**, #bortezomib** — (RB, RBD, RCD) [4, 11, 23, 37, 38]. See Appendix A3.

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4); for the RB regimen, Grade of Recommendation C (Level of Evidence 5)

• Patients with newly diagnosed WM presenting with generalized forms of the disease are recommended a combination of #rituximab** with purine analogs (#fludarabine**) with or without #cyclophosphamide** [39].

GPR CLoE 4Grade of Recommendation C (Level of Evidence 4).

• Patients with newly diagnosed WM presenting with low monoclonal protein levels, slowly progressive disease, or concomitant comorbidities are recommended monotherapy with #rituximab** [11, 47]

RG CLE 5Recommendation Grade C (Level of Evidence 5).

• Patients with newly diagnosed WM who are ineligible for chemotherapy are recommended ibrutinib** monotherapy [4, 41].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: these drugs should not be used as first-line therapy, as this may hinder adequate HSC collection in the event that high-dose chemotherapy with HSCT is decided upon for disease relapse in a cohort of young, somatically fit patients.

• For patients with WM younger than 65 years in the high- and intermediate-risk groups according to IPSSWM\Revised IPSSWM, if treatment intensification is necessary, a combined immunochemotherapy regimen in combination with ibrutinib** may be recommended — the rotating R-EPOCH + ibrutinib**/R-BAC + ibrutinib** scheme followed by high-dose consolidation according to the CEAM program or #daratumumab** + CEAM with autologous HSC support. [43, 44, 45] see Appendix A3.

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: data on the efficacy of this approach are currently limited, however, the high efficacy of the program and the lack of a standard of therapy for young patients with unfavorable prognostic factors make it possible to recommend this method.

• For patients with WM older than 65 years in the high- and intermediate-risk groups according to IPSSWM\Revised IPSSWM, it is possible to use a combined program containing #rituximab**, #bortezomib**, #bendamustine**, and #dexamethasone** (RBBd regimen); see Appendix A3 [44, 46].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: data on this approach are limited, however, the high efficacy demonstrated in a small group of patients allows this method to be recommended.

• For patients with WM younger than 65 years in the high- and intermediate-risk groups with histological signs of large-cell transformation, a combined immunochemotherapy regimen may be recommended — the rotating R-EPOCH + ibrutinib** + #venetoclax**/R-BAC + ibrutinib** + #venetoclax** scheme followed by high-dose consolidation according to the CEAM program or #daratumumab** + CEAM with autologous HSC support; see Appendix A3 [43, 44, 47].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: data on the efficacy of this approach are currently limited, however, the high efficacy of the program and the lack of a standard of therapy for young patients with signs of histological large-cell transformation make it possible to use this method.

3.3 Maintenance therapy

Comments: The issue of maintenance therapy with #rituximab** in WM is under discussion. In some centers, #rituximab** is prescribed to WM patients after successful treatment according to regimens including this drug at 375 mg/m² every 3 months for 2 years. One study showed that prescribing #rituximab** as maintenance therapy improves overall treatment efficacy, PFS, and OS. However, with long-term treatment with #rituximab**, an increase in infectious complications was noted compared to the group of patients who did not receive maintenance therapy. [48] Maintenance therapy with #rituximab** may be recommended for patients who have achieved a complete or very good partial response to induction #rituximab**-containing therapy.

3.4 Treatment of WM relapses

Patients with relapsed WM should undergo the same scope of examination as newly diagnosed patients.

The choice of a treatment program for relapsed WM depends on the efficacy of previous therapy, the duration of remission, the patient's condition and age, concomitant pathology, and complications accompanying the initial therapy. In late relapses developing one year or more after achieving an antitumor response, previously used treatment methods can be used. For the treatment of early WM relapses (with a remission duration of less than 1 year), as well as in refractory disease, an alternative program should be used. These programs must include medicinal products from other groups and can be used either as monotherapy or as a combination of drugs.

• For patients with relapsed WM, programs including #bortezomib** (RBD regimen) are recommended; see Appendix A3 [4, 11].

RG CLE 5Recommendation Grade C (Level of Evidence 5).

Comments: the use of #bortezomib**-containing programs in relapsed WM makes it possible to achieve an antitumor effect in 60% of patients, and in 60–70% of cases when combined with #dexamethasone** or #rituximab**.

• For patients with relapsed WM, programs based on #bendamustine** are recommended; see Appendix A3 [37].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: #bendamustine** in combination with #rituximab** is most effective in relapsed and refractory WM. As shown in a phase II study, an antitumor effect was achieved in 83.3% of patients, and the median PFS was 13.2 months.

• For patients over 18 years of age with relapsed WM, ibrutinib** monotherapy is recommended [4, 41].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: in 2015, the results of a phase II study evaluating the efficacy of ibrutinib** in patients who received at least one treatment option were published. Ibrutinib** was prescribed at 420 mg daily. The overall treatment efficacy was 90.5%, and a major response was achieved in 73% of patients. The 2-year PFS and OS rates were 69.1% and 95.2%, respectively.

• For patients with relapsed WM, FR (#fludarabine**, #rituximab**) or FCR (#fludarabine**, #cyclophosphamide**, #rituximab**) programs are recommended [11, 39]; see Appendix A3.

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: these therapy regimens have established themselves as highly effective programs. The results of a treatment study using the FR regimen, used both in patients with newly diagnosed WM and in those previously treated, showed overall treatment efficacy in 95% patients. CR and PR were achieved in 86% of cases. With a follow-up duration of 40.1 months, the median PFS was 51.2 months, and the median OS was not reached. Given the frequency of occurrence and duration of cytopenias, the study authors suggest using a 4-day administration of #fludarabine** and limiting the number of courses to 4.

• For patients with relapsed WM, IB (ibrutinib**, #rituximab**) programs are recommended; see Appendix A3 [4, 42].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

• For patients with relapsed WM, it is recommended to consider high-dose chemotherapy (HDCT) followed by autologous HSCT [11, 43].

GCR CLOE 4Grade of Recommendation C (Level of Evidence 4).

Comments: currently, studies are underway to evaluate the efficacy of high-dose chemotherapy with autologous HSCT in WM. The feasibility of using this treatment method in young patients with multiple relapses or primary refractory disease is being discussed. HDCT in relapses in young WM patients can be used in individual cases in agreement with the transplantation center.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

There are no special rehabilitation methods for WM. Rehabilitation for complications arising during the course of the disease and treatment is carried out within the framework of the corresponding nosologies. It is recommended to lead a healthy lifestyle and avoid excessive solar radiation and thermal physical therapy procedures.

5. Prevention and Dispensary Observation

There are currently no methods for preventing WM, since the etiological factor(s) leading to the development of the disease are unknown. Dispensary monitoring by a hematologist or oncologist is carried out during treatment and after the completion of Waldenström macroglobulinemia therapy.

During monitoring, determining the ratio of protein fractions by blood and urine electrophoresis and studying immunoglobulin monoclonality in blood and urine by immunofixation to detect monoclonal immunoglobulin must be performed every 3 months. Cytological examination of a bone marrow smear (myelogram), pathological examination of bone marrow biopsy (surgical) material using immunohistochemical methods are performed only to confirm CR, as well as in case of relapse/progression. Skeletal bone radiography or skeletal bone computed tomography is performed according to clinical indications. Computed tomography of the abdominal organs or ultrasound examination of the abdominal organs (comprehensive), ultrasound examination of all groups of peripheral, intra-abdominal, and retroperitoneal lymph nodes, abdominal organs (comprehensive) and retroperitoneal space, and determination of the size of the liver, spleen, and intra-abdominal lymph nodes are performed in case of initial lymphadenopathy or organ involvement to assess treatment efficacy and according to clinical indications.

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical approbation, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on August 8, 2024) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", is organized and provided:

1. in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;

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

3. based on these clinical guidelines;

4. 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 WM is detected in a patient or suspected, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation at an outpatient hematological/oncological care center or to a primary hematology office or primary hematology department of a medical organization to provide him/her with primary specialized health care.

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

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.

If Waldenström's macroglobulinemia (WM) 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 the management strategy and the need for additional specialized anti-tumor treatment methods.

Specialized, including high-tech, medical care is provided by hematologists in medical organizations that provide medical care to patients with WM, possess a license, the necessary material and technical base, certified specialists, in inpatient and day-care settings, and includes the prevention, diagnosis, 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 WM, the examination and treatment strategy is established by hematologists, involving other medical specialists if necessary, and with a medical concilium if required. The decision of the medical concilium is drawn up in a protocol, signed by the participants of the medical concilium, and entered into the patient's medical documentation.

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

Indications for emergency hospitalization:

1. Development of a severe infection (hospitalization in a therapeutic ward is possible).

2. Development of life-threatening cytopenias (profound anemia, hemorrhagic syndrome, neutropenia).

3. Development of life-threatening WM complications.

4. Development of therapy complications, including tumor lysis syndrome, severe infusion reactions, myelotoxic agranulocytosis with fever, and other life-threatening complications.

Indications for planned hospitalization:

1. Administration of therapy in cases requiring round-the-clock patient monitoring due to the severity of the condition caused by the tumor, or due to the risk of complications associated with the treatment program or comorbid conditions.

2. Patient examination, including biopsy and invasive interventions, in cases where it cannot be performed on an outpatient basis.

Indications for patient discharge from a medical organization:

1. Completion of a treatment course or one of the stages of specialized, including high-tech, medical care in a round-the-clock or day hospital, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting.

2. Refusal of the patient or their legal representative from specialized, including high-tech, medical care in a round-the-clock or day hospital setting established by the concilium of the medical organization providing oncological care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting.

3. The need to transfer the patient to another medical organization in the relevant medical specialty.

4. The medical commission's decision on the absence of indications for the patient to stay in the hospital due to the futility of treatment and the need to provide palliative care only.

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

7. Additional Information

7.1 Prognostic factors.

The main unfavorable prognostic factors upon establishing a WM diagnosis include: age over 65 years, Hb level ≤11.5 g/dL, platelet count ≤100×10⁹/L, serum β-2 microglobulin >3 mg/L, monoclonal IgM concentration >70 g/L. These disease features and patient age are included in the International Prognostic Scoring System for Waldenström's Macroglobulinemia (IPSSWM) (Appendix G2).

The use of this system makes it possible to predict patient life expectancy and response to therapy, but is not definitive when choosing a treatment strategy. The 5-year survival rate of WM patients, depending on the number of unfavorable features, ranges from 87% to 36% [50].

In 2020, the International WM Workshop presented the Revised IPSSWM, see Appendix G3. According to the Revised IPSSWM, patients are divided into 5 prognostic groups based on the total score considering criteria such as patient age — under 65 years, 65–75 years, over 75 years; β-2 microglobulin over 4 mg/L; LDH over 250 U/L; albumin under 35 g/L. The 5-year overall survival rate of patients depending on the prognostic group was 36%, 47%, 78%, 86%, 95% [51].

The 10-year overall survival rate of patients depending on the prognostic group was 9%, 19%, 37%, 59%, 84% [51].

7.2 Evaluation of treatment efficacy.

The evaluation of treatment efficacy in WM is carried out in accordance with international criteria proposed at the 6th International Workshop on Waldenström's Macroglobulinemia, based on changes in the level of monoclonal IgM in serum and urine, and the dynamics of lymph node and affected organ dimensions. In case of CR, sternal puncture and iliac crest trephine biopsy must be performed.

Complete Response (CR): normal IgM level, absence of monoclonal protein in serum and urine according to immunofixation data; absence of bone marrow infiltration according to histological examination data, absence of lymphadenopathy and organomegaly (if initially determined) according to CT data, absence of WM symptoms. To confirm CR, a repeat M-gradient study by immunofixation is required.

Very Good Partial Response (VGPR): a decrease in serum monoclonal IgM level by 90% or more and a reduction in the dimensions of lymphadenopathy/organomegaly (if initially determined) according to physical examination or CT data. Absence of new symptoms of active WM.

Partial Response (PR): a decrease in serum monoclonal IgM level by 50% or more and a reduction in the dimensions of lymphadenopathy/organomegaly (if initially determined) according to physical examination or CT data. Absence of new symptoms of active WM.

Minimal Response: a decrease in serum monoclonal IgM level by 25% or more, but less than 50%. Absence of new symptoms of active WM.

Stable Disease (SD): a decrease of less than 25% or an increase of less than 25% in the serum monoclonal IgM level, without signs of increasing lymphadenopathy/organomegaly, cytopenias, or clinically significant symptoms associated with WM.

Disease Progression (PD): an increase in the serum monoclonal IgM level by 25% or more upon repeat testing, or progression of clinically significant disease symptoms (unexplained fever 38.4 °C, night sweats, weight loss of 10% or more, or hyperviscosity syndrome, neuropathy, symptomatic cryoglobulinemia, or amyloidosis) associated with WM.

7.3 Prevention, diagnosis, and treatment of thrombotic complications

In hematological diseases, and in WM in particular, thrombotic complications frequently occur both initially and during the treatment process, requiring prevention and therapy. The frequency of thrombotic disorders in blood system tumors varies; chemotherapy (CT) increases the frequency of thrombotic complications almost twofold, from 2.21% to 4.24% relative to the baseline level.

Thrombotic complications have heterogeneous manifestations and are confirmed by various generally accepted laboratory (coagulological, molecular genetic, biochemical, cytological) and instrumental methods.

Risk assessment, prevention, diagnosis, and therapy of thrombotic complications are carried out taking into account the recommendations given in the guidelines for supportive care in the treatment of blood system disorders edited by E.N. Parovichnikova [53].

7.4 Diagnosis and treatment of infectious complications

Infections are leading complications in the treatment of blood system disorders. In patients with lymphomas, the frequency of infectious complications ranges from 10 to 30%; it is higher during the remission induction period, in the resistant variant of the tumor, during high-dose chemotherapy, with concomitant hypogammaglobulinemia, and during periods of forced immobility and continuous bed rest.

Diagnosis and therapy of infectious complications are carried out taking into account the recommendations given in the guidelines for supportive care in the treatment of blood system disorders edited by E.N. Parovichnikova [54].

7.5 Prophylaxis of infectious complications in patients with WM

Risk assessment and prevention of infectious complications are carried out taking into account the recommendations given in the guidelines for supportive care in the treatment of blood system disorders edited by E.N. Parovichnikova [54].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Elena N. Parovichnikova – MD, PhD, General Director of the National Medical Research Center for Hematology of the Russian Ministry of Health, Chairperson of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society", Chief freelance hematologist of the Russian Ministry of Health.

2. Irina V. Poddubnaya – Academician of the Russian Academy of Sciences, Honored Worker of Education of the RF, MD, PhD, Professor, Head of the Department of Oncology and Palliative Medicine, Vice-Rector for Clinical Work and International Cooperation at the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Chairperson of the Russian Society of Oncohematology.

3. Larisa P. Mendeleeva – MD, PhD, Deputy General Director for Research and Innovation at the National Research Center for Hematology of the Russian Ministry of Health, Member of the National Hematological Society, Member of the Russian Professional Society of Oncohematology.

4. Evgeny E. Zvonkov – MD, PhD, Head of the Department of Lymphoproliferative Diseases, Head of the Department of Hematology and Lymphoma Chemotherapy with a Bone Marrow and Hematopoietic Stem Cell Transplantation Unit at the National Medical Research Center for Hematology of the Russian Ministry of Health, Member of the Association for the Promotion of Hematology and Bone Marrow Transplantation Development "National Hematological Society".

5. Alexander E. Grachev – PhD in Medical Sciences, Hematologist at the Department of Chemotherapy of Hematological Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health.

6. Lyubov S. Al-Radi – PhD in Medical Sciences, Senior Researcher at the Department of Diagnosis and Treatment of Hematological Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health.

7. Olga M. Votyakova – PhD in Medical Sciences, Senior Researcher at the N.N. Blokhin Russian Cancer Research Center of the Russian Ministry of Health, Member of the Russian Professional Society of Oncohematology.

8. Elena A. Stadnik – PhD in Medical Sciences, Associate Professor at the Department of Faculty Therapy, Pavlov University of the Russian Ministry of Health, Senior Researcher at the Almazov National Medical Research Centre of the Russian Ministry of Health, Member of the Russian Society of Oncohematology.

9. Natalia A. Falaleeva – MD, PhD, Head of the Department of Antitumor Drug Therapy, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Member of the Association of Oncologists of Russia and the Russian Association of Therapeutic Radiation Oncologists.

10. Dmitry N. Stefanov – Researcher, Head of the Scientific and Organizational Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the Russian Society of Oncohematology.

11. Natalia V. Myakova – MD, PhD, Professor, Deputy Chief Medical Officer for Clinical Work, Head of the Department of Oncohematology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the National Society of Pediatric Hematologists and Oncologists.

12. Alexey A. Nevolskikh – MD, PhD, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

13. Sergey A. Ivanov – Professor of the Russian Academy of Sciences, MD, PhD, Director of the A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

14. Zhanna V. Khaylova – PhD in Medical Sciences, 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.

15. Tigran G. Gevorkyan – Deputy Director of the Institute of Clinical and Economic Research, N.N. Blokhin National Medical Research Center of Oncology.

There is no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Hematologists

2. Oncologists

3. Pediatric hematologist-oncologists

4. Medical students

Methodology for evidence collection

Methods used for the collection/selection of evidence:

Search for publications in specialized peer-reviewed periodicals with an impact factor >0.3, search in electronic databases.

Databases used for the collection/selection of evidence:

The evidence base for the guidelines includes publications indexed in the Cochrane Library, PUBMED, and MEDLINE databases. The search depth was 30 years.

Methods used for evidence analysis:

• Reviews of published meta-analyses;

• Systematic reviews with evidence tables.

Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Level of evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1. Drug treatment regimens for WM

#Rituximab** monotherapy [31,36]

#Rituximab** – 375 mg/m² IV infusion, once weekly for 4 weeks.

The course is repeated after 12 weeks

RBD [38]

#Rituximab** – 375 mg/m² IV, day 1

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

#Dexamethasone** – 40 mg IV, days 1, 4, 8, 11

Treatment is resumed on day 22. 4–6 cycles are administered

RB [34]

#Rituximab** – 375 mg/m² IV, day 0

#Bendamustine** – 90 mg/m² IV on days 1 and 2

Treatment is resumed on day 28; 4–6 cycles are administered.

RBBe [44, 46]

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

#Bendamustine** – 90 mg/m² IV on days 1 and 2

#Dexamethasone** – 20 mg IV or orally on days 1, 4, 8, 11

#Rituximab** – 375 mg/m² IV, day 1

Treatment is resumed on days 18–21 (7–10 day interval between cycles); 4–6 cycles are administered.

R-EPOCH + ibrutinib** / R-BAC + ibrutinib** (rotating cycles) [44, 45]

R-EPOCH + ibrutinib**

- #Rituximab** – 375 mg/m² IV, day – 0

- #Vincristine** 0.4 mg/m²/day IV on days 1–4 (continuous 96-hour infusion)

- #Cyclophosphamide** 750 mg/m²/day IV, on day 5

- #Prednisolone** 60 mg/m²/day IV on days 1–5

- Ibrutinib** 420 mg/day orally daily from days 0 to 14

On day 22, the R-BAC + ibrutinib** cycle begins

- #Rituximab** – 375 mg/m² IV, day – 0

- #Bendamustine** – 90 mg/m² IV on days 1 and 2

- #Cytarabine** 500 mg/m² IV on days 1, 2, 3

- Ibrutinib** 420 mg/day orally daily from days 0 to 14

On day 29, the R-EPOCH + #ibrutinib** cycle begins again, followed by R-BAC + #ibrutinib** on day 22.

R-EPOCH + ibrutinib** + #venetoclax**/R-BAC + ibrutinib** + #venetoclax** (rotating cycles) [44, 47]

R-EPOCH + ibrutinib** + #venetoclax**

- #Rituximab** – 375 mg/m² IV, day – 0

- #Vincristine** 0.4 mg/m²/day IV on days 1–4 (continuous 96-hour infusion)

- #Cyclophosphamide** 750 mg/m²/day IV, on day 5

- #Prednisolone** 60 mg/m²/day IV on days 1–5

- Ibrutinib** 420 mg/day orally daily from days 0 to 14

- #Venetoclax** 400 mg/day orally daily from days 0 to 14

On day 22, the R-BAC + ibrutinib** + #venetoclax** cycle begins

- #Rituximab** – 375 mg/m² IV, day – 0

- #Bendamustine** – 90 mg/m² IV on days 1 and 2

- #Cytarabine** 500 mg/m² IV on days 1, 2, 3

- Ibrutinib** 420 mg/day orally daily from days 0 to 14

- #Venetoclax** 400 mg/day orally daily from days 0 to 14

On day 29, the R-EPOCH + ibrutinib** #venetoclax** cycle begins again, followed by R-BAC + ibrutinib** + #venetoclax** on day 22.

A total of 4 cycles of immunochemotherapy are administered according to the R-EPOCH + ibrutinib** + #venetoclax/R-BAC + ibrutinib** + #venetoclax** rotating regimen

RCD [32, 34]

#Rituximab** – 375 mg/m² IV, day 1

Cyclophosphamide** – 100 mg/m² orally twice daily, days 1–5

#Dexamethasone** – 20 mg IV, day 1

Treatment is resumed on day 22. 6 cycles are administered

CP-R [36]

#Rituximab** – 375 mg/m² IV, day 1

Cyclophosphamide** – 1000 mg/m² IV on day 1 of the cycle (the dose of cyclophosphamide may be reduced depending on the clinical situation)

#Prednisolone** – 100 mg orally, days 1–5

Treatment is resumed on day 22. 4–6 cycles are administered.

FCR [39]

#Rituximab** – 375 mg/m² IV on day 1

#Fludarabine** – 25 mg/m² IV on days 2–4

#Cyclophosphamide** – 250 mg/m² IV, days 2–4

Treatment is resumed on day 29. 6 cycles are administered

Chlorambucil monotherapy** [40]

#Chlorambucil** – 0.1 mg/kg orally long-term under control of complete blood count until the plateau phase

Ibrutinib therapy** [41, 61]

Ibrutinib** 420 mg orally, daily, until disease progression or unacceptable toxicity

Ibrutinib** + #Rituximab** [42, 61]

Ibrutinib** 420 mg orally, daily, until disease progression or development of intolerable toxicity; #rituximab** 375 mg/m² IV on the first day of weeks 1, 2, 3, 4 and 17, 18, 19, 20 of therapy

#Zanubrutinib therapy [24]

#Zanubrutinib** 160 mg orally every 12 hours, daily, until disease progression or toxicity of therapy develops

#Acalabrutinib monotherapy [23]

#Acalabrutinib** 100 mg orally every 12 hours, daily, until disease progression or toxicity of therapy develops

Appendix A3.2 Prophylaxis and treatment of nausea and vomiting

One of the frequent clinically significant side effects of chemotherapy is nausea and vomiting. These adverse events not only lead to a deterioration in the patient's well-being and a decrease in quality of life, but also hinder the administration of oral medications and food intake. The emergence of new antineoplastic drug combinations improves treatment outcomes in Onco-hematology patients; however, severe nausea and vomiting may limit the use of antineoplastic agents at full doses and negatively affect patients' treatment adherence. Therefore, the control of nausea and vomiting plays a vital role in the supportive care of patients with hemoblastoses.

Prevention and treatment of nausea and vomiting are carried out taking into account the recommendations given in the guide to supportive care in the treatment of blood system diseases edited by E.N. Parovichnikova, G.M. Galstyan [56]

Appendix A3.3. Infusion therapy in hematological patients

A special place in the supportive care of patients with onco-hematological diseases is occupied by infusion therapy (IT). It is used in almost all hospitalized patients.

Infusion therapy is carried out taking into account the recommendations given in the guide to supportive care in the treatment of blood system diseases edited by E.N. Parovichnikova, G.M. Galstyan [58]

Appendix A3.4. Use of donor blood components in hematological patients

The main medical indication for red blood cell transfusion in hematological patients is inadequate oxygenation of organs and tissues and the associated risk of complications. Prophylactic transfusion of donor platelets in hematological patients is performed to prevent spontaneous hemorrhagic complications associated with severe thrombocytopenia induced by intensive chemotherapy, or for therapeutic purposes in patients with existing hemorrhagic complications. When it is necessary to replenish coagulation factor deficiencies, fresh frozen plasma (FFP) remains the universal agent to date. The choice of a specific type of blood component for blood transfusion (type of red blood cell-containing blood component, type of platelet concentrate, type of plasma product) is made by the attending physician or transfusionist 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 for Providing Medical Care to the Population Profile 'Transfusiology'," Order of the Russian Ministry of Health No. 1134n dated October 20, 2020 "On the Procedure for Medical Examination of the Recipient, Performing Tests for Individual Compatibility, Including Biological Test, During Transfusion of Donor Blood and (or) Its Components," recommendations "Clinical Use of Red Blood Cell-Containing Blood Components" (2018), 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 Invalidating Certain Acts of the Government of the Russian Federation," and other regulatory acts.

Replacement blood transfusion therapy is carried out taking into account the recommendations given in the guide to supportive care in the treatment of blood system diseases edited by E.N. Parovichnikova, G.M. Galstyan [59]

Appendix A3.5. Vascular access management

Vascular access management is an integral part of modern chemotherapy in onco-hematology patients. Antineoplastic drugs are administered, electrolyte disturbances are corrected, parenteral nutrition is provided, and blood samples for laboratory tests are drawn through a central venous catheter (CVC).

Vascular access is determined taking into account the recommendations given in the guidelines for supportive care in the treatment of hematopoietic system diseases edited by E.N. Parovischnikova, G.M. Galstyan [60].

Appendix A3.6. Autologous hematopoietic stem cell transplantation. Mobilization and collection of autologous hematopoietic stem cells.

Autologous hematopoietic stem cell transplantation in WM therapy is currently considered an option in refractory/relapsed disease. Cell collection is preferably performed in patients younger than 60 years after effective first-line therapy.

Appendix B. Physician Action Algorithms

Management algorithm for a patient with newly diagnosed WM:

Therapeutic algorithm.

Management algorithm for a patient with relapsed WM.

Appendix C. Patient Information

Waldenström macroglobulinemia (or Waldenström's disease) is an indolent, slowly progressive neoplastic disease that is a type of lymphoma. Currently, this disease is considered incurable, but modern innovative treatment methods, including new medicinal products and autologous hematopoietic stem cell transplantation, make it possible to achieve deep anti-tumor responses, control the disease, and ensure long-term survival while preserving the quality of life.

Clinical symptoms of Waldenström macroglobulinemia are diverse, appear unexpectedly, and may be perceived by patients as a manifestation of concomitant chronic conditions. If severe weakness, pallor of the skin, increased bleeding tendency, visual disturbances, or neurological symptoms occur, one should consult a physician and undergo a diagnostic examination.

The examination includes special blood and urine testing methods, bone marrow examination, ultrasound, and X-ray studies. The results of the examination will help determine the nature of the disease, specify treatment tactics, and establish the timing for initiating specific therapy.

In some cases, with minimal manifestations of the disease, specific therapy can be temporarily deferred. However, the patient must be monitored by a local hematologist and undergo follow-up examinations every 3–6 months. During treatment (regardless of the method chosen by the attending physician), as well as after completing the required course of therapy, the patient must regularly undergo blood tests to assess the effectiveness and duration of treatment.

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

Appendix G1. ECOG performance status scale

Clinical assessment of the general condition of a patient with WM is carried out according to the scale developed by the Eastern Cooperative Oncology Group.

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. Vol. 5, № 6. P. 649–65

Type: rating scale

Purpose: clinical assessment of the patient's general condition

Content and interpretation:

Appendix G2. International Prognostic Scale

Original title: International prognostic scoring system for Waldenström’s macroglobulinemia (IPSSWM)

Source: Morel P, Duhamel A, Gobbi P et al. International prognostic scoring system for Waldenström macroglobulinemia. Blood 2009; 113(18):4163—4170. [50]

Type: rating scale

Purpose: assessment of unfavorable prognostic factors at the time of WM diagnosis

Content and interpretation:

Appendix G3. Revised International Prognostic Scoring System.

Original title: Revised International prognostic scoring system for Waldenström’s macroglobulinemia (Revised IPSSWM)

Source: Kastritis E, Morel P, Duhamel A, Dimopoulos MA. et al. A revised international prognostic score system for Waldenström's macroglobulinemia. Leukemia. 2019 Nov;33(11):2654-2661. doi: 10.1038/s41375-019-0431-y. Epub 2019 May 22. [51]

Type: rating scale

Purpose: assessment of unfavorable prognostic factors at the time of WM diagnosis

Content and interpretation: