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JOURNAL PRESENTATION

Dr. Ishwor Man Singh

Resident (Phase B)

Department of Haematology,

BSMMU

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How I treat Waldenström macroglobulinemia�

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AUTHORS: Meletios A. Dimopoulos, Efstathios Kastritis

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PUBLISHED IN: Blood (2019) 134 (23): 2022–2035

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Abstract

  • WM is an uncommon lymphoma characterized by the infiltration of the bone marrow by clonal lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM).

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  • It may have an asymptomatic phase, or with symptoms and complications resulting from marrow or other tissue infiltration, or from physicochemical or immunological properties of the monoclonal IgM

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Abstract

  • Diagnosis of WM has been clearly defined, and genetic testing for somatic mutation of MYD88L265P is a useful tool for differential diagnosis from other conditions.

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  • Specific criteria that define symptomatic disease that needs treatment offer clinical guidance

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Abstract

  • The treatment options include anti-CD20 monoclonal antibody-based combinations and BTK inhibitors.
  • The choice of therapy is based on the need for rapid disease control, presence of specific disease complications, and patient’s age.

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  • With the use of BTK inhibitors, the use of continuous therapy has been introduced as another option over fixed-duration chemoimmunotherapy

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Introduction

  • WM is an uncommon lymphoma (∼1%-2% of hematological malignancies) with unique features, and accumulation of lymphoplasmacytic cells that produce monoclonal immunoglobulin M (IgM).

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  • Symptoms and complications are related to tumor burden or quantity or to the physicochemical or immunological properties of monoclonal IgM

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Introduction

  • The disease also may have a long asymptomatic course.

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  • WM is mostly a disease of the elderly and has higher prevalence among whites  and a familial predisposition 

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Diagnosis

  •  BM biopsy shows infiltration by clonal lymphoplasmacytic cells/lymphoplasmacytic lymphoma (LPL).

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  • Presence of any amount of monoclonal IgM, detected by immunofixation electrophoresis.

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Diagnosis

  • There is no threshold for BM clonal cell infiltration, but individuals with less than 10% clonal cells have an indolent course  compared with those with at least 10% infiltration.

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  • Two types of clonal cells (B cells and plasma cells with varying degree of differentiation ) are usually found.

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Clinical and laboratory findings of symptomatic WM from the database of Greek Myeloma Study Group

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Characteristics of patients with symptomatic WM

 N = 595

Age, median/range, yrs

69 (24-92)

Male/female, %

60/40

BM involvement, median

52%

MYD88 L265P* (N = 84)

77%

IgM, median

3480 mg/dL

IgG, median

790 mg/dL

IgA, median

85 mg/dL

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Characteristics of patients with symptomatic WM

 N = 595

Hemoglobin, median

10.1 g/dL

Hemoglobin <10 g/dL

46%

Platelets, X 109/L, median

215

Platelets, <100 X 109/L

12%

WBC, X 109/L, median

6.6

b2-microglobulin, median

3.36 mg/dL

Serum albumin

3.6 g/dL

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Characteristics of patients with symptomatic WM

 N = 595

Serum albumin <3.5 g/dL

40%

LDH, U/L (ULN < 225 IU/L), median

180

LDH > ULN

20%

Cryoglobulins present

5.5%

Cold agglutinins present

4%

Lymphadenopathy

36%

Splenomegaly

29%

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Clinical presentation at the time of symptomatic disease

 Anemia/cytopenias 

42% 

 B-symptoms 

25% 

 Hyperviscosity 

17% 

 Neuropathy 

12% 

 Amyloidosis 

1.5% 

 Symptomatic cryoglobulinemia 

1.3% 

 Symptomatic cold agglutinin disease 

0.6% 

 Other 

0.6% 

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Differential diagnosis of WM from other diseases that may share a similar phenotype�

 

 

 

BM biopsy

 

 Cytogene

tics

 

 

MYD88L265P

Immunophenotype (by IHC or flow cytometry in BM)

 

 

Clinical presentation

WM

Morphology: lymphoplasmas or cells with lymphoplasmacytic

differentiation, together with a small population of clonal plasma cells ≥10% LPL

Del6q (30%-50%)

70%-90%

B-cell population: CD20+, sIgM+, CD22+ (weak), CD79+, CD25+, CD27+, FMC7+, BCL-2+, CD52+, CD5+/-, CD10+/-, CD23+/-,CD103-;

plasma cell population: CD138+ CD38++, CD19+, CD45+, CD56-

Hyperviscosity, lymphadenopathy, splenomegaly, neuropathy

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Differential diagnosis of WM from other diseases that may share a similar phenotype�

 

 

 

BM biopsy

 

 

Cytogenetics

 

 

MYD88

Immunophenotype (by IHC or flow cytometry in BM)

 

 

Clinical presentation

IgM MGUS

<10% LPL in the BM and <3 g/dL IgM*

?

30%-60%

Usually few cells found

No symptoms or only IgM-related

Myeloma

Plasma cells

t(11;14) or other IgH translocations

0

CD138+, CD38+, CD19-

Lytic bone disease Cyclin D1 staining

positive in 75%

SMZL

Intrasinusoidal infiltration by CD20+ cells

Del7q(19%)+3q(19%), +5q(10%)

10%

CD19+, CD20+, CD22+, CD79a+, CD79b+, FMC7+

IgM+ CD5(weakly + in 10%-25%), CD10-, CD43-, BCL6-,

cyclin D1-,CD103-,but occasionally +CD11c+/- CD25+/-CD11c+

Splenomegaly more common; circulating cells of characteristic morphology may be found

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Follicular lymphoma

Small cleaved lymphocytes, paratrabecular localization in the BM

Translocations involving BCL-2 (70-90%)

0

CD5-, CD10+/-, CD11c+/-, CD103-, CD25-, CD138-, CD38+, CD45+, bcl2+, bcl6+

Lymphadenopathy predominates

Mantle cell lymphoma

Monotypic, medium-small- sized lymphocytes with abnormal nucleus

t(11;14)(q13;q32)

0

CD5+, CD10-, CD23-, CD25-, CD45+, CD103-, CD138-

Lymphadenopathy and extranodal involvement common

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Initial clinical and laboratory evaluation of WM

 Clinical evaluation

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History and physical examination

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Familial history for WM and other B-cell LPD

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Review for the presence of B symptoms, organomegaly, hyperviscosity symptoms, neuropathy, Raynaud’s disease, rash, peripheral edema, skin abnormalities, dyspnea

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Fundoscopic examination by ophthalmologist if IgM is high (ie, >3000 mg/dL) or hyperviscosity is suspected;

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Initial clinical and laboratory evaluation of WM

 Laboratory evaluation

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Complete blood count

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Complete metabolic panel (including LDH, serum albumin)

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Serum Ig levels (IgA, IgG, IgM)

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Serum and urine electrophoresis with immunofixation

Serum B2M level

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Viral serology (hepatitis B and C and HIV)

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Initial clinical and laboratory evaluation of WM

 Histology and molecular tests

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BM aspiration and biopsy IHC (required for diagnosis)

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Flow cytometry (optional; consider if IHC not available)

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Testing for MYD88L265P

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Initial clinical and laboratory evaluation of WM

 Optional tests, if clinically indicated

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In case of Raynaud’s, renal dysfunction, hematuria, skin rash, hyperviscosity consider evaluation for cryoglobulins

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Hemolysis, hyperviscosity: consider cold agglutinin titer

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Bleeding diathesis with prolonged aPTT ,PT and acq. VWD

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Suspicion of amyloidosis: 24-hour urine protein quantification, Serum FLCs, NTproBNP, Cardiac troponins

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Clinical indications for initiation of therapy

Recurrent fever, night sweats, weight loss, fatigue

Hyperviscosity

Lymphadenopathy: either symptomatic or bulky (≥5 cm in maximum diameter)

Symptomatic hepatomegaly and/or splenomegaly

Symptomatic organomegaly and/or organ or tissue infiltration

Peripheral neuropathy because of WM

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Laboratory indications for initiation of therapy

Symptomatic cryoglobulinemia

Symptomatic cold agglutinin anemia

Autoimmune hemolytic anemia and/or thrombocytopenia

Nephropathy that is related to WM

Amyloidosis that is related to WM

Hemoglobin ≤ 10 g/dL

Platelet count , < 100 X 109/L,

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Choice of therapy in previously untreated patient

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Choice of therapy in previously untreated patient

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Management of patient after relapse with Rituximab based therapy

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Management of patient after relapse with Rituximab based therapy

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THANK YOU