Introduction:

• Lymphoplasmacytic lymphoma is a neoplasm of small B-lymphocytes, plasmacytoid lymphocytes and plasma cells, usually lacking CD5 and monoclonal serum M protein.
• Waldenstrom macroglobulinemia is LPL with bone marrow involvement and IgM monoclonal gammopathy of any concentration.

Epidemiology:

• Incidence- 3.4/1 million
• 3-7/1million women    
• Accounts for 1.5% of nodal lymphomas
• Median age- 60yrs
• Slight male preponderance
• Familial predisposition is seen

Etiology:

• Infection – HCV
• Genetic susceptibility
• Occupational exposure
• Common in families with history of autoimmune disorders

Pathogenesis:

• MYD 88 mutation is seen in nearly 90% of LPL/WM
• It is a key component in Toll like receptor signalling machinery
• Mutation leads to gain of function
• Ibrutinib (BTK inhibitor) and Idalalisib (PI3K delta inhibitor) block MYD 88 mediated down-stream targets. 
• Mutations can be detected by next generation sequencing/ PCR

Most common mutation is L265P

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Conformation change in beta loop of TIR domain

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Spontaneous homodimerization and recruitment of IRAK1 and IRAK4

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Uncontrolled formation of MYD 88/IRAK complex

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Recruitment of TRAF6 constitutive phosphorylation of PAK1

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Elevation of NF Kappa beta activity

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Sustained tumor cell survival and proliferation

• Mutation of CXCR4- Seen in 30-40% of patients. Confers resistance to Ibrutinib therapy.
• TP53 mutation- Seen in 11% of patients. Associated with poor prognosis.

Subtypes:

• IgM type
• Non- IgM type- 5% cases, IgG/ IgA/non-secretory, less frequent hyperviscosity/ neuropathy symptoms

Clinical Features:

• Lymphadenopathy: Develops slowly over years
• Hyperviscosity symptoms due to increased IgM which may form aggregates and may bind water through their carbohydrate component and induction of red cell aggregation/ rouleaux formation. Symptoms are seen when IgM is >50gm/L or Viscosity is >4 centipoise
  • Headache
  • Oronasal mucosal bleed
  • Visual disturbances/ blurred vision
  • Leg cramps
  • Impaired mentation
  • Dizziness
• Anemia- Due to 
  • Cold agglutinin hemolytic anemia due to anti PR2 cold agglutinin 
  • Hyperviscosity leads to reduced synthesis of EPO from kidney
  • Infiltration in bone marrow
  • Increased hepcidin levels   
• Autoimmunity – Due to cryoglobulinemia
• Neuropathy – Due to reactivity of IgM paraprotein with myelin sheath antigens. Ex: Myeline associated glycoprotein
  • Sensory symptoms: Paresthesia, aching discomfort, dysesthesia, lancinating pain
  • Imbalance, gait ataxia, leg muscle atrophy
  • Other neuropathies include: 
    • Amyloid peripheral neuropathy
    • CANOMAD syndrome: chronic ataxic neuropathy with ophthalmoplegia, M-protein, cold agglutinins and disialosyl ganglioside antibodies
    • Cryoglobulin associated neuropathy 
    • Small fiber neuropathy
• Diarrhoea, malabsorption, obstruction and GI bleed – Due to deposition of IgM/amyloid in GIT.
• Coagulopathies- Due to binding of IgM to clotting factors, platelets & fibrin.
• Skin lesions:
  • Bullous lesions - Due to deposition of IgM on basement membrane
  • Papular lesions on extensor surfaces of extremities- Due to deposition of IgM in dermis (Schnitzler syndrome)
• Hepatosplenomegaly
• Type II cryoglobulinemia
  • Seen in 20% of patients
  • Acrocyanosis and necrosis of regions exposed to cold (Raynaud's phenomenon)
  • Vasculitis leading to purpura
  • Arthralgia
  • Fever
  • Livido reticularis
• Lung- 
  • Masses, nodules, diffuse infiltrates, pleural effusion
  • Presents with cough, dyspnea, chest pain
• Renal
  • Renal/ perirenal masses
  • Proteinuria- Due to  deposition of IgM in subendothelial region of glomerulus
  • Renal failure
• Joints
  • Invasion of articular and periarticular structures
• Eyes
  • Invasion of periorbital structures, lachrymal gland, retro-orbital lymphoid tissue leading to ocular nerve paralysis
• CNS
  • Bing Neal syndrome- Due to direct invasion of CNS. There is confusion, memory loss, disorientation, and motor dysfunction
• Amyloidosis: Unexplained cardiac failure, intestinal dysmotility, purpura, macroglossia

Investigations:

• Hemogram
  • Normocytic normochromic anemia 
  • False high MCV due to aggregation of RBCs
  • False high haemoglobin due to interaction with paraproteins
  • Mixture of small lymphocytes, plasma cells & plasmacytoid lymphocytes are seen, but count is much lesser than CLL
  • Neutropenia and thrombocytopenia in late cases
• Bone marrow aspiration and biopsy
  • Neoplastic cells- Small lymphocytes, plasmacytoid lymphocytes (Have abundant basophilic cytoplasm) and plasma cells, with / without PAS positive intranuclear inclusions (Dutcher bodies)
  • Paratrabecular nodular lymphoid aggregates and / or a diffuse interstitial lymphoid infiltration.
  • Increased number of reactive mast cells and hemosiderin laden histiocytes.
• Lymph Node biopsy
  • Diffuse (without pseudofollicles) growth of tumor cells.
• Immunophenotyping
  • Positive - surface Ig (IgM type) with light chain restriction, B cell associated antigens (CD19, CD20, CD22-weak CD79a, PAX5, FMC7), CD45, CD 38, CD25
  • Negative –IgG, CD5, CD10, CD23 (CD5 is important & it helps in differentiating it from CLL), CD 103
• ESR- Increased
• Coagulation profile- Prolonged thrombin time
• Test for cold agglutinin/ cryoglobulin- May be positive
• Urine Bence Jones proteins- Frequently present 
• Serum electrophoresis combined with Immunofixation (Serum and Urine) – Raised levels of IgM paraprotein (known as macroglobulin). Quantification must be done by densitometry/ nephelometry.
• S. Free light chain assay: Useful in conditions in which IgM component is difficult to measure (Ex: Cryoglobulins)
• Serum Viscosity
• Cytogenetics/FISH/ Molecular studies
  • MYD88 p.L265P by targeted next generation sequencing- Positive in 93-97% cases
  • IgH translocations are not seen- This helps to differentiate from multiple myeloma and follicular lymphoma
  • Variable region may show somatic mutations
  • Loss of all or part of chromosome- 17, 18, 19, 20, 21, 22, X and Y
  • Gains of 3, 4 and 12
  • t (9 : 14)- Rearrangement of PAX gene on chromosome 9 which encodes B-cell specific activator protein.
  • del 6q, trisomy 3 and 18, trisomy 4
  • Increased BCL2 expression
• MRI spine and CT abdomen and pelvis- To evaluate disease status
• Ophthalmoscopy- Distended, tortuous retinal veins, haemorrhages and papilledema

Criteria for Diagnosis

Lymphoplasmacytic lymphoma

Essential:

• Significant BM infiltration by clonal small lymphocytes with plasmacytoid and/or plasma cell differentiation
• Immunophenotype of LPL cells: IgM+, CD19+, CD20+, CD22+, CD25+, CD10-, CD23-, CD103-, CD138+/-

Desirable:

• Detection of MYD88 (NP_002459.2:p.L265P)
• Detection of CXCR4 somatic mutation.
• Serum electrophoresis and immunofixation showing presence of monoclonal IgM

Waldenstrom's macroglobulinemia:

• IgM monoclonal protein of any value in serum
• Bone marrow lymphocytes- ≥ 10% with plasmacytoid differentiation
• Diffuse, interstitial or nodular pattern of bone marrow infiltration

Prognosis:

• Poor prognostic factors
  • Advanced stage
  • Peripheral blood cytopenia especially anemia
  • Poor PS
  • High beta 2 microglobulins
  • Increased transformed cells/ immunoblasts
  • 6q deletion.
• Median survival – 5-10 years
• Transformation into diffuse large B-cell lymphoma may be seen
• No treatment can cure the disease
• International prognostic scoring system for WM- Each factor- 1 point
  • Age- >65yrs
  • Hemoglobin- <11.5gm/dL
  • Platelet count <1lac/cmm
  • Beta2microglobulin- >3mg/L
  • IgM>7gm/dL

Indications for Treatment:

• Hyperviscosity related symptoms
• Neuropathy
• Organomegaly
• Amyloidosis
• Cold agglutinin disease
• Cryoglobulinemia
• Anemia/ Cytopenia secondary to marrow infiltration
• Bulky lymphadenopathy
• Evidence of end organ damage                  

Pretreatment Work-up:

• History
• Examination
  • LN:
  • Spleen:
  • Fundoscopy:
• WHO P. S.
• BSA
• BMA and Bx
• IHC/Flow cytometry
• CT (CAP) or PET-CT (If agressive histology noted in histology)
• Hemoglobin
• TLC, DLC
• Platelet count
• LFT- Bili- T/D         SGPT:           SGOT:  Albumin:    Globulin:
• Creatinine
• Electrolytes: Na:        K:          Ca:Mg:               PO4:           
• Uric acid:
• Quantitative Ig
• S.P.E.
• Immunofixation E
• SFLC Assay
• Beta 2 Microglobulin
• S. Viscosity
• Cryocrit (If cryoglobulinemia is suspected)
• Cold agglutinins
• DCT
• Anti MAG antibodies,  Electromyelogram and Abdominal fat biopsy for Amyloid in pts with peripheral neuropathy
• Retinal examination- To note hyperviscosity (If IgM>3gm)
• CSF analysis (In patients with CNS manifestations)
• LDH
• HIV:
• HBsAg:
• HCV:
• UPT
• MYD88, L265P- PCR on BMA
• CXCR4 if Ibrutinib is considered
• Prognostic score
• ECHO(If anthracyclines planned)LVEF-              %
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan:

• Intent of treatment must be palliation of symptoms, not necessarily normalizing IgM levels.

Response Criteria:

• Complete response:
  • IgM in normal range and disappearance of monoclonal protein by immunofixation
  • No histological evidence of BM involvement
  • Resolution of lymphadenopathy and splenomegaly
  • No symptoms attributable to WM.
• Partial response:
  • >50% reduction in S. IgM levels
  • Decrease in lymphadenopathy and splenomegaly
  • No new symptoms or signs of active disease

About Each Modality of Treatment:

• Plasmapheresis:
  • Should be performed if patient has symptomatic hyperviscosity
  • If patient has IgM >4000mg/dL, plasmapheresis should be done prior to administering Rituximab/ Ofatumumab, as they cause IgM flare.
• Chemotherapy:
  • Choice of frontline therapy depends n 
    • Presence of cytopenia
    • Need for more rapid disease control
    • Age and fitness for autologous transplantation (In candidates of autologous transplantation, avoid chlorambucil and nucleoside analogues)
    • Avoid Bortezomib and vincristine in patients having significant peripheral neuropathy
    • Subcutaneous route is preferred method of administration of Bortezomib
  • Rituximab/Ofatumumab:
    • They may be withheld in patients with elevated IgM levels for initial treatment cycles
    • IgM flare occurs due to release of IL-6 by bystander immune cells. Return to baseline IgM is seen in 12 weeks.
  • Ibrutinib
    • Dose: 420mg- OD- Lifelong
    • Risk of atrial fibrillation- 12-20%
    • No response if patient has wild type MYD88
• Rituximab maintenance:
  • Given to only those patients who respond to rituximab containing regimens
  • 375mg/m2 given, once in 3 months for 2 years
• Autologous stem cell transplant
  • Done after HDT with Melphalan- 200mg/m2
  • Useful in relapse/ refractory states
  • May be used as first line therapy if there is associated amyloidosis

Other treatment options:

• Zanubrutinib
• Acalabrutinib
• Pirtobrutinib
• Venetoclax

Supportive Care:

• PCP prophylaxis is must for patients receiving bendamustine
• Herpes zoster prophylaxis has to be given to all patients receiving therapy.
• Yearly influenza and COVID-19 vaccinations must be given
• Pneumococcal vaccine 
• Inappropriate PRBC transfusion can increase hyperviscosity and precipitate cardiac failure. PRBC transfusion can be done after plasma exchange. 

Monitoring After Treatment/ Follow-up:

• IgM every 3 months for 3 years, then once in 6 months for 3 years, then once a year
• Progression based on IgM levels alone, without symptoms, is not an indication for retreatment 

Treatment of relapse:

• Relapse within 12 months of completion of initial therapy: Choose alternate therapy
• Relapse after 12 months: Use previous treatment

Related conditions:

IgM monoclonal gammopathy of undetermined significance

• All the following criteria must be met
  • the presence of an IgM paraprotein of less than 30  g/L
  • Absence of a lymphoplasmacytic bone marrow infiltration
  • Absence of signs or symptoms such as occur in WM itself
• No treatment is required

Histological transformation to DLBCL:

• Seen in 3-11% patients
• Associated with very high incidence of involvement of extranodal disease
• PET directed tissue biopsy is required for all patients
• Treatment is similar to denovo DLBCL
• Autologous SCt must be considered in patients achieving CR and are fit for high dose chemotherapy.

Figures:

Figure 6.6.1- Lymphoplasmacytic lymphoma- Peripheral smear showing both lymphocytes and plasma cells

Figure 6.6.2- Lymphoplasmacytic lymphoma- Bone marrow aspiration

Recent advances:

Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia

In this investigator-initiated trial, ibrutinib and venetoclax combination therapy was evaluated in symptomatic treatment-naïve patients with MYD88-mutated Waldenström macroglobulinemia (WM). Forty-five patients received ibrutinib followed by venetoclax, with the primary endpoint being the attainment of very good partial response (VGPR). The study demonstrated a high VGPR rate of 42%, with manageable adverse events including neutropenia, mucositis, and tumor lysis syndrome, but notable incidences of atrial fibrillation and ventricular arrhythmia. Progression-free survival (PFS) and overall survival (OS) rates at 24 months were favorable, although ventricular arrhythmia led to early termination of the study due to safety concerns.

https://doi.org/10.1182/blood.2023022420

Long-term results of Waldenström macroglobulinaemia treatment by bendamustine and rituximab

The bendamustine–rituximab (BR) regimen is a highly effective first-line therapy for Waldenström macroglobulinaemia (WM), with a previous analysis of 69 patients showing high response rates and favorable progression-free survival (PFS) and overall survival (OS). At a median follow-up of 76.1 months, 5-year PFS is 66.63% and OS is 80.01%. The incidence of secondary cancers is 17.66% at 66 months. Relapsed patients receiving ibrutinib as a second-line treatment benefited significantly, supporting the long-term efficacy of BR as a first-line treatment for WM.

https://doi.org/10.1111/bjh.19409 

Simplified Risk Stratification Model for Patients With Waldenström Macroglobulinemia

This study reviewed 889 treatment-naïve Waldenström macroglobulinemia (WM) patients to identify prognostic factors for overall survival (OS). Significant predictors—age, serum lactate dehydrogenase (LDH), and serum albumin—were used to create a prognostic model, the Modified Staging System for WM (MSS-WM). The model stratified patients into four risk groups with distinct OS outcomes and was validated in a separate cohort. MSS-WM is a simple, clinically useful tool that reliably predicts prognosis in symptomatic WM patients.

https://doi.org/10.1200/JCO.23.020

Rituximab and pembrolizumab in relapsed/refractory Waldenström's Macroglobulinaemia

The PembroWM trial assessed pembrolizumab (PD1-Inhibitor) plus rituximab in relapsed/refractory Waldenström's Macroglobulinaemia (WM) post-chemoimmunotherapy and covalent BTK inhibitors. Among 17 patients, the 24-week overall response rate was 50%, with a median response duration of 11.6 months. Progression-free survival was 13.6 months, and treatment was well tolerated. This study highlights the safety and potential efficacy of PD-1 modulation in WM.

https://doi.org/10.1111/bjh.19706