Lymphoplasmacytic lymphoma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Overview

Risk stratification determines the protocol of management used for lymphoplasmacytic lymphoma. There is no treatment for asymptomatic lymphoplasmacytic lymphoma. The mainstay of treatment for symptomatic lymphoplasmacytic lymphoma is Rituximab +/- Chemotherapy. Hyperviscosity syndrome is a medical emergency and requires prompt treatment with plasmapheresis. Drug of choice for the treatment of bing-neel syndrome is Ibrutinib with or without concurrent rituximab. Other treatment options include targeted therapy, immunotherapy and radiation therapy.

Medical Therapy

There's no cure for LPL with current therapies. Instead, the treatment goals are to control symptoms and prevent end-organ damage, while maximizing quality of life. There is no standard therapy for the treatment of LPL. While various drugs and combinations have demonstrated to have provided clinical benefit, hence, there are several different options for treating lymphoplasmacytic lymphoma depending on stage of the disease:

Summary of how to approach different patients with lymphoplasmacytic lymphoma

Patient's condition/parameters	How to proceed accordingly
IgM MGUS (<10% lymphoplasmacytic infiltrate) Smoldering/asymptomatic lymphoplasmacytic lymphoma Hemoglobin < or = 11g/dl Platelets > or = 120x10*9 /L	Observation
Symptomatic LPL patient Hemoglobin <11g/dl Platelets <120x10*9 /L IgM-related neuropathy Hemolytic anemia associated with Waldenstrom macroglobulinemia	Treat with single agent, rituximab (one cycle only, no maintenance therapy required) Plasmapheresis in case of occurrence of hyperviscosity with treatment
Bulky disease Hemoglobin < or = 10g/dl Platelets < 100x10*9/L Constitutional symptoms Hyperviscosity syndrome	Hperviscosity present: Plasmapheresis and DRC (dexamethasone + rituximab + cyclophosphamide) Hyperviscosity absent: DRC only
Patient with relapse of lymphoplasmacytic lymphoma (mSMART guidelines)	Consider clinical trial + stem cell transplant in selected patients: If the length of response to initial therapy is = or >2 years, repeat the same first-line agent as used before If the length of response to initial therapy is <2 years, use an alternative first-line agent

Watchful waiting/active surveillance for asymptomatic patients with LPL

There is no treatment for asymptomatic patients with LPL. As LPL develops slowly and may not need to be treated right away, it is monitored by healthcare team every 3-6 months which is known as watchful waiting/active surveillance and treatment is started when symptoms appear, such as hyperviscosity syndrome, or there are signs that the disease is progressing more quickly. Active surveillance includes monitoring of the following laboratory parameters:

• Complete blood count (CBC) with differential
• Complete metabolic panel (CMP)
• Immunoglobulin levels in the serum (quantitative)
• Serum protein electrophoresis

Symptomatic patients with LPL

Symptomatic patients with LPL are started on chemotherapy depending on the stage.

• Initial stage of LPL is associated with:

• Neuropathy
• Anemia or cytopenias
• Low-volume nodal involvement
• Asymptomatic splenomegaly

• Late stage of LPL is associated with:

• Adenopathy
• Symptomatic splenomegaly
• Cytopenias
• Hyperviscosity syndrome
• Neuropathy
• Constitutional symptoms

• Men and women with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures.

• Chemotherapy drugs that may be used with or without prednisone include:
  • Chlorambucil (Leukeran)
  • Fludarabine (Fludara)
  • Bendamustine (Treanda)
  • Cyclophosphamide (Cytoxan, Procytox)

• Combinations of chemotherapy drugs that may be used include:
  • DRC – dexamethasone (Decadron, Dexasone), rituximab (Rituxan) and cyclophosphamide
  • BRD – bortezomib (Velcade) and rituximab, with or without dexamethasone
  • CVP – cyclophosphamide, vincristine (Oncovin) and prednisone
  • R-CVP – CVP with rituximab
  • Thalidomide (Thalomid) and rituximab

Treatment Regimen	Drugs	Side effects
CHOP-R regimen	Cyclophosphamide Doxorubicin Vincristine Prednisone Rituximab	Nausea Alopecia Granulocytopenia Cardiotoxicity Mucositis
Ibrutinib	Ibrutinib	Fatigue Cytopenia Bleeding Atrial fibrillation Opportunistic infection
Rituximab	Rituximab	Infusion related reaction Hepatitis B reaction Progressive multi-focal leukoencephaloptahy
FR regimen	Fludarabine Rituximab	Neutropenia (63%) Thrombocytopenia Pneumonia
BDR regimen	Bortezomib Dexamethasone Rituximab	Peripheral neuropathy - reversible in 61% of patients Infections
DRC regimen	Dexamethasone Rituximab Cyclophosphamide	Neutropenia
CR regimen	Cladribine Rituximab	Anemia Neurological symptoms Symptomatic cryoglobulinemia Thrombocytopenia
IR regimen	Ibrutinib Rituximab	Anemia Neurological symptoms Symptomatic cryoglobulinemia Thrombocytopenia Atrial fibrillation

Interstitial pneumonitis, post-rituximab therapy in a lymphoplasmacytic lymphoma patient. Helical computed tomographic scanning showed ground-glass shadowing in bilateral lungs before prednisone treatment and recovery at 1-week post-treatment. [https://openi.nlm.nih.gov/detailedresult.php?img=PMC4352371_ccr30003-0133-f1&query=waldenstrom+macroglobulinaemia&it=xg&req=4&npos=61 Source: Bai X. et al, Department of Hematology, Beijing Tiantan Hospital, Capital Medical University 6 Tiantan Xili Dongcheng District, Beijing, 100050, China. ]

Hyperviscosity syndrome:

• Lymphoplasmacytic lymphoma complicated with hyperviscosity syndrome is a medical emergency and requires prompt treatment with plasmapheresis.
• Plasmapheresis temporarily lowers IgM levels by removing some of the abnormal IgM from the blood, which makes blood thinner.
• Plasmapheresis is usually given until chemotherapy starts to work.
• Plasmapheresis is combined with chemotherapy to control the disease for a longer period of time.
• Plasmapheresis is also used in WM patients with hemolysis.

Initial treatment of Lymphoplasmacytic lymphoma:

Does the patient has an indication for LPL treatment? B symptoms (recurrent fever, night sweats, weight loss, fatigue) Hyperviscosity Bulky/symptomatic lymphadenopathy Symptomatic hepatosplenomegaly Symptomatic organomegaly or organ/tissue infiltration WM associated peripheral neuropathy Cold agglutinin hemolytic anemia Symptomatic cryoglobulinemia Immune hemolytic anemia and/or thrombocytopenia LPL associated AL amyloidosis LPL associated nephropathy Hemoglobin = or < 10g/dl Platelet count = or < 100 x 10'9/L

Yes

No

Does the patient has symptoms associated with hyperviscosity such as: Oronasal bleeding, blurred vision, headaches, dizziness, paresthesias, retinal vein engorgement, flame-shaped hemorrhages, papilledema, stupor or coma.

No

Yes

For smoldering/asymptomatic WM/LPL, just follow up every 4-6 months with CBC and monoclonal protein levels

Assess degree of symptom burden in WM/LPL pateint

Consider emergent plasmapheresis for treatment of hyperviscosity

Low

Moderate/High

Following are the 2 options for patients with low tumor burden with minimal symptoms: Single agent Rituximab Rituximab + chemotherapy as with high burden disease

Following 2 are the preferred regimens for moderate/severe symptoms or high tumor burden: Bendamustine + rituximab Dexamethasone & rituximab + cyclophosphamide

Drug of choice for Bing-Neel Syndrome

• Many recent studies have shown to be Ibrutinib (560mg), an oral Bruton's tyrosine kinase inhibitor, with or without concurrent Rituximab, as a drug of choice for the treatment of Bing-Neel syndrome. It works by penetrating the blood brain barrier.

• One or more of the following treatments can be given for lymphoplasmacytic lymphoma.

Targeted therapy

• Targeted therapy uses drugs to target specific molecules (such as proteins) on the surface of cancer cells. These molecules help send signals that tell cells to grow or divide. By targeting these molecules, the drugs stop the growth and spread of cancer cells while limiting harm to normal cells.
• Targeted therapy drugs used alone or in combination to treat lymphoplasmacytic lymphoma include rituximab, bortezomib and ibrutinib (Imbruvica).

Immunotherapy

• Immunotherapy works by stimulating, boosting, restoring or acting like the body’s immune system to create a response against cancer cells. Immunomodulatory drugs are a type of immunotherapy that interferes with the growth and division of cancer cells.
• Thalidomide is a type of immunomodulatory drug that may be used to treat lymphoplasmacytic lymphoma.

Radiation therapy

• In some rare cases, external beam radiation therapy may be required to treat LPL that develops outside of the lymphatic system (called extralymphatic disease).