Lymphoplasmacytic Lymphoma with Amyloidosis

Research Inquiry

A 69 years old African American male with Chronic heart failure, Lymphoplasmacytic Lymphoma, and Amyloid on Lymph node biopsy. No evidence of cardiac amyloid.
This summarized report will review and present information regarding possible treatments for Lymphoplasmocytic Lymphoma and the safety of those therapies, considering the clinical status of the patient (Chronic heart failure and Amyloidosis).

Medical Meta Findings

Patient considerations: 

Regarding the specific health status of our patient, there are several considerations to be made before choosing the line of treatment:

Chronic heart failure
Myocardial dysfunction, Heart failure, and atrial fibrillation, frequently described as cardiotoxicity, are concerning cardiovascular complications of cancer therapies and cause an increase in morbidity and mortality. Specifically in Lymphoplasmacytic Lymphoma treatment, several cardiovascular side effects need to be considered :

    • In a cardiotoxicity review, published in the European Heart Journal in 2016 3, Cyclophosphamide can induce myocardial dysfunction and Heart failure (incidence cardiotoxicity of 7%-26%).

    • In a phase 3 clinical trial (150 patients) evaluating Ibrutinib plus Rituximab treatment for Waldenström’s Macroglobulinemia, published in The New England Journal of Medicine in 2018 4, common grade 3 cardio-vascular adverse events were atrial fibrillation (12% vs. 1% in the placebo group) and hypertension (13% vs. 4% in the placebo group).

    • Anti CD20 as a single therapy is considered less cardiotoxic. Nevertheless, there are still rare reports of cardiac arrhythmias associated with Rituximab, as reported in a review of the safety and side effects of monoclonal antibodies,
      published in Nature Reviews Drug Discovery in 2010 5.

    • Zanubrutinib is considered safer than Ibrutinib in regards to Atrial Fibrillation, in phase 3 clinical trial of Znubrutinib vs Ibrutinib in symptomatic Waldenström macroglobulinemia (ASPEN study), published in Blood journal in 2020 6, only 2% of the patients treated with Zanubrutinib had Atrial fibrillations, comparing to 15% of the patients treated with Ibrutinib. Another side effect that can be relevant to chronic heart failure in Zanubrutinib treatment is anemia. In a 3-year follow-up study, published in Blood journal in 2020 7, 9.1% had anemia that was considered a grade 3 adverse event (Hgb<8.0 g/dL).

    • According to Cancer Research UK Chemotherapy drugs database 8, Bendamustine can cause blood pressure changes and heart palpitations or chest pain in more than 1 in 100 people. However, in a clinical trial of Bendamustine plus rituximab in 69 newly-diagnosed Waldenström Macroglobulinaemia patients, published in the British Journal of Haematology in 20189, there were no serious cardiovascular adverse events.

Amyloid presence in lymph node biopsy
Although most subjects with Waldenström macroglobulinemia present with symptoms related to tumor burden, such as anemia or lymphadenopathy, approximately 3% develop immunoglobulin 10 (Ig) M–related disorders, including immunoglobulin light chain (AL) amyloidosis. There is only little evidence in the literature regarding the influence of amyloidosis on Waldenström macroglobulinemia and the changes in treatment:

  • An article published in Leukemia journal in 2018 11 reviewed the medical records of 997 patients that were diagnosed with Waldenström macroglobulinemia. 7.5% had also Amyloid light chains or both light and heavy chains. 60 of the 75 patients with light chains or both light and heavy chains (83%) received systemic therapy targeting the lymphoplasmacytic clone. The data from 21 patients was sufficient enough to assess the treatment response – partial response (PR) or very good PR (VGPR) was achieved in 57% (PR = 28.5%, VGPR = 28.5%), no response was observed in 9 patients (38%), and one patient suffered from disease progression. The researchers also mentioned the first-line treatments that were given to the patients:


  • In contrast, the coexistence of light chains, or both light and heavy chains, negatively impacted the outcome of Waldenström macroglobulinemia patients. The overall survival of such patients was markedly inferior (median 2.5 years) to that of Waldenström macroglobulinemia patients without ALAHL (median 12.1 years).

  • An article, published in International Waldenstrom’s Macroglobulinemia Foundation Torch magazine in 201312, reviewed amyloidosis associated with Waldenström Disease. The writer stated that light chain amyloidosis is a treatable disease, with a high survival rate in responding patients. There are four main claims in the article about treating  Waldenström macroglobulinemia with light-chain amyloidosis:


    • The most effective therapy, at present, is the suppression of the synthesis of the misfolded monoclonal light chains through anti-clonal chemotherapy; hence the therapies used for Waldenström macroglobulinemia are also effective for the treatment of this severe complication.

    • Rapidly acting agents are preferred since it is vital to suppress the production of the toxic light chains as soon as possible.

    • The intensity of the therapies may be limited by the presence of heart dysfunction caused by amyloidosis.

    • Treatment should be carefully monitored with frequent evaluation of serum-free light chain levels, cardiac markers (using NT-proBNP), and renal function (using urinary albumin level and serum creatinine).

  • A case study, published in Blood magazine in 201613, presents a 66-year-old woman with systemic AL amyloidosis associated with Waldenström macroglobulinemia, cardiomegaly, thickening of the esophagus, and slightly enlarged mediastinal lymph nodes (1.4 cm), without fluorodeoxyglucose-avid skeletal lesions. The patient was treated with rituximab, cyclophosphamide, and dexamethasone therapy.


Possible treatment lines

The treatments presented in this section are the most significant therapy lines found in terms of efficacy and safety data from clinical research and case reports. If needed, more information regarding additional treatments with a weaker evidence base can be presented in this review.
In general, Lymphoplasmocytic Lymphoma does not always require treatment. The indications for treatment initiation for Waldenström macroglobulinemia, which is the most common manifestation of Lymphoplasmacytic Lymphoma, as determined by the American Society of Hematology in 20141:

If the patient has a clinical or laboratory indication for treatment, it is mostly similar to other indolent small B cell lymphomas, as described in the National Comprehensive Cancer Network Guidelines for Waldenström Macroglobulinemia Lymphoplasmacytic Lymphoma 20222:

  1. Zanubrutinib (Bruton’s tyrosine kinase inhibitor).
  2. Ibrutinib (Bruton’s tyrosine kinase inhibitor) ± Rituximab (anti-CD20 agent).
  3. Bendamustine (Alkylating Agent) + Rituximab (anti-CD20 agent).
  4. Bortezomib + Dexamethasone (Corticosteroids) + Rituximab (anti-CD20 agent).
  5. Rituximab (anti-CD20 agent) + Cyclophosphamide (Alkylating Agent) + Dexamethasone (Corticosteroids).

Pre-treatment recommendations by the National Comprehensive Cancer Network Guidelines  for Waldenström Macroglobulinemia Lymphoplasmacytic Lymphoma 2022: 2

  1. Plasmapheresis should also be considered before treatment with rituximab for patients with an IgM ≥4,000 mg/dL or who are symptomatic to avoid the aggravation of serum viscosity based on rituximab-related IgM flare.
  2. A retinal examination is recommended if hyperviscosity is suspected or IgM levels are greater than or equal to 3.0 g/dL.
  3. Screening for HBV infection by testing for hepatitis B surface antigen (HBsAg) or antibody to hepatitis B core antigen (HBcAb) should be considered, especially before starting therapy with carfilzomib, rituximab, or ofatumumab.
  4. Herpes zoster prophylaxis should be considered for patients receiving proteasome inhibitor-based regimens and nucleoside analogs.
  5. Pneumocystis Jirovecii Pneumonia (PJP) prophylaxis should be considered for patients receiving bendamustine/rituximab.


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