Bortezomib Is Active in Patients With Untreated or Relapsed Waldenström's Macroglobulinemia: A Phase II Study of the National Cancer Institute of Canada Clinical Trials Group

PurposeTo evaluate the efficacy and toxicity of single-agent bortezomib in Waldenström's macroglobulinemia (WM).Patients and MethodsSymptomatic WM patients, untreated or previously treated, received bortezomib 1.3 mg/m2intravenously days 1, 4, 8, and 11 on a 21-day cycle until two cycles past complete response (CR), stable disease (SD) attained, progression (PD), or unacceptable toxicity. Responses were based on both paraprotein levels and bidimensional disease measurements.ResultsTwenty-seven patients were enrolled. A median of six cycles (range, two to 39) of bortezomib were administered. Twenty-one patients had a decrease in immunoglobulin M (IgM) of at least 25%, with 12 patients (44%) reaching at least 50% IgM reduction. Using both IgM and bidimensional criteria, responses included seven partial responses (PRs; 26%), 19 SDs (70%), and one PD (4%). Total response rate was 26%. IgM reductions were prompt, with nodal responses lagging. Hemoglobin levels increased by at least 10 g/L in 18 patients (66%). Most nonhematologic toxicities were grade 1 to 2, but 20 patients (74%) developed new or worsening peripheral neuropathy (five patients with grade 3, no grade 4), a common cause for dose reduction. Onset of neuropathy was within two to four cycles and reversible in the majority. Hematologic toxicities included grade 3 to 4 thrombocytopenia in eight patients (29.6%) and neutropenia in five (19%). Toxicity led to treatment discontinuation in 12 patients (44%), most commonly because of neuropathy.ConclusionBortezomib has efficacy in WM, but neurotoxicity can be dose limiting. The slower response in nodal disease may require prolonged therapy, perhaps with a less intensive dosing schedule to avoid early discontinuation because of toxicity. Future studies of bortezomib in combination with other agents are warranted.

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Primary therapy of Waldenström's macroglobulinemia with 2-chlorodeoxyadenosine.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.12.2694 ◽

1994 ◽

Vol 12 (12) ◽

pp. 2694-2698 ◽

Cited By ~ 100

Author(s):

M A Dimopoulos ◽

H Kantarjian ◽

D Weber ◽

S O'Brien ◽

E Estey ◽

...

Keyword(s):

Venous Catheter ◽

Complete Response ◽

Hematologic Toxicity ◽

Primary Therapy ◽

Waldenström’S Macroglobulinemia ◽

Highly Active ◽

Portable Pump ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

PURPOSE To assess the activity of 2-chlorodeoxyadenosine (2CdA) as primary therapy for patients with Waldenström's macroglobulinemia. PATIENTS AND METHODS 2CdA was given to 26 consecutive, previously untreated and symptomatic patients with Waldenström's macroglobulinemia. Two courses were administered to outpatients at a dose of 0.1 mg/kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed up without further therapy and were scheduled to receive two additional treatments with 2CdA on disease relapse. RESULTS Twenty-two of 26 patients responded to the 2CdA therapy (85%; 95% confidence interval [CI], 65% to 96%), including three patients who achieved a complete response and 19 patients who had a partial response. Treatment was well tolerated, with no acute hematologic toxicity. A marked and sustained reduction of CD4+ lymphocytes occurred in all patients and may have contributed to a fatal infection with disseminated herpes simplex in one patient. With a median follow-up of 13 months, five patients have relapsed and all re-treated patients have responded again to 2CdA. CONCLUSION 2CdA is highly active in previously untreated patients with Waldenström's macroglobulinemia. A limited program of treatment induced responses of good quality and long duration in more than 80% of patients.

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Primary systemic amyloidosis: a rare complication of immunoglobulin M monoclonal gammopathies and Waldenström's macroglobulinemia.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.5.914 ◽

1993 ◽

Vol 11 (5) ◽

pp. 914-920 ◽

Cited By ~ 120

Author(s):

M A Gertz ◽

R A Kyle ◽

P Noel

Keyword(s):

Bone Marrow ◽

Median Survival ◽

Subcutaneous Fat ◽

Immunoglobulin M ◽

Entire Group ◽

Waldenström’S Macroglobulinemia ◽

Cardiac Amyloid ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

PURPOSE To determine the natural history of amyloidosis associated with Waldenström's macroglobulinemia and immunoglobulin M (IgM) monoclonal gammopathy. PATIENTS AND METHODS From January 1968 to September 1990, 50 patients with a serum IgM monoclonal protein and biopsy-proven amyloidosis were evaluated at the Mayo Clinic. There were 32 men and 18 women (age range, 43 to 93 years). RESULTS Percentages of patients presenting with cardiac, renal, hepatic, and pulmonary amyloid were 44%, 32%, 14%, and 10%, respectively. Forty-two percent of the patients had an M protein value greater than 1.5 g/dL, and 12% had an M component greater than 3 g/dL. Subcutaneous fat, rectum, and bone marrow showed amyloid in 84%, 72%, and 50%, respectively, providing a simple technique for diagnosing amyloidosis. The bone marrow biopsy was consistent with Waldenström's macroglobulinemia in 10, a plasma-cell proliferative disorder in 10, and lymphoma or a lymphoproliferative disorder in 11; results were normal, nondiagnostic, or hypercellular in 17. Forty-three of 50 patients died. The median survival of the entire group was 24.6 months. Fifty-three percent of deaths were due to cardiac amyloid, 12% to respiratory failure, 7% to macroglobulinemia, 7% to liver failure, and 7% to kidney failure. CONCLUSION The presence of amyloid cardiomyopathy and an increased creatinine concentration at diagnosis had an adverse impact on survival. Of the 22 patients who presented with cardiomyopathy, the median survival was 11.1 months, with only two surviving longer than 5 years. The median survival of the 28 patients without cardiomyopathy at diagnosis was 27 months, with eight 5-year survivors (P = .013). All eight amyloid deposits studied stained for Ig light chain, indicating that this amyloidosis is of the primary (AL) type.

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Waldenström’s Macroglobulinemia: Clinical Features, Complications, and Management

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.1.214 ◽

2000 ◽

Vol 18 (1) ◽

pp. 214-214 ◽

Cited By ~ 232

Author(s):

Meletios A. Dimopoulos ◽

Panayiotis Panayiotidis ◽

Lia A. Moulopoulos ◽

Petros Sfikakis ◽

Marinos Dalakas

Keyword(s):

Clinical Features ◽

Nucleoside Analogs ◽

Low Grade ◽

Waldenström’S Macroglobulinemia ◽

Previously Treated Patients ◽

Previously Treated ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

The Impact ◽

Waldenström's Macroglobulinemia

PURPOSE: To review the clinical features, complications, and treatment of Waldenström’s macroglobulinemia, a low-grade lymphoproliferative disorder that produces monoclonal immunoglobulin (Ig) M. METHODS: A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus. RESULTS: The clinical manifestations associated with Waldenström’s macroglobulinemia can be classified according to those related to direct tumor infiltration, to the amount and specific properties of circulating IgM, and to the deposition of IgM in various tissues. Asymptomatic patients should be followed without treatment. For symptomatic patients, standard treatment consists primarily of oral chlorambucil; nucleoside analogs, such as fludarabine and cladribine, are effective in one third of previously treated patients and in up to 80% of previously untreated patients. Preliminary evidence suggests that anti-CD20 monoclonal antibody may be active in about 30% of previously treated patients and that high-dose therapy with autologous stem-cell rescue is effective in most patients, including some with resistance to nucleoside analogs. CONCLUSION: Waldenström’s macroglobulinemia has a wide clinical spectrum that practicing physicians need to recognize early to reach the correct diagnosis. When therapy is indicated, oral chlorambucil is the standard primary treatment, but cladribine or fludarabine can be used when a rapid cytoreduction is desirable. Prospective randomized trials are required to elucidate the impact of nucleoside analogs on patients’ survival. A nucleoside analog is the treatment of choice for patients who have been previously treated with an alkylating agent.

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Clinical Characteristics of Rituximab Intolerance in Patients with Waldenstrom's Macroglobulinemia

Blood ◽

10.1182/blood.v124.21.2610.2610 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2610-2610

Author(s):

Sandra Kanan ◽

Kirsten Meid ◽

Steven P Treon ◽

Jorge J. Castillo

Keyword(s):

Monoclonal Antibody ◽

Bone Marrow Involvement ◽

Single Agent ◽

Response To Therapy ◽

Waldenström’S Macroglobulinemia ◽

Facial Swelling ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Anti Cd20 ◽

Waldenström's Macroglobulinemia

Abstract Introduction: Rituximab is a chimeric anti-CD20 monoclonal antibody used for the treatment of both untreated and previously treated patients with Waldenström’s Macroglobulinemia (WM). Rituximab is often associated with infusion-related reactions (IRR) during the first infusion which is associated with a well described cytokine release syndrome. Rituximab is also associated with depletion of uninvolved immunoglobulins leading to symptomatic hypogammaglobulinemia associated with recurring infections in many patients. IRRs and hypogammaglobulinemia are common reasons for rituximab dicontinuation in patients with WM. In this study, we present data on WM patients who developed intolerance to rituximab defined as cessation of rituximab therapy outside of infusion related first-cycle IRRs, and symptomatic hypogammaglobulinemia. Methods: We performed a retrospective chart review within the clinical database of our center for patients with the consensus clinicopathological diagnosis of WM between 1996 and 2013, and for whom rituximab therapy was prematurely truncated. We excluded patients who experienced first-cycle IRRs and patients in whom rituximab was stopped due to symptomatic hypogammaglobulinemia. Clinical and laboratory data were collected and tabulated, and are presented using descriptive statistics. Results: From a database of 1,600 patients with WM, we have so far identified 40 WM patients who were considered intolerant to rituximab. The median age at WM diagnosis for these patients was 60.5 years (range 35-83 years). There was a male predominance of 2:1. The median number of therapies prior to becoming rituximab intolerant was 1 (range 0-5 lines). Fifty percent of patients were not previously exposed to rituximab. Fifty-three percent of patients became rituximab intolerant while receiving single agent rituximab, 18% while receiving bortezomib-based therapy, 15% while receiving cyclophosphamide-based therapy and 8% while receiving bendamustine-based therapy. Forty percent of patients developed rituximab intolerance while undergoing induction therapy, and the remaining 60% became intolerant during the maintenance phase. The most common reasons for stopping rituximab were fever, chills, facial swelling, shortness of breath, hypotension, back pain, hives, chest pain, and serum sickness-like symptoms. The median serum IgM prior to development of rituximab intolerance was 3,053 mg/dl (range 550-9,000 mg/dl), the median hemoglobin was 10.4 g/dl (8.2-14.5 g/dl), the median platelet count was 300 x 109/L (range 93-913 x 109/L), and the median bone marrow involvement was 35% (range 5-90%). Twenty-one percent of patients had familial WM, and 65% of patients were responding torituximab-based therapy at the time of intolerance. Importantly, 20% percent (n=8) of patients received ofatumumab, a fully human anti-CD20 monoclonal antibody, after developing rituximab intolerance, of whom 7 (87%) subsequently tolerated ofatumumab without incidence. Conclusions: We present data on 40 WM patients who became intolerant to rituximab outside of the context of first-cycle IRRs, and symptomatic hypogammaglobulinemia. Our study shows that rituximab can be associated with a variety of symptoms that prompt cessation of therapy, and that most patients show a response to therapy despite intolerance. The use of ofatumumab is feasible and well tolerated in WM patients intolerant to rituximab. Additional research is needed to better understand the pathophysiology behind rituximab intolerance in this patient population. Data collection continues. Disclosures No relevant conflicts of interest to declare.

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Long-lasting responses after four doses of rituximab in Waldenström's macroglobulinemia: Clinical value of minor responses: A follow-up of the Eastern Cooperative Oncology Group E3A98 trial

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8513 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8513-8513

Author(s):

M. A. Gertz ◽

R. Abonour ◽

L. T. Heffner ◽

P. R. Greipp ◽

H. Uno ◽

...

Keyword(s):

Objective Response ◽

Progression Free Survival ◽

Waldenström’S Macroglobulinemia ◽

Minor Response ◽

Free Survival ◽

Previously Treated ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

A Minor ◽

Waldenström's Macroglobulinemia

8513 Background: Waldenström's macroglobulinemia is a low-grade lymphoplasmacytic lymphoma that is responsive to rituximab. Uniform response criteria define an objective response as a 50% reduction in the IgM level, and a minor response as a 25% reduction in IgM level. No publications in the literature exist that justify the use of the minor response. Clinicians who treat patients that achieve a minor response are left uncertain as to whether the response is adequate and patients should be monitored for progression or whether they should be considered therapy failures and crossover to an alternate chemotherapy regimen in an effort to achieve a deeper response. Methods: 69 patients, 34 previously untreated, and 35 previously treated (but rituximab naive) were included. All patients were treated with a single four-week course of rituximab 375 mg/m2 and were monitored with no further therapy until progression. Results: There were 19 objective and 17 minor responses out of 69 eligible patients (52.2%). Response rate and progression-free survival (26.6 mo) were similar whether patients were previously untreated or previously treated. Previously treated rituximab-naïve and previously untreated patients had, five-year survivals of 48% and 85%, respectively. There was no difference in overall or progression free survival between patients who achieved an objective response when compared to those who achieved a minor response. There was no difference between objective and minor responders by age, time from diagnosis to treatment in the treated group, bone marrow lymphoplasmacytes, hemoglobin level, creatinine, IgM level, or M-spike. The pre-treatment level of IgM did not predict overall survival, progression-free survival, time to progression, or response rate (All p>0.05). This lack of significance was found whether IgM was assessed as a continuous or discrete variable. Conclusions: These results reconfirm rituximab's efficacy as a single-agent for the treatment of Waldenström's macroglobulinemia, and patients who have a 25–50% reduction in their IgM protein derive significant clinical benefits that are durable and appear to not have an impact on overall survival. No significant financial relationships to disclose.

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Combination chemotherapy (M-2) protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone) for Waldenstrom macroglobulinemia: preliminary report

Blood ◽

10.1182/blood.v59.5.934.934 ◽

1982 ◽

Vol 59 (5) ◽

pp. 934-937 ◽

Cited By ~ 14

Author(s):

DC Jr Case

Keyword(s):

Combination Chemotherapy ◽

Response Rate ◽

Waldenström’S Macroglobulinemia ◽

Symptomatic Disease ◽

Previously Treated ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Initiation Of Therapy ◽

Waldenström's Macroglobulinemia

Abstract Fourteen consecutively referred, symptomatic patients with Waldenstrom's macroglobulinemia (ages 52–87 yr) have been treated with the 5-drug M-2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone). Three patients were previously treated and 11 patients were untreated. The majority of patients were symptomatic from hyperviscosity. All patients have responded to therapy. Two patients have achieved complete remissions and 12 patients partial remissions to date. None of the patients with symptomatic hyperviscosity has required plasmapheresis since therapy with the M-2 has been initiated. Lymphadenopathy, hepatosplenomegaly, and anemia have also responded to treatment. Follow-up data are limited, with survival from initiation of therapy with the M-2 ranging from 2+ to 35% mo (median 17+ mo) 2+-40+ mo from time of diagnosis). Combination chemotherapy for Waldenstrom's macroglobulinemia with the M-2 protocol appears to increase the response rate in patients with symptomatic disease. Further survival analysis will be carried out.

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Immunoglobulin M ‘Flare’ after rituximab-associated acute tubular necrosis in Waldenström’s macroglobulinemia

International Journal of Hematology ◽

10.1007/s12185-008-0244-7 ◽

2009 ◽

Vol 89 (2) ◽

pp. 218-222 ◽

Cited By ~ 5

Author(s):

Hassane Izzedine ◽

Edward Bourry ◽

Lucile Amrouche ◽

Isabelle Brocheriou ◽

Madalina Uzunov ◽

...

Keyword(s):

Acute Tubular Necrosis ◽

Immunoglobulin M ◽

Waldenström’S Macroglobulinemia ◽

Tubular Necrosis ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

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Bendamustine-Based Therapy Is Highly Active In Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia

Blood ◽

10.1182/blood.v116.21.4700.4700 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4700-4700

Author(s):

Steven P. Treon ◽

Christina Hanzis ◽

Christina Trispsas ◽

Leukothea Ioakimidis ◽

Christopher Patterson ◽

...

Keyword(s):

Monoclonal Antibodies ◽

B Cell ◽

B Cell Lymphoma ◽

Response Rates ◽

Nucleoside Analogues ◽

Waldenström’S Macroglobulinemia ◽

Previously Treated ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

Abstract Abstract 4700 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell malignancy characterized by lymphoplasmacytic cell infiltration of the bone marrow and production of an IgM monoclonal protein. Despite advances in treatment, WM remains incurable and novel agents are needed for ongoing disease control. Bendamustine represents an important novel agent for the treatment of B-cell disorders whose activity in WM remains to be clarified. Patients and Methods: We examined the outcome of 30 previously treated patients with the clinicopathological diagnosis of WM who received bendamustine-based therapy. The median prior therapies was 2 (range 1–9), and 16 (53%) patients were refractory to their previous treatment. Baseline characteristics for all patients: Median BM involvement 60%; serum IgM 3,980 mg/dL; Hct 31.0%; serum B2M 3.5 g/L. Treatment consisted of bendamustine administered at 90 mg/m2 IV on days 1, 2 as part of a 4 week cycle, along with rituximab (375 mg/m2 IV) given once on either day 1 or 2 for 24 patients. In the remainder 6 patients, severe rituximab intolerance prevented re-administration of rituximab. In these patients, bendamustine was either administered alone (n=4) or with ofatumumab (1000 mg IV) given on day 1 (n=2) following a test dose of 300 mg IV on day -7 prior to cycle 1 only. Intended therapy consisted of 4–6 cycles of treatment. Plasmapheresis was performed prior to treatment in patients exhibiting symptomatic hyperviscosity, or who had an IgM level >5,000 mg/dL and were to receive monoclonal antibodies in order to prevent a symptomatic IgM flare. Responses were assessed using modified WM consensus criteria, and patients were eligible for response assessment if they completed > 2 cycles of therapy. Results: 21 patients completed intended therapy; 9 patients continue on treatment. The median number of treatment cycles for all patients is 4 (range 2–6). Following treatment, median serum IgM levels declined from 3,980 to 1,210 mg/dL (p<0.0001), and hematocrit rose from 31.9% to 34.7% (p=0.005) at best response. The overall and major response rates were 80% and 73%, respectively, with 3 VGPR; 19 PR; 2 MR. 6 patients were non-responders. Responders included those patients receiving bendamustine alone (4 PR), or with ofatumumab (1 PR; 1 MR). With a median follow-up of 5 months, 22/24 responders continue in response. Overall, treatment was well tolerated with grade <2 nausea and diarrhea being the most common toxicities encountered. Three patients developed superficial thrombophlebitis at the site of bendamustine infusion, warranting institution of anticoagulation in 1 patient. Prolonged myelosuppression occurred in 3 patients who received previous nucleoside analogue therapy. One patient previously treated with nucleoside analogues and cyclophosphamide developed MDS, and another patient who received previous cyclophosphamide and bortezomib based therapies transformed to diffuse large B-cell lymphoma following bendamustine-based therapy. Conclusion: Bendamustine-based therapy is active in patients with relapsed or refractory WM and produces high response rates and durable responses both as monotherapy, and in combination with CD20 directed monoclonal antibodies. In patients previously treated with nucleoside analogues, prolonged myelosuppression may occur. Long term toxicities of bendamustine-based therapy remain to be clarified in this patient population. Disclosures: No relevant conflicts of interest to declare.

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