Combination Therapy with Rituximab and Fludarabine in Waldenstrom’s Macroglobulinemia.

Abstract Rituximab and Fludarabine are active in Waldenstrom’s macroglobulinemia (WM) producing major response rates of 40–70%. Both pre-clinical and clinical studies in related low-grade B-cell malignancies suggest that additive, and even synergistic benefit with combination Fludarabine and Rituximab may result. As such, we conducted this combination study with Rituximab and Fludarabine in WM patients. WM patients who had received < 2 prior therapies, and who had not previously been treated with any nucleoside analogue or Rituximab were eligible. Intended therapy was as follows: Weeks 1–4 Rituximab (375 mg/m2/week) Weeks 5, 9, 13 Fludarabine daily for 5 days (25 mg/m2) Weeks 17, 18 Rituximab (375 mg/m2/week) Weeks 19, 23, 27 Fludarabine daily for 5 days (25 mg/m2) Week 30, 31 Rituximab (375 mg/m2/week) Patients were evaluated at week 12, and if they did not progress were eligible for further therapy and were evaluable for response. 43 WM patients were enrolled with a median age of 61 (range 52–75 yrs), and median prior therapies of 1 (range 0–2). 40/43 patients continued on therapy beyond week 12. Two patients (1 PR, 1 SD) died after completing protocol therapy including one elderly patient who had an influenza pneumonia and another debilitated patient who may have had a secondary malignancy. Delays in therapy due to neutropenia were common, and 58% of patients experienced Grade III/IV neutropenia. Protocol therapy was truncated after the 4th and 5th courses of fludarabine in several patients for persistent neutropenia and/or thrombocytopenia despite delays in therapy and/or use of G-CSF support. Other complications included: Herpes zoster outbreak in 3 of the first 21 patients, before prophylactic acyclovir or equivalent was initiated; parasthesias (n=3); pneumonitis (n=2); development of bladder cancer (n=1) and a high grade lymphoma (n=1); subdural hemorrhage in a patient who had a 3-fold increase in serum viscosity following the first 4 infusions of Rituximab. On an intent to treat basis, 39/43 (90.1%) patients demonstrated a response. Response categories were as follows: CR (n=3); PR (n=32); MR (n=4). One patient remains in stable disease at 20+ months. At a median follow-up of 17 months, 36 of 39 responding patients remain in remission. Rituximab in combination with fludarabine is highly active and produces durable responses in WM.

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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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Low-grade MALT lymphoma mimicking Waldenström's macroglobulinemia

Leukemia ◽

10.1038/sj.leu.2401206 ◽

1999 ◽

Vol 13 (3) ◽

pp. 484-485 ◽

Cited By ~ 20

Author(s):

M Allez ◽

X Mariette ◽

G Linares ◽

P Bertheau ◽

R Jian ◽

...

Keyword(s):

Malt Lymphoma ◽

Low Grade ◽

Waldenström’S Macroglobulinemia ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

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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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Treatment of Waldenstrom’s Macroglobulinemia With Thalidomide

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.16.3596 ◽

2001 ◽

Vol 19 (16) ◽

pp. 3596-3601 ◽

Cited By ~ 92

Author(s):

Meletios A. Dimopoulos ◽

Athanassios Zomas ◽

Nora A. Viniou ◽

Vassiliki Grigoraki ◽

Eleni Galani ◽

...

Keyword(s):

Waldenström’S Macroglobulinemia ◽

Mood Changes ◽

Starting Dose ◽

Prospective Phase ◽

Pretreated Patients ◽

Waldenstrom's Macroglobulinemia ◽

Treatment Responses ◽

Waldenstrom’S Macroglobulinemia ◽

Intent To Treat ◽

Waldenström's Macroglobulinemia

PURPOSE: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom’s macroglobulinemia (WM). PATIENTS AND METHODS: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. RESULTS: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. CONCLUSION: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.

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Hepatitis C Viral Infection Is Not Associated with Waldenstrom’s Macroglobulinemia.

Blood ◽

10.1182/blood.v106.11.4693.4693 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4693-4693

Author(s):

Xavier Leleu ◽

Kelly O’Connor ◽

Allen Ho ◽

Daniel D. Santos ◽

Robert Manning ◽

...

Keyword(s):

Hepatitis C ◽

Hcv Infection ◽

Antibody Detection ◽

Low Grade ◽

Waldenström’S Macroglobulinemia ◽

Hcv Antibody ◽

Pcr Assays ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

Abstract Infection with hepatitis C virus (HCV) has previously been associated with the pathogenesis of low grade B-cell lymphoproliferative diseases including Waldenstrom’s macroglobulinemia (WM). Most of these studies have utilized HCV antibody detection assays, which may not accurately assess HCV presence in patients with impaired humoral responses. In patients with WM, pronounced IgA and IgG hypogammaglobulinemia is present, which remains persistant despite therapy (Blood 104:306b). As such, we investigated the incidence of HCV in 88 randomly selected, and previously untreated patients with the consensus panel diagnosis of WM utilizing both HCV antibody detection and qualitative PCR assays (Quest Diagnostics, Cambridge, MA, USA). The median age for these patients was 61 (38 – 83 years) and the male: female sex ratio was 1.44. No patient had a known history of liver disease, hepatitis B, HCV or HIV infection. Liver function tests obtained at time of serum collection showed normal range SGOT and and SGPT levels for 86/88 patients. In contrast to previous reports, we failed to demonstrate HCV infection by both HCV antibody detection and the PCR assays. These studies therefore show no association of WM with HCV infection.

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Long-term responses to thalidomide and rituximab in Waldenstrom's macroglobulinemia

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.8017 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 8017-8017 ◽

Cited By ~ 4

Author(s):

J. D. Soumerai ◽

A. R. Branagan ◽

C. J. Patterson ◽

Z. R. Hunter ◽

S. P. Treon

Keyword(s):

Response Rates ◽

High Serum ◽

Waldenström’S Macroglobulinemia ◽

Highly Active ◽

Best Response ◽

Major Response ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

8017 Background: Rituximab is active in Waldenstrom's macroglobulinemia (WM), producing response rates of 40–50%. Lower response rates are observed among patients with the FcγRIIIA-158 FF polymorphism; high B2M (≥3.0 mg/dL), and high serum IgM levels (≥6,000 mg/dL). Thalidomide enhances rituximab-mediated ADCC of lymphoplasmacytic cells and produces response rates of 25% in WM. As such, we conducted this phase II study using thalidomide and rituximab in patients naïve to either agent. Methods: Intended therapy was: Weeks 1–52: Thalidomide (200 mg po qHS for 2 wks, then 400 mg po qHS) Weeks 2–5, 13- 16: Rituximab (375 mg/m2/wk) Twenty-five patients were enrolled, 20 of whom were previously untreated, with a baseline median age of 62 (range 44–86 yrs), BM involvement of 40 (range 5–80%), serum IgM of 3,670 (range 924–8,610 mg/dL), B2M of 2.6 (range 1.4–8.3 mg/L), Hct of 34.1 (range 23.6–42.6%). Results: Grade ≥2 toxicities to thalidomide included neuroparesthesias (n=11); somnolence (n=3); confusion (n=3); rash (n=2); tremors (n=2); bradycardia (n=2) and palpitations (n=1). Among patients experiencing neuroparesthesias, 10 demonstrated resolution to grade 1 (n=3) or complete resolution (n=7) at a median of 6.7 (range 0.4- 22.5 months). Dose reduction of thalidomide occurred in all patients and led to discontinuation in 11 patients. Twenty-three patients were evaluable. Responses among evaluable patients: CR (n=1); PR (n=15); MR (n=2); SD (n=1) for an overall and a major response rate of 78% and 70%, respectively. Median serum IgM decreased from 3,670 (924–8,610 mg/dL) to 1,590 (36–5,230 mg/dL) (p<0.001), while median hematocrit rose from 33.0 (23.6–42.6%) to 37.6 (29.3–44.3%) (p=0.004) at best response. With a median follow-up of 42+ months, the median TTP for all evaluable patients on study was 35 months, and 38+ months for responders. Overall response was associated with median cumulative thalidomide dose: CR/PR/MR (29,275 mg) vs. SD/NR (7,400 mg); p=0.004. Overall responses were unaffected by FcγRIIIA-158 polymorphism status (81% vs. 71% for VV/FV vs. FF); serum IgM (78% vs. 80% for <6,000 vs. ≥6,000 mg/dL); and B2M levels (71% vs. 89% for <3 vs. ≥3 g/dL); p=NS. Conclusions: Thalidomide in combination with rituximab is highly active and produces long- term responses in patients with WM. No significant financial relationships to disclose.

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Diagnosis and Management of Waldenstrom's Macroglobulinemia

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.144 ◽

2005 ◽

Vol 23 (7) ◽

pp. 1564-1577 ◽

Cited By ~ 157

Author(s):

Meletios A. Dimopoulos ◽

Robert A. Kyle ◽

Athanasios Anagnostopoulos ◽

Steven P. Treon

Keyword(s):

Stem Cell ◽

Alkylating Agents ◽

Nucleoside Analogs ◽

Primary Treatment ◽

Low Grade ◽

Waldenström’S Macroglobulinemia ◽

Monoclonal Protein ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

Purpose To review the diagnostic criteria, prognostic factors, response criteria, and treatment options of patients with Waldenstrom's macroglobulinemia (WM). 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 WM should be regarded as a distinct clinicopathologic entity and confined to those patients with lymphoplasmacytoid lymphoma who have demonstrable serum immunoglobulin M monoclonal protein. Treatment decisions should rely on specific clinical and laboratory criteria. Initiation of therapy should not be based on serum monoclonal protein levels per se. The three main choices for systemic primary treatment of symptomatic patients with WM include alkylating agents (chlorambucil), nucleoside analogs (fludarabine and cladribine), and the monoclonal antibody rituximab. There are no data from prospective randomized studies to recommend the use of one first-line agent over another, although consideration of a patient's candidacy for autologous stem-cell transplantation (ASCT) should be taken into account to avoid stem cell–damaging agents. There are preliminary data to suggest that combinations of nucleoside analogs and alkylating agents with or without rituximab may improve response rates at the expense of higher toxicity. Conclusion WM is a distinct low-grade lymphoproliferative disorder. When therapy is indicated, alkylating agents, nucleoside analogs, and rituximab are reasonable choices. Several factors, including the presence of cytopenias, need for rapid disease control, candidacy for ASCT, age, and comorbidities, should be taken into consideration when choosing the most appropriate primary treatment.

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Carfilzomib, Rituximab and Dexamethasone (CaRD) Is Highly Active and Offers a Neuropathy Sparing Approach For Proteasome-Inhibitor Based Therapy In Waldenstrom’s Macroglobulinemia

Blood ◽

10.1182/blood.v122.21.757.757 ◽

2013 ◽

Vol 122 (21) ◽

pp. 757-757 ◽

Cited By ~ 2

Author(s):

Steven Peter Treon ◽

Christina K Tripsas ◽

Kirsten Meid ◽

Steven J Cropper ◽

Patrick Mostyn ◽

...

Keyword(s):

Bone Marrow ◽

Proteasome Inhibitor ◽

International Workshop ◽

M Protein ◽

Waldenström’S Macroglobulinemia ◽

Symptomatic Disease ◽

Highly Active ◽

Waldenstrom's Macroglobulinemia ◽

Waldenstrom’S Macroglobulinemia ◽

Waldenström's Macroglobulinemia

Abstract Bortezomib is active in Waldenstrom’s macroglobulinemia (WM) but associated with considerable peripheral neuropathy (PN). The proteasome inhibitor carfilzomib (CFZ) is approved in the USA for relapsed/refractory myeloma. Herein, we examined the efficacy and safety of carfilzomib, rituximab, and dexamethasone (CaRD) in 31 proteasome inhibitor and rituximab naive WM patients with symptomatic disease. Median baseline characteristics: age 61, prior therapies 0 (range 0-1), hematocrit 32.3%, hemoglobin 10.7 g/dL, serum IgM 3375 mg/dL, serum M-protein 2.185 g/dL, B2M 3.6 mg/L, and bone marrow disease involvement 60%. Therapy consisted of IV CFZ 20 mg/m2 (cycle 1) then 36 mg/m2 (cycles 2 and beyond) with IV dexamethasone (dex) 20 mg given on days 1,2,8,9 and rituximab 375 mg/m2 on days 2,9 of each 21-day cycle. Treatment consisted of six induction cycles, then maintenance beginning 8 weeks after induction (given every 8 weeks for eight cycles; consisted of CFZ 36 mg/m2, and IV dex 20 mg on days 1,2 and rituximab 375 mg/m2 on day 2). Patients with IgM level >4000 mg/dL underwent plasmapheresis and/or had rituximab held until IgM <4000 mg/dL to prevent symptomatic IgM flare. Patients received oral acyclovir (400 mg twice daily) and famotidine (20 mg twice daily) as concomitant medications. For all 31 patients, median serum IgM levels and M-protein declined to 749 mg/dL and 0.7 g/dL, respectively (p<0.00001). Median hematocrit and hemoglobin rose to 40.9% and 13.7 g/dL, respectively (p<0.00001). A total of 30 patients concluded induction therapy with bone marrow tumor involvement reduced to a median of 7.5% (p=0.0003). The best overall response rate using criteria adapted from the 3rd International Workshop on WM was 81% (1 CR, 8 VGPR, 12 PR, 4 Minor Responses). With a median follow-up of 8 cycles, 22 patients remain on study, including 20 currently on maintenance therapy. Median time to response (for minor responders or better) was 2.1 months. Grade >2 treatment related toxicities included asymptomatic elevation in lipase (12.9%), dex-related hyperglycemia (6.45%), reversible neutropenia (9.67%), and cardiomyopathy (3.22%). There were no grade 2 or greater PN events. Treatment discontinuation occurred for non-response (n=8), cardiomyopathy in a patient with multiple cardiac risk factors (n=1), and progressive disease (n=1). CaRD is highly active and offers a neuropathy sparing approach for proteasome-inhibitor based therapy in WM. Disclosures: Off Label Use: Carfilzomib is a novel proteasome inhibitor, which offers a neuropathic sparing approach on waldenstrom macroglobulinemia disease when used in a combination therapy with rituximab and dexamethasome.

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