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

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8017-8017 ◽  
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.

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

1994 ◽  
Vol 12 (12) ◽  
pp. 2694-2698 ◽  
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.

Long Term Responses to Fludarabine and Rituximab in Waldenstrom’s Macroglobulinemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3057-3057 ◽  
Author(s):  
Steven Treon ◽  
Andrew Branagan ◽  
Leukothea Ioakimidis ◽  
Jacob Soumerai ◽  
Christopher Patterson ◽  
...  
Keyword(s):  
Myelogenous Leukemia ◽  
Aggressive Lymphoma ◽  
Unknown Primary ◽  
Waldenström’S Macroglobulinemia ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Fludarabine and rituximab are commonly used in combination in the treatment of Waldenstrom’s macroglobulinemia (WM), though long term outcome of this regimen remains to be defined. We therefore examined the outcome of 43 WM patients treated on a clinical trial whose eligibility included &lt; 2 prior therapies, and no previous nucleoside analogue or rituximab treatment. Therapy consisted of 6 cycles (25 mg/m2/day for 5 days) of fludarabine and 8 infusions (375 mg/m2/week) of rituximab over 31 weeks. 43 patients were enrolled with a median age of 61, and median prior therapies of 0. Responses were: CR (n=2); VGPR (n=14); PR (n=21); MR (n=4); for an overall and major response rate of 95.3% and 86.0%, respectively. At best response, median bone marrow disease involvement declined from 55% to 5% (p&lt;0.00001), while serum IgM decreased from 3,840 to 443 mg/dL (p&lt;0.00001), and hematocrit rose from 31.2% to 38.0% (p&lt;0.0008). The median time to progression for all patients was 51.2 months, and was longer for untreated versus previously treated patients (77.6 vs. 38.4 months; p=0.017), as well as for those patients who achieved ≥ VGPR versus &lt;VGPR (&gt;88.3 vs. 36.9 months; p=0.049). Grade ≥ 3 toxicities included neutropenia (n=27); thrombocytopenia (n=7); pneumonia (n=6), including two patients who succumbed to non-PCP interstitial pneumonia; peripheral neuropathy (n=2); limbic encephalitis (n=1); hemolytic anemia (n=1). With a median follow-up of 40.3 months, we observed transformation to aggressive lymphoma (n=3); myelodysplasia (n=1); acute myelogenous leukemia (n=2); bladder carcinoma (n=1); and carcinoma of unknown primary (n=1) among 8 patients. The results of this study demonstrate that fludarabine and rituximab is an active regimen in WM, though short and long term toxicities need to be carefully weighed against other available treatment options.

Diagnostic Tools of Waldenström’s Macroglobulinemia – Best Possibilities for Non-invasive and Long-term Disease Monitoring

2017 ◽  
Vol 30 (Suppl 2) ◽  
pp. 2S81-2S91 ◽  
Author(s):  
Kateřina Growková ◽  
Zuzana Kufová ◽  
Tereza Ševčíková ◽  
Jana Filipová ◽  
Michal Kaščák ◽  
...  
Keyword(s):  
Diagnostic Tools ◽  
Disease Monitoring ◽  
Waldenström’S Macroglobulinemia ◽  
Non Invasive ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

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

Blood ◽  
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.

Rituximab and Cyclophosphamide Based Regimens for Treatment of Waldensterom Macroglobulemia, Lessons from Clinical Literature: A Systemic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Qasim Khurshid ◽  
Abdul Jabbar Dar ◽  
Muhammad Ali Mirza ◽  
Muhaddis Ejaz Ahmad ◽  
Sobia Aamir ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Partial Response ◽  
Overall Response Rate ◽  
Response Rate ◽  
Waldenström’S Macroglobulinemia ◽  
Overall Response ◽  
Major Response ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Introduction: Waldenström's macroglobulinemia is a rare low-grade lymphoplasmacytic lymphoma characterized by CD20 expression on malignant cells and produces a monoclonal immunoglobulin M (IgM). Rituximab is a chimeric monoclonal antibody against CD20 antigen and the most widely used therapeutic agents in WM. Rituximab works by adhering to CD20, causes B-cell lysis mainly through antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. Cyclophosphamide is an alkylating agent binds to DNA. Its cytotoxic effect is mainly due to cross-linking of strands of DNA and RNA, and to inhibition of protein synthesis. Our objective is to analyze and summarize the published literature for the efficacy of regimens containing both rituximab and cyclophosphamide for the treatment of Waldenström's macroglobulinemia (WM). Methods:We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after January 2005, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library, and Web of Science. A total of 585 articles were identified initially, and after a detailed screening, we finalized 10 studies involving 425 WM patients. Results:The total number of patients were 425. The dose was 375 mg/m2. The complete response (CR) ranged from 3-19%, very good partial response (VGPR) ranged from 4-22%, and the partial response (PR) ranged from 8-82%. The overall response rate (ORR) ranged from 79-95%. Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP): In a retrospective study by Ioakimidis et al., included 23 WM patients were given R-CHOP. The ORR was 95%, with 69% achieving a major response, 43%, PR, and VGPR OF 9%. In a randomized control trial by Buske et al., N=23, the major response rate was 91%, and PR was 82%. Treon et al. (N=13) observed a major response rate of 27%. (Table 1). Fludarabine, Cyclophosphamide and Rituximab (FCR): In a retrospective study by Peinert et al., involving 29 patients receiving the FCR regimen, the ORR was 90%, with 79%, 3%, and 10% of patients achieving PR, CR, and NR, respectively. In a study by Tedeschi et al., involving 40 patients, ORR was 80%, and the major response rate was 80%. Souchet et al., N=82 reported an ORR of 84% and a PR of 46%. Progression-free survival (PFS) was 51.2 months for Tedeschi et al. Dexamethasone, Rituximab and Cyclophosphamide (DRC) In study Paludo et al., (N=50), receiving the DRC regimen, the highest ORR was 87%, PR 64%, and major response was 68%. In a phase II study by Dimopoulos et al., (N=72), the ORR of 82% and PR of 67% was observed. PFS was 24 months in this study. (Table 1) 4.Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) In study Ioakimidis et al, N=16, the ORR was 87%, the major response rate was 62%, and the PR was 43%. Rituximab, Cyclophosphamide, and Prednisone (RCP) Ioakimidis et al., reported 19 patients who were given RCP. The ORR, PR, and the major response rate was 94%, 73%, and 73%, respectively.Lenalidomide, Rituximab, Cyclophosphamide, and Dexamethasone (LR-CD) A study by Rosenthal et al., 15 patients were given LR-CD. ORR was 80%, with a major response rate in 80% and PR in 73% of patients. PFS was 38 months. Conclusion: Rituximab and cyclophosphamide, in combination regimens for the treatment of WM showed the overall response rate of 95%. Neutropenia was the dominant side effect reported in these regimens. There is a paucity of phase 3 randomized trials demonstrating a clinical benefit of anyone regimen over another. We recommend future randomized prospective trials better to understand the efficacy and safety profile of regimens containing both rituximab and cyclophosphamide base combinations. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 753-753 ◽  
Author(s):  
Steven P. Treon ◽  
Andrew Branagan ◽  
Parveen Wasi ◽  
Christos A. Emmanouilides ◽  
Stanley R. Frankel ◽  
...  
Keyword(s):  
Fold Increase ◽  
Secondary Malignancy ◽  
Subdural Hemorrhage ◽  
Low Grade ◽  
Waldenström’S Macroglobulinemia ◽  
Highly Active ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Intent To Treat ◽  
Waldenström'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.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 757-757 ◽  
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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