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.

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.

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

1993 ◽  
Vol 11 (5) ◽  
pp. 914-920 ◽  
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.

B-Lymphocyte Stimulator (BLyS) Is Highly Expressed in Waldenstrom’s Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2291-2291
Author(s):  
Stephen M. Ansell ◽  
Deanna M. Grote ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Robert A. Kyle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Waldenström’S Macroglobulinemia ◽  
B Lymphocyte Stimulator ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia ◽  
Normal Controls

Abstract Waldenstrom’s macroglobulinemia is a serious and frequently fatal illness, however many of the mechanisms leading to this disease are not yet known. It is clear, however, that there is dysregulation of the balance between cell proliferation and programmed cell death. BLyS (B-lymphocyte stimulator) is a newly identified TNF family member expressed by monocytes, macrophages, and dendritic cells. BLyS has been shown to be critical for maintenance of normal B cell development and homeostasis, and has been found to stimulate lymphocyte growth. BLyS is overexpressed in a variety of B-cell malignancies and has been shown to inhibit apoptosis in malignant B-cells. Studies of the effects of BLyS on B cell physiology have shown that it also regulates immunoglobulin secretion. To determine the relevance of the BLyS receptor-ligand system in Waldenstrom’s macroglobulinemia, we examined malignant B cells from 5 patients with Waldenstrom’s macroglobulinemia for their ability to bind soluble BLyS and for the expression of the known BLyS receptors, TACI, BAFF-R, or BCMA. The malignant B cells were found to bind BLyS and express BAFF-R and TACI. BCMA expression was undetectable. We then determined the expression of BLyS in bone marrow specimens from 5 patients with Waldenstrom’s macroglobulinemia by immunohistochemistry and compared it to the expression in 5 normal bone marrow specimens. The lymphoplasmacytic cell infiltrate in the bone marrow of patients with Waldenstrom’s macroglobulinemia showed significantly increased BLyS expression. We further determined the serum BLyS levels by ELISA in stored serum specimens from patients with Waldenstrom’s macroglobulinemia (n=20), and compared them to serum BLyS levels in other patients with lymphoplasmacytic lymphoma without elevated immunoglobulin levels (n=10) and to serum levels in normal controls (n=50). Serum BLyS levels in Waldenstrom’s patients (mean: 49.6ng/ml) as well as those in patients with lymphoplasmacytic lymphoma (mean; 46.7ng/ml) were significantly higher than normal controls (mean 12.6ng/ml). In conclusion, we have demonstrated that malignant B cells from patients with Waldenstrom’s macroglobulinemia express the receptors for BLyS and can bind soluble BLyS. Furthermore, we have found that serum BLyS levels are significantly elevated in patients with Waldenstrom’s macroglobulinemia when compared to controls. Strategies to inhibit BLyS may potentially have significant therapeutic efficacy in Waldenstrom’s macroglobulinemia.

Histone Deacetylase Inhibitors Demonstrate Significant Preclinical Activity as Single Agents, and in Combination with Bortezomib in Waldenstrom's Macroglobulinemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4785-4785
Author(s):  
Jenny Sun ◽  
Lian Xu ◽  
Hsiuyi Tseng ◽  
Bryan Ciccarelli ◽  
Mariateresa Fulciniti ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Histone Deacetylase Inhibitors ◽  
Conflicts Of Interest ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Waldenström’S Macroglobulinemia ◽  
Over Expression ◽  
Waldenstrom's Macroglobulinemia ◽  
Waldenstrom’S Macroglobulinemia ◽  
Waldenström's Macroglobulinemia

Abstract Abstract 4785 Waldenstrom's Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by bone marrow infiltration of CD19+ cells and production of a monoclonal IgM protein. Despite advances in treatment, WM remains incurable. As part of these efforts we sought to define the role of HDAC-inhibitors in WM. Gene expression profiling of bone marrow CD19+ cells from 30 WM patients and 10 healthy donors showed over-expression of HDAC4, HDAC9, and Sirt5 in WM patients. Evaluation of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA or Vorinostat), Trichostatin A (TSA), LBH-589 (Panobinostat), and sirtinol demonstrated dose dependent killing of BCWM.1 cells with IC50 of 3.5 uM, 70 nM, 0.8 uM, and 30 uM, respectively, whilst the combination of these agents with bortezomib resulted in at least additive tumor cell killing. TSA is more potent than bortezomib in inducing apoptosis in primary WM tumor cells in patients with prior treatment. TSA and bortezomib showed synergistic effect in 25% of the patients samples tested. We also observed that TSA and bortezomib-induced apoptosis of BCWM.1 cells depended on the activation of a similar set of caspases. Conversely, changes in cell cycle regulators were distinctly different between TSA and bortezomib treated BCWM.1 cells. The results of these studies demonstrate over-expression of distinct members of HDAC in WM cells, and provide a framework for the examination of HDAC-inhibitors as monotherapy, as well as combination therapy with bortezomib in the treatment of WM. Disclosures: No relevant conflicts of interest to declare.

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.

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