A Phase II Trial Of Bortezomib-Rituximab Followed By Autologous Stem Cell Harvest (SCH) and Cladribine-Cyclophosphamide-Rituximab (2CdA-Cy-Rit) Consolidation As Primary Therapy Of Waldenström's Macroglobulinemia (WM)
Authors: Thomas Sheeba K. , Haygood Tamara M , Qazilbash Muzaffar H. , Melendez A. Georgina , Galvis Roxana , Delasalle Kay B , Feng Lei , Richards Tiffany A. , Samaniego Felipe , Wang Luhua , Shah Jatin J. , Orlowski Robert Z. , Weber Donna M. 
Published: October 2019

Abstract

Background
Nucleoside analogue-based combinations provide excellent response and survival in patients (pts) with WM. However, an inability to subsequently harvest adequate stem cells for salvage autologous transplant is well described. Bortezomib provides effective induction therapy for WM when used in combination with rituximab with or without dexamethasone, with no apparent effect on stem cell harvest (SCH). In an effort to capitalize on the high response rates provided by nucleoside analogues while preserving the ability to successfully harvest stem cells in pts with previously untreated symptomatic WM, we initiated a program of bortezomib-rituximab (B-R), followed by SCH and consolidation with 2CdA-Cy-Rit.

Patients and Methods
Between 8/2006 and 6/2013, 38 pts were treated with bortezomib 1.6 mg/m2/d iv on d 1, 8, 15, 22 and rituximab 375 mg/m2 iv on d 8 and 22 in 35 d cycles. Pts achieving a 50% reduction of lymphadenopathy (LAD) and splenomegaly (SM), and/or a 50% reduction of IgM monoclonal protein on serum protein electrophoresis after either 2 or 3 cycles, underwent SCH for potential AuSCT at relapse. Pts not achieving >PR (as described above), within 6 months of completing B-R, received 2 cycles of rituximab 375 mg/m2 on d1, cyclophosphamide 350 mg/m2 q12 hours iv x 8 doses, vincristine 0.4 mg/d + doxorubicin 9 mg/m2/d by continuous infusion d1-4, and dexamethasone 20 mg/m2/d d1-4, 9-12, 17-20 (R-CVAD). Pts achieving 50% reduction in M protein and/or LAD/SM after R-CVAD also underwent SCH. Following successful SCH (defined as collection of >2 x 106 CD34+ cells per kg in ≤4 consecutive aphereses), patients received 2CdA 3 mg/m2/d iv x 5d, Cy 60 mg/m2/d po bid x 5d, and Rit 375 mg/m2 iv qwk x 4. All pts received valacyclovir prophylaxis. Pts who were not candidates for SCH after either B-R or R-CVAD were taken off study. The median age of pts was 61 (40-78) yrs and 74% were male. By the International Staging System (ISS) for WM, 11 pts (29%) were low-risk, 18 (47%) were intermediate-risk, and 9 (24%) were high-risk.

Results
After ≤3 cycles of B-R, 21 of 37 (57%) evaluable pts met criteria for response by reduction of M protein and/or extramedullary disease. Following R-CVAD, 9 additional pts (21%) achieved response; of these, 1 pt had a delayed response, occurring after the pt had been removed from study for lack of response. For 3 pts, health insurance denied coverage of SCH. Of the remaining 26 pts, 25 underwent successful SCH with filgrastim (18 pts), cycle 2 of induction R-CVAD + filgrastim (7 pts), or rituximab + filgrastim (1 pt) mobilization. Median CD34 cells/kg collected was 6x106 (1.85-24.04 x 106). Twenty-five pts completed consolidation with 2CdA-Cy-Rit, of whom 12 achieved VGPR and 13 achieved PR by International WM Working Group Response Criteria. Eleven of 12 pts (92%) achieving VGPR upgraded their response from PR after treatment with 2-CdA–Cy-Rit.
After a median f/u of 48 mos, 35 pts (92%) remain alive, with a median time to next therapy among 27 evaluable pts of 65.5 months. Three pts received salvage autologous transplant (SCT). Of these, 2 achieved VGPR and remain in remission 14 and 12 mos post-SCT respectively; a 3rd achieved transient VGPR, but died of progressive disease (PD) 13 months later (CNS involvement). Two other pts have also died [1 PD (progressive amyloid), 1 unknown cause during R-CVAD].
Grade 3-4 AEs (no. of events) during B-R were: fatigue (10), neutropenia (8), anemia (7), infection (4), nausea/vomiting (2), constipation (1), diarrhea (1), and peripheral neuropathy (1). In addition to the death, those during R-CVAD were neutropenia (4) and nausea (1). With 2CdA-Cy-Rit, they were fatigue (4), infection (3), neutropenia (1) and neuropathy (1). Second malignancies occurred in 3 pts: 1 ovarian cancer (CA) in a pt removed from study after cycle 1 of B-R, 1 skin basal cell CA during B-R, and 1 neuroendocrine CA after all therapy completed.

Conclusions
Bortezomib-rituximab is a well-tolerated, effective frontline treatment for pts with WM that allows subsequent successful SCH. Response can be achieved within 3 cycles, and continued response can be seen months after therapy has been stopped. In 12 (48%) of the 25 pts who completed therapy as planned, consolidation with 1 cycle of 2CdA-Cy-Rit was able to improve the degree of response achieved with B-R alone, and the overall program has provided durable remissions.

Disclosures:
Thomas: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Immunomedics: Research Funding; Celgene: Research Funding; Novartis Pharmaceuticals: Research Funding; Millenium: Research Funding; Onyx: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: This abstract describes bortezomib + rituximab as 1st line induction therapy for patients with Waldenstrom macroglobulinemia. Qazilbash:Millennium: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Wang:Celgene: Research Funding. Shah:Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Orlowski:Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Resverlogix: Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity’s Board of Directors or advisory committees.