Induction Therapy With Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) For Primary Plasma Cell Leukemia (pPCL)

Abstract

IntroductionPrimary plasma cell leukemia (pPCL) is an uncommon, highly aggressive plasma cell dyscrasia with a poor prognosis. A limited number of small retrospective studies have reported promising results in treating PCL using the novel agent bortezomib (btz). We therefore undertook a retrospective study of our cohort of patients (pts) with newly diagnosed pPCL treated with cyclophosphamide, btz, and dexamethasone (CyBorD) as front-line therapy. MethodsBetween August 2008 and June 2013, 10 newly diagnosed pts with pPCL (≥20% PCs in peripheral blood and/or absolute PCs ≥ 2.0x109/L) were referred to Princess Margaret Cancer Centre. Pts received a median of 4 (range 4-8) 28-day cycles of CyBorD induction consisting of weekly cyclophosphamide 300 mg/m2po, weekly btz 1.5 mg/m2IV or SQ, and dexamethasone in pulse fashion for cycles 1 and 2 and then weekly as well. Hematologic responses were assessed using IMWG consensus criteria for serological, and, if available, bone marrow, criteria. Survival times were measured from the time of first treatment. ResultsThe median age was 54 yrs (range 45-68); 6 were male. Median (range) hemoglobin was 85 g/L (27-135), creatinine 212 umol/L (57-404), albumin 37g/L (25-47), LDH 215 U/L (163-537) and β2-microglobulin 441 nmol/L (295-1136); median WBC was 10.6 (4.8-32.2), ANC 2.0 (1.4-3.3), and platelet count 94 (36-159) x 109/L. Abnormal cytogenetics were common; of 9 pts with FISH results available, 4 pts had deletion 13q (44.4%), 3 had deletion 17p (33.3%), 3 had t(14;16) (33.3%), 4 had t(11;14) (44.4%) and 2 had other changes (22.2%). The overall response rate (ORR defined as ≥ PR) after CyBorD induction was 100% and included PR in 3 pts (33.3%), VGPR in 5 pts (50%), and CR in 2 pt (20%). Nine pts underwent successful stem cell (SC) mobilization with cyclophosphamide + G-CSF (median CD 34+ cells 3.42 x 106/kg [range 2.16-7.31]); 1 pt, who has been given 8 cycles to date, is awaiting a second attempt at SC collection. Two other patients relapsed after completion of planned induction while awaiting transplant; these required additional therapy to control the disease before ASCT. In total, 9 pts have undergone subsequent ASCT, including tandem ASCT in 4 pts. After ASCT, 1 pt received maintenance therapy with thalidomide, while 6 more recently treated pts were given lenalidomide maintenance. Best responses post-ASCT were as follows: ≥ PR in all 9 pts (100%, specifically PR in 1 (11.1%), VGPR in 4 (44.4%), and CR in 4 (44.4%, including 1 pt with nonsecretory disease in documented CR pre-ASCT who was not formally reassessed but clinically remained in CR after ASCT). Five patients have relapsed post-ASCT with time to relapse from ASCT of 13.5 mos (range 3-38), including both pts who had progressed and required additional therapy before ASCT (time to relapse 3 and 4 months). The median PFS for all pts from the start of therapy was 18 mos (range 4-44 mos).Currently, 7 pts (70%) are alive after a median follow-up of 25 mos (range 8-58); 5 of these pts are alive without relapse after a median of 25 mos (range 8-28) while 2 pts (20%) are alive after ≥ 1 relapse at a median of 49 mos (range 39-58). Three pts (30%) have died from disease a median of 20 mos (range 7-24) after commencing therapy.During CyBorD induction, 5 pts required hospitalization for a median of 10 days (range 6-53); heme toxicity was generally mild, with only 1 grade 4 neutropenia and no grade 3 or 4 thrombocytopenia. Other toxicities included: mild peripheral neuropathy in 5 pts (50%) (grade 1 in 4; grade 2 in 1) in addition to grade 1 shingles (10%), grade 2 drug fever attributed to btz (10%), and anemia requiring transfusion (10%). ConclusionsAlthough compromised by the small sample size, our study suggests that induction with CyBorD for pts with pPCL produces a high initial ORR with a favorable toxicity profile. However, disease progression is common in this entity and can occur early, while waiting for ASCT; these pts have a particularly poor outcome even after reinduction and subsequent ASCT. Although CyBorD is an effective initial regimen for patients with pPCL, innovative therapies will be needed to maintain long-term disease control. Disclosures:Reece:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Millennium Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; BMS: Research Funding; Otsuka: Honoraria, Research Funding; Onyx: Consultancy. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Trudel:Sanofi: Honoraria; GSK: Research Funding; Celgene: Honoraria.