Forman, Stephen J.

Abstract Background: Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct designed to direct cytotoxic T cells to CD19-expressing B cells. In a study in minimal residual disease (MRD)-positive ALL, 80% of pts achieved MRD-negative status after receiving one treatment cycle of blinatumomab (Topp MS, et al. J Clin Oncol. 2011;29:2493-8). For pts with newly diagnosed ALL, persistence of MRD after first-line treatment predicts disease recurrence. However, only limited data are available about the relationship between MRD and outcome in adult pts with r/r ALL. Therefore, the aim of this secondary analysis was to evaluate MRD responses and their relationships to other efficacy indices in adult pts with r/r ALL receiving blinatumomab in this phase 2 study. Methods: Eligibility criteria included adult pts ≥18 years, with Philadelphia chromosome negative B-cell r/r ALL who were primary refractory or refractory to first salvage, had their first relapse within 12 months of first remission or allogeneic hematologic stem cell transplantation (HSCT), or received second or later salvage. Blinatumomab was dosed via continuous IV infusion at 28 μg/d (cycle 1 only: 9 μg/d on days 1-7, 28 μg/d on days 8-28) for up to five cycles (one cycle: 4 weeks on, 2 weeks off). The primary endpoint was complete remission (CR: ≤5% blasts with platelets >100,000/µL, absolute neutrophil count >1000/µL) or CR with partial hematologic recovery (CRh*: platelets >50,000/µL, absolute neutrophil count >500/µL) within the first two treatment cycles. MRD in bone marrow was assessed at a central laboratory using allele-specific real-time quantitative PCR. Two MRD-based exploratory endpoints were analyzed: MRD response (no PCR amplification at a minimum sensitivity of 10-4 or <10-4 leukemic cells by PCR) and complete MRD response (no PCR amplification at a minimum sensitivity of 10-4) within the first two treatment cycles. Results: Of 189 treated pts (median [range] age = 39 [18–79] years), 81 (43%) pts had a CR (n = 63, 33%) or a CRh* (n = 18, 10%) during the first two treatment cycles. In the subgroup of pts with a CR/CRh* and evaluable MRD data (n = 73), 60 (82%) pts had an MRD response. Of those, 51 (70%) pts had a complete MRD response. The majority of those who achieved a CR/CRh* also achieved a complete MRD response regardless of the number of prior lines of salvage therapy (Table 1). Of all treated pts, 64 (34%) pts had prior HSCT. In pts who achieved CR/CRh*, the rate of MRD response was 81% in pts without and 85% in pts with prior HSCT. In pts who achieved CR/CRh*, the median (95% CI) duration of overall survival was 11.4 (8.5, not estimable) months for those with a MRD response and 6.7 (2.0, not estimable) months for those with no MRD response. The median (95% CI) duration of relapse-free survival was 6.9 (5.5, 10.1) months in patients with a MRD response and 2.3 (1.2, not estimable) months in patients with no MRD response. The HSCT realization rate did not differ significantly between pts with CR/CRh* and a MRD response and those with CR/CRh* and no MRD response (31% and 43%, respectively). Seventeen pts classified as nonresponders per protocol had ≤5% blasts and no evidence of disease, but recovery of peripheral counts did not meet criteria for CRh*. Ten of these 17 pts had evaluable MRD assessments; 50% (5/10) had MRD response and 20% (2/10) had complete MRD response. The clinical significance of this finding remains open. Grade ≥3 adverse events regardless of causality and occurring in >10% of all treated pts during treatment until 30 days after treatment were febrile neutropenia (25%), neutropenia (16%), and anemia (14%). Grade 3 cytokine release syndrome (CRS) was reported in three (1.6%) patients. Three (1.6%) patients had grade 4 neurologic events, all resolved. Twenty-one (11%) patients had grade 3 neurologic events, 17 were resolved, with 4 events unresolved at death or unknown. Conclusion: In this largest study to date of adult pts with r/r ALL with PCR-based central assessment of MRD, pts who achieved CR/CRh* during single-agent treatment with blinatumomab had high MRD response rates. The exploratory analyses suggested that within pts with a CR/CRh*, those who did not achieve MRD responses tended to have shorter durations of overall and relapse-free survival. These results are consistent with prior reports highlighting the importance of achieving an MRD response in first-line therapy. Disclosures Goekbuget: Amgen Inc.: Consultancy, Honoraria, Research Funding. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities. Kantarjian:Amgen Inc.: Research Funding. Brüggemann:Amgen Inc.: Consultancy, Research Funding. Stein:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Bargou:Amgen Inc.: Consultancy, Honoraria. Dombret:Amgen Inc.: Research Funding. Heffner:Amgen Inc.: Honoraria, Research Funding; Biotest: Research Funding; Dana Farber CI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Idera: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Research Funding; Spectrum: Research Funding; Talon Therapeutics: Research Funding. Rigal-Huguet:Amgen, Inc.: Consultancy; Ariad: Consultancy; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Litzow:Amgen Inc.: Honoraria, Research Funding. Zugmaier:Amgen Reseach (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Jia:Amgen Inc.: Employment, Equity Ownership. Maniar:Amgen Inc.: Employment, Equity Ownership. Huber:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment, Equity Ownership, Related to blinatumomab Patents & Royalties. Topp:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Current therapies for patients with r/r ALL who have had prior allogeneic hematopoietic stem cell transplantation (alloHSCT) have very poor outcomes. Improvements in the therapeutic options available for adult r/r ALL are required. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. The aim of the present analysis was to characterize a subset of patients with r/r ALL and prior alloHSCT before treatment with blinatumomab from a large confirmatory open-label, single-arm, multicenter phase 2 study (Topp MS et al Lancet Oncol 2015;16(1):57-66). Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r ALL with 1 of the following negative prognostic factors: primary refractory, first relapse within 12 months of first remission, relapse within 12 months of alloHSCT, or second or greater salvage. Patients with active acute or chronic graft-versus-host disease (GvHD) were excluded. Patients were required to stop all immunosuppressive GvHD therapy within 2 weeks before starting blinatumomab. A total of 189 patients were enrolled and received blinatumomab by continuous intravenous infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh) within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), and adverse events (AEs). Results: 64 (34%) patients had received alloHSCT before study enrollment; 10 patients had 2 prior alloHSCTs. Donor types primarily included 29 (45%) matched sibling and 31 (48%) unrelated, with 34 (59%) patients receiving myeloablative conditioning regimens (donor chimerism data were unavailable). Among those with prior alloHSCT, median age (range) was 32 (19-74) years. At baseline, 23 (36%) patients had 1 prior relapse, 24 (38%) had 2 prior relapses, and 17 (27%) had ≥3 prior relapses; 28 (44%) patients had relapsed post-alloHSCT. Of the 55 patients who had received previous salvage therapy, 38 (69%) had received salvage therapy after last alloHSCT and prior to blinatumomab. Median time (range) between the last alloHSCT and subsequent relapse was 6 (1-33) months. Median time from last prior alloHSCT to first dose of blinatumomab was 10 (3-40) months. Nineteen (30%) patients had a history of GvHD, and 42 (66%) had ≥50% bone marrow blasts at start of treatment as assessed by a central laboratory. Patients received blinatumomab for a median of 2 (1-5) cycles. Efficacy data are presented in Table 1. Overall, 45% (29/64; 95% confidence interval [CI], 33-58) of patients achieved CR/CRh within the first 2 cycles, with similar rates of remission also observed in the alloHSCT-naïve (42%; 52/125) group. With a median follow-up of 8.8 months, median (95% CI) OS was 8.4 (4.2-9.4) months for the 64 patients with prior alloHSCT treated with blinatumomab. Of the 29 responders (CR, n=18 and CRh, n=11), 22 (76%) had a minimal residual disease (MRD) response and 19 (66%) achieved a complete MRD response. Median RFS (95% CI) was 6.1 (5.0-7.7) months. 9/29 (31%) responders subsequently underwent another alloHSCT. In total, 56 (88%) patients had grade ≥3 treatment-emergent AEs, with the most frequent including neutropenia (22%), febrile neutropenia (20%), anemia (17%), and thrombocytopenia (14%). Six patients reported treatment-emergent GvHD (two grade ≥ 3) during blinatumomab treatment, 3 of whom had GvHD in skin. Eight patients had fatal treatment-emergent AEs, which included 1 due to gastrointestinal hemorrhage, 1 due to respiratory failure, and 6 due to infection/infestation; 1 of these (candida infection) was considered to be possibly related to treatment by the investigator. Of the subjects who had treatment-emergent fatal AEs, none were in remission at the time of death. Summary: In this heavily pretreated group of patients with r/r ALL and prior alloHSCT, single-agent blinatumomab was able to induce a CR/CRh rate of 45%, with an AE profile consistent with that previously reported. Post-alloHSCT patients who had relapsed performed equally as well as those without prior alloHSCT. To prolong remission in this poor outcome patient group, the addition of other immunotherapies to the treatment regimen may be considered for future investigations. Disclosures Stein: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Goekbuget:Erytech: Consultancy; Gilead Sciences: Consultancy; Kite: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Equity Ownership; Sanofi: Equity Ownership; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding. Bargou:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Patents & Royalties: Patent for blinatumomab; University of Wuerzburg, Germany: Employment; GEMoaB GmbH: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rambaldi:Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Pierre Fabre: Honoraria. Zhang:Amgen: Employment, Equity Ownership. Zimmerman:Amgen: Employment, Equity Ownership. Forman:Mustang: Research Funding; Amgen: Consultancy.

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P < .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Abstract Background: We recently clarified the use of consolidative autologous stem cell transplantation (ASCT) as first remission consolidation therapy for high grade diffuse aggressive T and B non-Hodgkin's lymphoma (NHL)in patients with high-intermediate (HI) or High (H) age adjusted IPI disease (Stiff et al, NEJM 369:1681). After receiving CHOP or R-CHOP for 5 cycles responding patients were randomized to either 3 more induction cycles or 1 cycle followed by an ASCT using either a BCNU or TBI based preparative regimen. We found a PFS but not OS advantage for those randomized to transplant and no differential treatment effect for those with T-NHL patients as compared to B-NHL in the initial analysis of this study. In light of Phase II data suggesting a value of early ASCT for T-NHL, a lack of randomized ASCT trials for T-NHL and the inferior prognosis for T-NHL as compared to B cell disease, we further evaluated this sub group, since a post hoc analysis of the entire trial did find a survival advantage for those with H IPI disease. This then provided a unique opportunity to evaluate the role of ASCT consolidation for T-cell NHL in the setting of a prospective randomized trial. Method: Among the 370 eligible B-NHL and T-NHL patients with HI/H IPI disease treated on this trial, 40 had a T-NHL phenotype and were the subject of this analysis. Individual patient files were re-reviewed and those randomized after the first 5 cycles of CHOP were further analyzed for stage, IPI group, histology (centrally reviewed), and response to induction and consolidation and updated survival outcome. Results: Of the 40 T-NHL patients enrolled on study, 28 (70%) were randomized after induction therapy, a similar ratio to the entire trial (68%). Twelve were not randomized; 1 was ineligible for study, and of the eligible 11, 9 were HI IPI and 8 had peripheral T cell (PTCL-NOS). These 11 were not randomized due to patient choice in 2, and all of the remaining 9 pts progressed early: 2 after C1; 3 after C3, 1 after C4, and 3 after C5. For the 28 randomized, their median age was 50 and 19 were males. Of the group, 21/28 had B symptoms at diagnosis, 14 had stage IV disease, and 18 and 10 were in the HI and H IPI groups respectively. Histologies included 11 with PTCL-NOS, 7 angioimmunoblastic and 10 anaplastic large cell NHL. At randomization 13 were to continue CHOP and 15, ASCT. Of the 15 assigned to ASCT, 3 did not undergo transplant (2-refusals, 1- unable to mobilize); 7 received the BCNU-etoposide-cyclophosphamide and 5 the TBI-etoposide-cyclophosphamide preparative regimen. The 5 year estimates of PFS and OS for the randomized ASCT vs CHOP only groups (intent to treat) were 40% vs 38% (p=0.56) and 40% vs 45% (p=0.98) respectively. We found no difference in outcome based on IPI group, histology or stage of disease. Interestingly, only 1/7 patients who received BCV as the ASCT preparative regimen are long term survivors vs 4/5 receiving the TBI-based regimen. Conclusions: We did not observe a PFS/OS advantage for those with high-risk T-NHL in first remission randomized to ASCT following CHOP induction vs CHOP alone in this retrospective analysis. In addition, the 30% early drop out rate before randomization due primarily to early progression strongly suggests that more optimal induction regimens need to be developed for this disease. While the numbers are small the finding that TBI based preparative regimens might be associated with a higher PFS is of interest and deserves further study. Support: NIH/NCI grants CA180888 and CA180819; Bristol-Myers Squibb. Contributions of Dr. Raymond R Tubbs, deceased, are gratefully acknowledged. Figure 1 Figure 1. Disclosures Porcu: miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; Seattle Genetics: Research Funding; GSK: Research Funding. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Smith:Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Gilead: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Pharmacyclics: Consultancy. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board.

Abstract Total body irradiation (TBI)-based conditioning regimens are considered the standard of care for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic cell transplantation (HCT). However, due to concerns regarding acute and long-term toxicities, non-TBI regimens, commonly including busulfan (BU), have been increasingly explored. We performed a retrospective cohort analysis with the hypothesis that there would be equivalence of these two myeloablative approaches by reviewing outcomes for adult patients (pts), aged 18-60 years, undergoing a first, well-matched sibling, related or unrelated donor HCT in CR1 or CR2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005-2014. Eight hundred nineteen pts received TBI (63% 9-12 Gy, 37% ≥13 Gy) combined with etoposide (25%) or cyclophosphamide (Cy) (75%) and 299 pts received intravenous BU combined with a second alkylator Cy (15%) or melphalan (Mel) (13%), or a nucleoside analogue fludarabine (Flu) (41%) or clofarabine (Clo)(30%). The majority of the BU-based pts were treated at the Moffitt or MD Anderson Cancer Center. The BU-based regimens were grouped together for analyses since no significant differences in basic outcomes among the different chemotherapy-only regimens were noted. Patients in the BU-containing group were older but had better performance status, took longer to achieve CR1 and longer to receive HCT; more received peripheral blood than marrow grafts, peri-HCT ATG, pre- and post HCT tyrosine kinase inhibitors ( TKI), and were treated more recently than pts in the TBI-based group (Table 1). With median follow-up of 3.6 years for the BU-based group and 5.3 years for the TBI-based group, adjusted 3 year outcomes showed treatment-related mortality (TRM) BU 19% vs. TBI 25% (p=.04); relapse BU 37% vs. TBI 28% (p=.007); disease-free survival (DFS) Bu 45% vs. TBI 48% (p=.35); and overall survival (OS) BU 57% vs. TBI 53% (p=.35) (Figures A-B). Patients in the BU group had significantly more grade II-IV acute GVHD (47% vs. 40%, p=.025), but marginally less chronic GVHD (49% vs. 55% at 3 years, p=.073). In multivariate analysis, the BU group had a significantly higher rate of acute GVHD after day 50 (RR 1.75, 95% CI 1.19-2.58, p=.004), but marginally less chronic GVHD (RR 0.83, 95% CI 0.68-1.01 p=.059) and higher risk of relapse (RR 1.46, 95% CI 1.15-1.85 p=.002) compared with TBI-based regimens. Despite the observed higher risks of acute GVHD and relapse, BU-based conditioning led to similar TRM, OS, and DFS following HCT for ALL. Table 1 Table 1. Figure Figure. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Seftel:Otsuka: Research Funding. Pulsipher:Medac: Other: Housing support for conference; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Abstract Triplet regimens combining an immunomodulatory agent, a proteasome inhibitor (PI), and a steroid are used to treat newly diagnosed and relapsed multiple myeloma (MM). Although ixazomib (Ix), an oral PI with single agent activity, can be combined with lenalidomide (LEN), patients (pts) with relapsed/refractory (R/R) MM are often LEN-refractory. Pomalidomide (POM) has single agent activity in LEN-refractory disease, and both POM and Ix also show activity in poor cytogenetic risk pts. Methods: Primary objectives: 1) determine the maximum tolerated dose (MTD) of Ix in combination with standard dose POM and dexamethasone (DEX), and 2) evaluate the anti-tumor activity of the triplet. The treatment regimen included two dose levels (3 mg and 4 mg) of Ix on days 1, 8, 15; POM 4 mg days 1-21; and DEX 40 mg days 1, 8, 15, 22, of a 28 day cycle. Eligibility: R/R MM after >1 prior therapy, LEN-refractory, and ≤ grade(gr) 1 peripheral neuropathy (PN). Pts were treated until progression or unacceptable toxicity. Design: Phase I study utilizing a standard 3+3 design; dose limiting toxicities (DLTs) defined during cycle 1. Results: 32 pts treated, 31 evaluable for toxicity and response. Pts received a median 4 cycles (range 1-13); median follow-up is 5.5 months (range 1.8-21.1). Six pts treated on DL1, 25 treated on DL2, the MTD/Phase II dose (P2D). Median age: 62 years (range 38-84); median time from diagnosis: 3.7 years (range 1.0-8.9); median number prior therapies: 3 (range 1-5); prior transplant: n = 23 (74%); double (LEN/Bortezomib[BOR]) or triple (LEN/BOR/Carfilzomib[CFZ]) refractory: 19 (61%). Phase I: DL1 expanded to n=6 after 1/3 pts experienced DLT (gr3 lung infection); no further DLT seen on DL 1 or 2. Adverse events (AEs) related to POM and/or Ix: ANC decrease Gr1/2 n=11 (35%), Gr3/4 n=10 (32%), platelet decrease Gr1/2 n=9 (29%), lymphocyte decrease Gr1/2 n=8 (26%), Gr3/4 n=11 (35%), PN Gr1/2 n=9 (29%), no Gr3/4. Response: Phase I and II, n=31 pts treated. ORR: 45% (6 VGPR, 8 PR); Clinical Benefit Rate (CBR): 81% (6 VGPR, 8 PR, 3 MR, 8 SD). In the pts with high risk cytogenetics (7[23%] 1q, 3[10%] 17p, 2[6%] t(4;14)) an ORR of 58% (3 VGPR, 4 PR) was seen, and the CBR was 83%. In the double or triple refractory pts, an ORR of 26% and CBR of 79% (1 VGPR, 4 PR, 3 MR, 7 SD) were observed. Conclusions: Ix/POM/DEX is a well-tolerated oral combination therapy, and responses were seen even at DL1 and in high risk patients, including those with poor-risk cytogenetics or advanced refractory disease. Disclosures Kapoor: Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding. Lonial:Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy. Nathwani:Carevive Systems, Inc.: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.

Abstract Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P &lt; .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Abstract Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT). Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research. Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P &lt; 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P &lt; 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P &lt; 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years). Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.