Abstract: We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. Patients and Methods Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). Results Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. Conclusion Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.

Abstract: Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT). Patients and Methods Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities. Results Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity. Conclusion CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.

Abstract: We have shown safety of unrelated donor hematopoietic cell transplantation (HCT) using nonmyeloablative conditioning with fludarabine (FLU, 90 mg/m2) and 2 Gy total body irradiation (TBI) and post-HCT immunosuppression with MMF (15 mg/kg) and cyclosporine (CSP 5–6.25 mg/kg) both given BID (Maris Blood 2003 Vol 102, No 6). The graft rejection rate in the first 89 pts was 23% and more frequent for marrow (8/18; 44%) than PBSC (13/71; 18%) recipients. Multivariate analysis identified recipients of marrow grafts and those without preceding chemotherapy at highest risk for graft rejection (p=0.006 for each). The t½ of mycophenolic acid, the active metabolite of MMF, was 3 hours, and its binding to IMPDH II rapidly reversible. This led to the hypothesis that exclusive use of PBSC grafts and TID dosing of MMF might result in higher engraftment and lower acute GVHD rates. The current protocol (MMF TID) was identical to the original one (MMF BID) except that all pts received PBSC and were given MMF TID. The protocol’s primary goal was to achieve graft rejection 〈 10% and 〈 20% for pts with and without prior chemotherapy, respectively, and its secondary goal to reduce the incidence of acute GVHD. Pts with malignant diseases (n=103), matched with their donors for HLA-A, -B, -C antigens and -DRB1 and -DQB1 alleles, were entered on study. Median donor T cell chimerism at day 28 was 92% compared to 75% for 71 PBSC recipients given MMF BID on the prior protocol (p=0.02). When BID and TID MMF pts were considered together, donor T cell chimerism 〈 50% was highly predictive for graft rejection (p 〈 0.0001). The durable engraftment rate for pts given MMF TID versus BID was 95% (98/103) compared to 82%, respectively (p=0.004). For pts with and without prior chemotherapy given MMF TID versus BID, rejection rates were 3% compared to 10% (p=0.08) and 17% compared to 53% (p=0.05), respectively. Cumulative probabilities of grades II, III and IV acute and chronic extensive GVHD were 39%, 10%, 2%, and 45%, respectively, and were similar to rates in BID MMF pts, suggesting further improvements in GVHD prevention are needed. For the 103 pts given MMF TID, 1-year overall survival, progression-free survival, relapse/progression, and non-relapse mortality were 64%, 54%, 27%, and 19%, respectively. Kaplan-Meier 1-year survivals were as follows: acute leukemia (n=24) 79%, B cell malignancies (n=47: CLL, n=13; Hodgkin disease, n=8; NHL, n=27) 63%, multiple myeloma (n=11) 55%, CML (n=5) 100%, MDS/myeloproliferative syndromes (MPS) (n=12) 50%, and RCC 50%. Kaplan-Meier 1-year progression free survivals were as follows: acute leukemia 71%, B cell malignancies 61%, multiple myeloma 46%, CML 60%, MDS/MPS 33%, and RCC 25%. The use of unrelated donor PBSC grafts and administration of MMF TID after nonmyeloablative conditioning significantly improved donor T cell chimerism and engraftment rates over the preceding protocol. However, further improvements in immunosuppression after HCT are needed to reduce acute GVHD rates.

Abstract: Background: SL-401 is a novel targeted therapy directed to the interleukin-3 receptor (CD123), a target overexpressed on acute myeloid leukemia (AML) blasts and AML cancer stem cells (CSCs), and a variety of additional hematologic malignancies. While conventional chemotherapy can induce remission in a majority of treatment-naive AML patients, relapse rates remain high. Outcomes are particularly poor when minimal residual disease (MRD), as determined by genetic and/or flow cytometric analyses, remains after therapy, with high rates of relapse and short disease-free survival. Conceivably, a therapy directed at lowering MRD burden may improve long-term outcomes. Given the association of MRD with CD123+ AML CSCs, SL-401 is being evaluated in patients with AML in first or second complete remission (CR1 or CR2, respectively) with high risk of relapse including persistent MRD. Preliminary results are reported here. Methods & Results: This multicenter, single-arm Phase 2 trial of AML patients in CR1 or CR2 with high risk of relapse includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients (MRD+ or MRD-) receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day for days 1- 5 of a 28 day cycle in a 3x3 design. In stage 2, patients (MRD+ only) receive SL-401 at the dose determined in stage 1. Presence of MRD for eligibility requires either molecular (by cytogenetics, FISH, PCR, or next-generation sequencing of AML-associated mutations) or multiparameter flow cytometry (MFC) evidence of persistent abnormalities in the setting of morphologic CR. In stage 2, MRD assessment will include MFC of bone marrow aspirates conducted at a central laboratory for uniformity. Objectives include characterization of SL-401 safety with determination of the maximum tolerated or tested dose, and preliminary assessment of efficacy including changes in MRD burden and response duration. As of 7/27/16, stage 1 has been completed and stage 2 is open for enrollment. Nine patients (stage 1) received SL-401 (7 ug/kg, n=3; 9 ug/kg, n=3; 12ug/kg, n=3). The median age was 63 years (range: 51-78 years); 6 males and 3 females were treated; 8 patients were in CR1 and 1 patient was in CR2 at enrollment. The 12 ug/kg dose level was the highest tested dose with no DLTs; MTD was not reached. The most common treatment-related AEs, all grades, were thrombocytopenia (3/9; 33%) and hypoalbuminemia (3/9; 33%); the most common ≥ grade 3 treatment-related AE was thrombocytopenia (1/9; 11%); there was no DLT. Patients treated at all doses received 1+ to 5+ cycles (ongoing) of SL-401, including 3 MRD+ patients treated at 7 ug/kg (n=1) or 9 ug/kg (n=2) who received 1-5 cycles, and 1 MRD+ patient treated at 12 ug/kg who is receiving ongoing SL-401 for 4+ cycles. For all 3 patients treated at 12 ug/kg (MRD+, n=1; MRD-, n=2), 2 patients remain on SL-401 and have received 1+ and 4+ cycles (both ongoing); one other patient treated at 12 ug/kg discontinued the study because of infection unrelated to study drug. Notably, the one MRD+ patient treated at 12 ug/kg (ongoing at 4+ cycles) had marked MRD reduction as determined by MFC at the local institution; this patient is being considered for stem cell transplant (SCT). Conclusions: Stage 1 is complete without DLT or MTD, and stage 2 (expansion) is open to enroll AML patients in CR1 or CR2 who are MRD+ at the highest tested dose of 12 ug/kg. The safety profile has been similar to that observed in other SL-401 clinical studies, with no unexpected AEs. Targeting MRD with SL-401 has the potential to reduce this chemo-resistant cell population and offer improved long-term outcomes for AML patients in remission with high risk of relapse. Updated data will be presented. Clinical trial information: NCT02270463. Disclosures Lane: N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Lindsay:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Stone:Novartis: Consultancy; Juno Therapeutics: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

Abstract: Background Post-remission therapies for patients with AML such as high-dose cytarabine (HiDAC) and allogeneic stem cell transplant (alloSCT) have led to improved outcomes for younger patients, but disease recurrence remains prevalent with ~40% 5-year OS. CD33 is a cell surface receptor expressed in ~90% of AML, representing a promising target for therapy. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Methods This phase 1b dose-escalation study (NCT02326584) evaluates the safety and anti-leukemic activity of 33A in combination with consolidation therapy (HiDAC) or as a single agent for maintenance therapy. AML patients (ECOG status 0-1) must be in 1st remission (CR or CRi) after standard induction therapy and be able to receive HiDAC (consolidation cohort) or be in 1st remission and have completed planned post-remission therapies, either chemotherapy and/or alloSCT (maintenance cohort). For maintenance post-alloSCT, patients were between Day 60 and 100 post-transplant without significant GVHD. Prior to HiDAC administration (3 gm/m2 q12h Day 1, 3, 5), 33A is given on Day 1 for up to 4 cycles (28-day cycle). For maintenance therapy, 33A is given as a single agent on Day 1 for up to 8 cycles (6-wk cycle). Results Consolidation cohort: 21 patients (57% male) with a median age of 52 years (range, 21-64) were treated with 5, 10, or 20 mcg/kg of 33A with HiDAC. Patients received a median of 2 cycles (range, 1-4). As anticipated, all patients experienced Grade 4 myelosuppression. At 20 mcg/kg, 1 DLT (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred in Cycle 1. At 10 mcg/kg, no DLTs were observed but delay of subsequent cycles of treatment occurred in 4 of 10 patients, primarily due to thrombocytopenia. No DLTs were observed in the 8 patients treated at 5 mcg/kg and 1 non-hematologic-related dose delay was reported (otitis externa). Non-hematologic treatment-emergent adverse events (AE) in ≥25% of patients regardless of relationship included nausea (38%) and fatigue (33%). No infusion-related reactions (IRRs) or events of veno-occlusive disease were reported. The 30- and 60-day mortality rates were 0%. Of the 19 efficacy evaluable patients, 15 (79%) have maintained remission, 18 patients are alive and 3 patients (14%) remain on treatment. Reasons for treatment discontinuation were completion of planned consolidation therapy (38%), AE (thrombocytopenia, 14%), leukemic relapse (5%), and other non-AE (29%). Nine patients (43%) went on to receive an alloSCT. Maintenance cohort: 22 patients (41% male) with a median age of 45.5 years (range, 23-71) have been treated with 5 mcg/kg of 33A. Patients were a median of 6.2 months from diagnosis (range, 3.4-21.5); 12 patients completed chemotherapy-based treatment alone and 10 patients completed standard chemotherapy with an alloSCT in 1st remission. Patients received a median of 3 cycles (range, 1-6); no DLTs were reported. AEs reported in ≥15% of patients were fatigue (41%), neutropenia (41% [36% ≥G3]), nausea (36%), thrombocytopenia (36% [27% ≥G3] ), diarrhea, dyspnea, headache, and vomiting (18% each); no IRRs were observed. Of the 20 efficacy evaluable patients, 15 (75%) have maintained remission. Reasons for treatment discontinuation were AEs (41%, primarily myelosuppression), leukemic relapse (14%), completion of planned therapy (9%), and other non-AE reasons (19%); 4 patients (18%) remain on treatment. Median OS is not yet reached and 19 patients are alive. Pharmacokinetic data in patients receiving post-remission therapy with 33A demonstrate that exposure appears to be greater than in patients with active disease, possibly due to a decrease in target-mediated disposition. Conclusions 33A can be safely administered in combination with HiDAC and as monotherapy in the post-remission setting. In combination with HiDAC, non-hematologic toxicities of 33A were consistent with effects reported with HiDAC alone. As a single agent, 33A administered as maintenance post-chemotherapy and/or alloSCT results in predictable on-target myelosuppression, with mild non-hematologic adverse effects. Disclosures Yang: Seattle Genetics: Research Funding. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. Walter:Emergent Biosolutions: Consultancy; Seattle Genetics: Research Funding; CSL Behring: Research Funding; Celator Pharmaceuticals: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Covagen AG: Consultancy; Agios: Consultancy; Arog: Research Funding. Faderl:Seattle Genetics: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Celator Pharmaceuticals: Research Funding; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; Amgen: Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Erba:Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Celator: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. Levy:Amgen: Speakers Bureau; Jansen: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Research Funding. Wood:Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership.

Abstract: Background For patients who are less than 65 years with newly diagnosed AML, standard induction treatment is continuous infusion cytarabine for 7 days and an anthracycline for 3 days (7+3). Although a high percentage of patients achieve an initial CR by morphologic criteria, some requiring a 2nd induction, a significant number of patients are either primarily resistant to treatment or achieve a morphologic CR but with flow cytometric or molecular evidence of minimal residual disease (MRD). CD33, a cell surface antigen, is expressed in approximately 90% of AML, representing a promising target of therapy regardless of genetic or mutational heterogeneity. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Addition of 33A to 7+3 chemotherapy could result in enhanced and deeper (MRD negative) remissions, resulting in reduced relapse rates and improved overall survival. Methods This phase 1b study (NCT02326584) evaluated the safety and antileukemic activity of escalating doses of 33A in combination with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2). AML patients (ECOG status 0-1) must be eligible to receive induction therapy. 33A is given on Days 1 and 4 concomitantly with the combination treatment. Response assessments occur on Days 15 and 28; investigator assessment of response is per IWG criteria (Cheson 2003). A 2nd induction regimen and post-remission therapies were per investigator choice and did not include additional administration of 33A. MRD was assessed centrally by bone marrow examination using a multi-parametric flow cytometric assay at Days 15 and Day 28. Results To date, 42 patients (36% male) with a median age of 45.5 years (range, 18-65) have been treated with 10+10 (n=4) and 20+10 (n=38) mcg/kg of 33A. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by MRC criteria and 17% of patients had secondary AML. As expected, all patients experienced Grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from Day 1 of therapy was 33 days for neutrophils (≥1K) and 35 days for platelets (≥100K). Three DLTs (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred at the 20+10 mcg/kg dose level, which was determined to be the maximum tolerated dose (MTD) of 33A in combination with 7+3. No non-hematologic treatment emergent adverse events (AEs) ≥Grade 3 were reported in 〉 15% of patients; Grade 1 or 2 non-hematologic AEs occurring in 〉 15% of patients were nausea (55%), diarrhea (33%), constipation (31%), decreased appetite (19%), fatigue (19%), and vomiting (17%); no infusion-related reactions occurred. No veno-occlusive disease (VOD) or significant hepatotoxicity was observed. The 30- and 60-day mortality rates were 0% and 7%, respectively. Of the 40 efficacy evaluable patients, best responses include 24 CR (60%), 7 CRi (18%), and 4 morphologic leukemia-free state (10%) with a CR+CRi (CRc) rate of 78%; 94% of CR or CRi responses occurred with 1 cycle of induction therapy. Twenty-three of 31 (74%) patients attaining CR or CRi achieved MRD negative status. Median OS is not yet reached; 36 patients were alive at the time of this data cut with 6 patients (14%) still on treatment. Pharmacokinetic data demonstrate rapid elimination of 33A. Conclusions 33A can be safely combined with 7+3 with acceptable count recovery and the recommended phase 2 dose is 20+10 mcg/kg on Days 1 and 4. An alternate schedule of single-day dosing on Day 1 is under investigation and enrollment continues. Extramedullary AEs, including hepatic toxicity, and induction mortality rates were similar to reported rates for 7+3 alone in this AML population. A high remission rate within the 1st induction cycle was observed, the majority of which were MRD negative. Disclosures Erba: Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Jannsen: Consultancy, Research Funding; Gylcomimetics: Other: DSMB; Agios: Research Funding; Astellas: Research Funding; Juno: Research Funding. Levy:Millennium: Speakers Bureau; Amgen: Speakers Bureau; Jansen: Speakers Bureau; Seattle Genetics: Research Funding. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Celgene: Consultancy, Research Funding; Merck: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Bexalata: Other: Advisory Board participation. Advani:Seattle Genetics: Consultancy, Research Funding. Faderl:JW Pharma: Consultancy; Amgen: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Ambit Bioscience: Research Funding; BMS: Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Research Funding. Smith:Seattle Genetics: Research Funding; Celgene: Consultancy, Speakers Bureau. Wood:Juno: Other: Laboratory Services Agreement; Seattle Genetics: Honoraria, Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement. Walter:Covagen AG: Consultancy; Astra-Zeneca: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Research Funding; Amgen: Research Funding; Celator Pharmaceuticals: Research Funding; CSL Behring: Research Funding; Seattle Genetics: Research Funding; Emergent Biosolutions: Consultancy; Agios: Consultancy; Arog: Research Funding. Yang:Seattle Genetics: Research Funding. Feldman:Seattle Genetics: Employment, Equity Ownership. Voellinger:Seattle Genetics: Employment, Equity Ownership. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding.

Abstract: Several studies have investigated the feasibility of allogeneic hematopoietic cell transplantations (HCTs) after reduced-intensity conditioning in patients who experienced relapse after myeloablative HCT. Although most studies showed relatively low nonrelapse mortality (NRM) rates and encouraging short-term results, it has yet to be defined which patients would benefit most from these approaches. Patients and Methods We analyzed data from 147 patients with hematologic malignancies who experienced treatment failure with conventional autologous (n = 135), allogeneic (n = 10), or syngeneic (n = 2) HCT and were treated with HLA-matched related (n = 62) or unrelated (n = 85) grafts after conditioning with 2 Gy of total-body irradiation with or without fludarabine. Results Three-year probabilities of NRM, relapse, and overall survival were 32%, 48%, and 27%, respectively, for related recipients, and 28%, 44%, and 44%, respectively, for unrelated recipients. The best outcomes were observed in patients with non-Hodgkin's lymphoma, whereas patients with multiple myeloma and Hodgkin's disease had worse outcomes as a result of high incidences of relapse and progression. Being in partial remission (PR) or complete remission (CR) at HCT (P = .002) and developing chronic graft-versus-host disease (GVHD; P = .03) resulted in lower risks of relapse and progression. Factors associated with better overall survival were PR or CR (P = .01) and lack of comorbidity (P = .03) at HCT and absence of acute GVHD after HCT (P = .06). Conclusion Encouraging outcomes were seen with allogeneic HCT after nonmyeloablative conditioning in selected patients who had experienced relapse after a high-dose HCT, particularly in patients with non-Hodgkin's lymphoma. Results with unrelated grafts were comparable with results with related grafts.

Abstract: A randomized 3-arm Phase II trial involving 208 older or medically infirm patients (pts) with hematological malignancies given unrelated HCT after minimal intensity conditioning demonstrated that adding sirolimus to tacrolimus and MMF resulted in less grades II-IV GVHD, less steroid use, and less CMV reactivation (Hematologica 2014; 99(10); 1624). Based on this trial we designed a Phase III multi-site trial comparing triple therapy with sirolimus/MMF/CSP (Arm2) to the standard immunosuppressive regimen of MMF/CSP (Arm1). The primary objective of the trial was to compare the respective incidences of grades II-IV acute GVHD. Secondary objectives included comparing non-relapse mortality, survival, and progression-free survival. Pts in both Arms received CSP 5 mg/kg bid starting on day -3 through day 96 with a taper through day 150. In the first 28 days after HCT CSP was targeted to 400 and 350ng/ml in Arm1 and Arm2, respectively and 120-360ng/ml after day 28 in both arms. Arm 1: MMF was given daily at 15 mg/kg Q8 hours until day +30, reduced to 15 mg/kg Q12 hours until day 150, then tapered through day 180. Arm 2: MMF was given daily at 15 mg/kg Q8 hours until day +30, reduced to 15 mg/kg Q12 hours until day 40, then discontinued (no taper). In addition to the MMF/CSP, sirolimus was administered starting on day -3 at 2.0 mg/day through day 150 with a target level of 3-12ng/ml, with tapering off by day 180. The target enrollment was 300 pts with a built-in interim analysis for futility. At the time of the interim analysis, 158 pts ineligible for high-dose conditioning had been enrolled (Nov. 2010 to Jan. 2016: Arm1 n=74, Arm2 n=84) Their median age was 62 (range 18-79) yrs. The median HCT comorbidity index (HCT-CI) was 3 (range 0-10). Five pts had 6 previous allogeneic HCT and 32 pts (20%) had 36 previous autologous HCT. All pts were matched for HLA-DRB1 and -DQB1 at the allele level: 8 had single allele mismatches at HLA-A, -B or -C and the remainder (n=150) were fully HLA-matched. Diagnoses included AML (n=64), MDS/MPD (n=30), NHL (n=23), MM (n=13), CLL (n=13), ALL (n=11), HL (n=2), and CML (n=2). Randomization was stratified by transplant center. Unmodified PBSC grafts contained a median of 8.0 ×106 CD34 and 2.9 × 108 CD3 cells/kg. Conditioning consisted of fludarabine 90mg/m2 and 2-3 Gy TBI. Sustained donor engraftment occurred in 99% of pts. The median follow-up of surviving pts was 24 (range, 1-65) months. Table 1 and Figures 1 and 2 summarize results. The day-100 cumulative incidences of grades II-IV acute GVHD were in Arm1: 53%, and Arm2: 25% (p=0.0001) and the grades III-IV acute GVHD were in Arm1: 8%, Arm2: 2% (p=0.04). The 1-year cumulative incidence of chronic extensive GVHD was similar between Arm1: 49%, and Arm2: 48% (p=0.94). The 1-year cumulative incidence of non-relapse mortality was lower in Arm2 (Arm1: 15% and Arm2: 5%; p=0.007), while relapse/progression was similar at 1 year for Arm1: 21%, and Arm2: 19% (p=0.86). The 1-year overall and progression-free survivals for Arm1 vs. Arm2 were: 72% vs. 85% (p=0.03), and 65% vs. 77% (p=0.08); respectively. T-cell (CD3) donor chimerism was lower in Arm 2 on day 28 (median, Arm1 85%; Arm2 80%; p=0.05) with no differences seen in granulocyte (CD33: Arm1 98%, Arm2 95%) or NK cell (CD56: Arm1 96%, Arm2 97%) donor chimerisms. In summary, the interim analysis showed that adding sirolimus to MMF and CSP not only reduced the risks of grades II-IV but also of grades III-IV acute GVHD and of non-relapse mortality without increasing the risk of relapse or progressive malignancy. Based on these findings and the significantly improved survival, the DSMB recommended the trial be closed. This triple immunosuppressive regimen should, therefore, be considered in the future as the standard of care in pts given unrelated donor grafts after minimal intensity conditioning. Disclosures Pulsipher: Novartis: Consultancy, Other: Study Steering Committee; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Medac: Other: Housing support for conference.

Abstract: Nonmyeloablative allogeneic HCT from both related or unrelated HLA-matched donors after pretransplant conditioning with 2 Gy TBI with or without fludarabine and with posttransplantation CSP/MMF has resulted in initial mixed donor/host chimerism in the majority of recipients. While the risk of rejection of HLA-matched related or unrelated donor grafts was 〈 5% with the regimen, low donor CD3 chimerism appeared to predict rejection. We previously analyzed the outcomes in patients given DLI for either persistent/recurrent disease or low donor chimerism (Blood. 2004; 103:790). Among patients given DLI for low or falling donor CD3 chimerism, success was seen only with pre-DLI CD3 chimerism levels 〉 40%. Among patients receiving DLI for disease, those with disease responses had chimerism levels 〉 90% after DLI, supporting the concept that full chimerism was necessary to eradicate malignant cells and exert graft-vs-tumor effects. Therefore, a protocol was developed to evaluate safety and efficacy of the immunosuppressive drug pentostatin given before DLI to reverse pending graft rejection. Patients considered at risk for rejection had low ( 〈 50%) or declining ( 〉 20%) donor CD3 chimerism and persistent or stable (including CR) malignant disease; they had no ongoing acute grades II-IV GVHD nor chronic extensive GVHD. Eight patients have been treated a median of 100 (range 54–339) days after HCT. They were originally conditioned for HCT with 2 Gy TBI with (n=7) or without (n=1) fludarabine (30 mg/m2 per day x 3 days) and given both donor and host immunosuppression with MMF and CSP after HCT. Donors were HLA-matched related (n=6) or unrelated (n=2). Diagnoses included NHL (n=2), CLL (n=2), AML (n=1), CML (n=1), and multiple myeloma (n=1); median patient age was 54.5 (range 44–66) years. The patients received pentostatin (4 mg/m2) 2 days before DLI (107 CD3 cells/kg); no post-DLI immunosuppression was given. The median donor CD3 chimerism level before pentostatin and DLI was 29.5 (range 5–34)%. Five patients developed neutropenia and the median number of days of ANC 〈 500 was 11 (0–36) days. Four of 8 patients showed increases of donor CD3 chimerism levels ranging from 63–100%. All 4 patients developed acute GVHD (Grades II n=2; III n=2), and two, chronic extensive GVHD. Currently all 4 patients are alive (CR=3; PR=1) a median of 218 (66–293) days after DLI and 305 (127–377) days after HCT. In the remaining 4 patients, donor CD3 chimerism remained at 5–25% following DLI; two patients received second HCT from the original donors for persistent low chimerism and aplasia, one patient died in CR from infectious complications, and the second is alive in CR with persistent low donor chimerism day 141 following the second HCT. The remaining two patients with low donor chimerism are alive in relapse 157 and 395 days after DLI and 255 and 734 days, respectively, after HCT. In summary, preliminary findings suggest that immunosuppression with pentostatin followed by DLI may be more effective for conversion to full donor chimerism then DLI alone for patients at risk for graft rejection after a nonmyeloablative HCT.