Abstract: Background: Pev (TAK-924/MLN4924), a novel investigational NAE inhibitor, enhances the anti-leukemic effects of aza in AML cell lines and murine xenografts (Smith et al, Blood 2011). Single-agent pev activity was confirmed in relapsed/refractory AML pts (Swords et al, Br J Haematol 2015). This open-label, multi-center, dose-escalation study (NCT01814826) investigated pev + aza in treatment-naïve older AML pts. Dose-limiting toxicities (DLTs)includedG2 hyperbilirubinemia and G4 AST elevation (n=1 each) at pev 30 mg/m2. The maximum tolerated dose (MTD) for the combination was pev 20 mg/m2 + aza 75 mg/m2 (Swords et al, ASH 2014).We present updated safety/efficacy results for the MTD cohort (fully enrolled). Methods: Primary objectives included safety and tolerability assessments of pev + aza in addition to defining the MTD. Secondary objectives included pharmacokinetics (PK) and disease response assessments. Treatment-naïve pts ≥60 yrs unlikely to benefit from standard induction therapy (defined by ≥1 of: antecedent hematologic disease; known adverse cytogenetic risk; ECOG PS 2; ≥75 yrs), received pev 20 or 30 mg/m2 IV on d 1, 3 and 5, + fixed-dose aza (75 mg/m2 IV/SC) on d 1-5, 8 and 9, every 28 d until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed per NCI-CTCAE v4.03; response per IWG criteria for AML. Bone marrow samples were collected at screening to assess cytogenetic risk (CALGB) and mutation profile; serial samples for PK analysis were drawn in cycle 1. Results: Demographics:As of May 17 2016, 61 pts (median age 75 yrs [range 61-89]; 54% male; 77% ECOG PS 0/1, 23% ECOG PS 2; 57% de novo, 43% secondary AML; median marrow blasts 36% [range 5-92] ) had received pev 20 mg/m2, of whom 48% had intermediate-, 30% adverse-, and 3% favorable-risk cytogenetics. Safety/PK: Pts received a median of 4 cycles (range 1-33), and 23/61 pts (38%) received ≥6 cycles of pev + aza. The most common AEs were constipation (46%), nausea (44%), fatigue (43%), and anemia (39%). Fifty pts (82%) experienced ≥G3 AEs; the most frequent (≥15%) were anemia, febrile neutropenia (each 28%), thrombocytopenia (21%), neutropenia (18%), and pneumonia (15%). ≥G3 AST/ALT elevations were reported in 5% of pts. Forty-one pts (67%) experienced serious AEs; the most frequent (≥10%) were febrile neutropenia, neutropenia (each 25%), and pneumonia (11%). Two pts discontinued due to pev related toxicity (G3 febrile neutropenia). There were 11 on-study deaths unrelated to study therapy. In the MTD expansion phase (n=55), 2 pts experienced DLTs of transient G3/4 transaminase elevations, and were successfully re-challenged following dose reduction to remain on study. Pev PK was not altered by the addition of aza. Responses: Overall response rate (ORR) in 52 response-evaluable pts was 60% (18CR, 5CRi, 8PR; Figure 1), with a median duration of remission of 8.3 mos (95% CI: 5.75, 12.06); 19/31 (61%) responses occurred within the first 2 cycles.Of the 23 pts with CR/CRi, 14 had responses lasting ≥4 cycles, 2 went on to have allogeneic stem cell transplant, 9 had intermediate-, 7 adverse-, and 1 favorable-risk cytogenetics. ORR was: 64% (14/22; 7CR, 3CRi, 4PR) vs 57% (17/30; 11CR, 2CRi, 4PR) for pts with low- ( 〈 30%) vs high- (≥30%) marrow blasts; 58% (18/31; 11CR, 3CRi, 4PR) vs 62% (13/21; 7CR, 2CRi, 4PR) for de novo vs secondary AML pts; 61% (14/23; 8CR, 1CRi, 5PR) vs 50% (8/16; 5CR, 2CRi, 1PR) for intermediate- vs adverse-risk cytogenetic pts; 83% (19/23; 14CR, 2CRi, 3PR) vs 41% (12/29; 5CR, 3CRi, 4PR) for pts who received ≥6 cycles vs 〈 6 cycles of aza, respectively. Responses were seen in pts with typically refractory disease; 7/11 pts with TP53 mutations achieved either a CR/CRi (n=3) or PR (n=4); 4 stayed on study for 〉 10 cycles. After a median follow-up of 16.4 mos, 6-mo survival was 52%. Median overall survival was: 7.0 mos for the MTD cohort; 8.5 vs 5.2 mos for pts with low- ( 〈 30%) vs high- (≥30%) marrow blasts (Figure 2); 5.6 vs 11.2 mos for de novo vs secondary AML pts (Figure 3); and 16.1 vs 5.3 mos for pts aged 65-74 vs ≥75 yrs, respectively. Conclusion: Pev + aza was well tolerated. Response rates and durable remissions were observed with limited additional toxicity beyond what is expected for aza alone. The timing and frequency of responses suggests benefit from the addition of pev compared to aza alone (Dombret et al, Blood 2015). At the time of writing, a randomized phase 2 study in low-blast AML/high-risk myelodysplastic syndromes is ongoing. Disclosures Coutre: Janssen: Consultancy; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Zeidner:Tolero: Research Funding; Merck: Research Funding; Takeda: Research Funding; Otsuka: Consultancy; Agios: Honoraria. Foran:medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; pfizer: Honoraria; karyopharm: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Cruz:Millennium Pharmaceuticals, Inc.: Honoraria; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Erba:Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Ariad: Consultancy; Jannsen: Consultancy, Research Funding. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Vardhanabhuti:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dobler:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faessel:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dash:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sedarati:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dezube:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Savona:Takeda: Research Funding; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Abstract: RP2D of PEV 20 mg/m2 in PEV/AZA combo did not alter toxicity profile of AZA; dose-limiting toxicities were transiently elevated AST/ALT. In treatment-naive older AML patients, the intent-to-treat ORR was 50%.

Abstract: Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naïve AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts 〉 80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. Table 1 Common all-grade AEs n (%) Most frequent (≥10%) drug-related grade ≥3 AEs n (%) Febrile neutropenia 9 (36) Febrile neutropenia 4 (16) Constipation 8 (32) Thrombocytopenia 3 (12) Decreased appetite 7 (28) – – Thrombocytopenia 7 (28) – – Table 2 Responders* Tumor Type Cytogenetic Risk Group Current Status Response Molecular CR 1st Response 1st CR 1 De novo AML Adverse C12 C4 – – 2 Undetermined C4† C1 C1 Y 3 Adverse C9 C1 C1 Y 4 Undetermined C5‡ C1 C2 Y 5 Intermediate C5† C1 C2 N 6 Intermediate C7 C1 C4 Y 7 Intermediate C2 C2 – – 8 Secondary AML Undetermined C4 C2 C2 – 9 Normal C4 C1 – – 10 De novo AML – C1 C1 – – Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran:Takeda Pharmaceuticals International Co.: Research Funding. Hua:Takeda Pharmaceuticals International Co.: Employment. Faessel:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash:Takeda Pharmaceuticals International Co.: Employment. Sedarati:Takeda Pharmaceuticals International Co.: Employment. Dezube:Takeda Pharmaceuticals International Co.: Employment. Medeiros:Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

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: 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.

Abstract: The HCT-CI stratifies patients into 3 groups for risks of grades 3 to 4 GVHD regardless of conditioning intensity, donor, or graft types. Comorbidity burden and development of grades 2 to 4 acute GVHD have cumulative effects on mortality rates.

Abstract: Idiopathic pneumonia syndrome (IPS) is a significant noninfectious complication of hematopoietic stem cell transplantation (HSCT). We compared the incidences and outcomes of IPS among patients who underwent allogeneic HSCT after nonmyeloablative (n = 183) compared with conventional (n = 917) conditioning between December 1997 and December 2001. Patients given nonmyeloablative conditioning were older than those given conventional conditioning (median ages, 53 vs 41 years; P = .001). The cumulative incidence of IPS was significantly lower at 120 days after nonmyeloablative conditioning than conventional conditioning (2.2% vs 8.4%; P = .003). In addition, greater patient age (older than 40 years), diagnosis of acute leukemia or myelodys-plastic syndrome, and severe acute graft-versus-host disease were associated with significantly increased risks for IPS. Among older patients (older than 40 years) given conventional conditioning, high-dose total body irradiation (TBI) was associated with an increased risk for IPS than were non-TBI–based regimens (16% vs 5.8%; P = .001). IPS occurred early after transplantation, progressed rapidly, and was associated with a high mortality rate (75%) despite aggressive support. Initiation of mechanical ventilation and the presence of renal insufficiency at IPS onset were associated with increased risks for death after IPS. These findings support the concept that lung damage from the conditioning regimen plays a crucial role in the development of IPS after HSCT.

Abstract: Nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly being explored as therapy in patients who are not eligible for conventional myeloablative HSCT. Whether these transplants are associated with reduced risk of transplantation-related infections is unknown. We analyzed the incidence of posttransplantation cytomegalovirus (CMV) infections in 56 consecutive mycophenolate mofetil (MMF) patients with hematologic malignancies who underwent nonmyeloablative HSCT (TBI, 2Gy, day 0; MMF/cyclosporine after transplantation). In addition, 18 of 56 patients received 30 mg/m2/d fludarabine on days −4 to −2. Most donors were HLA matched and related (93%). Each case patient was matched to 2 controls who were treated by conventional HSCT during the same time period (January 1997 through April 2000). Matching criteria included CMV risk group, HSC source, donor type, age, and underlying diseases. No CMV disease occurred in the low (donor and recipient serologically negative) and intermediate (donor serologically positive and recipient negative) CMV risk groups during the first 100 days. Among cases at high risk for CMV (seropositive recipients), trends to less CMV antigenemia (P = .11), viremia (P = .16), and disease (P = .08) compared with controls were observed; all severe manifestations combined (CMV viremia and disease) were significantly reduced among cases (P = .01). However, by day 365, the overall incidence of CMV disease became similar in both groups. The onset of CMV disease was significantly delayed among case patients compared with controls (median, 130 days versus 52 days; P = .02). It was concluded that CMV disease was significantly delayed in nonmyeloablative cases, but that the overall 1-year incidence was similar to myeloablative HSCT patients. Therefore, nonmyeloablative HSCT patients should receive CMV surveillance beyond day 100 and pre-emptive ganciclovir treatment similar to that of myeloablative HSCT patients.