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Purpose: Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. Patients and Methods: We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. Results: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%. Conclusions: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Representativeness of Study Participants

Supplemental Figure 2: Overall and progression-free survival for patients according to NPM1 mutational status

Purpose:Isocitrate dehydrogenase 1 (IDH1) mutations occur in 5% to 10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML.Methods:We conducted a multicenter, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to 12 28-day cycles. The first dose level was 500 mg daily, with level reduction to 250 mg daily, if needed, in a 3 × 3 de-escalation design. Ten additional patients would then receive the MTD or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib.Results:Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose-limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500 mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and 2-year CI of all cGVHD was 63%. Two-year CI of relapse and nonrelapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and 2-year overall survival (OS) was 88%.Conclusions:Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase I study.

Supplemental Figure 1: Overall and progression-free survival for patients, according to whether the transplant followed first line or second line treatment.

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).

Key Points Adding venetoclax to FluBu2 reduced-intensity conditioning transplant did not impair engraftment or induce excessive graft-versus-host disease.Monitoring measurable residual disease by ultra-sensitive duplex sequencing revealed complex clonal dynamics before and after transplant., Visual Abstract, Adding the selective BCL-2 inhibitor venetoclax to reduced-intensity conditioning chemotherapy (fludarabine and busulfan [FluBu2]) may enhance antileukemic cytotoxicity and thereby reduce the risk of posttransplant relapse. This phase 1 study investigated the recommended phase 2 dose (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day −8 for 6-7 doses) in combination with fludarabine 30 mg/m2 per day for 4 doses and busulfan 0.8 mg/kg twice daily for 8 doses on day −5 to day −2 (FluBu2). Transplant related–toxicity was evaluated from the first venetoclax dose on day −8 to day 28. Twenty-two patients were treated. At study entry, 5 patients with MDS and MDS/MPN had 5% to 10% marrow blasts, and 18 (82%) of 22 had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea, and liver transaminitis (n = 3 each). Neutrophil/platelet recovery and acute/chronic graft-versus-host-disease rates were similar to those of standard FluBu2. No dose-limiting toxicities were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (range, 8.6-24.8 months), median overall survival was not reached, and progression-free survival was 12.2 months (95% confidence interval, 6.0-not estimable). In patients with high-risk AML, MDS, and MDS/MPN, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is ongoing. This study was registered at clinicaltrials.gov as #NCT03613532.

Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete granulocyte–macrophage colony-stimulating factor (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase 2 trial of GVAX after HSCT for myelodysplastic syndrome with excess blasts or relapsed/refractory acute myeloid leukemia. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs placebo (1:1) was stratified according to disease, transplant center, and conditioning. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate. GVAX or placebo vaccination was started between day 30 and 45 if there was engraftment and no GVHD. Vaccines were administered subcutaneously/intradermally weekly × 3, then every 2 weeks × 3. Tacrolimus taper began after vaccine completion. A total of 123 patients were enrolled, 92 proceeded to HSCT, and 57 (GVAX, n = 30; placebo, n = 27) received at least 1 vaccination. No Common Toxicity Criteria grade 3 or worse vaccine-related adverse events were reported, but injection site reactions were more common after GVAX (10 vs 1; P = .006). With a median follow-up of 39 months (range, 9-89 months), 18-month progression-free survival, overall survival, and relapse incidence were 53% vs 55% (P = .79), 63% vs 59% (P = .86), and 30% vs 37% (P = .51) for GVAX and placebo, respectively. Nonrelapse mortality at 18 months was 17% vs 7.7% (P = .18), grade II to IV acute GVHD at 12 months was 34% vs 12% (P = .13), and chronic GVHD at 3 years was 49% vs 57% for GVAX and placebo (P = .26). Reconstitution of T, B, and natural killer cells was not decreased or enhanced by GVAX. There were no differences in serum major histocompatibility chain-related protein A/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for myelodysplastic syndrome/acute myeloid leukemia. This trial was registered at www.clinicaltrials.gov as #NCT01773395.

Background: The outcomes for patients (pts) with myeloid malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT) is poor, and relapse occurs more frequently for those with high-risk mutations or cytogenetics. The oral selective BCL-2 inhibitor and BH3 mimetic venetoclax (VEN) increases mitochondrial apoptotic priming even in chemoresistant myeloblasts. Reasoning that VEN would selectively increase the anti-leukemic effect of HCT conditioning chemotherapy without undue toxicity, we evaluated the safety and efficacy of adding VEN to fludarabine and busulfan (FluBu2) reduced intensity conditioning (RIC) chemotherapy. Here, we report on the completed dose-escalation and expansion cohorts from the phase 1 trial. Methods: Pts received escalating doses of VEN (dose level (DL)1, 200 mg on Days -8 to -3 (n=3); DL2, 200 mg on Days -8 to -2 (n=3); DL3, 400 mg on Days -8 to -2 (n=16)) in combination with FluBu2 (fludarabine 30 mg/m2/d on Days -5 to -2 and IV busulfan 0.8 mg/kg bid on Days -5 to -2), followed by PBSC infusion on Day 0 and tacrolimus/methotrexate GVHD prophylaxis. Eligible pts included those with adverse risk AML per ELN criteria or secondary AML in complete remission (CR); MDS (t-MDS; Int-2 or higher IPSS; presence of TP53 or RAS pathway gene mutation) or MDS/MPN (including +8; chr 7 abnl; complex karyotype; or ASXL1 mutation) with £10% blasts pre-transplant; and an 8/8 HLA-matched donor. Dose-limiting toxicity (DLT) was defined (first dose of VEN until Day +28) as any treatment-related death, failure to achieve an absolute neutrophil count (ANC) ≥ 500/mL on 2 consecutive occasions, or any gr 4 non-heme toxicity or tumor lysis syndrome. Targeted sequencing of 88 genes on a clinical assay (sensitivity 1-3%) was performed on pre-VEN and day +100 marrow samples. Flow cytometry-based BH3 profiling was performed on pre-VEN treatment bone marrow in pts with measurable residual myeloblasts. Results: Twenty-two pts (median age 64 y, range 25-71) were treated including 9 AML, 11 MDS, and 2 MDS/MPN cases. 45% of the cohort had an ECOG 2 (n=10). A mutation in TP53 was identified immediately pre-transplant in 55% of pts (n=12). Median HCT-CI score was 4 (range 1-8). 35% and 65.2% had intermediate- and adverse- cytogenetic risk. 20 received HLA-matched unrelated and 2 received HLA-matched related grafts. Median bone marrow leukemia blasts prior to study was 5% (range 5-10). The most common grade 3 or higher non-heme toxicity observed were grade 3 ALT (n=3), diarrhea (n=3), and rash (n=4). Neutrophil engraftment was achieved in all 22 patients (100%). Median days to neutrophil and platelet recovery were 15 (range 12-33) and 14 (range 10-19), respectively. Median donor-derived myeloid chimerism at day +28 was 100% (range, 97-100). No DLTs were observed at DL1-DL3. Acute and chronic GVHD were detected in 12 (GrI, n=7; GrII, n=4; GrIII, n=1) and 6 patients (NIH moderate, n=4; severe, n=2), respectively. At day +100, 16 out of 21 (76%) evaluable patients were in CR. Of the total 22 pts treated to date, 6 have died (5 from disease relapse and 1 from GVHD-related complications). Overall, 7 of 22 pts have relapsed; 2 of these 7 pts subsequently achieved CR2 (one after tapering immunosuppression alone and another after receiving chemotherapy). Median follow-up time among 16 surviving pts is 7.4mo (range, 2.6-19.5). Median OS has not been reached. Median PFS is 11.9 mo (95% CI 6.0 mo, not estimable) (Fig 1). For the entire cohort, the 6-month OS and PFS were 84% and 76%, respectively. Univariable analysis demonstrates pts with an ECOG 0/1 predicted OS and PFS in univariate analysis (p=0.025, 0.001, respectively). Of 21 pts with available paired pre-VEN and day +100 samples, 5 had persistent mutation by NGS (Fig 2). BH3 profiling analysis is underway. Conclusions: The addition of VEN (400 mg; RP2D) to the backbone of FluBu2 conditioning chemotherapy for allo-HCT is not associated with increased toxicity. VEN/FluBu2 combination demonstrates promising clinical activity supporting further evaluation for high risk disease features. To further reduce disease relapse, we are testing VEN/FluBu2 conditioning chemotherapy with VEN/hypomethylating agent maintenance therapy. Disclosures Garcia: Eli Lily: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stone:Astellas: Consultancy; Argenix: Other; Syros: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Celgene: Consultancy, Other; Daiichi-Sankyo: Consultancy; Syndax: Consultancy, Research Funding; Macrogenics: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Aztra-Zeneca: Consultancy; Jazz: Consultancy; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Biolinerx: Consultancy; Takeda: Other: DSMB; Syntrix: Other: DSMB; Agios: Consultancy, Research Funding; Gemoab: Consultancy; Abbvie: Consultancy, Research Funding. Koreth:EMD Serono: Consultancy; Cugene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Research Support; Equillium: Consultancy; Biolojic Design Inc: Consultancy; Therakos: Membership on an entity's Board of Directors or advisory committees; BMS: Other: Research Support; Amgen: Consultancy; Moderna Therapeutics: Consultancy; Miltenyi: Other: Research Support; Clinigen: Other. Nikiforow:Nkarta Therapeutics: Honoraria; Novartis: Honoraria; Kite/Gilead: Honoraria. Steensma:Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company; Astex Pharmaceuticals, Onconova Therapeutics, Pfizer, Stemline Therapeutics, Summer Road: Consultancy; H3 Biosciences: Research Funding. Letai:AbbVie: Consultancy; AstraZeneca: Consultancy; Chugai: Other; Dialectic: Membership on an entity's Board of Directors or advisory committees; Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Zentalis: Membership on an entity's Board of Directors or advisory committees. Lindsley:Jazz Pharmaceuticals: Consultancy, Research Funding; MedImmune: Research Funding; Takeda Pharmaceuticals: Consultancy; Bluebird Bio: Consultancy. Soiffer:Celgene: Other; Juno: Other; Alexion: Consultancy; Novartis: Consultancy; VOR Biopharma: Consultancy; Mana Therapeutics: Consultancy; Precision Bioscience: Consultancy; Cugene: Consultancy; Rheos Therapeutics: Consultancy; Gilead: Consultancy; Be The Match/National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Forty-Seven: Consultancy; Shire: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Takeda: Consultancy; Abbvie: Research Funding; Glycomimetics: Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy; Jazz: Consultancy; Agios: Consultancy; Amgen: Consultancy; Autolos: Consultancy. OffLabel Disclosure: venetoclax with conditioning chemotherapy in the context of a clinical trial

Background Relapse of acute myeloid leukemia (AML) after allogeneic stem cell transplant has a poor prognosis with limited treatment options. Cytokine-induced memory like natural killer (CIML NK) cells are a novel therapy with enhanced cytotoxicity independent of KIR ligand interactions able to induce remission of relapsed/refractory AML (Romee et al, Science TM 2016). We are evaluating the safety and potential efficacy of donor-derived CIML NK cells in patients with relapsed myeloid malignancies after haploidentical donor transplant (haploSCT) in a phase 1/1b study (clinicaltrials.gov: NCT040247761). Here we report on manufacturing, safety, and in vivo correlative biology of the adoptively transferred CIML NK cells in the first 3 enrolled patients. Methods The primary endpoint is to identify the maximum-tolerated dose (MTD) of CIML NK cells in patients with MDS, MPN, or AML who relapsed after haplo-SCT. NK cells were enriched from donor-derived non-mobilized leukapheresis product via two-step CD3 depletion followed by selection of CD56+ cells using the CliniMACS reagent system (Miltenyi Biotec). The enriched NK cell product was cultured for 12-16 hours in X-VIVO 15 media containing rhIL-12, rhIL-15, and rhIL-18 to generate CIML NK cells (Figure 1A). Patients in the current cohort were lymphodepleted with fludarabine 25mg/m2 daily for 3-5 days and cyclophosphamide 60mg/kg daily for 2 days followed by CIML NK cells at a dose of 5-10 x 106 cells/kg and IL-2 106 IU/m2 QOD for 7 doses. Dose-limiting toxicities were evaluated for 6 weeks following NK cell infusion. Response to therapy was assessed at day+28 following CIML NK cell infusion. Results Patient #001 has FLT3-ITD AML that relapsed 5 months after a reduced intensity (RIC) haploSCT. She received 7.4x106 NK cells/kg followed by IL-2 106 IU/m2 QOD for 7 doses. Her day+28 bone marrow had no leukemia blasts although FLT3-ITD mutation remained detectable. Two months post-CIML NK the leukocyte and granulocyte chimerism were 88% and 89%, respectively. Patient #002 has AML with multiple pathogenic variants, including a potentially pathogenic variant in TP53. His disease relapsed 15 months post haplo-SCT with repeat marrow showing all the original mutations, including the TP53 variant (VAF 50.5%). He received 9.5x106 NK cells/kg followed by IL-2 106 IU/m2 QOD for 7 doses. His day+28 marrow had trilineage hematopoiesis without any mutations, including no TP53 mutation (Figure 1B). Two months post-CIML NK the leukocyte and granulocyte chimerism were both 99%. Patient #003 has MDS whose disease relapsed 8 months post RIC haploSCT with persistence of all her diagnostic pathogenic mutations. She received approximately 9.2x106 NK cells/kg and has only just completed IL-2 106 IU/m2 QOD for 7 doses. Among the 3 patients, the main toxicity was prolonged cytopenia requiring stem cell boost in one case. Donor NK cells demonstrated a dramatic shift from a predominantly CD56dimCD16hi (88% of NK cells) to a CD56dimCD16lo phenotype (49% of NK cells) as CIML NK cells. Infused CIML NK cells expanded massively, with approximately 50-fold, 10-fold, and 15-fold maximum in vivo expansion in the first three patients, respectively (Figure 1C). CIML NK cells were the major population in the day+28 marrows in both patients #001 and #002, with CD56+CD7+ cells constituting 89% of the cellularity in the former and 48% in the latter (Figure 1C). CIML NK cells persisted for 3 and 6 months post-infusion in the first two patients. The NK cells were predominantly mature, with most expressing CD16 and low levels of the inhibitory receptor NKG2A. PD-1 expression was much lower on the expanded NK cells vs the pre-infusion donor-derived NK cells. There was minimal concurrent expansion of CD4+CD25+ T-regulatory cells (Figure 1D). Conclusion We show with the first 3 patients in this trial that CIML NK cells can be generated and infused safely, can expand massively in the peripheral blood and bone marrow within the first 30 days post-infusion, and can persist for several months. In addition, CIML NK cell infusion can reduce the burden of pathogenic variant alleles to below the limit of detection, including the burden of high-risk mutations such as in TP53. Though our results are preliminary, the massive in vivo expansion and long-term persistence of adoptively transferred CIML NK cells underscores the unique biology of these cells that makes them an attractive option for cellular therapy protocols. Disclosures Nikiforow: Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees. Rambaldi:Equillium: Research Funding. Cutler:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Koreth:Cugene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Research Support; Clinigen: Other; Miltenyi: Other: Research Support; BMS: Other: Research Support; Therakos: Membership on an entity's Board of Directors or advisory committees; Equillium: Consultancy; EMD Serono: Consultancy; Biolojic Design Inc: Consultancy; Amgen: Consultancy; Moderna Therapeutics: Consultancy. Wu:Pharmacyclics: Research Funding; BionTech: Current equity holder in publicly-traded company. Soiffer:Juno: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; VOR Biopharma: Consultancy; Mana Therapeutics: Consultancy; Precision Bioscience: Consultancy; Cugene: Consultancy; Rheos Therapeutics: Consultancy; Kiadis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; alexion: Consultancy; Be the Match/ National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Ritz:TScan Therapeutics: Consultancy; Talaris Therapeutics: Consultancy; Rheos Medicines: Consultancy; LifeVault Bio: Consultancy; Avrobio: Consultancy; Kite Pharma: Research Funding; Equillium: Research Funding; Amgen: Research Funding; Falcon Therapeutics: Consultancy; Infinity Pharmaceuticals: Consultancy.

Background: Patients (pts) with myeloid malignancies characterized by high risk mutations or cytogenetics who undergo allogeneic hematopoietic cell transplantation (HCT) have poor outcome primarily due to risk of relapse. Strategies to limit relapse include post-transplant maintenance or novel conditioning regimens. The selective BCL-2 inhibitor venetoclax (VEN), a BH3 mimetic, promotes mitochondrial apoptosis in myeloblasts in the presence of cytotoxic stress and is associated with high response rates when combined with hypomethylating agents or low dose cytarabine in untreated elderly AML. We found that VEN could induce apoptotic priming in myeloblasts regardless of poor risk mutations such as TP53 by BH3 profiling, which measures the mitochondrial response to perturbation by a panel of BH3 domain peptides. We thus hypothesized that VEN would promote the anti-leukemic effect of conditioning chemotherapy and therefore reduce the risk of relapse without undue toxicity. Methods: The primary objective of this phase 1 study is to determine the safety of adding VEN to the RIC regimen of fludarabine and busulfex (FluBu2). This study uses a 3+3 design with dose expansion. Eligible pts included: AML in CR (adverse risk per ELN or secondary AML) or MDS (t-MDS; Int-2 or higher IPSS; TP53 mutation; or RAS pathway gene mutation) or MDS/MPN (including +8; chr 7 abnl; complex karyotype; or ASXL1 mutation) with up to 10% blasts at the time of transplant. Dose-limiting toxicity (DLT) was defined as any treatment-related death, failure to engraft (defined as absolute neutrophil count (ANC) ≥ 500/μL on 2 consecutive measurements), or any gr 4 non-heme toxicity or tumor lysis syndrome from day -8 until day +28. Conditioning chemotherapy consisted of fludarabine 30 mg/m2/d, days -5 to -2 and busulfex 0.8 mg/kg bid, days -5 to -2, followed by PBSC infusion on day 0. VEN is scheduled to maximize overlap with FluBu2. VEN dose levels (DL) are 200 mg on days -8 through -3 (DL1); 200 mg on days -8 through -2 (DL2); and 400 mg on days -8 through -2 (DL3). Flow cytometry-based BH3 profiling was performed on pre-VEN treatment bone marrow in pts with measurable residual myeloblasts. NGS using a 95-gene TruSeq panel was performed on pre-VEN treatment and day +100 marrow samples. Results: Nine pts (67% male, median age of 65 y (range 41-71)) have been treated including 3 AML (1 with -17 and 2 with mutations in TP53, RUNX1, and/or ASXL1), 5 MDS (all mutant TP53), and 1 CMML (with mutant ASXL1) in DL1-DL3. 8 donors were matched unrelated and 1 was a matched related. Donors were 44% male. No DLTs were observed at DL1-DL3; dose expansion at DL3 is ongoing. VEN-related toxicities included gr 1 diarrhea (n=3), gr 1 fatigue (n=1), and gr 1 nausea (n=2). Median time to ANC ≥ 500/μL was 16 days (range 13, 25; 1 pt did not nadir) and median donor-derived myeloid chimerism was 100% (range 97, 100) at day +28. Median time to platelet ≥ 20K/μL was 14 days (range 13, 18; 3 did not nadir). 3 developed gr 1 acute graft-versus host disease (GVHD) involving skin and gastric sites. In the 4 followed beyond day +100, 3 developed chronic GVHD (2 moderate, 1 severe) and 1 died from complications of acute GVHD of the gut (stage 3) on day +183. With a median follow-up time of 5 months (range 1.3, 7.8), 2 of 9 pts had disease progression and 1 died. Five out of 6 pts with available paired day +100 samples had no detectable mutation by NGS with >200X mean coverage at the later time point (Fig A). Pt 3 had persistent mutations in TP53 at day +100. Myeloblasts that are more primed require lower doses of [BIM] or [PUMA] peptide to induce cytochrome c release. BH3 profiling of residual myeloblasts on pre-VEN treatment marrow using pro-apoptotic BIM and PUMA peptides (Fig B-C) showed differential individual baseline priming status, which we will correlate with response. Conclusions: VEN at doses up to 400 mg can be safely added to RIC conditioning with FluBu2 resulting in a high molecular negativity rate at day +100 without impairing neutrophil engraftment. Additional correlative studies include targeted deep sequencing to better evaluate measurable residual disease for individual genes and BH3 profiling analysis of myeloblasts collected pre-VEN and post-VEN/pre-FluBu2 to evaluate for a VEN-induced increase in apoptotic priming. To further minimize disease relapse in these high risk pts, we amended the trial to include maintenance therapy with a combination of VEN and azacitidine. Figure Disclosures Garcia: Abbvie: Research Funding; Genentech: Research Funding. Ryan:Vivid Biosciences: Consultancy. Letai:Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member; AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding. Lindsley:Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding; Jazz Pharmaceuticals: Research Funding. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Koreth:Cugene: Consultancy; Amgen: Consultancy; Equillium: Consultancy. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Galinsky:ABIM: Other: Member on specialty oncology board; AbbVie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Merus Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Steensma:Summer Road: Consultancy; Arrowhead: Equity Ownership; H3 Biosciences: Other: Research funding to institution, not investigator.; Onconova: Consultancy; Astex: Consultancy; Pfizer: Consultancy; Stemline: Consultancy; Aprea: Research Funding. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Soiffer:Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Kiadis: Other: supervisory board; Mana therapeutic: Consultancy; Cugene: Consultancy; Jazz: Consultancy. Cutler:BiolineRx: Other: DSMB; Cellect: Other: DSMB; Jazz: Consultancy; BMS: Consultancy; Genentech: Consultancy; ElsaLys: Consultancy; Kalytera: Other: DSMB; Pharmacyclics: Consultancy; Fate Therapeutics: Consultancy; Incyte: Consultancy; Kadmon: Consultancy; Omeros: Consultancy. DeAngelo:Amgen, Autolus, Celgene, Forty-seven, Incyte, Jazzs, Pfizer, Shire, Takeda: Consultancy; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Glycomimetics: Research Funding; Blueprint: Consultancy, Research Funding. OffLabel Disclosure: Venetoclax is a BH3 mimetic and selective BCL-2 inhibitor that was added to standard conditioning chemotherapy (fludarabine and busulfan) on a clinical trial.

Background: Colorectal cancer (CRC) is the third leading cause of cancer-related death in both sexes in the United States. While the overall CRC incidence rates have declined over the past 10 years, the disparity between African Americans (AAs) and non-Hispanic whites has increased and the incidence in AAs remains higher than in other populations. Very few studies have specifically addressed CRC in AAs, and important studies on CRC almost never include significant numbers of AAs to draw any firm conclusions. Objective: To establish a large, robust and well-characterized database and bio-repository collection of CRC from AA patients and controls strengthening a collaborative working group, the Chicago Colorectal Cancer Consortium (CCCC), which spans 5 of the main hospitals of the Chicago area. We collect clinical, demographic and dietary data; and a biological repository of specimens consisting of tumor and non-tumor genomic DNA, RNA, plasma, serum, and paraffin-embedded samples. Specific Aims: The primary goal of the project is to study how genetic and environmental factors and their interaction result in the development of CRC. We will also study prognosis determinants in the AA population. Results: Recruitment and data collection: So far we have recruited 56 AA and 17 white-non Hispanic adenocarcinoma colorectal patients. We have also recruited 84 AAs and 32 white patients with adenomatous polyps, and 44 AAs and 30 white controls (individuals without polyps or previous history of polyps). From all individuals we have collected demographic/socioeconomic data, clinical data, family history of cancer, medication and toxic substance history, and dietary data using the Block Brief 2000 Food Frequency Questionnaire. Preliminary analyses: To identify potential variables that could influence the cancer disparity between AAs and whites, we performed a preliminary analysis of all these data using a Fisher exact test. A systematic molecular analysis of BRAF and KRAS mutations, microsatellite instability and presence of CpG island methylation phenotype in all CRC tumors is being performed. We are also analyzing protein expression of the mismatch repair genes through immunohistochemistry. We will test for an association between these molecular features and clinical variables. Moreover, 1 year follow-up data is already available and being collected on 23 cases. Therefore, we will soon be able to start investigating the relationship of those molecular features with survival and specific chemotherapy response. Summary: The preliminary analysis has highlighted some significant differences between AA and white CRC patients. In comparison with white patients, a higher proportion of AA patients are less than 50 years at diagnosis, take NSAIDS, and fulfill Bethesda criteria, which is a set of criteria to select out patients to be pre-screened for mismatch repair deficiency and eventually for genetic testing to rule out Lynch syndrome. It has also highlighted that CRC patients have a lower level of education than cancer-free individuals in both ethnicities. This type of sociocultural disparities could potentially be associated with different life styles. In fact, AA CRC cases consumed more carbohydrates than controls reflecting this potential life style difference. Cancer Relevance: Understanding the key molecular features and environmental factors that impact CRC development in the AA population is of paramount importance given the scarce information available. Understanding the role genetic factors will be crucial to help risk stratify patients, recommend screening modalities, and recommend preventive measures. When this information is combined with environmental factors, such as dietary habits, we will be able to offer a comprehensive personalized medicine approach for AA CRC patients. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B73.