Abstract: 7011 Background: IVO, a mutant IDH1 (mIDH1) inhibitor, is approved for the treatment of relapsed/refractory mIDH1 AML. We report results from an ongoing phase 1b study of patients (pts) with mIDH1 ND AML ineligible for intensive treatment who received combination IVO+AZA (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m 2 on D1–7 in 28-d cycles. ORR comprised CR + CRi/CRp + PR+ MLFS. CR with partial hematologic recovery (CRh) was defined as CR with ANC 〉 0.5×10 9 /L and platelets 〉 50×10 9 /L. Exploratory analysis included digital PCR assessment of m IDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of 9Oct2018, 23 pts received IVO+AZA (11 male; median age 76 yrs [range 61–88]). Median duration of exposure was 11 mo (0.3–25.3); 12 pts remained on treatment at data cutoff. All-grade adverse events (AEs) regardless of cause in ≥30% pts were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included ECG QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% pts were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18): CR 57%, CRi/CRp 13%, and MLFS 9%. CR+CRh rate was 70% (n = 16). Median time to response was 1.8 mo (0.7–3.8) and to CR 3.5 mo (0.8–6.0); median response duration not yet reached. m IDH1 clearance was seen in 10/16 pts (63%) with CR/CRh, including 9/13 (69%) with CR. Conclusions: IVO+AZA was well tolerated with a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other non-intensive therapies. CR and ORR rates exceeded those of AZA alone (Dombret et al., Blood 2015) and most responders achieved m IDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO +AZA (AGILE, NCT03173248) is actively enrolling pts. Clinical trial information: NCT02677922.

Abstract: 7028 Background: IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with mIDH1 relapsed or refractory AML. We report the safety and efficacy of IVO in pts with ND AML not eligible for standard therapy enrolled in the first-in-human, phase 1, dose escalation and expansion study of pts with mIDH1 advanced hematologic malignancies (NCT02074839). Methods: Enrollment completed on 08May2017. Overall response rate (ORR) comprised complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was CR except absolute neutrophil count 〉 0.5 × 10 9 /L and platelet count 〉 50 × 10 9 /L. Results: Baseline characteristics for 34 pts with ND AML who received IVO 500 mg once daily were: 19 men/15 women; median age 76.5 yrs (range 64-87); 56% ≥75 yrs of age; 76% had secondary AML and 53% prior MDS; 47% had ≥1 hypomethylating agent for an antecedent hematologic disorder. As of 02Nov2018, 7/34 (21%) pts remained on treatment; 3 (9%) had discontinued treatment for allogeneic stem cell transplant. Median duration of IVO exposure was 4.3 mo (range 0.3–40.9). Adverse events of any grade and causality in ≥25% of pts were diarrhea (53%), fatigue (47%), nausea (38%), decreased appetite (35%), leukocytosis, anemia, thrombocytopenia, peripheral edema (all 26%). Most were grade 1–2 and unrelated to treatment. IDH differentiation syndrome (DS) was seen in 6/34 (18%) pts, grade ≥3 in 3 (9%); IVO was held due to DS in 3 pts. QT prolongation was seen in 6 pts. In 33 pts confirmed mIDH1-positive by the companion diagnostic test, CR rate was 30% (95% CI 16%, 49%), CR+CRh 42% (95% CI 26%, 61%), and ORR 55% (95% CI 36%, 72%), with median durations not estimable (95% CI lower bound 4.2, 4.6, and 4.6 mo, respectively); 12-mo response durations were 78%, 62%, and 63%, respectively. Of 21 pts who were transfusion dependent at baseline, 43% became transfusion independent for ≥56 consecutive days on treatment. Updated co-occurring mutation and mutation clearance data will be reported. Conclusions: IVO was well tolerated and induced durable remissions in elderly pts with poor-prognosis mIDH1 ND AML. Clinical trial information: NCT02074839.

Abstract: 7004 Background: Recurrent mutations in isocitrate dehydrogenase 2 (m IDH2) occur in 8-15% of AML pts. mIDH2 proteins synthesize an oncometabolite, 2-hydroxyglutarate (2HG), causing DNA and histone hypermethylation and blocked myeloid differentiation. Enasidenib (AG-221) is an oral, selective, small-molecule inhibitor of mIDH2 protein. Methods: This phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in pts with m IDH2 myeloid malignancies. Safety for all pts and efficacy outcomes for R/R AML pts from the phase 1 dose-escalation and expansion phases are reported. Results: In all, 239 pts received enasidenib. In the dose-escalation (n=113), the MTD was not reached at doses up to 650 mg daily. Median 2HG reductions from baseline were 92%, 90%, and 93% for pts receiving 〈 100 mg, 100 mg, and 〉 100 mg daily, respectively. Enasidenib 100 mg QD was chosen for the expansion phase (n=126) based on PK/PD profiles and demonstrated efficacy. Median number of enasidenib cycles was 5 (range 1–25). Grade 3-4 drug-related investigator reported AEs included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (ie, retinoic acid syndrome; 7%). For R/R AML pts, overall response rate (ORR) was 40.3%, including 34 (19.3%) complete remissions (CR; Table). Response was associated with cellular differentiation, typically with no evidence of aplasia. Median overall survival (OS) for R/R AML pts was 9.3 months (mos). For pts who attained CR, OS was 19.7 mos. Pts who had received ≥2 prior AML regimens (n=94; 53%) had median OS of 8.0 mos. Conclusions: Enasidenib was well tolerated, induced CRs, and was associated with OS of 〉 9 mos in pts who had failed prior AML therapies. Differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib. Clinical trial information: NCT01915498. [Table: see text]

Abstract: 7030 Background: Inactivation of p53 and overexpression of Mcl1 are common mechanisms that cancer cells use to evade apoptosis. BTX-A51 is a novel, oral, direct inhibitor of casein kinase 1α (CK1α) and cyclin dependent kinase 7 and 9 that robustly increases p53 protein levels via CK1α inhibition while preferentially decreasing super-enhancer transcription of Myc and Mcl1, enabling selective apoptosis of leukemia cells. Here, we report the interim results of the first-in-human (FIH) study of BTX-A51 in patients (pts) with R/R AML. Methods: The study utilizes a hybrid accelerated titration with single pt cohorts and a Bayesian optimal interval design in dose escalation. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating the antileukemic activity, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 25 January 2022, 30 pts (28 with AML; 2 with HR-MDS) enrolled at dose levels between 1 and 42 mg; 2 pts remain on treatment. Monotherapy doses between 1 and 42 mg were administered orally 3 days/week (wk) (3 wk in a 28-day cycle) and at 21 mg (4 wk in a 28-day cycle). Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The most common treatment-emergent AEs (TEAEs) were hypokalemia, nausea, vomiting, diarrhea, and hypotension. The most common Grade 3 or higher TEAEs were anemia, febrile neutropenia, platelet count decreased, and hypokalemia. DLTs included grade 3 hepatic failure at the 42 mg dose in 1 pt and grade 3 alkaline phosphatase elevation in 1 pt at the 21 mg dose. All events resolved after holding study drug. Plasma PK of BTX-A51 was roughly dose-proportional between 1 and 42 mg with accumulation based on AUC between Day 1 and Day 5. Estimated half-life was between 18 and 55 hours. Among the 30 pts with R/R AML and MDS, CR/CRi rate was 10% (3/30) with 1 pt at the 11 mg and 2 pts at the 21 mg dose levels attaining CRi. Bone marrow (BM) blast reduction 〉 50% occurred in 4 patients including the 3 responders, all at the 11 and 21 mg dose levels. All 4 pts with 〉 50% BM blast reduction had RUNX1 mutations; 9 pt with RUNX1 enrolled in the trial. The median duration of response for pts achieving CR/CRi was approximately 1.5 month. Responses were not observed in MDS pts. PD data will be provided in the full presentation. Based on the clinical data from dose escalation, the RP2D is 21 mg administered 3 days/wk for 4 wk of a 28-day cycle. Conclusions: In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining 〉 50% BM blast reduction. Clinical trial information: NCT04243785.

Abstract: 7032 Background: Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown improved overall survival vs SOC in pts with r/r ALL in a randomized phase 3 study ( Haematologica 2016;101:S129). To better evaluate safety, we compared AEs of blin vs SOC after adjusting for varying treatment exposure times. Methods: Adults ≥ 18 yrs with r/r ALL (refractory, 1 st relapse 〈 1 yr, ≥ 2 relapses or relapse after transplant) were randomized to receive blin or SOC (1 of 4 predefined regimens). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 µg/d on d1−7 in cycle 1, then 28 µg/d); up to 4 maintenance cycles (4 wks on/8 wks off) were allowed for ≤ 12 mo. Exposure-adjusted (exp-adj) event rates were calculated as no. of events*100/total exposure time (Table). Results: Median (range) no. of cycles were 1 (1−4) for SOC and 2 (1−9) for blin. The highest exp-adj rates (per 100 pt-yrs) were for pyrexia (507 SOC vs 376 blin), anemia (987 vs 229), thrombocytopenia (750 vs 126) and neutropenia (351 vs 121), all lower in blin. Febrile neutropenia (365 vs 93) and infections (1216 vs 436) were also both lower in blin (p 〈 0.0001). Exp-adj rates for neurologic events were 743 SOC vs 472 blin, with median time (range) to onset of 7 (1−43) d and 7 (1−190) d, respectively, and gr ≥ 3 cytokine release syndrome (CRS) rates were 0 SOC vs 10 blin. The most frequent AEs in both cycles 1 and 2 were pyrexia, nausea and anemia in both arms; CRS events decreased in the blin arm between cycles 1 and 2 (14% vs 2%). Most fatal AEs were related to infection in both arms. Conclusions: Here blin showed an AE profile consistent with that previously reported for r/r ALL, including similar rates of manageable CRS and neurologic events. Exp-adj AE rates were generally higher in SOC vs blin, including for cytopenias and infections. Clinical trial information: NCT02013167. [Table: see text]

Abstract: Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that has shown antileukemic activity. Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57). We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2nd or later (2+) generation TKI. Methods. Eligible adult pts (≥18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib. All pts had to have 〉 5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2. Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter). The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints. Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10-5. Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation). 53% of pts were men. Median (range) age was 55 (23-78) years (≥65 years, 27%). Ten pts (22%) had a BCR-ABL gene with T315I mutation. All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy. 38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT. Efficacy outcomes for key endpoints are shown in the table. 16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1. The patient who never received 2+ generation TKI did not respond to treatment. 12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response. Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response. Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response). One patient died in CR post alloHSCT. Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months). Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%). Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator. Three pts discontinued because of AEs. Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2). 21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption. Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity. AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab. Table 1. Table 1. Disclosures Martinelli: Novartis: Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Bayer: Equity Ownership; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Erytech: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Gilead Sciences: Consultancy; Sanofi: Equity Ownership; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Fielding:Amgen: Consultancy, Honoraria. Sterling:Amgen: Employment, Equity Ownership. Benjamin:Amgen: Employment, Equity Ownership. Stein:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding.

Abstract: Tipifarnib (R115777, Zarnestra) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 37 patients were accrued, with 32 evaluable for toxicity. Median age at treatment is 62 (range 33–77), with 15 F, 22 M. RESULTS: The MTD on this schedule was 1200 mg B.I.D., with the major dose limiting toxicity determined by course one being creatinine elevation. At the 6 pts treated at the MTD there was one DLT (grade 3 creatinine), one grade 3 nausea (not a DLT), and grade 2 toxicities including liver enzyme abnormalities, nausea/vomiting, and rash. At dose level 1, metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy was observed. Two patients treated at the MTD had a complete remission: a 69-yr old male who relapsed after 231 days, and a 66-yr old male who relapsed after 258 days, but who responded to re-treatment with tipifarnib and is disease-free 548 days (18 months) since enrolling in the study. At 1000mg BID dose, a 69-yr old woman with relapsed AML after autologous transplant had a CR after 2 cycles and went on receive a successful allogeneic transplant and is in remission 2yrs from her first cycle of tipifarnib. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. Higher doses resulted in a higher incidence of dose limiting renal toxicity, fewer courses, and no complete remissions. Additional patients are accruing at the MTD to further understand the toxicities on this schedule. In AML patients, a two-fold increase in tipifarnib dosing can be tolerated on this dosing schedule with responses seen at the higher doses. A monotherapy phase 2 or tipifarnib combination study in AML using this schedule appears warranted.

Abstract: Abstract 222 We have previously reported the feasibility and safety of augmenting the reduced-intensity regimen (RIC) of FM by addition of total marrow irradiation, a targeted form of TBI, using a helical tomotherapy (HT) device (Rosenthal, Blood. 2011;117(1):309–315). In this study we compared outcomes in patients with acute leukemia undergoing HCT receiving either TFM or FM. Patients and Methods: We analyzed 72 patients with acute leukemia or MDS who received either FM (N=36) or TFM (N=36) HCT. Eligibility criteria for TFM were age 〉 50 years of age or compromised organ function (COF); high-risk remission or marrow blasts ≤10%. TFM patients were matched to a set of FM patients based on age, gender, diagnosis and disease risk (low, intermediate, high). All patients received FM with fludarabine 25 mg/m2/d × 5 days and melphalan140 mg/m2/d × 1 day, and TMI was delivered at 150cGy/fraction in 8 fractions over 4 days in the TFM group. Supportive care and treatment for prevention of GVHD were given according to our institution standard guidelines for both groups. Results: Demographic characteristics were similar, including gender (20 females, 55.6%) and age (median 58 years, range: 22–68 in TFM and 20–68 in FM). The proportions of patients by diagnoses were similar: AML (n=27), ALL (n=7), MDS (n=2). Disease risk assignments in both groups were: Low risk (n=15), intermediate (n=6), high (n=15). There were 15 and 13 pts with active disease in FM and TFM, respectively. HLA-identical siblings (n=16, 44.4%) or matched unrelated donor (n=20, 55.6%) were used in each group. Outcomes are reported for the TFM and FM recipients, respectively as follows: myeloid recovery was documented on day 13.5 (9–24) and 15 (8–20). Transplant-related toxicities were limited to grade 3 or less in both groups. The most common grade 3 toxicities were: mucositis, n=9 and n=7 and bacterial infection, n=10 and n=11, respectively. Acute GvHD grade II-IV occurred in 20 pts (55%) and 19 (53%). Extensive chronic GVHD was documented in 24 (67%) and 20 (56%) pts. Twenty-one and 18 patients are alive at a median of 30.2 months and 35.3 months in the TFM and FM, respectively. The relapse cumulative incidence at 2 years post HCT was 11.1% (TFM) compared to 30.6% (FM) (p=0.06) (insert ). With a median follow-up of 31.7 months (4.1 – 62.5) for alive patients, the 2-year overall and progression-free survival estimates are 57.2 % (95% CI, 46.6–66.4) -TFM, and 62.8% (95% CI, 51.8–72.0) -FM, and 57.7% (95% CI, 47.2–67.0) -TFM, and 48.5% (95% CI, 40.2–56.3) -FM, respectively. Conclusion: The addition of TMI at a dose of 1200 cGy to FM is safe and tolerable and may decrease the risk of relapse related mortality. Disclosures: No relevant conflicts of interest to declare.