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PURPOSE Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML. MATERIALS AND METHODS The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML. RESULTS Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. CONCLUSION Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.

Background: Hypomethylating agents such as decitabine are standard of care for older patients with newly diagnosed acute myeloid leukemia. Single-arm studies have suggested that a 10-day schedule of decitabine may result in better outcomes than the standard 5-day schedule. The aim of this study was to assess the relative efficacy and safety of these two schedules of decitabine in older adults with acute myeloid leukemia unfit for intensive chemotherapy. Methods: Between February 28, 2013 and April 12, 2018, older adults with acute myeloid leukemia unfit for intensive chemotherapy were randomized using a Bayesian adaptive design to receive decitabine 20 mg/m2 intravenously as induction for either 5 consecutive days or 10 consecutive days. Initially 40 patients were allocated equally to the two treatment arms using block randomization. After the completion of the equal randomization, the response-adaptive randomization algorithm was employed to unbalance the randomization probabilities in favor of the arm with a superior response rate. Responding patients received decitabine on a 5-day schedule as consolidation for up to 24 cycles. The primary endpoint was composite response rate (defined as complete remission [CR], CR with incomplete platelet recovery [CRp], and CR with incomplete hematologic recovery [CRi]) of the two schedules achieved at any time during therapy in the intention-to-treat population. This trial is closed to new patient entry and was registered at ClinicalTrials.gov (NCT01786343). Findings: Seventy one patients received either decitabine for 5 days (n=28) or for 10 days (n=43) and were evaluable for efficacy and safety. The overall response rate at any time during therapy was similar in the 5-day and 10-day arms (43% [95% credible interval (0.26, 0.60)] versus 40% [95% credible interval (0.26, 0.60)], respectively; P=0.78). The difference in overall response rate between groups was 3% (95% credible interval [−0.21, 0.27]). With a total duration of follow-up of 38.2 months, the median overall survival (OS) in the 5-day and 10-day decitabine arms was 5.5 months (interquartile range [IQR], 2.1–11.7) and 6.0 months (IQR, 1.9–11.7), respectively, and 1-year OS rates were 25% in both arms (P=0.47). No significant differences in response rates or OS were observed when stratified by cytogenetics, de novo versus therapy-related/secondary acute myeloid leukemia, or TP53 status. The most common grade 3–4 adverse events were neutropenic fever (7 patients [25%] in the 5-arm and 14 patients [33%] in the 10-day arm) and infection (5 [18%] versus 16 [37%]). In the 5-day arm, 1 patient (4%) each died from sepsis in the context of neutropenic fever, infection, and hemorrhage; in the 10-day arm, 6 patients (14%) died from infection. Early mortality was similar between the two schedules. Interpretation: In older patients with newly diagnosed acute myeloid leukemia, decitabine given on either a 5-day or 10-day schedule did not result in significantly different response rates or survival. These findings suggest ...

BACKGROUND: TP53 mutation (TP53 mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53 mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53 mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m 2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53 mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53 mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53 mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53 mut versus wildtype TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53 mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53 mut AML have lower response rates and shorter survival with DEC10-VEN.

FLT3 mutations occur in 20-35% patients with newly diagnosed (ND) acute myeloid leukemia (AML) and confer a higher risk of relapse and inferior overall survival (OS). Given modest benefit with first-generation multikinase inhibitors, second-generation FLT3 inhibitors (FLT3i) have been combined with low-intensity therapies (LIT) with encouraging results but are not curative 1-4. Venetoclax with hypomethylating agent (HMA) has emerged as the new standard for older/unfit patients with AML 5. Pre-clinical studies in FLT3 mut cell lines, primary samples, and xenografts have shown synergy between FLT3i's and venetoclax through downregulation of Mcl-1 and Bcl-x L 6-9. Clinical studies have demonstrated safety and activity of the combination of FLT3i and HMA with composite complete remission (CRc) rates of 65-80% and median OS 8.5-20 months 1,4,10 , as well as FLT3i and venetoclax which showed CRc rate of 85% in relapsed/ refractory (R/R) FLT3 mut AML including in patients with prior FLT3i exposure 11. We hypothesized that triplet therapy combining FLT3i, venetoclax, and HMA may further improve outcomes. Hence, we added FLT3i to our regimen of 10-day decitabine with venetoclax (DEC10-VEN) for FLT3 mut AML. We herein describe the first report of such a 'triplet' combination regimen for FLT3 mut AML. This phase 2 trial (NCT03404193) enrolled ND patients with AML > 60 years and R/R patients >18 years. Patients needed to have ECOG performance status ≤3. Patients with favorable-risk cytogenetics and prior Bcl-2 inhibitor exposure were excluded. Patients received decitabine 20 mg/m 2 IV for 10-days every 4-6 weeks for induction followed by decitabine for 5-days after CR/CRi, as described previously 12. Venetoclax dose was 400 mg PO daily or equivalent (with azole co-administration). Reduction of venetoclax duration to <21 days per cycle was permitted in cases of persistent myelosuppression, after confirming ≤5% blasts or hypo/acellular marrow. Addition of FLT3i of clinician's choice was allowed (Fig. S1). ND patients were admitted for the first cycle and R/R patients were admitted for the initial venetoclax rampup. Cytoreduction to WBC <10 × 10 9 /L was required prior to starting therapy and all patients received prophylaxis for tumor lysis syndrome, and antimicrobial prophylaxis. Responses were graded per the IWG criteria for AML with adapted CRc criteria per the gilteritinib ADMIRAL and quizartinib QUANTUM-R studies 13,14. The CRc included CR, CR with incomplete platelet recovery, and CR with incomplete hematologic recovery 13. OS was measured from start of therapy until death or censored at last follow-up. Progression-free survival was defined from the time of response until relapse, death, or censored at last follow-up. Duration of response was determined from the time of response till relapse or censored at last followup or at the time of death without relapse. Measurable residual disease (MRD) was assessed on bone marrow (BM) specimens using 8-color multiparametric flow

Hypomethylating agents (HMA) with venetoclax is a new standard for older/unfit patients with acute myeloid leukemia (AML). However, it is unknown how HMA with venetoclax compare to intensive chemotherapy (IC) in patients who are “fit” or “unfit” for IC. We compared outcomes of older patients with newly diagnosed AML receiving 10‐day decitabine with venetoclax (DEC10‐VEN) vs IC. DEC10‐VEN consisted of daily venetoclax with decitabine 20 mg/m2 for 10 days for induction and decitabine for 5 days as consolidation. The IC cohort received regimens containing cytarabine ≥1 g/m2/d. A validated treatment‐related mortality score (TRMS) was used to classify patients at high‐risk or low‐risk for TRM with IC. Propensity scores were used to match patients to minimize bias. Median age of the DEC10‐VEN cohort (n = 85) was 72 years (range 63‐89) and 28% patients were at high‐risk of TRM with IC. The comparator IC group (n = 85) matched closely in terms of baseline characteristics. DEC10‐VEN was associated with significantly higher CR/CRi compared to IC (81% vs 52%, P < .001), and lower rate of relapse (34% vs 56%, P = .01), 30‐day mortality (1% vs 24%, P < .01), and longer overall survival (OS; 12.4 vs 4.5 months, HR = 0.48, 95%CI 0.29‐0.79, P < .01). In patients at both at high‐risk and low‐risk of TRM, DEC10‐VEN showed significantly higher CR/CRi, lower 30‐day mortality, and longer OS compared to IC. Patients at both high‐risk and low‐risk of TRM had comparable outcomes with DEC10‐VEN. In conclusion, DEC10‐VEN offers better outcomes compared to intensive chemotherapy in older patients with newly diagnosed AML, particularly in those at high‐risk of TRM.

Assessment of measurable residual disease (MRD) provides prognostic information in acute myeloid leukemia (AML). However, the utility of MRD with venetoclax-based lower intensity regimens is unknown. We analyzed the prognostic value of achieving a negative MRD in older/“unfit” patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. MRD was evaluated in bone marrow specimens using multicolor flow cytometry (sensitivity 0.1%). Ninety-seven patients achieving either a complete remission (CR) or CR with incomplete hematologic recovery (CRi) or morphologic leukemia-free state were included. Median age was 72 years (interquartile range, 68-78 years), and 64% had adverse-risk AML. Eighty-three patients achieved CR/CRi, and 52 (54%) became MRD negative. Median time to becoming MRD negative was 2.0 months (interquartile range, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.12-0.78; P = .004), longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P &lt; .001), as well as longer overall survival (OS) (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P &lt; .001). Patients achieving an MRD-negative CR had longer OS compared with those with an inferior response (median OS, 25.1 vs 11.6 months; HR, 0.33; 95% CI, 0.19-0.58; P &lt; .0005). Patients becoming MRD negative within 1 month had an improved OS compared with MRD-positive patients (median OS, 25.1 vs 3.4 months; HR, 0.15; 95% CI, 0.03-0.64; P &lt; .0001). Differential impact of MRD status on survival outcomes persisted at a later 4-month time point of evaluation. In conclusion, MRD-negative status at 1, 2, and 4 months after starting therapy confers significantly better survival in older/unfit patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT03404193.

Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24–88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07–0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML.Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433