Cortes, Jörge E.

e18521 Background: The FDA-approved drug trabectedin is a DNA minor groove binder (MGB) with activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB, with activity against myeloid leukemia cells. A phase I clinical trial was initiated to determine recommended doses in MDS/AML. Further assessment of its safety, tolerability, and pharmacogenetics were studied. Methods: In total, 42 patients with relapsed/refractory MDS/AML received lurbinectedin, using a 3+3 study design. It was administered as a 1-hour IV infusion first at 3.5, 5, 6, and 7mg per dose on days 1 and 8. Subsequently, it was administered on days 1, 2, and 3, using 1, 1.5, 2, or 3mg per dose per patient. Results: Three patients had dose-limiting toxicities (DLTs), which were rhabdomyolysis (up to gr 4), hyperbilirubinemia (gr 3), and oral herpes (gr 3). All DLTs occurred in the 6 and 7mg cohorts. Adverse events included febrile neutropenia/infections (n = 3), GI (n = 6) and pulmonary (n = 2) toxicity, hyperhidrosis (n = 1), and QT prolongation (n = 1). Overall, 33 of 42 patients (79%) had reduction of blasts in peripheral blood (PB) or bone marrow (BM) at nadir, including 23 (55%) with > 50% reduction in PB blasts alone (n = 18) or both BM and PB blasts (n = 5). One patient had PR, 2 patients had morphologic leukemia-free survival, and most (n = 30) were discontinued for progressive disease. Early deaths occurred from disease-related causes, not attributable to lurbinectedin. Thirty-two patients treated at MD Anderson were analyzed for clinical characteristics and responses. Notably, among patients with follow-up bone marrow biopsy, those with a cytogenetic abnormality at chromosome 11q21-23 had significantly greater bone marrow blast reduction than those without such abnormality (change in percentage blasts: -31±14% [n = 4] vs. 8±8% [n = 16], respectively; P= 0.04). Conclusions: Lurbinectedin is generally safe and tolerated at dose levels tested. While no sustained remissions > 3 cycles were observed in these highest-risk patients, single-agent lurbinectedin was transiently leukemia suppressive for some patients, including some with abnormal chr11q or TP53 mutation. Rational combinations and situational uses of lurbinectedin are under consideration. Clinical trial information: NCT01314599.

7003 Background: Gilteritinib, a highly selective FLT3/AXL inhibitor, has displayed antileukemic activity in FLT3 mutation-positive (FLT3mut+) relapsed/refractory (R/R) AML in the CHRYSALIS Phase I/II study (NCT02014558), specifically at doses ≥80 mg/d. This exploratory analysis assessed molecular response to gilteritinib in a CHRYSALIS subpopulation. Methods: Molecular response was assessed from bone marrow aspirates obtained at baseline and at ≥1 additional time point from FLT3mut+ patients (≥18 y) treated with 120 or 200 mg/d gilteritinib. These doses were identified due to their ability to induce consistent, potent FLT3 inhibition and high clinical response rates. FLT3-ITD and total FLT3 were quantified by NGS to assess molecular response. A Cox regression model of overall survival (OS) by Kaplan-Meier estimation established a FLT3-ITD:total FLT3 ratio (ITD signal ratio) of 10−2as the threshold for improved survival. Results: Of 147 FLT3-ITDmut+ patients who received gilteritinib 120 or 200 mg/d, 80 were included in this analysis. Composite response rate for these 80 patients was 55%. During response, 20 patients (25%) had an ITD signal ratio of ≤10−2. Of these 20 patients, 18 had a ratio of ≤10−3 (major molecular response [MMR]) and 13 had a ratio of ≤10−4 (minimal residual disease [MRD] negative). Median time to achieve minimum signal ratio was 54 days. Elimination of morphologic leukemia was observed in 80% of patients with ITD signal ratios <10−2. Patients who had a signal ratio ≤10−2, MMR, or were MRD negative had significantly longer median OS than those who did not (Table). Conclusions: Molecular responses to gilteritinib in FLT3-ITDmut+ R/R AML correlated with clinical response and improved OS. This is the first demonstration of molecular response to a FLT3 inhibitor in AML. These data suggest ITD signal ratio may predict durable clinical benefit of gilteritinib. Clinical trial information: NCT02014558. [Table: see text]

AbstractNovel therapies have potential to improve outcomes in patients with acute myeloid leukemia (AML) harboring FLT3‐ITD mutations that have high risk of relapse and poor survival following standard of care (SOC) cytarabine/anthracycline‐based induction/consolidation chemotherapy. Quizartinib is a selective and highly potent FLT3 inhibitor that has shown strong single‐agent activity in relapsed or refractory (R/R) AML. This phase 1, open‐label, sequential group dose‐escalation trial (NCT 01390337) is the first evaluating safety and tolerability of quizartinib in combination with SOC chemotherapy in newly diagnosed AML (ndAML). Nineteen patients unselected for FLT3 mutational status received one of three quizartinib dihydrochloride dose levels (DL): 60 mg/d for 7 days (DL1; n = 6), 60 mg/d for 14 days (DL2; n = 7), and 40 mg/d for 14 days (DL‐1; n = 6); administered orally starting on day 4 of chemotherapy. Median age was 43.8 years. Ten patients completed induction and consolidation. Three patients experienced dose‐limiting toxicities (DLTs): 2 at DL2 (1 pericardial effusion; 1 febrile neutropenia, decreased platelet count, and QT prolongation); 1 at DL‐1 (pericarditis). Maximum tolerated dose (MTD) was identified as DL‐1. Most common grade 3/4 adverse events were febrile neutropenia (47%), neutropenia (42%), thrombocytopenia (32%), and anemia (26%). There were no apparent additional toxicities with addition of quizartinib to chemotherapy although grade ≤1 QT prolongation was observed at MTD. Sixteen patients (84%) achieved a response; 14 (74%) composite complete response; 2 (11%) morphologic leukemia‐free state. The phase 3 QuANTUM‐First trial (NCT02668653) is further evaluating the effect of quizartinib plus SOC chemotherapy in ndAML FLT3‐ITD mutated patients.

Purpose To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). Patients and Methods We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. Results Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 109/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. Conclusion The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.

Key Points In combination with cyclophosphamide, intravenous busulfan is associated with better leukemia-free and overall survival in AML than TBI.

RAS is an oncogene frequently mutated in human cancer. RAS mutations have been reported in 10–15% of cases of acute myeloid leukemia (AML) but they appear to be less frequent among patients with myelodysplastic syndrome (MDS). The impact of RAS mutations in patients with MDS is unclear. We conducted a retrospective study in 1,067 patients with newly diagnosed MDS for whom RAS mutational analysis was available. Overall, 4% of patients carried mutant RAS alleles. Notably, FLT3 mutations, which were found in 2% of patients, were mutually exclusive with RAS mutations. Patients with RAS mutations had a higher white blood cell count as well as bone marrow blasts compared with patients carrying wild‐type RAS. However, no differences were observed between both groups regarding the risk of AML transformation (9% vs. 7%) and overall survival (395 days vs. 500 days, P = 0.057). In summary, RAS mutations are infrequent in patients with MDS and do not appear to negatively impact their outcome. Am. J. Hematol. 88:365–369, 2013. © 2013 Wiley Periodicals, Inc.

Purpose Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor. Patients and Methods In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post–polycythemia vera/essential thrombocythemia myelofibrosis. Results Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months. Conclusion TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.