Damon, Lloyd E.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Abstract Intensification of therapy for adults with ALL using pediatric regimens with intensive asparagine depletion is feasible. Targeted therapies are improving outcomes. We hypothesized that the UCSF 8707 regimen (Linker et al.JCO 2002;20:2462) could be safely intensified with the addition of pegylated asparaginase (peg asp), cyclophosphamide, rituximab, dasatinib, and intrathecal liposomal cytarabine. Methods: Patients (pts) enrolled at 4 centers. The primary objective was 3-year (yr) EFS (goal >55%). Eligible pts were age 18-60 yrs with untreated ALL or LBL. Treatment consisted of induction Course 1A (C1A): daunorubicin 60 mg/m2 IV d1-3, vincristine (VCR) 1.4 mg/m2 (2 mg if age >50 yrs) IV day 1,8,15,22, prednisone 60 mg/m2 orally (PO) d1-28, peg-asp 2,000 IU/m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d15, cyclophosphamide 750 mg/m2 IV d1,15 (or 500 mg/m2 IV q12h d15,16 if d14 marrow M2 or M3). ALL pts in CR/CRi and LBL pts in CR or PR proceeded to post-remission Course 1B (C1B): methotrexate (MTX) 220 mg/m2 IV bolus then 60 mg/m2/hr CIV for 36 hrs d1,15 with leucovorin rescue, 6-mercaptopurine (6-MP) 60 mg/m2 PO d1-7, 15-21, peg-asp 2,000 IU/ m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d16. Course 1C (C1C) consisted of cytarabine 2,000 mg/m2 IV d1-4 and etoposide 500 mg/m2 IV d1-4. Courses A-C repeated once then a third course B given. Maintenance POMP (6-MP 60 mg/m2 PO daily, VCR 1.4 mg/m2 (2 mg age >50 yrs) IV monthly, MTX 20 mg/m2 PO weekly, prednisone 60 mg/m2 PO d1-5) repeated monthly for 12 months then POMP with every other month VCR and prednisone for 12 months. Peg asp was given d16 of maintenance month 1. If B-ALL (+/- CD20 expression), rituximab 375 mg/m2 IV was given every 2 weeks for 8 doses starting day 1 of C1A. If Ph+ ALL, dasatinib 140 mg PO daily was given but held during high-dose MTX then restarted when serum [MTX] was </= 0.1 μM. CNS prophylaxis was liposomal cytarabine 25 mg intrathecal C1A d1,15, C2A d1,15 then 50 mg monthly for 4 doses in maintenance. Bone marrow biopsies were performed C1A d14 and after C1A, C1B, C3B, and maintenance. Measurable residual disease (MRD) was evaluated centrally by multi-parameter flow cytometry. BCR-ABL1 QPCR was performed locally. EFS is the time from start of therapy to failure of response by induction day 28, relapse, or death censored for HCT. RFS is the time from response to relapse or death censored for HCT. OS is the time from start of therapy until death. Survival was estimated by the method of Kaplan and Meier. Toxicity was graded with NCI CTCAE version 4.0. Results: Between 4/2014 and 2/2017, 31 pts enrolled and 29 were eligible. Median age was 28 yrs (20-54), 62% were male, 52% were Hispanic, and 86% had ALL. The end induction ORR (CR + PR) was 90% (2 ALL with PR, 1 early death). ORR for LBL was 100% (n= 4). The CR rate for ALL was 88%. For Ph- B-ALL (n=16), the CR rate was 86% with MRD <0.1% and <0.01% in 90% and 80% of CR pts, respectively. For Ph+ B-cell ALL (n=7), the CR rate was 88% (1 early death) with MRD <0.1% and <0.01% in 100% and a CMR rate of 67% at CR. The 2 T-ALL pts achieved CR with MRD >0.1%. Five pts underwent allogeneic HCT in first CR to study therapy. With a median follow up of 32 months (16-44), the 2- and 3-yr EFS were 59%. EFS was similar for B-ALL, T- ALL, LBL, Ph- B-ALL, and Ph+ B-ALL. Five pts relapsed. The 2- and 3-yr RFS were 66%. Concomitant marrow and CNS relapse occurred in 1 pt. No isolated CNS relapses occurred. Transplant-censored 2- and 3-yr OS were 80% and 72%. Uncensored 2- and 3-yr OS were 75% and 70%. Among eligible pts, 8 died: 4 after relapse, 1 in induction from infection, 2 in CR from infection, and 1 from allogeneic HCT complications. Three reversible grade 3-4 events were attributed to liposomal cytarabine, all grade 3: syncope, pseudotumor cerebri, and headache. Grade 3-5 possible peg asp toxicities were transaminitis (58%), hyperbilirubinemia (42%), hyperglycemia (29%), hypertriglyceridemia (26%), elevated GGT/alkaline phosphatase (19%), thrombosis (19%, 1 cerebral venous), hypoalbuminemia (10%), hypersensitivity (6.5%), elevated lipase (6.5%), pancreatitis (3.2%), encephalopathy (3.2%), and avascular necrosis (3.2%). One pt died from encephalopathy. Conclusions: Intensification of UCSF 8707 is feasible and effective. Post-induction remissions were deep with high MRD-negativity rates. EFS, RFS, and OS are favorable with follow up and accrual ongoing (NCT02043587). Strategies to limit peg asp toxicity are needed. Disclosures Wieduwilt: Amgen: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership; Leadiant: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Mannis:AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; NKarta: Membership on an entity's Board of Directors or advisory committees. Curtin:Amgen: Research Funding; Onconova: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Andreadis:Genentech: Consultancy, Employment; Bayer: Consultancy; Astellas: Consultancy; Gilead: Consultancy; Juno: Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Novartis: Consultancy, Research Funding; Kite: Consultancy; Seattle Genetics: Consultancy. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Damon:Actelion: Other: spouse's relationship with company; Boston Scientific: Other: spouse's relationship with company; Novartis: Other: spouse's relationship with company; Gilead Sciences Inc: Other: spouse's relationship with company.