Essell, James

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.

PURPOSE: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. METHODS: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. RESULTS: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [ P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). CONCLUSION: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

Abstract Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p<0.001 compared to historical rate of 40%). Twenty-five (37%) had a matched related donor, 31 (45%) had a matched unrelated donor, 3 (4%) had a mismatched related donor, 8 (12%) had a mismatched unrelated donor, and 1 (1%) received an umbilical cord blood transplant. Sixty-six high-risk patients transplanted in CR/CRi have detailed data. Median time to HCT from CR1 was 76 days (range, 20-365). Fifty-seven patients (86%) received a myeloablative regimen and 9 (14%) reduced-intensity conditioning. Reasons for 39 high-risk CR1 patients not receiving a transplant in CR1 were: co-morbidities (n=1), death (n=6), no insurance (n=1), no donor (n=1), physician decision (n=3), patient decision (n=3), relapse (n=6), other (n=10), or unknown (n=8). The 2-year RFS estimate in the entire high-risk cohort is 32%, significantly higher than the 22% historical rate (p=0.05). Median RFS in the high-risk CR1 cohort (n=107) was 10 months [range, 1-32* (censored) months]. RFS and OS were similar among HCT patients using matched related [1 year estimates: 40% (95% CI 27%, 74%) and 56% (37%, 74%), respectively] and matched unrelated [1 year estimates: 52% (37%, 75%) and 56% (37%, 74%), respectively] donors in CR1. The HR (reference = unrelated) for RFS was 0.67 (0.32, 1.37) and for OS was 0.88 (0.41, 1.90). Median overall survival (OS) among all patients in the high-risk cohort (n=159) was 12 months [range, 1-33* (censored) months] and was 18 months [range 3-33* (censored) months] for those transplanted in CR1 (Fig. 1). Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Figure 1 Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Figure 1. Overall Survival (OS) among all patients in the high-risk cohort, all high-risk patients achieving CR1, and in those high-risk patients transplanted in CR1. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.

Abstract Background: A majority of younger pts with AML receive initial therapy with a 7+3 scheme. Escalated doses of daunorubicin (dauno) in combination with standard doses of ara-C may lead to improved outcomes (Fernandez; NEJM 2009). A phase II trial of idarubicin and high-dose ara-C (IA) in combination with the histone deacetylase inhibitor vorinostat (IA+V) resulted in historically high response rates compared to IA or 7+3 (Garcia-Manero; JCO 2011). SWOG 1203 tested whether a high-dose ara-C induction with or without vorinostat could result in improved outcomes for younger AML pts compared to 7+3. Methods: The primary endpoints were comparison of event-free survival (EFS) of 7+3 vs IA vs IA+V and evaluating the frequency of allogeneic hematopoietic cell transplantation. Secondary endpoints included toxicity, remission rate, relapse-free survival (RFS), and overall survival (OS) according to treatment arm, and by cytogenetic and molecular subgroups. Because of the historical trend of cured pts in S0106, EFS was modeled with an exponential cure model, and it was assumed IA or IA+vorinostat increased the proportion of pts cured from 35% to 45% and increased median EFS among those not cured from 4.7 months to 7.1 months. Main inclusion criteria included a diagnosis of previously untreated non-APL AML by WHO criteria, age 15 to 60 years, and preserved cardiac function but no severe comorbidities. Pts with known CBF rearranged or FLT3 mutant leukemias were eligible if no other alternative clinical trials existed. Treatment was as follows: Induction: 7+3 arm: dauno 90 mg/m2 IV QD x 3 on days 1-3 with ara-C CI 100 mg/m2 QD x 7 days on days 1 to 7. IA arm: ida 12 mg/m2 QD x 3 on days 1 to 3 with 24 hours CI ara-C 1.5 gm/m2 QD for 4 days on days 1 to 4. IA+vorinostat was as IA but with vorinostat 500 mg orally TID for 3 days on days 1 to 3. Consolidation: 7+3 arm: standard high-dose ara-c at 3 gm/m2 over 3 hrs q12 hours x 6 doses for 1 to 4 cycles depending on transplant availability. IA arm: idarubicin 8 mg/m2 IV QD x 2 days on days 1 to 2 with ara-C 0.75 gm/m2 CI for 3 days on days 1 to 3 for 4 cycles. The number of consolidation cycles depended on transplant indication; a secondary aim of the study was to transplant all cytogenetically-determined high risk pts (presented in a different abstract). Results: Of 754 pts randomized, 738 were eligible (261 to 7+3, 261 to IA, and 216 to IA+V). Baseline characteristics were well balanced among all three groups. Most (75%) pts were between 40 and 60 years, 51% were male, median (range) WBC and platelets were 10.8 (0.3-800) and 49 (3-3900), respectively; marrow blast percentage was 60% (0%-100%); cytogenetics were favorable in 13% of pts, intermediate in 63%, and high-risk in 22%; FLT-3 was mutated in 21% and unknown in 31%; NPM1 was mutated in 20% and was unknown in 37%. Complete remission (CR) rates were 75% for 7+3, 79% for IA, and 77% for IA+V (p=0.58). Significantly more pts received reinduction with 7+3 (24%) versus 11% with IA and 9% with IA+V (p=0.001). 48% of intermediate and unfavorable risk pts received transplant in CR1, with no significant differences among arms (p=0.44). There were no significant differences in EFS, RFS or OS among all three arms (Figure 1, all p>0.5). By cytogenetic or molecular group, there were no differences in outcome for any standard risk subset (FLT-3, NPM1, or CEBPα or cytogenetic subset), although pts with favorable cytogenetics had significantly better EFS, RFS and OS with 7+3 therapy compared to IA or IA+V (Figure 2, all p≤0.015). 30% of pts received 1 consolidation cycle, 18% 2, 16% 3, and 37% 4 cycles. Grade 5 induction toxicity rates were 4% (7+3), 8% (IA), and 9% (IA+V) by arm (p=0.07), and for toxicities related to therapy, 2%, 7%, 8%, respectively (p=0.01). Grade 4 induction toxicity rates were similar across arms (p=0.38). Conclusion: Treatment with IA is not more effective than 7+3 in younger pts with AML. Outcomes with IA or IA plus vorinostat are similar. In pts with favorable cytogenetics, outcomes were inferior with IA or IA+V when compared to 7+3, perhaps related to use of lower doses of ara-C during consolidation. Clinical Trials Registry: NCT #0180233 Support: NIH/NCI grants CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI grant #021039 Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy; BMS: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; Baxalta: Consultancy; Cyclacel: Research Funding; Celator: Research Funding; Abbvie: Research Funding; Ambit: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria; Pfizer: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Jazz: Consultancy; Lundbeck: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Stone:Amgen: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Jansen: Consultancy; Xenetic Biosciences: Consultancy; Celator: Consultancy; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; ONO: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Ariad: Consultancy; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Astellas: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Agios: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Agios: Research Funding; Jannsen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Juno: Research Funding; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Agios: Research Funding; Celator: Research Funding; Daiichi Sankyo: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Celator: Research Funding; Jannsen: Consultancy, Research Funding; Sunesis: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astellas: Research Funding; Ariad: Consultancy; Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Pfizer: Consultancy; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB.