Levis, Mark J.

Abstract INTRODUCTION Allogeneic hematopoietic cell transplantation (alloHCT) is indicated in patients (pts) with FLT3-ITD mutated AML. The randomized BMT CTN 1506 trial (Levis et al. JCO) demonstrated that maintenance with FLT3 inhibitor gilteritinib (gilt) significantly improved relapse-free survival (RFS) among pts with detectable peri-alloHCT minimal residual disease (MRD) but was also associated with a greater degree of myelosuppression and infections. In older pts, aged >60 years, increasing post-HCT toxicity may adversely impact outcomes. On this basis, we performed a post-hoc analysis of pts aged > 60 years enrolled onto BMT CTN 1506 to examine the impact of gilteritinib maintenance in older pts. METHODS Pts ≥60 years randomized on BMT CTN 1506 (gilt=47, placebo=57; N=104) were included. The primary endpoint of this post-hoc analysis was RFS. We additionally assessed overall survival (OS), incidence of relapse, non-relapse mortality (NRM) in all pts and in pts with detectable MRD. RESULTS Baseline characteristics were balanced. Age was similar (65.2 vs 64.7 years; p = 0.12), as was prior TKI exposure, and NPM1 mutation status. Myeloablative conditioning (MAC) was used in 8 (17%) pts randomized to gilt and 18 (32%) pts randomized to placebo (p=0.08). Median f/u of survivors was 43.8 months (range:1-61 mo.). Estimated RFS and OS at 48 months were not different between groups (RFS: gilt: 57.0%, 95%CI 44.1-73.7%, placebo: 57.1%, 95%CI 45.4-71.8%; OS: gilt: 56.9%, 95%CI 42.9-46.7%, placebo: 58.4%, 95%CI 46.7-73.1%). While gilt assignment did not affect survival, several predictors of poorer survival were identified including use of reduced intensity conditioning (RIC) (HR = 3.46; p = 0.014), use of calcineurin inhibitor/MTX for graft-vs-host disease (GVHD) prophylaxis (HR = 2.29; p = 0.041), high-risk cytogenetics (HR = 2.64; p = 0.021), and MRD (+) pre-HCT (HR = 2.29; p = 0.018). Finally, relative to gilt assignment, opposing rates of relapse and NRM were observed. The incidence of relapse was lower with gilt (16%, 95%CI 6.8-28% vs 32%, 95%CI 20-45%, p=0.046) but NRM was higher (27%, 95%CI 15-41% vs 11%, 95% CI 4.3-21%, p=0.033). We next analyzed the 49 pts (gilt=22, placebo=27) with detectable peri-HCT MRD. RFS and OS again were not different (RFS: gilt: 44.4%, 95%CI 27.1-72.7%, placebo: 43.8%, 95%CI 28.4-67.5%, OS: gilt: 49.2%,95%CI, 31.3-77.4%, placebo: 55.6%, 95%CI 39.4-77.8%). The incidence of relapse trended lower in gilt pts (25%, 95%CI, 5.3-44.7% vs 45% (95%CI, 25-63%), p=0.2) while NRM trended higher (31%, 95%CI 12-52% vs 11%, 95%CI, 2.7-26%, p=0.12). Seventeen (36%) patients completed planned 2 year maintenance with gilt compared to 29 (51%) completing therapy with placebo. Median time on gilt was 13.2 months. The most common reason for discontinuation was adverse events (n=19, 40%), of which cytopenias (n=8) and infections (n=4) were most frequent. Non-relapse causes of death among gilt treated pts included infections (n=8), intracranial hemorrhage related to thrombocytopenia (n=1), second cancer (n=1), and Guillain-Barre syndrome (n=1). Most infections (n=5) were attributed to GVHD as an underlying cause. CONCLUSION Among pts aged ≥60 years, gilt maintenance did not improve RFS or OS. Gilt use was associated with reduced relapse regardless of peri-HCT MRD status demonstrating disease effect; however, higher NRM limited overall benefit. In older FLT3 mutated pts, employing strategies to mitigate HCT related toxicity, e.g. alternative GVHD prophylaxis strategies, may better accommodate use of maintenance therapy including gilt. Lower doses of gilt (particularly with azole co-use) may be worth exploring to mitigate drug AEs, improve compliance, thus further improving benefit.

Abstract Aims BMT CTN 1506 (“MORPHO”) was a global phase 3 study of post-hematopoietic cell transplantation (HCT) maintenance with gilteritinib versus placebo for patients with FLT3-ITD-mutated AML in CR1. The study did not meet its primary endpoint of improved relapse-free survival (RFS) for post-HCT gilteritinib, but subgroup analysis indicated a benefit for participants with pre-HCT measurable residual disease (MRD). Subgroup analysis also indicated a statistically significant benefit of post-HCT gilteritinib for participants in North America, but no benefit for those in Europe or Asia. RFS for the control arms in Europe and Asia was higher than anticipated, suggesting that participants with different disease biology may have accrued to the study in these different geographic regions. In the primary analysis of the study, pre-HCT FLT3 inhibitor use and MRD across the entire study population were both found to have impacted outcomes. Time from diagnosis to HCT, a reflection of local practice patterns, is also known to impact outcomes for FLT3-ITD AML. We hypothesized that local practice patterns of pre-HCT FLT3 inhibitor use and time from AML diagnosis to HCT could have influenced the disease biology of study pts at the time of enrollment. This would be predicted to result in pre-HCT MRD levels and could provide an explanation for the regional differences observed in the study outcome. Methods We conducted a post-hoc analysis of the data focusing on days from AML diagnosis to HCT, pre-HCT FLT3 inhibitor use, and FLT3-ITD MRD assessed by a high-sensitivity assay. Eligibility requirements included FLT3-ITD-mutated AML in first remission after intensive chemotherapy and HCT occurring within 12 months of achieving remission. Patients refractory to induction therapy, or those with a history of relapse, were ineligible. Results Accrual took place in 16 different countries, with 5 countries accounting for 79.7% of the total accrual: USA 42.7%; Japan 15.7%; Korea 8.4%; UK 6.7%; Germany 6.2%; other countries 20.2%. In two countries, USA and Germany (48.9% of total enrollment), participants underwent HCT a median of 119 days after AML diagnosis, and 90.2% were treated with a FLT3 inhibitor pre-HCT. In contrast, in Japan, Korea, the UK and the other 11 countries all combined, participants underwent HCT a median of 152.5 days after AML diagnosis, and only 30.8% received any FLT3 inhibitor pre-HCT. Amongst all participants, those transplanted < 120 days from AML diagnosis and/or those treated with FLT3 inhibition pre-HCT were more likely to have improved RFS from post-HCT gilteritinib. RFS was improved with post-HCT gilteritinib in the US and Germany (HR 0.397; CI 0.220-0.718), whereas no benefit was evident in all other countries combined (HR 1.184; CI 0.685-2.048). Pre-HCT MRD levels were significantly higher (P = 0.011) in participants transplanted within 120 days from diagnosis as well as in those treated with a FLT3 inhibitor pre-HCT and also transplanted within 120 days (P = 0.019). Pre-HCT MRD was dependent on both FLT3 inhibitor use and time to HCT, as participants treated with successive courses of chemotherapy + FLT3 inhibition had successively lower MRD by the time of HCT. Conclusions The time from AML diagnosis to HCT and FLT3 inhibitor use pre-HCT both appeared to impact MRD levels immediately prior to HCT, and geographic differences in these two practice patterns likely accounted for the regional differences in benefit from post-HCT gilteritinib observed in BMT CTN 1506. Successive courses of chemotherapy without FLT3 inhibition appears to have selected a more favorable risk (e.g., MRD-lower) population for enrollment. Successive courses of chemotherapy combined with FLT3 inhibition progressively eradicated MRD, such that a majority of participants undergoing HCT after 3 or 4 courses were MRD negative and therefore unlikely to benefit from post-HCT gilteritinib. These findings have implications for clinical practice. Increasing the number of courses of chemotherapy combined with FLT3 inhibition before HCT may lower MRD sufficiently to eliminate the need for post-HCT inhibition for some patients but, alternatively, the additional delay could increase the risk of pre-HCT relapse, preventing patients from receiving HCT in first remission.