A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation

Overall survival was defined as the time from the date of randomization until the date of death from any cause (death date - randomization date + 1). For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact (date of last contact - randomized date + 1). The date of last contact was the latest date that the participant was known to be alive. The last contact date was derived for participants alive at the analysis cutoff date. Survival rate and 95% CI were estimated using the Kaplan-Meier method and the Greenwood formula.

Time frame: From randomization to until the date of death from any cause (median time of follow-up for OS was 17.8 months)

Population: The analysis population was the Intention to Treatment (ITT) which consisted of all randomized participants.

The CR/CRh rate was defined as the number of participants who achieved either CR or CRh divided by the number of participants in the analysis population. CR: For participants to be classified as being in CR at, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10\^9/L and platelet count ≥ 100 x 10\^9/L and normal marrow differential with \< 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia. CRh: Participants were classified as CRh if they had marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5 x 10\^9/L and platelets ≥ 50 x 10\^9/L, no evidence of extramedullary leukemia and could not be classified as CR.

Time frame: From the date of randomization up to at least 112 days

Population: The analysis population was the response analysis set (RAS) which consisted of participants who were who were at least 112 days past the first dose of gilteritinib or randomization (for participants who did not receive gilteritinib). The participants were analyzed based on the randomized treatments.

The Brief Fatigue Inventory (BFI) was a screening tool designed to assess the severity and impact of fatigue on daily functioning of participants with cancer during the 24 hours. There are 9 items on the scale. The first three questions asked participants to rate their fatigues on a scale from 0 (no fatigue) - 10 (as bad as you can imagine), with higher scores indicating worse outcome. The remaining six questions asked participants to rate how much fatigue has interfered with their daily activities on a scale from 0 (Does not interfere) to 10 (Completely interferes). A global fatigue score can be obtained by averaging all the items on the BFI. The total score range is 0-10 with a higher BFI fatigue score indicates worse outcome. The global BFI score was calculated only if at least 5 of the 9 items are answered.

Time frame: Baseline, Cycle 1 Day 8 and Cycle 2 Day 1

Population: The analysis population was the ITT, with participants with data at baseline.

EFS: time from randomization date up to date of documented relapse (excluding relapse after PR)/ treatment failure (failure to achieve CR, CRp, CRi /PR) /death, whichever occurred first. Relapse: leukemic blasts in peripheral blood 5/ ≥ 25% blasts in bone marrow (BM) aspirate due to no other cause/reappearance/new appearance of extramedullary leukemia. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥1x10\^9/L, platelet count ≥100x10\^9/L, normal marrow differential with \<5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp: achieved CR except incomplete platelet recovery (\<100x 0\^9/L). CRi: criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia \<1x10\^9/L with /without complete platelet recovery. PR: BM regenerating normal hematopoietic cells, peripheral recovery, no circulating blasts and decrease of 50% blasts in with total blasts between 5% -25% or, 5% if Auer rods present.

Time frame: From the date of randomization until the date of documented relapse, treatment failure or death from any cause (median time of follow-up was 17.8 months)

Population: The analysis population was the ITT with available data.

LFS: time from the date of first CRc until the date of documented relapse or death for subjects who achieve CRc. For a subject who is not known to have relapsed or died, LFS is censored on the date of last relapse-free disease assessment date. CRc: achieved CR, CRp or CRi. Relapse: leukemic blasts in peripheral blood/ ≥ 25% blasts in bone marrow (BM) aspirate not due to any other cause/reappearance/new appearance of extramedullary leukemia. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥ 1 x 10\^9/L, platelet count ≥ 100 x 10\^9/L, normal marrow differential with \< 5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp: achieved CR except incomplete platelet recovery (\< 100 x 10\^9/L). CRi : criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia \< 1 x 10\^9/L with /without complete platelet recovery..

Time frame: From the date of first CRc until the date of documented relapse or death for participants who achieved CRc (median time of follow-up was 17.8 months)

Population: The analysis population was the ITT, with participants with best response of CRc.

Duration of remission included duration of CRc, CR/CRh, CRh, CR, CRi, CRp (defined as the time from the date of first CRc until the date of first documented relapse for participants who achieved CRc, CR/CRh, CRh, CR, CRi, CRp respectively) and duration of response (CRc + PR). CRc: achieved CR, CRp or CRi at the visit. CR: BM regenerating normal hematopoietic cells, morphologic leukemia-free state, ANC ≥1x10\^9/L, platelet count ≥100x10\^9/L, normal marrow differential with \<5% blasts, and RBC/platelet transfusion independent with no extramedullary leukemia. CRp: achieved CR except incomplete platelet recovery (\<100x 0\^9/L). CRi: criteria for CR fulfilled except incomplete hematological recovery with residual neutropenia \<1x10\^9/L with /without complete platelet recovery. PR: BM regenerating normal hematopoietic cells, peripheral recovery, no circulating blasts and decrease of 50% blasts in with total blasts between 5% -25% or, 5% if Auer rods present.

Time frame: From the date of first response until the date of documented relapse for participants who achieved CRc or PR (median time of follow-up was 17.8 months)

Population: The analysis population was the ITT, Duration of CR was only applicable to participants with best overall response of CR.

An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study drug, whether or not related to it. It could be any unfavorable/unintended sign (including abnormal laboratory finding), symptom, or disease (new/exacerbated) temporally associated with use of the study drug. A treatment-emergent adverse event (TEAE) : AEs observed after starting administration of study drug (gilteritinib or salvage chemotherapy). Serious AEs (SAEs): AEs which caused death, were life-threatening, resulted in persistent/significant disability/incapacity or disruption of the ability to conduct normal life functions, congenital anomaly, birth defect, required inpatient hospitalization/led to prolongation of hospitalization. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE

Time frame: From first dose of study drug up to 30 days after the last dose of study drug (median treatment duration for gilteritinib was (126.00 [4.0, 885.0]) days versus salvage chemotherapy 28.0 [5.0, 217.0] days)

Population: The analysis population was the safety analysis set (SAF), which consisted of participants who received who received at least 1 dose of study drug (gilteritinib or salvage chemotherapy).

Transfusion conversion & maintenance rate was defined for gilteritinib arm. Participants were classified as transfusion independent if there were no RBC or platelet transfusions within 28 days prior to the first dose to 28 days after the first dose; otherwise they were classified as transfusion dependent at baseline. Participants were considered independent postbaseline if they had 1 consecutive 8 week period without any RBC or platelet transfusion from 29 days after the first dose until the last dose date. For participants who were on treatment ≤ 4 weeks or \> 4 weeks but \< 12 weeks and there was no RBC or platelet transfusion within postbaseline period, they were considered not evaluable; otherwise, they were considered postbaseline transfusion dependent. Transfusion conversion rate was defined for participants who had evaluable postbaseline transfusion status. Transfusion status (independent vs. dependent) at baseline and postbaseline was reported in a 2 by 2 contingency table.

Time frame: From 29 days post first dose of study drug until last dose(median treatment duration was (126.00 [4.0, 885.0])

Population: The analysis population was the ITT, with participants who had evaluable postbaseline transfusion status.

Transplantation rate is defined as the percentage of participants undergoing Hematopoietic stem cell transplant (HSCT) during the study period.

Time frame: From the date of randomization until end of study (median time of follow-up was 17.8 months)

Population: The analysis population is the ITT.

The CR rate was defined as the number of participants who achieved the best response of CR divided by the number of participants in the analysis population. CR: For participants to be classified as being in CR, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10\^9/L and platelet count ≥ 100 x 10\^9/L and normal marrow differential with \< 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia.

Time frame: From the date of randomization up to at least 6 months

Population: The analysis population was the ITT.

CRh rate was defined as the number of participants who achieved CRh at any of the postbaseline visits and did not have a best response of CR divided by the number of participants in the analysis population. CR: For participants to be classified as being in CR at a post-baseline visit, they must have had bone marrow regenerating normal hematopoietic cells and achieved a morphologic leukemia-free state and must had an ANC ≥ 1 x 10\^9/L and platelet count ≥ 100 x 10\^9/L and normal marrow differential with \< 5% blasts, and they were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There was no evidence of extramedullary leukemia. CRh: At a post baseline visit, participantss were classified as CRh if they had marrow blasts \< 5%, partial hematologic recovery ANC ≥ 0.5 x 10\^9/L and platelets ≥ 50 x 10\^9/L, no evidence of extramedullary leukemia and could not be classified as CR.

Time frame: From the date of randomization up to at least 6 months

Population: The analysis population was the ITT.

CRc rate: Number of participants with best response of CRc (CR,complete remission with incomplete platelet recovery \[CRp\] or complete remission with incomplete hematologic recovery \[CRi\]) divided by number of participants in the analysis population. CRc : Participants who achieved CR, CRp or CRi at a post-baseline visit. CR: Participants having bone marrow regenerating normal hematopoietic cells, a morphologic leukemia-free state, an ANC ≥ 1 x 10\^9/L and platelet count ≥ 100 x 10\^9/L, normal marrow differential with \< 5% blasts, and being RBC and platelet transfusion independent with no evidence of extramedullary leukemia at a post-baseline visit. CRp: Participants achieving CR except for incomplete platelet recovery (\< 100 x 10\^9/L) at a post-baseline visit. CRi : Participants, who fulfilled all criteria for CR except incomplete hematological recovery with residual neutropenia \< 1 x 10\^9/L with or without complete platelet recovery at a post-baseline visit.

Time frame: From the date of randomization up to at least 6 months

Population: The analysis population was the ITT.