Transplant Rates and Outcomes of Young Acute Myeloid Leukemia (AML) Patients with Intermediate and Poor Risk Disease Referred to a Coordinated Acute Leukemia and Hematopoietic Stem Cell Transplant (HSCT) Program

Patients with intermediate and poor risk AML have unsatisfactory outcomes with conventional chemotherapy-based treatment. Allogeneic HSCT offers the best chance of long-term survival for patients who achieve complete remission (CR) and are eligible for such a procedure. There are several potential barriers to receiving an allogeneic HSCT, including but not limited to: achieving CR, timely referral to a transplant center, identifying a donor, and performing the HSCT prior to relapse or significant complications arising from induction and consolidation therapy. To better understand the outcomes of young, newly diagnosed non-favorable risk AML patients, we evaluated 271 consecutive adult patients (age ≤65 years) referred to our center between January of 2009 and July of 2017 for management. Patients were treated in an integrated acute leukemia and transplant management unit and it is our policy to offer intensive chemotherapy to all potentially eligible patients and HSCT to all transplant-eligible, non-favorable risk AML patients that achieve CR, with or without complete blood count recovery. Patient characteristics were as follows: Median age 55 (19, 65) years, male sex 50%, NCCN risk (intermediate 51%, poor 49%), FLT 3 ITD positive 15% and normal cytogenetics in 39%. Remission induction chemotherapy was given to 262patients with FLAG+/-IDA being the most commonly used regimen in 161 patients (61%) followed by 3+7 in 63 (24%)patients. Following induction, 211 (81%) achieved a CR1 after one (n=178), two (n=26) or three (n=7) courses of induction with a median follow up for survivors of 44.5 months. For patients with intermediate and poor risk NCCN categories, CR was achieved in 86% and 73% respectively. HSCT was performed on 146 (69%) patients (NCCN intermediate risk n=83, poor risk n=63): Myeloablative conditioning n=103 (71%), autologous (n=10), matched related donor (n=45), matched unrelated donor (n=51) and haploidentical mismatched related donor (n=40). Of the 65 patients in CR1 who did not receive HSCT, the reasons for not receiving HSCT were as follows: relapse prior to transplant (n=23), lack of psychosocial support (n=14), persistent active infection or organ dysfunction (n=16) at time of transplant evaluation, patient declined transplant (n=7) and poor performance status post induction (n=5). The 3 year estimates for OS and DFS were 50% and 44% respectively. Patients who received HSCT had a better 3 year OS and DFS of 59% and 52% compared to 27% and 27% for patients not receiving HSCT (p<0.001). In multivariate analysis, we analyzed factors associated with OS and DFS among patients in CR1 after induction. The variables considered were age at CR1 (≤49, 50-64, ≥65), gender, race (white, black), NCCN risk, induction regimen, cytogenetics at diagnosis (normal, abnormal), FISH at diagnosis (normal, abnormal), FLT3 ITD status, number of cycles to CR1 (1, ≥2), transplantation and year of CR1 (2008-2011, 2012-2014, 2015-2017). ). Transplantation was modelled as a time-dependent covariate where hazard of mortality for transplantation was only evaluated after transplantation was conducted. A forward stepwise algorithm was implemented and variables were selected if p values were less than 0.05. Factors associated with superior overall survival were age at CR1 (≤49 vs ≥60; HR 0.38, p<0.001), NCCN risk (intermediate vs poor HR 0.51, P<0.001), number of cycles to reach CR1 (1 vs ≥2, HR 0.58, p0.025) and receiving HSCT (Yes vs No, HR 0.71, p0.049). Factors associated with improved DFS were age at CR1 (≤49 vs ≥60 years, HR 0.45, p<0.001), NCCN risk (intermediate vs poor, HR0.53, p0.008) and receiving HSCT (yes vs no, HR 0.57, p0.006). This analysis shows that a timely coordinated approach of remission induction followed by HSCT in the majority of patients with non-favorable risk AML can lead to superior outcomes with more than half of the patients achieving long term survival.