FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML

Abstract

Allogeneic HCT has been increasingly used in the setting of FLT3 mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein, we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD mutational testing. FLT3 mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs. 37%, P<0.001), and with a shorter median time to relapse (100 vs. 121 days). FLT3 mutational status remained significantly associated with this outcome after controlling for patient, disease, and transplant-related risk factors (P<0.05). Multivariate analysis showed a significant association of FLT3 mutation with increased 3-year RR (HR 3.63, 95% CI: 2.13, 6.19, P<0.001), and inferior disease-free survival (HR 2.05, 95% CI: 1.29, 3.27, P<0.01) and overall survival (HR 1.92, 95% CI: 1.14, 3.24, P<0.05). These data demonstrate high risk of early relapse after allogeneic HCT for FLT3 mutated AML that translates into adverse disease-free and overall survival outcomes. Additional targeted and coordinated interventions are needed to maintain durable remission after allogeneic HCT in this high-risk population.

Response‐guided chemotherapy for pediatric acute myeloid leukemia without hematopoietic stem cell transplantation in first complete remission: Results from protocol DB AML‐01

“…The presence of FLT3 ‐ITD/ NPM1 ‐WT did not significantly affect CR rates, however, due to increased relapse rates and poor salvage rates, the EFS as well as the OS in patients with FLT3 ‐ITD/ NPM1 ‐WT AML was low as shown in previous studies . Remarkably, previous trials observed an identical high relapse rate of >60% and OS < 40% for FLT3 ‐ITD‐positive patients receiving allo‐HSCT in CR1 and those not receiving a transplant in CR1 . At present, several FLT3 ‐inhibiting tyrosine kinase inhibitors, such as sorafenib and PKC412, are being evaluated in clinical trials .…”

FLT3 Inhibitors in Acute Myeloid Leukemia: Current Status and Future Directions

“…Genomic instability may result from increased DNA double-strand breaks associated with increased reactive oxygen species generation and from error-prone DNA double-strand break repair [8]. HSCT is the preferred treatment for FLT3-ITD AML patients in remission, but outcomes are inferior to those of patients without FLT3-ITD due to a high rate of early relapses, suggesting the potential utility of treatments targeting FLT3 signaling after transplant [9]. …”

Midostaurin and cyclosporine drug interaction: A case report

“…Allogeneic hematopoietic stem cell transplant (alloHSCT) is often recommended for patients with FLT3‐ITD + acute myeloid leukaemia (AML) due to poor prognosis but the presence of FLT3‐ITD also portends a poor post‐transplant outcome . In addition, patients with FLT3‐ITD AML tend to have a poor outcome despite hematopoietic stem cell transplant (HSCT) with higher rates of relapse . As a result, clinicians have studied various medications in an attempt to reduce rates of relapse using various tyrosine kinase inhibitors (TKIs) to block the constitutively activated FLT3 kinase.…”