Utility of Early Bone Marrow Responses in FLT3 Mutant Acute Myeloid Leukemia
Authors: Lok Vincent , Medawar Georgio , Sastow Dahniel L , Perez Preston , Hahn Su Bin , Demers Abigail , Tremblay Douglas , Coltoff Alexander , Swoboda David M 
Published: December 2024

Background:

Acute myeloid leukemia (AML) is often treated with induction chemotherapy, with early bone marrow biopsies (BMBx) performed on Days 14 or 21 (D14/21) to evaluate blast clearance and determine the need for reinduction. However, prior studies have demonstrated for those with residual bone marrow blasts &gt; 5%, early BMBx poorly predict true response and risk overtreatment. FLT3 inhibitors such as midostaurin have conferred an overall survival (OS) benefit in combination with 7+3 chemotherapy with D21 BMBx being standard clinical practice (Stone et al., NEJM 2017). However, whether D21 BMBx are an accurate predictor of response in the FLT3 mutant (FLT3-mt) setting is still not well-defined.

Methods:

We reviewed FLT3-mt AML patients who underwent induction chemotherapy with midostaurin and received either D21 or D14 BMBx at Tampa General Hospital, Mount Sinai, and Medical University of South Carolina between 2018 and 2024. Blast % was based on morphological evaluation or flow cytometry of bone marrow aspirates. The primary endpoint was the negative predictive value (NPV) of blast clearance (&lt; 5%) at D21 BMBx for complete remission (CR) at response BMBx. D14 BMBx patients were evaluated as a comparison cohort. Fisher's exact test and Pearson's Chi-squared test were used to compare the outcomes of the two cohorts.

Results:

The present study identified 74 newly diagnosed FLT3-mt AML patients with 64 evaluable for downstream analysis having both received D21/14 and response BMBx. Patients were split into D21 BMBx (n = 32) and D14 BMBx (n = 32) cohorts.

Baseline characteristics were balanced between cohorts, with similar median age (56 vs 56, p = 0.799), incidence of complex cytogenetics (1/28 (3%) vs 0/32 (0%), p = 0.475), incidence of FLT3 ITD mutation (24/30 (80%) vs 24/31 (77%), p = 1), median FLT3 ITD ratio of (0.394 vs 0.397, p = 1), rates of CR post-induction (28/32 (87%) vs 32/32 (100%), p = 0.113) and overall survival (10.7 months vs 11 months, p = 0.446). For D21 BMBx, 21/22 (95%) patients with ≤ 5% blasts at D21 achieved a CR based on recovery marrow, resulting in an NPV of 95%. In patients with residual disease of blasts &gt; 5% at D21 (n = 10), 7/10 (70%) patients ultimately achieved a CR. Thus, the PPV for residual disease with D21 was 30%. Of these patients with residual blasts &gt; 5% at D21 (n = 10), 3 received reinduction therapy but 2 had residual disease at response BMBx.

For D14 BMBx, 28/29 (96%) patients with blast ≤ 5% at D14 achieved a CR based on recovery marrow with a NPV of 96%. In patients with residual disease (n = 3), 2/3 (66%) patients ultimately achieved a CR. Thus, the PPV for residual disease with D14 was 33% (1/3). Of these patients with residual blasts &gt; 5% at D14 (n = 3), 1 received reinduction therapy but had residual disease at response BMBx.

We then regrouped cohorts based on morphological clear D21/14 status (51 cleared, 13 not cleared) and found no other significant differences in initial disease characteristics such as peripheral blast percentage (54.5% vs 57%, p = 0.214). Additionally, patients who failed to clear at these early time points did not display any differences regarding minimal residual disease (8/27 vs 2/4, p = 0.577) and overall survival OS (10.8 months vs 10.1 months, p = 0.891).

Conclusion:

Our study evaluated the NPV/PPV of D21 and 14 BMBx in FLT3-mt AML treated with 7+3-midostaurin to understand their utility. D21/14 BMBx may accurately predict complete remission in patient that clear blasts however poorly predicted residual leukemia. Whether clinicians should abandon D21 BMBx in this population or if D14 BMBx outperform D21 BMBx in response assessment requires future studies. Ultimately, additional evaluation in combination with D21/14 BMBx in FLT3-mt AML is required prior to reinduction to avoid overtreatment.