Assessing the Utility of Interim Bone Marrow Results in Acute Myeloid Leukemia Induction
Authors: Lalla Mumtu , Uriel Matan , Goldfinger Mendel , Shastri Aditi , Gritsman Kira , Shah Nishi , Kornblum Noah , Shapiro Lauren , Sica R. Alejandro , Munoz Annemarie , Chambers Nicole , Dhawan Aradhika , Fehn Karen , Tirone Balda , Shah Lamisha , Clark Shaunmonique , Verma Amit , Kim Mimi , Cooper Dennis L , Feldman Eric J. , Konopleva Marina , Mantzaris Ioannis 
Published: December 2024

Interim bone marrow (BM) biopsy (bx) on day (D) 14-21 from treatment initiation is a standard practice in acute myeloid leukemia (AML) remission-induction (RI) to assess for residual disease (blasts ≥5%) and determine whether patients (pts) require additional therapy to achieve complete remission (CR). However, the interpretation of results is notoriously difficult, so the value of this practice has been disputed and remains controversial, (Luger 2011, Ofran and Rowe 2016, Othus, Mukherjee et al. 2016) as acknowledged by NCCN guidelines. (Network. 2024) This post-hoc analysis of a single-center, ongoing prospective clinical trial (NCT05342584) aimed to assess the value of interim BMbx in predicting CR when venetoclax (Ven) was added to “7+3” intensive chemotherapy (IC) for RI.

Thirty-eight pts with newly diagnosed AML received Ven+IC from 7/2022-4/2024. All pts had BM bx on D14-21 as well as D28-42 of RI. Blast-percentage was determined by immunohistochemistry (IHC) on core bx and high-sensitivity (hs) multiparameter flow cytometry (MFC) (estimated lower level of enumeration &lt;0.02%, Hematologics, Inc). Residual disease on D14-21 was defined as blasts≥5% by a) either IHC or hsMFC, whichever was greater (n=38) and b) hsMFC alone (n=35; 3 patients had no hsMFC available). Response at the end of induction (D28-42) was based on ELN2022 recommendations. (Döhner, Wei et al. 2022) No patient received second induction for residual disease based on D14-21 BM bx. We evaluated concordance of disease assessment between the two timepoints.

Thirty-three pts achieved CR, one with incomplete count recovery (CRh) (87% composite CR [CRc] rate); 29/33 (88%) were measurable residual disease (MRD) negative (-) by hsMFC at the end of induction. The five patients that did not achieve CR all had residual disease on their interim marrow by either IHC or hsMFC (sensitivity 100%, 95% CI [47.8-100%]), though only three patients had residual disease detected by hsMFC (sensitivity 60%, 95% CI [14.7-94.7%]). Of the 33 patients that achieved CR, only 16 had absence of residual disease on their interim marrow by either IHC or hsMFC (specificity 48.5%, 95% CI [30.8-66.5%]); the remaining 17 patients had on average 10% residual blasts (range: 5-60%). Among the 30/33 patients who achieved CR and had interim marrow assessment by hsMFC alone, no disease was detected in 23 patients (specificity 76.7%, 95% CI [57.7-90.1%]); there were 7 patients with residual disease who had on average 14% residual blasts (range 5.8-31%). The increased specificity of hsMFC likely reflects its superiority over IHC in differentiating leukemic from regenerative blasts. The decreased sensitivity of hsMFC may be attributed to the susceptibility of the test to hemodilution. Regardless, whereas the absence of increased blasts in interim marrow predicted CR at the end of induction (negative predictive value IHC +/- hsMFC: 100%, 95% CI [79.4 - 100%], hsMFC: 92%, 95% CI [74.0-99%]), the positive predictive value of residual disease on D14-21 was low by either approach (IHC +/- hsMFC: 22.7%, 95% CI [7.8 - 45.4%], hsMFC: 30%, 95% CI [6.7-66.3%]). A low concordance between interim and end-induction marrow evaluation was also shown when the Kappa statistic (κ) was calculated for both assessment approaches (IHC +/- hsMFC: κ = 0.20, 95% CI [0.03-0.37] and hsMFC: κ = 0.26, 95% CI [-0.08-0.60]).

Within the limitations of a single-center study and a small patient cohort, our results suggest that interim marrow assessment in AML induction is a poor predictor of CR when patients are treated with IC plus Ven. False positive results can come at a cost of exposure to unnecessary chemotherapy-related toxicity, as well as contribute to increasing patient anxiety. Our results should be confirmed in future, larger, multi-center studies, but it is possible that with more efficacious induction strategies this already controversial practice will become obsolete.