Evaluating the role of <scp>Day</scp> 14 bone marrow biopsy and <scp>European LeukemiaNet</scp> risk classification in predicting overall and relapse‐free survival in acute myeloid leukemia
Authors: Metodi Balev, Victor Zibara, Grace Van Hyfte, Jonathan Feld, Marina Kremyanskaya, Michelle Becker, Alla Keyzner, Alan H. Shih, Bridget Marcellino, Hannah Levavi, Lewis Silverman, John Mascarenhas, Douglas Tremblay
Journal: American Journal of Hematology (2024)

Multivariable analysis for overall survival and relapse-free survival demonstrating lack of significant for D14 BM status. The most recent National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) patients undergoing cytarabine-based induction therapy recommend the performance of a bone marrow biopsy 14–21 days after the initiation of therapy.1 These "Day 14" bone marrow biopsies (D14 BM Bx) are routinely performed to assess early response to induction therapy. The presence of residual disease (RD) has been historically associated with decreased rates of complete remission (CR) at count recovery and has been utilized to justify the pursuit of prompt reinduction therapy. In recent years, both the prognostic value of D14 BM Bx and the clinical utility of reinduction decisions based on its findings have been called into question. The limitations have centered on the practice's limited specificity for predicting CR, with several studies suggesting that up to one third of patients with RD at D14 can go on to achieve CR without reinduction therapy.2, 3 There is still a paucity of randomized clinical trial data to indicate whether reinduction for D14 RD confers benefit to major clinical endpoints such as overall survival (OS) and relapse-free survival (RFS). D14 BM Bx nonetheless remains one of the few posttreatment variables available to guide decisions regarding the course of induction therapy. Although its limitations in isolation are well appreciated, it remains unclear whether the degree of chemoresistance reflected in D14 RD independently informs the clinical heterogeneity still observed in other widely validated prognostic criteria such as European LeukemiaNet (ELN) risk classification.4 To explore this question, we retrospectively identified adult patients with AML who received intensive induction therapy with a "7 + 3" (cytarabine and an anthracycline) regimen and D14 BM Bx at Mount Sinai Hospital from January 2009 to July 2022 and analyzed the relationship between D14 disease status, 2022 ELN risk classification, and receipt of reinduction therapy on major clinical endpoints. D14 RD was defined as an elevated marrow cellularity >20% and/or blast counts >5%. Patients were classified according to the 2022 ELN risk stratification guidelines. For all survival analyses, patients were censored at last follow-up, death, or time of stem cell transplantation (SCT). The baseline characteristics of our cohort are outlined in Table S1. The study population consisted of 200 patients with a median age of 57 years and 52.7% were female. Most patients had de novo AML (76%). Patients' risk groups were classified based on 2022 ELN guidelines (19% favorable, 49% intermediate, 29% adverse, 4% not available). In total, 113 patients (57%) had no evidence of disease (NED) at D14 and 87 patients (43%) had RD. When comparing baseline characteristics, patients with NED were more likely to have favorable ELN risk group (p = .01) than those with RD; however, there were no significant differences in age, sex, race/ethnicity, presenting lab values, type of AML (primary vs. secondary), or diagnostic bone marrow biopsy parameters. Rates of CR at count recovery were similar between those with NED versus RD (85% vs. 78%; p = .22), and a multivariable model for predictors of CR showed only adverse ELN risk to have a statistically significant independent relationship with achievement of CR (OR = 0.145; p = .02; Table S2). Among those with RD, 56 patients (64%) received reinduction therapy. Of those 46 patients (82%) were treated with an intensive regimen and 10 patients (18%) were treated with a non-intensive regimen (Table S3). Patients with RD who received reinduction had higher rates of intermediate/adverse risk AML (p = .01) and higher median D14 blast percentage (36% vs. 6%, p < .01) and cellularity (30% vs. 20%, p = .04) compared with those who did not. Those who received reinduction therapy were more likely to achieve a CR (86% vs. 63% without; p = .02). There was no statistically significant difference in median OS between patients with NED and RD (3.8 vs. 1.4 years; p = .24). Among patients who achieved CR, those with NED had an increased RFS (2.6 vs. 0.8 years; p = .01). Within individual ELN risk classes, we did not observe a difference in OS when stratified by D14 disease status. Among patients with intermediate risk disease, those with NED at D14 had a longer RFS (2.6 vs. 0.5 years with RD; p = .03). Neither of the aforementioned RFS differences remained statistically significant when censoring at time of SCT was not performed (p = .24 and .22, respectively). There was no difference in RFS among patients with favorable or adverse risk disease when stratified by D14 disease status. A summary of these clinical endpoints can be found in Table S4, and pertinent survival analyses are depicted in Figures S1–S3. Among patients with RD, those who received reinduction therapy trended toward decreased OS (1.2 years vs. nonestimable [NE]; p = .15) and had decreased RFS (0.4 vs. 1.2 years; p = .02) relative to those who did not. When not censoring at time of SCT, this difference in RFS was no longer statistically significant (1.0 years vs. NE; p = .13). When comparing those with NED and those with RD who did not receive reinduction therapy, there was no difference in OS (p = .55) or RFS (p = .73). In the unadjusted Cox regression model, OS was not significantly affected by D14 BM status (hazard ratio [HR] = 1.3; p = .28). In those with RD, reinduction was associated with an increased hazard of all-cause mortality (HR = 2.2; p = .0004). The multivariable OS model (Table 1) showed no evidence of higher mortality risk among patients with RD (vs. NED, HR = 0.98; p = .97) or those with RD who received reinduction therapy (vs. RD without; HR = 1.9; p = .18). In the unadjusted Cox regression model, hazard of relapse was significantly increased among patients with RD (vs. NED; HR = 1.9; p = .02). In those with RD, reinduction was associated with an increased hazard of relapse (vs. no reinduction; HR = 2.8; p < .01). The multivariable RFS model showed no difference in hazard of relapse regardless of D14 disease or, among those with RD, receipt of reinduction therapy (Table 1). The clinical role of D14 BM Bx remains unclear, and these findings further question this routine practice by showing similar clinical outcomes irrespective of D14 disease status. Our cohort showed similar OS and rates of CR regardless of D14 disease status. Although those with NED showed decrease hazard of relapse on univariable analysis, this relationship was not seen on multivariable analysis. Additionally, while those with RD were more likely to have intermediate or adverse ELN risk disease, there was no major difference in median OS or RFS within these groups when stratifying by D14 disease status save for an increased RFS among patients with intermediate risk disease and NED at D14. Given that this relationship did not hold true when censoring at time of SCT was deferred in the survival analysis, it suggests that clinicians may have been motivated to pursue expeditious SCT in intermediate risk patients with RD. Overall, these findings suggest that D14 RD is more likely a reflection of underlying disease severity rather than an independent variable that can further refine the clinical heterogeneity still observed within individual ELN risk groups. Our findings also raise questions regarding the benefit of reinduction therapy for D14 RD. There were increased rates of CR among those with RD who received reinduction compared with those who did not—rates comparable to those seen in patients with NED at D14. However, these impressive rates of CR did not reliably extrapolate to long-term clinical endpoints. There was a trend toward decreased OS and a statistically significant decrease in RFS among those with RD who received reinduction therapy compared with those with NED and those with RD who did not receive reinduction therapy. Survival analysis also showed no significant difference in median OS or RFS between patients with NED at D14 and those who had RD but did not receive reinduction therapy. Interpretation of these findings is limited given that higher relative blast counts at D14 likely influenced the decision to provide reinduction therapy to patients. Most patients with RD who did not receive reinduction therapy were composed of patients with high marrow cellularity and low blast percentage on D14—sometimes referred to as an "indeterminate disease" category that has previously shown similar outcomes with reinduction or observation.5 It is possible that reinduction therapy may have exerted a salvage effect on these patients with a higher burden of RD that may have increased rates of CR and, in turn, improved long-term clinical endpoints compared with what outcomes would have been in the absence of reinduction therapy. Such a salvage effect alludes to prior studies that have shown similar long-term outcomes among patients who achieve CR regardless of whether they did so with one or two induction cycles.6 Given the retrospective nature of our study, our findings are limited by selection bias and had a disproportionate focus on patients receiving reinduction with intensive regimens. Use of additional induction agents beyond cytarabine and an anthracycline was also not uniformly documented in our cohort. Nonetheless, replication of these analyses with larger cohorts and in a prospective randomized trial format is merited to more robustly evaluate the prognostic and clinical value of D14 BM Bx as AML risk stratification models and therapeutic options continue to evolve. JM receives research funding paid to the institution from Incyte, Novartis, Celgene, BMS, Kartos, Karyopharm, PharmaEssentia, Abbvie, Geron, CTI Bio, and consulting fees from Incyte, Kartos, Karyopharm, Geron, Roche, Abbvie, CTI Bio, GSK, Pfizer, PharmaEssentia, Galecto, Celgene, BMS, and Novartis. DT receives contracted research funding paid to his institution from CTI Biopharma, Astellas Pharma, and Gilead and consulting fees from CTI Biopharma, Novartis, AbbVie, Sierra Oncology, GSK, and Cogent Biosciences. JF receives contracted research funding paid to his institution from Syros and Oryzon pharmaceuticals. MK receives research funding paid to the institution from Incyte, Celgene, BMS, Morphosys, Protagonist, Ionis, Silence therapeutics, Kura oncology and consulting fees from Incyte, Abbvie, Morphosys, and Protagonist. LS has served on advisory boards for Jazz Pharmaceuticals, Servier, and Beam Therapeutics. The remaining authors have no conflicts of interest to report. As a retrospective study, no consent was obtained from subjects in accordance with a waiver obtained from the Program for the Protection of Human Subjects at the Icahn School of Medicine at Mount Sinai. Table S1. Baseline characteristics of overall cohort. Table S2A. Univariable model for complete remission. Table S2B. Multivariable model for complete remission. Table S3. Reinduction regimens utilized. Table S4. Summary of clinical endpoint by presence of residual disease at Day 14 and receipt of reinduction therapy. Figure S1. (A) Overall survival stratified by residual disease at Day 14. (B) Relapse-free survival stratified by residual disease at Day 14. Figure S2. (A) Overall survival stratified by presence of residual disease at Day 14 and receipt of reinduction therapy. (B) Relapse-free survival stratified by presence of residual disease at Day 14 and receipt of reinduction therapy. Figure S3. Kaplan–Meier curves of overall and relapse-free survival stratified by presence of residual disease at D14 among each ELN risk group. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.