Evaluating the Impact of Fewer Frontline Intensive Chemotherapy Plus Venetoclax Consolidation Cycles on Outcomes in <scp>AML</scp>

Intensive induction and consolidation chemotherapy has long been the standard of care for fit patients with newly diagnosed acute myeloid leukemia (AML) [1-3]. Modifications to the traditional cytarabine-anthracycline backbone, including incorporation of purine analogs and high-dose cytarabine in consolidation, have been utilized to improve remission depth and long-term outcomes [4-6]. Achieving measurable residual disease (MRD)-negative remissions remains the major goal, as they consistently correlate with lower relapse rates and improved survival [7, 8]. More recently, venetoclax (VEN) has been added to multidrug intensive chemotherapy (IC) including cladribine, cytarabine, and idarubicin (CLIA + VEN) or fludarabine, cytarabine, idarubicin, and filgrastim (FLAG-IDA + VEN) [9]. Both regimens have demonstrated remarkable efficacy, achieving composite complete remission (CR) rates of 93% and 95% and MRD negativity in 82% and 90% of responders, respectively [10-13]. Compared to the historic efficacy of “7 + 3,” IC + VEN regimens have the potential to be transformative if optimally administered [9, 14, 15]. These regimens classically include one IC + VEN induction cycle, followed by up to five IC + VEN consolidation cycles if not transitioned to allogeneic stem cell transplant (SCT). However, with larger cohorts, it is increasingly apparent that a significant fraction of non-transplanted patients is unable to complete all planned consolidation cycles. Despite low induction mortality, both trials report significant rates of serious adverse events, including > 70% incidence of neutropenic fever, 28%–36% bacteremia, and 12%–22% pneumonia. Therefore, the high rates of CR and MRD-negative CR rates must be balanced with the risks of toxicity, myelosuppression, and infection that cumulative doses of IC + VEN may pose. Herein, we retrospectively investigate hematopoietic recovery in IC + VEN, and whether patients who received fewer consolidation cycles experience worse relapse free survival (RFS) and overall survival (OS). Full methods are provided in Supplemental Appendix in Data S1. From January 2019 to February 2023, 157 newly diagnosed AML patients received frontline IC + VEN (Figure 1). A total of 136 (87%) achieved a composite CR (81 CLIA + VEN [60%]; 55 FLAG-IDA + VEN [40%]). Forty-nine patients discontinued frontline IC + VEN for reasons other than SCT (Cohort 1), while 83 patients proceeded directly to SCT after their last IC + VEN cycle (Cohort 2). Each cohort was separated into those who received ≤ 1 cycle of intensive consolidation (i.e., up to two total IC + VEN cycles) or ≥ 2 cycles of intensive consolidation (i.e., three or more total IC + VEN cycles). Four patients who died prior to completing their first intensive consolidation from infectious complications were excluded. Demographic and mutational data are provided in Table 1 and Supplemental Figure 1 in Data S1. The median age was 45 years (range 19–67) and 94% had de novo AML. By the ELN 2022, 25% had favorable-risk disease, 29% intermediate, and 53% adverse. The median number of IC + VEN cycles received was 2 (range 1–7). Only 14 (11%) of the responding patients had detectable MRD at best response. Patients who stopped frontline therapy for SCT received fewer IC + VEN cycles than those who stopped for other reasons (median 2 vs. 3, p = 0.002) (Supplemental Figure 2A in Data S1). While all patients who stopped IC + VEN for reasons other than SCT were included in Cohort 1, there were 12 (24%) patients that did ultimately receive a SCT at a later timepoint. Reasons for delayed transplant included MRD recurrence (n = 3), persistent or recurrent detectable mutations (n = 2), insurance-related issues (n = 2), or initial transplant delays due to prolonged cytopenias or infections (n = 5). The median duration of cycle 1 was 34 days, increasing to 42 days for consolidation cycles 2–4 (Supplemental Table 1 and Figure 2B in Data S1). Compared to a historical cohort of patients treated with CLIA alone, the duration of Cycle 1 was shorter with IC + VEN (median 34 vs. 38 days, p = 0.002) (Supplemental Tables 1 and 2 and Figure 3 in Data S1). However, subsequent consolidation cycle lengths were longer with IC + VEN than IC alone (median 42 vs. 35 days, p = 0.001). Median days to ANC recovery was shorter during induction (Cycle 1) with IC + VEN compared to historic IC alone (25 vs. 29 days, p < 0.001) (Figure 2, Supplemental Table 3 in Data S1). Yet again, in subsequent consolidation cycles, ANC recovery times with IC + VEN lengthened, with a median time to ANC recovery of 40 days in Cycle 2. This was significantly longer than with IC alone (median 29 days, p = 0.013). Time to platelet recovery was also shorter with IC + VEN during Cycle 1 compared to IC alone (median 24 vs. 26 days, p = 0.038). However, like ANC recovery, platelet recovery times during subsequent consolidation cycles progressively lengthened. In Cycle 2 the median time to platelet recovery was 46 days with IC + VEN compared to 26 days with IC alone (p < 0.001). Notably, several patients (n = 9/52, 17%) never achieved this level of platelet recovery after 2 cycles of IC + VEN, although the majority were subsequently transplanted, and all remained transfusion independent. In Cohort 1, 19 patients (39%) received ≤ 1 cycle of intensive consolidation, while 30 patients (61%) received ≥ 2 cycles (Supplemental Table 4 in Data S1). The most common reasons for stopping frontline IC + VEN were switching to a maintenance regimen (53%), completion of the regimen (23%), and relapse (14%). Among those who received maintenance, 77% were treated with hypomethylating agent (HMA) plus VEN for a median of 7 cycles (range 1–46) (Supplemental Table 5 in Data S1). A greater proportion of patients who received ≤ 1 IC + VEN consolidation cycle had a delayed SCT compared to those who received ≥ 2 cycles (42% vs. 13%, p = 0.039). At a median follow-up of 33.5 months, the median OS and RFS were not reached (NR) for patients receiving ≤ 1 or ≥ 2 cycles of IC + VEN consolidation (Figure 2C,D). No significant differences in survival outcomes were observed between the ≤ 1 or ≥ 2 cycle groups, with 2-year OS rates of 69% versus 67% (p = 0.93) and 2-year RFS rates of 63% vs. 58% (p = 0.95), respectively. Similarly, there was no difference in cumulative incidence of relapse (CIR) between groups, including when analyzed in a competing risks model against death from other causes (p = 0.69) (Supplemental Figure 4 in Data S1). These results were consistent in patients who achieved MRD negativity (Supplemental Figure 5 in Data S1). In Cohort 2, 55 patients (67%) received ≤ 1 cycle of intensive consolidation prior to SCT; 27 patients (33%) received ≥ 2 cycles (i.e.,3 or more total IC + VEN cycles). There were no differences in baseline demographics, ELN 2022 risk, conditioning regimen, or MRD negativity between groups (Supplemental Table 6 in Data S1). At a median follow-up of 36.0 months, the median OS and RFS landmarked at the median time to SCT remained NR (Figure 2E,F) with no difference between those receiving ≤ 1 or ≥ 2 cycles of IC + VEN consolidation prior to SCT. There was no difference in CIR post-SCT either on its own or when analyzed in a competing risks model with death of other causes (p = 0.60) (Supplemental Figure 6 in Data S1). Similarly, there was no difference in outcomes for patients who received ≤ 1 or ≥ 2 cycles of IC + VEN consolidation based on MRD (Supplemental Figure 7 in Data S1). Finally, in multivariate analyses accounting for the potential impact of age and ELN risk on outcomes, the number of IC + VEN consolidation cycles was not significantly associated with the hazard of risk of death or death/relapse in either cohort (Supplemental Figures 8 and 9 in Data S1). As previously published, IC + VEN regimens yielded high MRD-negative CR rates [10-13]. This efficacy is accompanied by rapid recovery of normal hematopoiesis after induction, with shorter time to neutrophil and platelet recovery compared to IC alone. However, subsequent consolidation cycles are conversely associated with prolonged myelosuppression and higher rates of infection, highlighting the potential cumulative toxicity of IC + VEN regimens despite their striking efficacy and low treatment-related mortality. In this analysis, both patients who discontinued frontline IC + VEN for reasons other than SCT and those who proceeded directly to SCT showed no differences in OS or RFS when comparing ≤ 1 versus ≥ 2 consolidation cycles. Efforts to optimize IC duration in AML are not new. In the MRC AML12 trial, five versus four courses of consolidation did not improve OS or RFS, and may have been detrimental in patients > 40 years [16]. Similarly, the UK NCRI trial randomizing patients to two induction cycles followed by either one or two high-dose cytarabine consolidations showed a significantly improved RFS but not OS [17]. Notably, none of these studies incorporated VEN into either induction or consolidation therapy. Given the high MRD-negative CR rates with IC + VEN, our findings suggest that fewer VEN-based consolidation cycles may be equally effective and potentially less toxic. There are inherent limitations to this non-randomized study. Patients receiving ≤ 2 total IC + VEN cycles, who did not transition to early SCT represent a selected population where the treating physician decided that they either could not or did not need further IC + VEN when presumably they were fit enough to receive intensive therapy initially. This resulted in substantial heterogeneity in the succeeding remission strategies, including frequently utilized maintenance regimens. While maintenance therapy in this context is not currently considered standard of care, this type of approach may be an alternative and better tolerated option for supporting durable remissions [18, 19]. In conclusion, outcomes for patients with newly diagnosed AML were not adversely affected by fewer cycles of IC + VEN consolidation. Given the potential cumulative toxicity, this data supports considering treating with fewer cycles of IC + VEN in patients attaining MRD-negative CR and switching to alternative consolidation therapy such as SCT, IC alone, or maintenance regimens. Prospective MRD-guided trials are needed to determine the optimal number of IC + VEN cycles and post-remission strategy. All authors reviewed and approved the final version of the manuscript. This research is supported in part by the MD Anderson Cancer Center Leukemia Support Grant (CA100632). JMP is supported by a T32 Training Grant (CA009666). The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1: Supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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