Multicenter Retrospective Evaluation of Treatment for High‐Risk Acute Promyelocytic Leukemia: Real‐World Outcomes From the <scp>HERO</scp> Consortium
Authors: Lydia L. Benitez, Kayleigh R. Marx, Caitlin R. Rausch, Kaitlyn M. Buhlinger, Stephen M. Clark, Justin H. Reid, Mimi Lo, Katie S. Gatwood, Sarah Profitt, Richa Shah, Jenna Ciervo, Jeffrey Baron, Bernard L. Marini, Anthony J. Perissinotti, Ashley Soule, Madeline Waldron, Benyam Muluneh
Journal: American Journal of Hematology (2025)

Estimated 36-month Survival Comparison between ATRA/ATO/GO and APML4 regimens. Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia characterized by a translocation between chromosomes 17q21 and 15q24, resulting in the PML-RARA fusion gene, which inhibits differentiation. The PML-RARA fusion protein is highly sensitive to all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) [1]. Optimal treatment for high-risk disease (WBC > 10 × 109/L) remains unclear. Two guideline-recommended regimens for high-risk APL follow an ATRA/ATO backbone [2]. The APML4 regimen has a three-phase approach: ATRA, ATO, and idarubicin in induction, ATRA/ATO-based consolidation, and maintenance with ATRA, methotrexate, and mercaptopurine [3]. An alternative to APML4 includes gemtuzumab ozogamicin (GO) +/− idarubicin (referred to onwards as ATRA + ATO + GO) [4]. The two regimens differ in intensity and duration, with the reduced emphasis on anthracyclines potentially lowering the risk of treatment-related complications. It is unknown if these advantages are outweighed by an increased risk of relapse, toxicities, or GO-specific adverse events. The Hematology Research Outcomes (HERO) Consortium conducted a retrospective review of these two treatment approaches. Herein, we present the results of this study. This multicenter, retrospective cohort study included patients ≥ 18 years with newly diagnosed high-risk APL characterized by t(15;17) (q24.1;q21.2) and a WBC > 10 000 at diagnosis treated between April 2014 and June 2022 among nine HERO consortium centers. Patients were divided into 2 cohorts based on induction: APML4 or ATRA + ATO + GO. Patients were treatment-naïve and received ≥ 1 dose of induction under the institution's standard-of-care high-risk protocol or as part of NCT00413166 or NCT01409161. Exclusion criteria are in the online supplement. The study protocol was IRB approved at each participating center. The primary endpoint was a composite incidence of one or more of the following: mortality, intensive care unit (ICU) admission after treatment initiation, and confirmed infection during induction. Secondary endpoints included individual components of the primary endpoint, time to count recovery, toxicities, and complete response (CR) rates, relapse rates, and overall survival (OS) defined using the 2003 Revised IWG Criteria [5]. Results were analyzed as intent-to-treat including all patients who entered induction regardless of consolidation strategies. Expanded definitions and statistical analysis details are available in the online supplement. Seventy-nine patients with high-risk APL were identified; two were excluded due to incomplete records. Seventy-seven patients were analyzed; n = 52 received APML4 induction, and n = 25 received ATRA+ATO + GO induction (Figure S1 and Table S1). Baseline characteristics were similar between cohorts (Table S2). The median age for the entire cohort was 45 years (range 19–78 years) with 21% (n = 16) over 60 years. There was a higher percentage of non-Hispanic white patients in the APML4 cohort (p = 0.003) and a higher percentage of Hispanic/LatinX patients in the ATRA + ATO + GO cohort (p = 0.022). The median body mass index was higher in the ATRA + ATO + GO cohort (p = 0.026). Burden of disease was similar between cohorts (Table S2). The two groups were clinically balanced across various characteristics. FMS-like tyrosine kinase (FLT3) mutation was seen in 81% (38/47) of patients tested; internal tandem duplication mutations (FLT3-ITD) were present in 77% (36/47) and tyrosine-kinase domain mutations (FLT3-TKD) were present in 20% (9/44) of which the majority were seen concurrently with FLT3-ITD mutations. Supportive care intervention details during induction are available in the online supplement. Additional cytoreductive therapy was employed in most patients, 71% (n = 37) in the APML4 cohort and 84% (n = 21) in the ATRA + ATO + GO cohort (p = 0.269) (Table S2). Patients receiving APML4 were more likely to receive hydroxyurea (69% [n = 36], p = 0.006) whereas idarubicin was commonly utilized in the ATRA + ATO + GO cohort (68% [n = 17], p < 0.001). Induction lasted a median of 31 days (range 15–46), longer in the APML4 cohort (median 34 days, range 27–46) versus 22 days (range 15–44) in the ATRA + ATO + GO cohort (p < 0.001). The composite safety endpoint defined as mortality, confirmed infection, and/or ICU admission during induction therapy occurred in 58% (n = 30) of patients receiving APML4 and 36% (n = 9) of patients receiving ATRA + ATO + GO induction (p = 0.075) (Table 1A). No individual component of the composite endpoint was significantly different between the cohorts. Induction mortality was low at 7.8% (n = 6). Infection occurred in 40% (n = 31) of patients. Prophylactic corticosteroid use was not associated with increased infections (p = 0.781). ICU admission was similar between arms, with 17% of all patients requiring admission after treatment start. Time to blood count recovery was shorter in the ATRA + ATO + GO cohort for both platelet (PLT) and absolute neutrophil count (ANC) (p < 0.001 for both). The incidence of neutropenic fever during induction was also lower in the ATRA + ATO + GO cohort compared to the APML4 cohort (p = 0.023). All other safety endpoints were similar. Corticosteroid prophylaxis was associated with a lower incidence of differentiation syndrome (27% occurrence in patients receiving vs. 77% in those not receiving; p < 0.001). Complete hematologic remission was achieved by 90% (n = 47) and 96% (n = 24) of patients in APML4 and ATRA + ATO + GO induction cohorts, respectively (p = 0.389 [Table 1B]). With a median follow-up of 31 months (APML4 cohort median 36.4 months [range 0.4–96.3 months]; ATRA+ATO + GO cohort median 22.5 months [range 0.1–88.1]), the 36-month estimated survival of the entire study population was 92% (95% CI 86.2%–98.2%) which was similar between the cohorts: 90% (95% CI 82.4%–98.4%) for APML4 and 96% for ATRA + ATO + GO (95% CI 88.4%–100%) (Figure S2). Consolidation strategies and toxicity are available in Table S3. With limited comparative data guiding treatment selection in high-risk APL and a high cure rate, toxicity becomes a crucial factor in choosing a regimen. In this multi-center comparison of APML4 and ATRA + ATO + GO, the composite safety endpoint of induction therapy was similar between cohorts. Efficacy was excellent in both cohorts, with similar 36-month estimated OS (Figure S2). The results presented herein mirror those of individual single-arm publications for APML4 and ATRA + ATO + GO therapies [3, 4]. The tolerability of APML4-style induction compares favorably to reported outcomes by Iland et al. Long-term efficacy was also similar to prior publications. The patient population is also similar to single-arm prospective evaluations of these regimens. Of note, both prospective evaluations for APML4 and ATRA + ATO + GO included low-risk patients, so disease variables (e.g., WBC, LDH, molecular profiles, etc.) observed cannot be compared. Most patients in our retrospective review were found to have FLT3 mutations, predominantly FLT3-ITD, which is consistent with other reports [6]. Institutional practices were likely associated with some differences between cohorts given the majority of the ATRA + ATO + GO cohort came from a single institution (n = 22/25, Table S1) and 48% of patients in this cohort were treated as part of a clinical trial. Some institutional differences are reflected in the choice of agent utilized for additional cytoreduction. Idarubicin was the agent of choice for most patients treated with ATRA + ATO + GO compared to hydroxyurea in the APML4 cohort. Similarly, prophylactic corticosteroid use was more common in the ATRA + ATO + GO cohort. Although the incidence of differentiation syndrome was similar between the two cohorts, the use of prophylactic corticosteroid was associated with a significantly lower incidence of differentiation syndrome. Additionally, despite similar baseline and disease characteristics, patients treated with ATRA + ATO + GO were more commonly admitted to the ICU prior to starting induction (Table S2), potentially reflecting a more conservative approach to supportive care management. ANC and PLT recovery occurred faster in the ATRA + ATO + GO cohort. APML4 induction was associated with a higher probability of neutropenic fever without an increased risk of an identified infection. This observation is likely two-fold. Firstly, the APML4 cohort received higher cumulative doses of idarubicin (~48 mg/m2) compared to a median of 12 mg/m2 of idarubicin in 68% of patients in the ATRA + ATO + GO cohort. Secondly, patients in the ATRA + ATO + GO cohort were evaluated for response between days 21 and 28 of induction, and therapy was stopped if < 5% promyelocytes were present in the bone marrow, resulting in reduced overall exposure to ATO comparatively. Given outcomes seen with both approaches, it is possible that patients may be de-escalated from APML4 therapy. While currently available only as an abstract, the phase III APOLLO trial compared ATRA + ATO + idarubicin induction therapy to ATRA + chemotherapy and found comparable CR/CRi rates, improved 2-year event-free survival, and less toxicity with the experimental arm which did not include maintenance. This demonstrates that induction with only two doses of idarubicin in addition to ATRA + ATO may be sufficient [7]. Our review similarly demonstrated excellent outcomes with APML4, with less than 50% of our patients having documented receipt of maintenance therapy. Several important limitations of this observational study must be noted. It is possible that differences exist that were not captured. This study was not powered to detect cardiac changes with anthracycline exposure. Additionally, it is important to note that many patients in the ATRA + ATO + GO arm also received anthracycline, albeit with much lower exposure. Finally, many patients followed up locally after induction or consolidation, thus leading to a limited analysis of post-induction outcomes. Limitations aside, this study presents the first reported comparison between idarubicin-based and GO-based guideline-recommended regimens for high-risk APL [2]. The format of the HERO Consortium allowed for the comparison of real-world approaches to treating high-risk APL to better inform and optimize clinical practice. Excellent short-and long-term outcomes with APML4 and ATRA + ATO + GO induction suggest both treatments are appropriate for high-risk APL management. ATRA + ATO + GO induction, which included a lower cumulative dose of idarubicin and duration of ATO therapy, was associated with a shorter time to blood count recovery and a lower rate of neutropenic fever. Approaches that de-escalate cytotoxic chemotherapy in APL represent significant patient-centered advances in care. Study was IRB approved with the University of Michigan serving as the coordinating center. All participating centers' IRBs (MD Anderson, UNC, UCSF, Vanderbilt, MSK, Roswell Park, University of Kentucky, Cleveland Clinic) also reviewed and updated the protocol. Consent was waived by the IRB since it was a retrospective review of EHR data. Clark: Horizon CME: Honoraria, Speakers Bureau. Gatwood: Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau, Other: Advisory Board; BioLineRx: Consultancy, Honoraria, Speakers Bureau, Other: Advisory Board; Kite: Honoraria, Speakers Bureau. Profitt: Genentech Inc.: Consultancy, Other: Advisory Board. Rigel Pharmaceuticals Inc.: Consultancy, Other: Advisory Board; Eli Lilly & Company: Consultancy, Other: Advisory Board. Perissinotti: Pfizer: Consultancy, Other: Advisory Board; Abbvie: Consultancy, Other: Advisory Board; Amgen: Consultancy, Other: Advisory Board; Beigene: Consultancy, Other: Advisory Board. Waldron: AstraZeneca: Speakers Bureau; Sanofi: Other: Advisory Board; UroGen: Other: Advisory Board; SeaGen: Other: Advisory Board. Muluneh: Servier: Consultancy, Other: Advisory Board; Novartis: Other: spouse is employee and stockholder of Novartis Pharmaceuticals. 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. Any queries (other than missing content) should be directed to the corresponding author for the article.