Therapeutic strategies in high-risk acute myeloid leukaemia eligible for intensive chemotherapy

INTRODUCTION

Standard of care for acute myeloid leukaemia is still intensive chemotherapy (IC) followed by allogeneic stem cell transplantation depending on the cytogenetic and molecular profiles of the disease. Nevertheless, a hypomethylating agent in combination with venetoclax (VEN) could be an option in patients not eligible for intensive chemotherapy and/or in patients with adverse risk based on the ELN classification. The definition of high-risk leukaemia is not well standardised but usually, we define this subgroup of patients as adverse risk based on the ELN classification. Recently, ELN classification evolved to include new molecular abnormalities such as TP53 mutation, myelodysplasia-related gene mutations, and myelodysplasia-related cytogenetic abnormalities.¹ Complete remission (CR) rate obtained after induction chemotherapy was 67.5% with DAC (daunorubicin, fludarabine, cladribine)², 74% with MDACC FIA (fludarabine, cytarabine, idarubicin)³, 82% with FLAI + GO (fludarabine, cytarabine, idarubicin, gemtuzumab ozogamycin)⁴ and 84% with FLAG-IDA (fludarabine, cytarabine, idarubicin, G-CSF).⁵ Overall survival (OS) reported with DAC was 45% at 3 years, with MDACC FIA was 57% at 2 years, with FLAI + GO was 63% at 2 years and with FLAG-IDA was 44% at 8 years. The goals of improving IC in AML are efficacy in improving CR rates and irradicating measurable residual disease (MRD); safety in reducing early mortality and durability in preventing relapse and transitioning to alloHSCT if indicated. The primary goal is to decrease relapse and increase cure rates.

VENETOCLAX IN COMBINATION WITH INTENSIVE CHEMOTHERAPY

Some studies combined VEN with intensive chemotherapy (IC). Twenty-nine patients were treated with FLAG-IDA + VEN⁶ showing 90% of composite CR (cCR), 96% of negative MRD and 1-year OS at 94%. Fifty patients were treated with CLIA + VEN⁷ showing 94% cCR, 82% negative MRD and 1-year OS at 85%. Fifty-one patients were treated with « 5+2 » + VEN⁸ showing 72% cCR, and a median OS at 11.2 months. A retrospective study which compared IC vs IC + VEN in 279 patients was performed.⁹ No significant difference was observed in terms of overall response rate (ORR) 86% vs 95% or in terms of cCR 86% vs 91%. Nevertheless, we observed significantly more CR MRD- in IC + VEN 86% vs 61% (p=0.0028). Moreover, CR MRD- was significantly higher in ELN adverse 87% vs 48% (p=0.0059). More patients could undergo alloSCT after IC + VEN 72% vs 58% (p=0.012), and 82% vs 46% (p<0.0001) in ELN adverse AML. We observed a significant improvement with median event-free survival (EFS) not reached vs 12 months (p=0.002) and a median OS not reached vs 21 months (p=0.03) in IC + VEN and IC subgroups, respectively.

CPX-351

CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukaemia cells to a greater extent than normal bone marrow cells. CPX-351 is approved in newly diagnosed AML-MRC (myelodysplasia-related changes) and therapy-related AML patients. In the phase 3 clinical trial, CPX-351 was associated with a higher ORR (CR/CRi) (47.7% vs 33.3%) and a higher rate of subsequent allo-SCT (34% vs 25%) vs « 3+7 ».¹⁰ We observed an increase of median OS in the global cohort 9.33 months vs 5.95 months, more pronounced in allotransplanted patients not reached vs 10.25 months in CPX-351 vs « 3+7 », respectively.¹¹ These results were confirmed in the real-life experience from several countries. In France, 103 patients were reported from 12 centres. ORR was 59% and 57% of patients obtained MRD <10-3. Median OS was 16.1 months and was not reached in allotransplanted patients.¹² In Italy, 71 patients were reported from 31 centres. ORR was 65% and 62.5% of patients obtained MRD <10-3. Median OS was not reached in the global cohort and in allotransplanted patients.¹³

EXTENSION OF CPX-351 INDICATION IN ALL HIGH-RISK AML DEFINED BY ELN 2022

We designed a new study to extend CPX-351 indication to treatment-naive patients ≥50 years of age with de novo AML except t-AML or secondary AML eligible for intensive therapy. We stratified by genomic the population based on the presence of SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, STAG2 or RUNX1 mutation. Patients are randomized 1:1 between CPX-351 vs “3+7”. We estimated that 48% of patients achieve MRD using leukaemia-associated immunophenotype (LAIP) <10-3 with one cycle of conventional 7+3 and the primary objective is to demonstrate a 20% increase in MRD LAIP<10-3 with CPX-351 to 68% after the first course. We plan to include 210 patients to answer to this question. This clinical trial is currently enrolling (NCT05260528).

FOCUS ON TP53-MUTATED AML ELIGIBLE FOR IC

TP53 mutated AML are very poor disease with a low rate of CR/CRi and a short median duration of response and OS. Any treatment compared to AZA alone or usual IC as “3+7” showed an improvement in this setting. For patients eligible for IC, we observed 29% of CR using CPX-351 and 40% using « 3+7 », with a median OS at 4.5 months using CPX-351 and 5.1 months using « 3+7 ».¹⁴ For patients not eligible for IC, even if we observed a higher rate of CR using VEN in combination with hypomethylaling agents (CR/CRi rate: 17%, 41% and 57% for AZA alone, AZA + VEN or decitabine + VEN, respectively), we didn’t find an improvement in term of OS (median OS: 4.9, 5.2 and 5.2 months for AZA alone, AZA + VEN or decitabine + VEN, respectively).^15-17 Magrolimab, an anti-CD47 antibody targeting the « don’t eat me » signal interacting with macrophages showed promising results in combination with AZA alone with a CR/CRi rate at 42% and a median OS at 10.8 months¹⁸; and in combination with AZA + VEN showing CR/CRi rate at 64% and a median OS at 10.4 months.¹⁹ Two randomized phase clinical trials evaluating AZA + magrolimab (ENHANCE-2, NCT04778397) and AZA + VEN + magrolimab (ENHANCE-3, NCT04435691) were designed and enrolled some patients but FDA halted them following negative results of ENHANCE (NCT04313881) clinical trial in myelodysplastic syndromes and about safety concerns.

CONCLUSIONS

To summarize, IC needs to be improved in high-risk AML. Venetocax seems to be a good partner to IC. CPX-351 showed a better response, OS and better safety and should be a backbone for the development of new combinations in this setting. Molecular high-risk AML defined by ELN 2022 could be considered in future clinical trials as ALFA 2101. MRD could guide therapy including allogeneic stem cell transplantation as part of the strategy for intensively treated patients. Unfortunately, treatment of TP53-mutated AML remains a challenge.

CONFLICT OF INTEREST

The author declares a conflict of interest with Jazz Pharma, Abbvie, BMS/Celgene and Gilead.

FUNDING

None

ACKNOWLEDGEMENTS

The author (TC) wrote the manuscript and agreed on the final version. The author acknowledges EuroLeuk conference and Alessandro Isidori for the organization.

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Posted on 30 April, 202430 April, 2024