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31 Replacing the Anthracycline By Gemtuzumab Ozogamicin in Older Patients with De Novo Standard-Risk Acute Myeloid Leukemia Treated Intensively – Results of the Randomized ALFA1401-Mylofrance 4 StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Innovative induction regimens in AML: data from real life and clinical trials
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Adults, AML, Non-Biological, Clinical Research, Chemotherapy, Diseases, Therapies, Myeloid Malignancies, Monoclonal Antibody Therapy, Study Population
Saturday, December 11, 2021: 9:30 AM

Juliette Lambert1*, Jérôme Lambert, MD, PhD2*, Emilie Lemasle, MD3*, Magalie Joris, MD4*, Sylvain Chantepie, MD5*, Cecile Pautas, MD6*, Xavier Thomas, MD, PhD7, Jean Valere Malfuson, MD, PhD8*, Lauris Gastaud, MD9*, Denis Caillot, MD10*, Emmanuelle Tavernier, MD11*, Pascal Turlure12*, Diana Carp, MD13*, Celine Berthon, MD, PhD14,15*, Olivier Legrand, MD, PhD16*, Ambroise Marçais, MD, PhD17*, Iona Vaida, MD18*, Sarah Barbieux, MD19*, Philippe Rousselot20*, Claude Gardin, MD21*, Christine Terré, PharmD, PhD22*, Nicolas Duployez23*, Claude Preudhomme, PharmD, PhD23, Karine Celli-Lebras, CRA24*, Sylvie Castaigne, MD1* and Herve Dombret, MD, PhD25

1Hematology Department, Versailles Hospital, Le Chesnay, France
2Biostatistics Department, Saint Louis University Hospital, Paris, France
3Hematology Department, Henri-Becquerel Cancer Center, Rouen, France
4Hematology department, CHU Amiens, Amiens, France
5Hematology Department, Caen University Hospital, Caen, France
6Hematology Department, Henri Mondor University Hospital, CRETEIL, France
7Hematology Department, Lyon-Sud University Hospital, Hospices Civils de Lyon, Pierre-Benite, France
8Hematology Department, Percy Hospital, Clamart, France
9Medical Oncology Department, Antoine Lacassagne Hospital, Nice, France
10Hematology Department, Le Bocage University Hospital, Dijon, France
11Hematology Department, Oncology institute of Loire, Saint Priest en Jarez, France
12Department of Clinical Hematology, Limoges University Hospital, Limoges, France
13Oncology Department, Orleans Hospital, Orleans, PA, France
14Hematology Department, Lille University Hospital, Lille, France
15UMR9020-U1277 - CANTHER, INSERM CNRS, Lille, France
16Hematology Department, Saint-Antoine University Hospital, Paris, France
17Hematology Department, Necker University Hospital, PARIS, France
18Hematology Department, Pontoise Hospital, Pontoise, France
19Hematology Department, Dunkerque Hospital, Dunkerque, France
20Hematology Department, Centre Hospitalier de Versailles, LE CHESNAY CEDEX, France
21Hematology Department, Avicenne Hospital, Bobigny, France
22Laboratory of Hematology, Versailles Hospital, Le Chesnay, France
23Laboratory of Hematology, Lille University Hospital, Lille, France
24ALFA coordination, Saint-Louis University Hospital, Paris, France
25Saint-Louis University Hospital, APHP, Université de Paris, Paris, France

Introduction

Based on the results of the ALFA-0701 trial (Castaigne et al. Lancet 2012), the addition of fractionated doses of the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO, Mylotarg®) to conventional chemotherapy has been approved in 2017 for frontline treatment of adults with CD33-positive acute myeloid leukemia (AML). Prolonged event-free survival (EFS) was observed in patients with AML of favorable or intermediate risk, while not in those with adverse cytogenetics. Nevertheless, more frequent added toxicities could make the addition of GO a questionable option in patients over 60-65 years of age. In this ALFA-1401/Mylofrance 4 trial (NCT02473146), we investigated if the replacement of the anthracycline by GO might also improve EFS in older patients.

Methods

Between January 2016 and March 2019, 225 patients were randomized 2:1 to receive an experimental GO-cytarabine combination (154 patients) or a standard anthracycline-cytarabine treatment (71 patients). Patients aged 65 to 80 years old (later extended to patients aged 60-64 years old), with previously untreated de novo AML of favorable or intermediate cytogenetics were eligible for the trial. Standard treatment arm consisted in a 7+3 using idarubicin at 12 mg/m2/d on day 1 to 3 and cytarabine 200 mg/m2/d on day 1 to 7. Experimental arm (GO arm) consisted of two doses of GO 3 mg/m2/d on day 1 and 4 and cytarabine 200 mg/m2/d on day 1 to 7. Post-remission therapy comprised two courses of intermediate-dose cytarabine (IDAC) at 1.5 g/m2/12h on day 1, 3 and 5. In the GO arm, a third dose of 3mg/m2/d GO was administered on day 1 of the first IDAC course. The first IDAC course could serve as second induction in patients not responding to the first one. The decision to perform allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission was left to the discretion of the physician. The efficacy analysis was conducted in the modified intent-to-treat (mITT) population excluding patients who did not meet the cytogenetic eligibility criteria. The primary study endpoint was EFS. Secondary endpoints were response rate defined by complete remission (CR), CR with incomplete platelets recovery (CRp) and CR with incomplete hematological recovery (CRi), early mortality, relapse incidence, overall survival (OS) and safety.

Results

Among the 225 randomized patients, 214 (71 standard arm, 143 GO arm) were included in the mITT population. There were 126 men and 88 women. Median age was 70 years (61-80). Cytogenetics was of favorable and intermediate risk in 14 and 200 patients, respectively. One hundred and eighty-one patients reached CR/CRp/CRi, 64 (90%) in standard arm and 117 (82%) in GO arm (p=0.17). Median follow-up time was 38 months. At 2 years, estimated EFS was 38% [95% CI, 28-51] in the standard arm vs. 29% [22-37] in the GO arm (Hazard Ratio (HR), 1.37 [0.98-1.93]; p= 0.067) (Figure 1A). Overall, 118 patients relapsed, 36 (51%) in standard arm and 82 (57%) in GO arm. At 2 years, estimated cumulative incidence of relapse was 48% [36-61] in standard arm vs. 61% [52-70] in GO arm (csHR, 1.32 [0.90-1.93]; p= 0.078). Overall, 122 patients died, 38 (54%) in standard arm, 84 (59%) in GO arm. Sixty-day mortality was 4% in standard arm vs. 10% in GO arm (p=0.13). At 2 years, estimated OS was 65% [55-77] in standard arm vs. 52% [45-61] in GO arm (HR, 1.27 [0.86-1.87]; p= 0.23). In subgroup analysis for EFS (Figure 1B), we found a significant interaction with gender, GO having a detrimental effect in women which persisted after adjustment on known prognostic factors. A total of 33 patients received allo-HSCT in first remission, 19 (30%) in standard arm and 14 (12%) in GO arm (p=0.006). When censoring these patients at transplant time, HR of GO on EFS was 1.27 ([0.88-1.83]; p=0.19). Regarding safety, 76% and 80% of patients had at least one grade 3 to 5 adverse event (p=0.81), including infection in 30% vs. 21% and bleeding in 7% vs. 29% in standard arm and GO arm respectively. Serious adverse events were reported in 34% of patients in standard arm vs. 49% in GO arm (p=0.031). Sinusoidal obstruction syndrome occurred in 2 patients in the GO arm.

Conclusion

Frontline use of GO instead of idarubicin, when combined to cytarabine, does not benefit older patients with de novo standard-risk AML. At the reduced dose schedule used in this study, GO remains associated with significant toxicities while non-significant higher relapse incidence, shorter EFS and shorter OS were observed.

Disclosures: Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy; PFIZER: Speakers Bureau. Pautas: ABBVIE: Consultancy; PFIZER: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Barbieux: ASTRA-ZENECCA: Consultancy. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; Daiichi Sankyo: Honoraria; BMS-Celgene: Honoraria.

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