Dexaml-02 : A Phase II Study of Dexamethasone Added to Induction and Postremission Therapy in Older Patients with Newly Diagnosed AML. a French Innovative Leukemia Organization (FILO) Study

Background In a recent retrospective study, we have showed that the addition of dexamethasone to intensive chemotherapy was significantly associated with a better outcome in AML patients with hyperleukocytosis at diagnosis (Bertoli S, Haematologica 2018). Moreover, preclinical studies demonstrated that specific AML oncogenic alterations (RUNX1-RUNX1T1, RUNX1, NPM1, or SRSF2 mutations as well as NF-kB activation in leukemic stem cells) or therapeutic stress (cytarabine, FLT3 inhibitors) are associated with up-regulation of the inflammatory gene response and expression of the glucocorticoid receptor which induce sensitization to glucocorticoids (Récher C, Front Oncol 2021). Therefore, dexamethasone, used as a chemo sensitizer in combination with intensive chemotherapy, may improve treatment response and outcome regardless of the white blood cell count.

Methods DEXAML-02 (LAM-SA 2018) is a non-randomized phase II multicenter trial to assess the impact on outcome of dexamethasone added to induction chemotherapy in older patients with AML (NCT03609060). Key inclusion criteria were: > 60 years of age, newly diagnosed AML (either de novo or therapy-related AML), favorable or intermediate cytogenetic risk according to MRC 2010 classification, ECOG performance status < 3; HCT-CI score < 3, adequate baseline organ function. Key exclusion criteria were: AML with adverse cytogenetic risk, AML arising from MDS, MPN or CMML, AML with BCR-ABL1, known active central nervous system leukemia. Induction chemotherapy regimen consisted in one cycle of idarubicin 8 mg/m²/day, D1 to D5, cytarabine 100 mg/m²/d, CIV D1 to D7, lomustine 200 mg/m²/d, orally at D1 and dexamethasone 10 mg/12h, IV, D1 to D3. The use of G-CSF, anti-fungal, anti-viral and anti-pneumocystis jiroveci prophylaxis were recommended. Patients who failed to reach complete remission (CR/CRi) after this single cycle of induction were off-study whereas CR/CRi patients were planned to receive up to 6 courses of mini-consolidation administrated every 30 to 45 days with idarubicin 8 mg/m², D1, cytarabine 50 mg/m²/12h, subcutaneous, D1 to D5, dexamethasone 20 mg/d, D1. The addition of midostaurin in patients with FLT3-ITD or FLT3-TKD mutations was allowed during induction, consolidation and maintenance. Allogeneic stem-cell transplantation was allowed after 2 to 4 cycles in patients with intermediate or adverse risk according to ELN 2017 classification. Patients with CBF-AML could receive 2-3 cycles of intermediate dose cytarabine (with dexamethasone) instead of 6 cycles of mini-consolidations according to investigator choice.

Results From August 2018 to February 2020, 120 patients were included. 75 patients were male (62.5%). Median age was 70y (min-max, 61-80). Median WBC was 4.9 G/L (0.64-137). Most patients had an intermediate cytogenetic risk (91.7%). NPM1 and FLT3 mutations (per local analysis) were observed in 45 (37.5%) and 33 patients (27.5%), respectively. NGS of a 91 myeloid panel genes was centrally performed in 111 patients. 24 patients received midostaurin.

Following the induction cycle, 100 patients (83.3%) achieved CR/CRi, 14 failed (11.7%) and 6 died early (5 %). In NPM1mut patients, 43 achieved CR/CRi (95.6%). During induction, grade III-IV adverse events were: infections (50.8%), mucositis (16.7%), gastro-intestinal (14.2%), hepatic (11.7%), hyperglycemia (10.8%), pulmonary (7.5%), cardiac (5.8%), cutaneous (5%) or bleedings (5%).

Of the 100 CR/CRi patients, 86 entered the consolidation phase of whom 59 and 38 received 3 and 6 cycles, respectively. 23 patients received an allogeneic-SCT in first CR. The median follow up time was 31.4 months. Median RFS and OS were 20.2 and 30.7 months, respectively. In NPM1mut patients, median RFS was 20.1 months while median OS was not reached.

Conclusion In older AML patients who are eligible for intensive treatment, adding dexamethasone to induction and consolidation chemotherapy is feasible and associated with a high response rate after a single induction cycle and encouraging overall survival. A historical comparison with the patient population of the LAM-SA 2007 trial (Pigneux A, JCO 2018) will be presented during the meeting to highlight a potential signal of activity.

Recher:Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Janssen, Jazz Pharmaceuticals, Novartis, BMS-Celgene, Otsuka, Astellas, Daiichi-Sankyo, Macrogenics, Roche, Takeda, Servier, Pfizer: Other: Advisory role; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Amgen, Novartis, BMS-Celgene, Jazz Pharmaceuticals, Agios, MaatPharma, Astellas, Roche, Iqvia, Daiichi-Sankyo: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bertoli:Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guieze:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie, Beigene, Janssen, Gilead, Roche, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Desbrosses:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carre:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mathilde:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vincent:Sandoz: Other: Education course paid by sandoz; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Financing meeting participation; Sanofi: Honoraria, Other: Financing meeting participation; Pfizer: Other: Financing meeting participation, congress participation; Amgen: Membership on an entity's Board of Directors or advisory committees. Largeaud:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vergez:Pierre Fabre: Research Funding. Vey:Novartis: Honoraria, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria; BMS: Honoraria; Roche: Honoraria; Amgen: Honoraria. Pigneux:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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