Azacitidine in Pediatric Hematologic Myeloid Malignancies: A Retrospective Study
Authors: Saucier Emilie , Rabian Florence , Boutroux Hélène , Strullu Marion , Morand Karine , Chevillon Florian , Brethon Benoit , Boissel Nicolas , Leverger Guy , Baruchel André 
Published: November 2019

Purpose: Hypomethylating agents are approved in adults with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS). By contrast, data in pediatric hematologic malignancies are scarce. Herein, we report the off-label administration of Azacitidine (Aza) in a cohort of children, adolescents and young adults (AYA).
Methods: Patients from Robert-Debré, Saint-Louis and Armand-Trousseau University Hospitals (Assistance Publique-Hôpitaux de Paris), 25 year-old or younger at initiation of treatment and who received Aza between 2009 and 2019 were included. Data on indication, efficacy and toxicity of the treatment were retrospectively collected.
Results: As 3 patients (pts) were treated twice with Aza at different stages of their disease, 35 treatments in 32 patients were analyzed. Median age at diagnosis was 11.7 y (range 0.1-22.4). Diagnosis were: 16 Acute Myeloid Leukemias (AML), 6 Juvenile Myelomonocytic Leukemias (JMML), 7 Myelodysplastic Syndromes (MDS), 2 Mixed Phenotype Acute Leukemias (MPAL) and 1 Interdigitating Dendritic Cells Sarcoma. Aza was administrated after a median of 2 lines of treatment (range 0-6) and front line in 5 out of 32 pts (16%; MDS = 4, JMML = 1). Concomitant therapy was administrated in 15/35 treatments (43%) (Sorafenib = 6, Gemtuzumab Ozogamicin = 2, donor lymphocyte infusions = 2, other = 5). Fourteen out of 35 treatments (40%) were delivered in patients with a history of hematopoietic stem cell transplantation (HSCT). Aza was administrated either intravenously (n = 11) or subcutaneously (n = 24) at a dose of 75mg/m² for 7 (20/35, 57%) or 5 (6/35, 17%) consecutive days every 28 days, i.e. same daily dose as in adults; at reduced doses (≤ 50mg/m²) in 3/35 patients; at a dosing scheme varying from one cycle to another in 6/35 patients. Patients received a median of 3 cycles of Aza per treatment (range 1-31). A total of 137 cycles was delivered. Aza was well tolerated with only 5/137 cycles delayed due to hematological (n = 3) or non-hematological (n = 2) toxicity. Aza was discontinued due to toxicity in 2/137 cycles (1 rectal bleeding, 1 severe sepsis). Anemia was noted in 68/130 cycles (52%), thrombocytopenia in 68/128 cycles (53%), neutropenia in 84/127 cycles (66%) and febrile neutropenia in 25/131 cycles (19%). Two grade 5 side effects were observed: 1 patient died from cerebral hemorrhage in a context of anti-platelet poly-immunization, another from septic shock in a context of neutropenia. Most common non-hematological side effects included: nausea, vomiting, diarrhea, subcutaneous injections lesions (local inflammation or hematoma) and infections.
Responses to Aza are detailed in the attached table. Best responses to Aza included: 2 complete remissions (CR) both after 3 cycles, 3 CR with incomplete hematologic recovery (CRi) after a median of 2 cycles (range 1-2), 2 partial remissions (PR) after 2 and 3 cycles, 6 stable diseases (SD) during a median of 2 cycles (range 2-12) and 2 hematologic improvements. Overall response rate (sum of CR, CRi, PRs), was 19% (6/32) (3 non evaluable responses). Three out of the 6 patients treated with Aza combined with Sorafenib (AML = 4, MPAL = 2) obtained a response (CR: 2, CRi: 1). The association led to HSCT for 2 of them; the third patient had a CR maintained almost 3 years without HSCT, before relapsing on therapy. One patient with MDS had a SD for 12 months after palliative treatment with Aza. Overall, Aza treatment allowed to proceed to HSCT in 8 out of 32 patients (25%), 7 out of 8 proceeding to a first HSCT [CR: 1 patient, CRi: 3 patients, PR: 2 patients, SD: 1 patient, progressive disease: 1 patient]. These 8 pts included: 4 pts with AML, alive in CR after a median follow-up of 29.5 months (2 of them received concomitant targeted therapy); 2 pts with JMML (1 alive in CR after a follow-up of 25 months); 2 pts with MDS (both died, 7 and 30 months after Aza initiation). Finally, 24 out of 32 patients died and overall survival at 5 years was 23% (IC95% [11;48]) with no difference according to diagnosis.
Conclusion: In a cohort of pediatric and AYA patients with heavily pretreated myeloid malignancies, Aza was well tolerated, and allowed to bridge 25% of patients to HSCT. Further prospective studies are needed to explore combination of Aza with targeted therapy in pediatric patients.

Disclosures
Boissel: NOVARTIS: Consultancy.