RESPONSE TO UP-FRONT AZACITIDINE IN JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML): INTERIM ANALYSIS OF THE PROSPECTIVE EUROPEAN MULTICENTER STUDY AZA-JMML-001
Author(s): ,
Charlotte M. Niemeyer
Affiliations:
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology,Medical Center, University of Freiburg,Freiburg,Germany
,
Christian Flotho
Affiliations:
Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology,Medical Center, University of Freiburg,Freiburg,Germany
,
Daniel B. Lipka
Affiliations:
Division of Cancer Epigenomics,German Cancer Research Center (DKFZ),Heidelberg,Germany
,
Jan Starý
Affiliations:
Department of Pediatric Hematology and Oncology,Fakultní nemocnice v Motole,Prague,Czech Republic
,
Claudia Rössig
Affiliations:
Department of Pediatric Hematology and Oncology,University Children´s Hospital Münster,Münster,Germany
,
André Baruchel
Affiliations:
Department of Pediatric Hematology-Immunology,CHU Paris - Hôpital Universitaire Robert-Debré (APHP),Paris,France
,
Thomas Klingebiel
Affiliations:
Department of Pediatrics,Universitätsklinikum Frankfurt,Frankfurt,Germany
,
Concetta Micalizzi
Affiliations:
Department of Pediatric Sciences,Istituto Giannina Gaslini,Genoa,Italy
,
Gérard Michel
Affiliations:
Pediatrics and Pediatric Oncology,Hôpital de la Timone,Marseilles,France
,
Karsten Nysom
Affiliations:
Department of Pediatrics and Adolescent Medicine,Rigshospitalet,Copenhagen,Denmark
,
Susana Rives
Affiliations:
Pediatric Hematology and Oncology,Hospital Sant Joan de Deu de Barcelona, Institut de Recerca Hospital Sant Joan de Deu,Barcelona,Spain
,
Markus Schmugge Liner
Affiliations:
Division of Haematology,Kinderspital Zürich,Zürich,Switzerland
,
Marco Zecca
Affiliations:
Pediatric Hematology/Oncology,Fondazione IRCCS Policlinico San Matteo,Pavia,Italy
,
Irith Baumann
Affiliations:
Department of Pathology,Böblingen Hospital,Sindelfingen,Germany
,
Bouchra Benettaib
Affiliations:
Celgene Corporation,Summit,United States
,
Noha Biserna
Affiliations:
Celgene Corporation,Summit,United States
,
Jennifer Poon
Affiliations:
Celgene Corporation,Summit,United States
,
Mathew Simcock
Affiliations:
Celgene Corporation,Uxbridge,United Kingdom
,
Meera Patturajan
Affiliations:
Celgene Corporation,Summit,United States
,
Marry M. van den Heuvel-Eibrink
Affiliations:
Hematology-Oncology,Prinses Máxima Center for Pediatric Oncology/Hematology,Utrecht,Netherlands
Franco Locatelli
Affiliations:
Department of Pediatric Hematology and Oncology,IRCCS Ospedale Pediatrico Bambino Gesù,Rome,Italy;Sapienza, University of Rome,Rome,Italy
EHA Library. M. Niemeyer C. Jun 15, 2019; 267072; PS1455
Charlotte M. Niemeyer
Charlotte M. Niemeyer
Contributions
×
Abstract

Abstract: PS1455

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
JMML is a chemotherapy-resistant neoplasia of early childhood. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy, being able to cure approximately 50% of these children. Relapse is the major cause of treatment failure, with chemotherapy prior to HSCT being notably unsuccessful. Novel therapies controlling JMML prior to HSCT are urgently needed.

Aims
We conducted a phase 2, multicenter, open-label study to evaluate pharmacodynamics, safety, and antileukemia activity of azacitidine monotherapy prior to HSCT in patients with newly diagnosed JMML.

Methods
Azacitidine was administered at 75 mg/m2/day intravenously on Days 1–7 of a 28-day cycle for 3 to 6 cycles. The primary endpoint was the number of patients achieving clinical complete remission or clinical partial remission (cPR) at Cycle 3 Day 28 (C3D28); secondary endpoints included overall survival following HSCT.

Results
Between September 2015 and November 2017, 18 JMML patients (13 PTPN11-, 3 NRAS-, 1 KRAS-, 1 NF1-mutated), aged 0.2–7.0 years, were enrolled in the study. Median (range) white blood cell (WBC) count, platelet count, and spleen size were: 19.7 (4.3–59.0) × 109/L, 28 (7–85) × 109/L, and 4 (2–14) cm below the costal margin, respectively. DNA methylation class (Lipka et al. Nat Comm. 2017;8:2126; n=18) was high, intermediate, or low in 11, 5, and 2 patients, respectively. Sixteen patients completed 3 cycles of therapy and 5 of them completed 6 cycles. Two patients discontinued treatment before completing 3 cycles due to disease progression. Six patients (33%) experienced ≥1 grade 3 or 4 manageable adverse event, consistent with the known azacitidine safety profile. Eleven patients (61%) achieved cPR at C3D28 and 7 had progressive disease either at C3D28 or prior. Importantly, 8 of the 15 patients who needed platelet transfusions before or shortly after treatment initiation did not require transfusions at the time of HSCT. Seven of these 8 platelet responders had normalized their platelet count (≥130 × 109/L). Palpable spleen size decreased in 11 responders by a median of 3.5 cm after 3 cycles and ranged from 0 to 2 cm below the costal margin after 6 cycles. Seventeen patients received allo-HSCT from a human leukocyte antigen-compatible related or unrelated donor following a busulfan- (n=15) or treosulfan-based (n=2) preparative regimen after a median of 57 days (36–112) from last azacitidine dose. Fourteen out of 16 transplanted patients were leukemia-free at median follow-up of 15.6 months (0.8–22.5) after HSCT. Two children (both high-methylation class) given HSCT relapsed after the allograft. Sixteen of the 18 patients were alive at a median follow-up of 22.2 months (14.2–33.1). One patient who discontinued treatment before Cycle 3 died from disease progression, and 1 non-responder child died from graft failure.

Conclusion
This study showed azacitidine monotherapy was well tolerated in children with newly diagnosed JMML. Although the long-term advantage of azacitidine therapy remains to be fully assessed, both decrease in spleen size and significant platelet responses observed demonstrate that the drug was effective in JMML and provided clinical benefit to patients with JMML in this study. This clinical trial has shown that azacitidine therapy prior to HSCT may be considered for patients with JMML.

Session topic: 16. Myeloproliferative neoplasms - Clinical

Keyword(s): Azacitidine, DNA methylation, HSCT, JMML

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies