Single-Center Experience With Epigenetic Treatment for Juvenile Myelomonocytic Leukemia.
Andra Marcu, Andrei Colita, Letitia Elena Radu, Cristina Georgiana Jercan, Ana Maria Bica, Minodora Asan, Daniel Coriu, Alina Daniela Tanase, Carmen C Diaconu, Cristina Mambet, Anca Botezatu, Sergiu Pasca, Patric Teodorescu, Gabriela Anton, Petruta Gurban, Anca Colita
Author Information
Andra Marcu: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Andrei Colita: Department of Stem Cell Transplantation, Coltea Hospital, Bucharest, Romania.
Letitia Elena Radu: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Cristina Georgiana Jercan: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Ana Maria Bica: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Minodora Asan: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Daniel Coriu: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Alina Daniela Tanase: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Carmen C Diaconu: Cellular and Molecular Pathology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.
Cristina Mambet: Cellular and Molecular Pathology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.
Anca Botezatu: Molecular Virology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.
Sergiu Pasca: Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
Patric Teodorescu: Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.
Gabriela Anton: Molecular Virology Department, Stefan S Nicolau Institute of Virology, Bucharest, Romania.
Petruta Gurban: Personal Genetics-Medical Genetics Center, Bucharest, Romania.
Anca Colita: Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.
Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm diagnosed in young children, characterized by somatic or germline mutations that lead to hyperactive RAS signaling. The only curative option is hematopoietic stem cell transplantation (HSCT). Recent data showing that aberrant DNA methylation plays a significant role in pathogenesis and correlates with clinical risk suggest a possible benefit of hypomethylating agents (HMA) in JMML treatment. The aim is to report the results of HMA-based therapy with 5-azacytidine (AZA) in three JMML patients treated in a single center, non-participating in EWOG-MDS study. The diagnosis and treatment response were evaluated according to international consensus criteria. AZA 75 mg/m intravenous (i.v.) was administered once daily on days 1-7 of each 28-day cycle. All patients were monitored for hematologic response, spleen size, and evolution of extramedullary disease. Targeted next generation sequencing (NGS) were performed after the 3rd AZA cycle and before SCT to evaluate the molecular alterations and genetic response. Three patients diagnosed with JMML were treated with AZA (off-label indication) in Pediatric Department of Fundeni Clinical Institute, Bucharest, Romania between 2017 and 2019. There were two females and one male with median age 11 months, range 2-16 months. The cytogenetic analysis showed normal karyotype in all patients. Molecular analysis confirmed KRAS G13D mutation in two patients and NRAS G12D mutation in one patient. The clinical evaluation showed important splenomegaly and hepatomegaly in all 3 pts. One patient received AZA for early relapse after haploidentical HSCT and the other two patients received upfront AZA, as bridging therapy before HSCT. After HMA therapy, 2/3 patients achieved clinical partial response (cPR), 1/3 had clinical stable disease (cSD) and all had genetic stable disease (gSD) after 3 cycles and were able to receive the planned HSTC. One patient achieved clinical and genetic complete response before HSCT. During 22 cycles of AZA there were only four adverse events but only one determined dose reduction and treatment delay. Our data show that AZA monotherapy is safe and effective in controlling disease both in upfront and relapsed patients in order to proceed to HSCT.
