Results of allogeneic hematopoietic stem cell transplantation in patients with juvenile myelomonocytic leukemia
Anna A. Osipova, Tatyana A. Bykova, Varvara N. Ovechkina, Anastasia S. Borovkova, Olesya V. Paina, Polina V. Kozhokar, Anastasia S. Frolova, Kirill A. Ekushov, Aleхander N. Galimov, Zhemal Z. Rahmanova, Svetlana V. Razumova, Alexander L. Alyanskiy, Elena V. Morozova, Elena V. Babenko, Tatyana L. Gindina, Elena V. Semenova, Ludmila S. Zubarovskaya, Boris V. Afanasyev
Raisa Gorbacheva Memorial Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia
Contact: Dr. Anna A. Osipova
Juvenile myelomonocytic leukemia (JMML) is an aggressive malignant disease bearing the features of myeloproliferative disease and myelodysplastic syndrome. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the standard treatment for patients with JMML. Relapses of the disease and non-engraftment remain main causes of the treatment failure.
Our goal was to analyze the effectiveness of HSCT and identify factors affecting the outcome in children with JMML.
Patients and methods
The study included 22 patients (pts), age 8 month to 12 years (median, 4 years) who received 30 allo-HSCT (22 cases, first transplant; 8 cases, second HSCT) from 2002 to 2019. The diagnosis was established in accordance with international criteria. Patients’ gender: boys, 18; girls, 4. Cytogenetic findings: normal karyotype, in 10 pts (45%); monosomy 7, in 7 cases (31%), other cytogenetic changes, in 5 pts (23%). Molecular genetic analysis was performed for 14 pts showing: PTPN11 (n=8), NRAS (n=3), KRAS (n=1), NF1 (n=2), CBL (n=1), SETB1 n=1), ASLХ1 (n=1), RUNX1 (n=1), no detectable mutations (n=1). At the time of diagnosis, platelet (PLT) count was 11 to 419 (median 59×109/l); white blood cells (WBC) 2.6-175.0 (median 28.0×109/L). Most patients received chemotherapy before allo-HSCT. Depending on clinical manifestations at the time of diagnosis they were divided into 2 groups. First group (13 pts) received differentiation therapy: cis-retinoic acid, low dose cytarabine, hypomethylating agent, or hadn’t any previous therapy. The 2nd group (9 pts) received AML-like intensive chemotherapy (FLAM/ADE/HAM). The time from diagnosis to allo-HSCT was 2 to 86 months (median, 8 month). Bone marrow (BM) was used in 20 pts (91%), peripheral blood stem cells (PBSC), in 3 cases (9%). Donors’ type: matched related HSCT, in 5 pts (20%); haploidentical, in 5 cases (20%), and matched unrelated donors were used for 12 pts (60%). Myeloablative conditioning regimen (MAC) was used in 19 pts (86%); reduced-intensity conditioning (RIC), in 3 pts (15 %). Median follow-up continued for 8 months (range 1 to 130).
Four-year overall survival of JMML pts (OS) was 56%. Engraftment was achieved in 12 pts (59%). Full donor chimerism at day 30 was shown in 7 pts (31%). Mixed chimerism appeared with delay in 2 pts (9%), with subsequent loss and development of relapse; one patient (4.5%) had a secondary transplant rejection with further recovery of autologous hemopoiesis. 2nd transplant was made for 8 pts (36%), with subsequent non-engraftment in 4 cases, and loss of the graft, in 4 patients. OS in the group of patients who received high-dose chemotherapy was 78%, with other therapies, 45% (p=0.635). There was a trend for improving OS when an unrelated donor had been used, i.e., 75% versus 0% (p=0.281). When assessing some factors affecting OS, the level of platelets at the time of diagnosis seems to be informative: OS at initial PLT level of >30×109/L was 65%, when compared with OS rates of 30% at initial PLT of <30×109/L (p=0.034). The levels of WBC, fetal hemoglobin, splenomegaly did not affect OS (probably, due to limited data). OS in pts with acute GVHD stage 1-2 was 100%; in cases of GVHD stage 3-4, it was 0%, being 33% in GVHD-free cases (p=0.003).
Allo-HSCT remains the main therapeutic option for patients with JMML. Chemotherapy is justified as a pre-transplant therapy and is considered in each case individually, depending on the degree of myeloproliferative syndrome.
Conflict of interest
No conflict of interest.
Juvenile myelomonocytic leukemia, treatment, allo-HSCT.