Jun 13, 2005 - Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy that occurs during early child- hood, representing about 2% of ...
Bone Marrow Transplantation (2005) 36, 453–454 & 2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00
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Correspondence Successful treatment of JMML with related bone marrow transplantation after reduced-intensity conditioning Bone Marrow Transplantation (2005) 36, 453–454. doi:10.1038/sj.bmt.1705047; published online 13 June 2005 Juvenile myelomonocytic leukemia (JMML) is a rare hematopoietic malignancy that occurs during early childhood, representing about 2% of all childhood hematologic malignancies.1 Allogeneic hematopoietic stem cell transplantation (HSCT) is presently the only curative treatment for JMML, because the disease usually progresses rapidly. Leukemia recurrence represents the main cause of treatment failure in children with JMML given HSCT, with the relapse rate being as high as 50%.2 Relapse occurs early, generally within the first year after the allograft.3,4 On the other hand, HSCT is associated with high transplantationrelated mortality (TRM) because the patients received myeloablative conditioning regimen that contained total body irradiation (TBI) or busulfan.2,5,6 The recent paper by Korthof et al6 represented that intensive chemotherapy given before the start of the conditioning for HSCT had a significant adverse effect on the relapse rate after HSCT. However, they noted that this finding was not in agreement with the findings of other authors and needed further study. In a recent multicenter overview from the European Working Group on Childhood MDS and the European Blood and Marrow Transplantation Group, no significant differences in terms of event-free survival, cumulative incidence of relapse, and TRM were observed between children given acute myeloid leukemia (AML)-type chemotherapy or less intensive treatment.7 They also described that neither splenectomy prior to HSCT nor spleen size at the time of transplantation influenced the outcome. However, it is a retrospective and multi-institutional study. Moreover, they reported that 47% had achieved a second sustained hematologic remission thanks to a second transplantation. They hypothesized that less intensive graft-versus-host-disease (GVHD) prophylaxis could have contributed to the sustained remission after the second allograft in these patients by better preserving graft-versus-leukemia effect. The remaining controversial issues are the role of pretransplant therapies. Although cytoreductive therapy before HSCT remains unproven, consensus clinical opinion recommends the use of AML-like chemotherapy to reduce the tumor burden before HSCT. In our institute, three of six patients who were given AML-type chemotherapy achieved complete remission (CR). These three patients have maintained CR for more than 5 years after HSCT utilizing a preparative regimen including TBI, thiotepa, and melphalan. However, all of them grow poorly. Their actual height is greater than two standard deviations below the mean. Long-term late effects including growth retardation, infertility, and second
malignancies are major concerns following myeloablativeconditioning therapy.8–10 Therefore, we decided to perform HSCT using reducedintensity conditioning regimens for a newly diagnosed JMML patient who achieved CR after chemotherapy. A 3-year-old girl was admitted to our institute because of hepatosplenomegaly, thrombocytopenia, and leukocytosis (white blood cell count 29.4 109/l) with a monocyte count of 5.6 109/l. Fetal hemoglobin was 41.8%. Chromosome analysis showed no abnormalities. A bone marrow aspirate revealed a hypercellular marrow with dysplastic changes and 18.3% blast cells. Spontaneous colony formation was demonstrated in granulocyte–macrophage colony-forming unit cultures. Based on these findings, she was diagnosed with JMML. She underwent AML-type chemotherapy (cytarabine, etoposide, and mitoxantrone), resulting in CR, and hepatosplenomegaly disappeared. We performed HSCT from her HLA-identical brother using reducedintensity conditioning regimens after obtaining the parents’ consent. Preconditioning regimens consisted of fludarabine (30 mg/m2 4) and melphalan (70 mg/m2 2). Cyclosporin was administered for GVHD prophylaxis. Engraftment was uneventful. Neutrophil recovery to 0.5 109/l occurred on day þ 12 and fluorescence in situ hibridization of sex chromosomes showed complete donor type in peripheral blood on day þ 14. Stage 4 gut and stage 2 skin (overall grade III) acute GVHD was noted on day þ 19, but resolved with methylprednisolone and replacing cyclosporin by tacrolimus. She has maintained CR for more than 9 months after HSCT with complete donor chimerism and no GVHD although further careful observation is needed. In conclusion, patients with JMML who respond to chemotherapy should be considered as candidates for nonmyeloablative preparative regimens in terms of comorbidity and improved outcomes. It ought to be beneficial for JMML patients undergoing HSCT. M Koyama1 T Nakano2 Y Takeshita1 A Sakata1 A Sawada1 M Yasui1 T Okamura1 M Inoue1 K Kawa1
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Department of Pediatrics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan; and 2 Department of Pediatrics, Kansai Medical University Hospital, Osaka, Japan
References 1 Arico M, Biondi A, Pui CH. Juvenile myelomonocytic leukemia. Blood 1997; 90: 479–488. 2 Smith FO, King R, Nelson G et al. Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Hematol 2002; 116: 716–724.
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454 3 Locatelli F, Niemeyer C, Angelucci E et al. Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European working group on myelodysplastic syndrome in childhood. J Clin Oncol 1997; 15: 566–573. 4 Manabe A, Okamura J, Yumura-Yagi K et al. Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the international JMML working group. Leukemia 2002; 16: 645–649. 5 Matthes-Martin S, Mann G, Peters C et al. Allogeneic bone marrow transplantation for juvenile myelomonocytic leukaemia: a single centre experience and review of the literature. Bone Marrow Transplant 2000; 26: 377–382. 6 Korthof ET, Snijder PP, de Graaff AA et al. Allogeneic bone marrow transplantation for juvenile myelomonocytic
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leukemia: a single center experience of 23 patients. Bone Marrow Transplant 2005; 35: 455–461. Locatelli F, Nollke P, Zecca M et al. Hematopoietic stem cell transplantation(HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 2005; 105: 410–419. Huma Z, Boulad F, Black P et al. Growth in children after bone marrow transplantation for acute leukemia. Blood 1995; 86: 819–824. Sanders JE, Hawley J, Levy W et al. Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996; 87: 3045–3052. Deeg HJ, Socie G. Malignancies after hematopoietic stem cell transplantation: many questions, some answers. Blood 1998; 91: 1833–1844.
Response Response to the letter by M Koyama et al Bone Marrow Transplantation (2005) 36, 454. doi:10.1038/sj.bmt.1705048; published online 11 July 2005 We thank Koyama et al for their comments on our paper1 and on another recently published patient series,2 and for adding their own interesting case. Since the relapse incidence in hematopoietic stem cell transplantation (HSCT) for juvenile myelomonocytic leukemia (JMML) is around 35% in almost every recent series,1 it is important to keep the discussion alive to continue improving the treatment of children with JMML. First of all, in our series, intensive chemotherapy given to children with JMML before HSCT did not provide better results in terms of event-free survival, relapse incidence, and transplant-related mortality in comparison with less intensive or no chemotherapy at all.2 That was the basis of our conclusion that in terms of toxicity and morbidity it would be better to omit intensive chemotherapy. Similarly, based on the outcome of a large multicenter EWOG-MDS/ EBMT trial Locatelli et al concluded with the same arguments that intensive chemotherapy prior to allogeneic HSCT cannot be recommended. In contrast, Koyama et al state without giving an appropriate reference, that consensus clinical opinion recommends the use of intensive AML-like chemotherapy. Secondly, late effects after myelo-ablative conditioning are indeed of concern. However, as relapse after HSCT is the major cause of treatment failure, and in line with the EWOG-MDS/EBMT, we believe that both intensive myeloablative conditioning and a graft-versus-leukemia (GVL) effect are currently still needed to eradicate the disease. The case presented by Koyama et al is intriguing, however. The grade III acute GVHD and possible GVL
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effect in their patient will have played its role after this transplant using reduced intensity conditioning (RIC) and intensive pre-HSCT AML-like chemotherapy. Additional data might further support this strategy. The ideal preparative regimen to treat JMML clearly needs to be elucidated. The future will learn whether RIC is preferable over the more toxic myeloablation, and whether reduction of leukemic load or achievement of full remission with AML-like pretreatment is needed for RIC to be successful. At this moment, we follow the EWOG-MDS/ EBMT policy of no or mild pretreatment and full myeloablation as we feel that in this rare disease entity, international collaboration is necessary to provide the final answer. ET Korthof PP Snijder AA de Graaff AC Lankester RGM Bredius LM Ball JWLT Lie JM Vossen RM Egeler
Department of Pediatric Stem Cell Transplantation, Leiden University Medical Center, Leiden, The Netherlands
References 1 Korthof ET, Snijder PP, de Graaff AA et al. Allogeneic bone marrow transplantation for juvenile myelomonocytic leukemia: a single center experience of 23 patients. Bone Marrow Transplant 2005; 35: 455–461. 2 Locatelli F, Nollke P, Zecca M et al. Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial. Blood 2005; 105: 410–419.
