Pediatr Transplantation 2014: 18: 651–652
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12312
Letter to the Editor Successful second unrelated cord blood transplantation in a child with juvenile myelomonocytic leukemia To the editor, We describe a two-yr-old child with juvenile myelomonocytic leukemia (JMML) who underwent second unrelated cord blood transplantation (UCBT) after graft failure with the first UCBT. He presented initially at the age of two months with hepatosplenomegaly and monocytosis. Bone marrow study showed no evidence of acute leukemia. Cytogenetic analysis showed normal 46, XY male karyotype with no clonal abnormality, and FISH for BCR/ABL fusion gene and monosomy 7 were negative. He was started on mercaptopurine and had partial response with persistent splenomegaly. No HLAmatched related donor was available so he underwent the first UCBT at one yr of age using myeloablative conditioning with intravenous (IV) busulfan (1 mg/kg every six h on days 8 to 5), cyclophosphamide (60 mg/kg/day on days 4 and 3), melphalan (140 mg/m2 on day 2), and thymoglobulin (3 mg/kg/day on days 3 to 1). GVHD prophylaxis included cyclosporine (CSA) (starting day 3) and oral mycophenolate mofetil (MMF) (starting day 3). HLA matching (low resolution for HLA-A and HLA-B and high resolution for HLA-DRB1) was 5/6 in the graft rejection direction and 6/6 in the graft versus host disease (GVHD) direction (mismatch at HLA-B). The cryopreserved total nucleated cell (TNC) was 16.6 9 107/kg, and CD34 was 4.5 9 105/kg of recipient weight. Granulocyte-colony stimulating factor was administered starting day +1. He failed to show any signs of engraftment. There was no evidence of active disease in our patient after the first UCBT, apart from the persistence of splenomegaly. In preparation for a second UCBT, he underwent splenectomy followed by second UCBT (on day +75 post-first-UCBT) using cord blood with HLA 6/6 in the graft rejection direction and 5/6 in the GVHD direction (mismatch at HLADRB1). TNC was 19.1 9 107/kg, and CD34 was 6.7 9 105/kg. Conditioning regimen was alemtuzumab (0.2 mg/kg/day on days 8 to 4),
fludarabine (30 mg/m2/day on days 7 to 3), and melphalan (140 mg/m2 on day 2). GVHD prophylaxis was IV MMF (starting day 3) and CSA (starting day 2). He had successful neutrophil engraftment on day +37 and platelet engraftment on day +28. Donor chimerism on day +60 was 100% for both myeloid and T cells. His MMF was stopped on day +45, and CSA was tapered and discontinued by day +75. Supportive care included piperacillin-tazobactam during the period of neutropenia in addition to voriconazole and acyclovir prophylaxis. Interferon alfa2a was given on day +90, 93, 96, and 99 followed by pegylated alfa-2a on day +120 and day +127 post-second-UCBT because of transient increase in monocyte count and presence of peripheral blasts with concern of relapse and lead to normalization of monocyte count and disappearance of blasts; however, interferon was held because of severe diarrhea although biopsy was negative for GVHD. No evidence of acute or chronic GVHD. He is currently day +270 post-transplant with no evidence of disease. A recent analysis by Eurocord, EBMT, EWOG-MDS, and CIBMTR of 110 patients with JMML who underwent UCBT showed that 44% of patients can be cured. There was a trend for higher disease-free survival among splenectomized children (56%) compared with 36% in patients who did not undergo splenectomy; however, this did not reach statistical significance (1). Presence of splenomegaly prior to the first UCBT in our patient might have contributed to the graft rejection, and this was the reason for performing splenectomy prior to the second UCBT. It is not clear whether a more intensive pretransplant acute myeloid leukemia-like chemotherapy could have influenced the outcome of first UCBT, as this area is still controversial (2). We showed that using alemtuzumab, fludarabine, and melphalan as a non total body irradiation (TBI)-based conditioning regimen for second UCBT in addition to splenectomy is safe and effective treatment of graft failure after UCBT in 651
Letter to the Editor
JMML. EWOG-MDS group reported a leukemiafree survival of 32% at five yr after the use of second stem cell transplantation for the treatment of post-transplant relapse in 24 patients with JMML using mostly a TBI-based regimen, and stem cell source was either bone marrow or peripheral blood, predominantly from the same first donor, and none were cord (3). We also showed that withdrawal of immunosuppression and interferon can be used as a treatment of relapse post-transplant similar to previous reports, although interferon treatment was discontinued because of severe diarrhea (4, 5). Abdulrahman Alsultan1,2, Mohammed Jarrar1, Walid Mushaqbah3, Reem Al-Sudairy1 and Dunia Jawdat3 1 Department of Oncology, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia, 2 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia, 3King Abdullah International Medical Research Center, Riyadh, Saudi Arabia E-mail: [email protected]
652
References 1. LOCATELLI F, CROTTA A, RUGGERI A, et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: A EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood 2013: 122: 2135–2141. 2. DVORAK CC, LOH ML. Juvenile myelomonocytic leukemia: Molecular pathogenesis informs current approaches to therapy and hematopoietic cell transplantation. Front Pediatr 2014: 2: 25. 3. YOSHIMI A, MOHAMED M, BIERINGS M, et al. Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia. Leukemia 2007: 21: 556–560. 4. ORCHARD PJ, MILLER JS, MCGLENNEN R, DAVIES SM, RAMSAY NK. Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia. Bone Marrow Transplant 1998: 22: 201–203. 5. PULSIPHER MA, ADAMS RH, ASCH J, PETERSEN FB. Successful treatment of JMML relapsed after unrelated allogeneic transplant with cytoreduction followed by DLI and interferon-alpha: Evidence for a graft-versus-leukemia effect in non-monosomy-7 JMML. Bone Marrow Transplant 2004: 33: 113–115.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12312
Letter to the Editor Successful second unrelated cord blood transplantation in a child with juvenile myelomonocytic leukemia To the editor, We describe a two-yr-old child with juvenile myelomonocytic leukemia (JMML) who underwent second unrelated cord blood transplantation (UCBT) after graft failure with the first UCBT. He presented initially at the age of two months with hepatosplenomegaly and monocytosis. Bone marrow study showed no evidence of acute leukemia. Cytogenetic analysis showed normal 46, XY male karyotype with no clonal abnormality, and FISH for BCR/ABL fusion gene and monosomy 7 were negative. He was started on mercaptopurine and had partial response with persistent splenomegaly. No HLAmatched related donor was available so he underwent the first UCBT at one yr of age using myeloablative conditioning with intravenous (IV) busulfan (1 mg/kg every six h on days 8 to 5), cyclophosphamide (60 mg/kg/day on days 4 and 3), melphalan (140 mg/m2 on day 2), and thymoglobulin (3 mg/kg/day on days 3 to 1). GVHD prophylaxis included cyclosporine (CSA) (starting day 3) and oral mycophenolate mofetil (MMF) (starting day 3). HLA matching (low resolution for HLA-A and HLA-B and high resolution for HLA-DRB1) was 5/6 in the graft rejection direction and 6/6 in the graft versus host disease (GVHD) direction (mismatch at HLA-B). The cryopreserved total nucleated cell (TNC) was 16.6 9 107/kg, and CD34 was 4.5 9 105/kg of recipient weight. Granulocyte-colony stimulating factor was administered starting day +1. He failed to show any signs of engraftment. There was no evidence of active disease in our patient after the first UCBT, apart from the persistence of splenomegaly. In preparation for a second UCBT, he underwent splenectomy followed by second UCBT (on day +75 post-first-UCBT) using cord blood with HLA 6/6 in the graft rejection direction and 5/6 in the GVHD direction (mismatch at HLADRB1). TNC was 19.1 9 107/kg, and CD34 was 6.7 9 105/kg. Conditioning regimen was alemtuzumab (0.2 mg/kg/day on days 8 to 4),
fludarabine (30 mg/m2/day on days 7 to 3), and melphalan (140 mg/m2 on day 2). GVHD prophylaxis was IV MMF (starting day 3) and CSA (starting day 2). He had successful neutrophil engraftment on day +37 and platelet engraftment on day +28. Donor chimerism on day +60 was 100% for both myeloid and T cells. His MMF was stopped on day +45, and CSA was tapered and discontinued by day +75. Supportive care included piperacillin-tazobactam during the period of neutropenia in addition to voriconazole and acyclovir prophylaxis. Interferon alfa2a was given on day +90, 93, 96, and 99 followed by pegylated alfa-2a on day +120 and day +127 post-second-UCBT because of transient increase in monocyte count and presence of peripheral blasts with concern of relapse and lead to normalization of monocyte count and disappearance of blasts; however, interferon was held because of severe diarrhea although biopsy was negative for GVHD. No evidence of acute or chronic GVHD. He is currently day +270 post-transplant with no evidence of disease. A recent analysis by Eurocord, EBMT, EWOG-MDS, and CIBMTR of 110 patients with JMML who underwent UCBT showed that 44% of patients can be cured. There was a trend for higher disease-free survival among splenectomized children (56%) compared with 36% in patients who did not undergo splenectomy; however, this did not reach statistical significance (1). Presence of splenomegaly prior to the first UCBT in our patient might have contributed to the graft rejection, and this was the reason for performing splenectomy prior to the second UCBT. It is not clear whether a more intensive pretransplant acute myeloid leukemia-like chemotherapy could have influenced the outcome of first UCBT, as this area is still controversial (2). We showed that using alemtuzumab, fludarabine, and melphalan as a non total body irradiation (TBI)-based conditioning regimen for second UCBT in addition to splenectomy is safe and effective treatment of graft failure after UCBT in 651
Letter to the Editor
JMML. EWOG-MDS group reported a leukemiafree survival of 32% at five yr after the use of second stem cell transplantation for the treatment of post-transplant relapse in 24 patients with JMML using mostly a TBI-based regimen, and stem cell source was either bone marrow or peripheral blood, predominantly from the same first donor, and none were cord (3). We also showed that withdrawal of immunosuppression and interferon can be used as a treatment of relapse post-transplant similar to previous reports, although interferon treatment was discontinued because of severe diarrhea (4, 5). Abdulrahman Alsultan1,2, Mohammed Jarrar1, Walid Mushaqbah3, Reem Al-Sudairy1 and Dunia Jawdat3 1 Department of Oncology, King Abdulaziz Medical City, National Guard Health Affairs, Riyadh, Saudi Arabia, 2 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia, 3King Abdullah International Medical Research Center, Riyadh, Saudi Arabia E-mail: [email protected]
652
References 1. LOCATELLI F, CROTTA A, RUGGERI A, et al. Analysis of risk factors influencing outcomes after cord blood transplantation in children with juvenile myelomonocytic leukemia: A EUROCORD, EBMT, EWOG-MDS, CIBMTR study. Blood 2013: 122: 2135–2141. 2. DVORAK CC, LOH ML. Juvenile myelomonocytic leukemia: Molecular pathogenesis informs current approaches to therapy and hematopoietic cell transplantation. Front Pediatr 2014: 2: 25. 3. YOSHIMI A, MOHAMED M, BIERINGS M, et al. Second allogeneic hematopoietic stem cell transplantation (HSCT) results in outcome similar to that of first HSCT for patients with juvenile myelomonocytic leukemia. Leukemia 2007: 21: 556–560. 4. ORCHARD PJ, MILLER JS, MCGLENNEN R, DAVIES SM, RAMSAY NK. Graft-versus-leukemia is sufficient to induce remission in juvenile myelomonocytic leukemia. Bone Marrow Transplant 1998: 22: 201–203. 5. PULSIPHER MA, ADAMS RH, ASCH J, PETERSEN FB. Successful treatment of JMML relapsed after unrelated allogeneic transplant with cytoreduction followed by DLI and interferon-alpha: Evidence for a graft-versus-leukemia effect in non-monosomy-7 JMML. Bone Marrow Transplant 2004: 33: 113–115.
