Pediatr Blood Cancer 2015;62:1303–1304
LETTER TO THE EDITOR Late Complications of Mixed Chimerism Following Allogeneic Bone Marrow Transplantation for Thalassemia Major
months post-HSCT: high-risk if >25%, low-risk if 11 years post-transplant. One patient was reported with late unstable mixed chimerism 22 years after matched sibling allo-HSCT for thalassemia, despite early full donor chimerism. This patient recovered full donor chimerism after DLI, though suffered both acute and chronic GVHD [2]. Our patients received a low-dose TBI-based regimen with initial stable mixed chimerism, but developed very late complications
Diagnosis of MDS Restarted transfusions
parvovirus IgM (+)
100 80
12
60 10 40 8
20
6 0
1
2
3
4
5
6
B14
7
8
9
10
11
12
13
14
15
16
0 17
Years post-transplant 100
Restarted Transfusions
80
12
60 10 40 8
20
6 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Donor Chimerism (%)
hemoglobin (g/dL)
14
Donor chimerism (%)
A
hemoglobin (g/dL)
Allo-HSCT is a well-established therapeutic approach for patients with hemoglobinopathies. Post-transplant mixed chimerism (MC) has been described in a subset of thalassemia patients receiving allo-HSCT that appears stable after an initial period of fluctuation. We describe the late complications of two patients with thalassemia who developed MC following allo-HSCT but ultimately lost their grafts, raising concern regarding the long-term stability of post-transplant MC. Two patients received allo-HSCT at our institution for bthalassemia major in the 1980s. These patients received matched sibling BMTs following cytoreduction with TBI 720 cGy and cyclophosphamide 120 mg/kg. Patients were 6 years old at the time of transplant; Lucarelli Risk classification was class I for patient 1 and class II for patient 2. Cell doses were 4 108 and 2 108 nucleated cells/kg respectively and GVHD prophylaxis consisted of methotrexate þ/ cyclosporine. At three months post-HSCT, patient 1 had 97% donor cells in unsorted PB. Six years post-HSCT his BM chimerism status was 80% donor. At 16 years post-HSCT, he required resumption of regular transfusions with >90% host PB chimerism (Fig. 1A). One year after restarting transfusions, BM studies revealed host-derived therapy-related MDS with cytogenetic abnormalities and 100% host chimerism. He subsequently received cytoreduction and a secondary graft from his original donor with engraftment and full donor chimerism and remains alive and well. Patient 2 had an early decrease in BM donor chimerism from 97% on day þ14 to 50% at 2 months. He was able to sustain his hemoglobin at 9.5 g/dL despite a decrease of donor chimerism to 13% in unsorted PB at 2 years post-HSCT. Subsequently he had progressive loss of donor chimerism, and a gradual decline in his hemoglobin until he required resumption of regular transfusions at 15 years post-HSCT with 0% donor cells and no evidence of MDS (Fig. 1B). Allo-HSCT is the only currently established curative approach for patients with hemoglobinopathies, and despite myeloablative conditioning, mixed donor-host chimerism is a known potential complication. Patients with early MC may develop late graft failure, and are risk-stratified by percentage of residual host cells at two
0 17
Years post-transplant Donor Chimerism Hemoglobin
Fig. 1. Hemoglobin and chimerism over time. Hemoglobin levels (g/dL) and chimerism status (percent donor cells) of patient 1 (panel A) and patient 2 (panel B) over time in years post-HSCT.
Abbreviations: Allo-HSCT, allogeneic hematopoietic stem cell transplantation; MC, mixed chimerism; BM, bone marrow; BMT, bone marrow transplant; GVHD, graft vs. host disease; TBI, total body irradiation; MDS, myelodysplastic syndrome; PB, peripheral blood; DLI, donor lymphocyte infusion Author Contributions: FB, PJG, and RJO provided patient care, BS and FB wrote the manuscript, BS, FB, and RJO edited the manuscript. No authors have any relevant conflict of interest to report.
Correspondence and reprint requests to: Farid Boulad, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: [email protected] Received 18 September 2014; Accepted 4 February 2015
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25498 Published online 21 March 2015 in Wiley Online Library (wileyonlinelibrary.com).
1304
Spitzer et al.
including graft failure and MDS >15 years post-HSCT. The course of these patients demonstrates the potential long-term risks of persistent post-transplant MC in thalassemia. Although limited to two patients, this experience raises caution regarding the advisability of reduced intensity cytoreductive regimens for the intentional induction of mixed chimerism for the treatment of patients with hemoglobinopathies.
Richard J O’Reilly, MD, Farid Boulad, MD* Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, Bone Marrow Transplant Service, New York New York-Presbyterian Hospital-Weill Cornell Medical College, Department of Pediatrics, New York
Barbara Spitzer, MD Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, Bone Marrow Transplant Service, New York
References
Patricia J Giardina, MD New York-Presbyterian Hospital-Weill Cornell Medical College, Department of Pediatrics, New York
Pediatr Blood Cancer DOI 10.1002/pbc
1. Andreani M, Nesci S, Lucarelli G, Tonucci P, Rapa S, Angelucci E, Persini B, Agostinelli F, Donati M, Manna M. Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation. Bone Marrow Transplant 2000;25: 401–404. 2. Inamoto Y, Yannucci J, Storb RF, Flowers ME. Recurrence of beta-thalassemia major more than 20 years after HLA-identical sibling BMT treated successfully with donor lymphocyte infusion. Bone Marrow Transplant 2011;46: 1037–1038.
LETTER TO THE EDITOR Late Complications of Mixed Chimerism Following Allogeneic Bone Marrow Transplantation for Thalassemia Major
months post-HSCT: high-risk if >25%, low-risk if 11 years post-transplant. One patient was reported with late unstable mixed chimerism 22 years after matched sibling allo-HSCT for thalassemia, despite early full donor chimerism. This patient recovered full donor chimerism after DLI, though suffered both acute and chronic GVHD [2]. Our patients received a low-dose TBI-based regimen with initial stable mixed chimerism, but developed very late complications
Diagnosis of MDS Restarted transfusions
parvovirus IgM (+)
100 80
12
60 10 40 8
20
6 0
1
2
3
4
5
6
B14
7
8
9
10
11
12
13
14
15
16
0 17
Years post-transplant 100
Restarted Transfusions
80
12
60 10 40 8
20
6 0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Donor Chimerism (%)
hemoglobin (g/dL)
14
Donor chimerism (%)
A
hemoglobin (g/dL)
Allo-HSCT is a well-established therapeutic approach for patients with hemoglobinopathies. Post-transplant mixed chimerism (MC) has been described in a subset of thalassemia patients receiving allo-HSCT that appears stable after an initial period of fluctuation. We describe the late complications of two patients with thalassemia who developed MC following allo-HSCT but ultimately lost their grafts, raising concern regarding the long-term stability of post-transplant MC. Two patients received allo-HSCT at our institution for bthalassemia major in the 1980s. These patients received matched sibling BMTs following cytoreduction with TBI 720 cGy and cyclophosphamide 120 mg/kg. Patients were 6 years old at the time of transplant; Lucarelli Risk classification was class I for patient 1 and class II for patient 2. Cell doses were 4 108 and 2 108 nucleated cells/kg respectively and GVHD prophylaxis consisted of methotrexate þ/ cyclosporine. At three months post-HSCT, patient 1 had 97% donor cells in unsorted PB. Six years post-HSCT his BM chimerism status was 80% donor. At 16 years post-HSCT, he required resumption of regular transfusions with >90% host PB chimerism (Fig. 1A). One year after restarting transfusions, BM studies revealed host-derived therapy-related MDS with cytogenetic abnormalities and 100% host chimerism. He subsequently received cytoreduction and a secondary graft from his original donor with engraftment and full donor chimerism and remains alive and well. Patient 2 had an early decrease in BM donor chimerism from 97% on day þ14 to 50% at 2 months. He was able to sustain his hemoglobin at 9.5 g/dL despite a decrease of donor chimerism to 13% in unsorted PB at 2 years post-HSCT. Subsequently he had progressive loss of donor chimerism, and a gradual decline in his hemoglobin until he required resumption of regular transfusions at 15 years post-HSCT with 0% donor cells and no evidence of MDS (Fig. 1B). Allo-HSCT is the only currently established curative approach for patients with hemoglobinopathies, and despite myeloablative conditioning, mixed donor-host chimerism is a known potential complication. Patients with early MC may develop late graft failure, and are risk-stratified by percentage of residual host cells at two
0 17
Years post-transplant Donor Chimerism Hemoglobin
Fig. 1. Hemoglobin and chimerism over time. Hemoglobin levels (g/dL) and chimerism status (percent donor cells) of patient 1 (panel A) and patient 2 (panel B) over time in years post-HSCT.
Abbreviations: Allo-HSCT, allogeneic hematopoietic stem cell transplantation; MC, mixed chimerism; BM, bone marrow; BMT, bone marrow transplant; GVHD, graft vs. host disease; TBI, total body irradiation; MDS, myelodysplastic syndrome; PB, peripheral blood; DLI, donor lymphocyte infusion Author Contributions: FB, PJG, and RJO provided patient care, BS and FB wrote the manuscript, BS, FB, and RJO edited the manuscript. No authors have any relevant conflict of interest to report.
Correspondence and reprint requests to: Farid Boulad, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: [email protected] Received 18 September 2014; Accepted 4 February 2015
C
2015 Wiley Periodicals, Inc. DOI 10.1002/pbc.25498 Published online 21 March 2015 in Wiley Online Library (wileyonlinelibrary.com).
1304
Spitzer et al.
including graft failure and MDS >15 years post-HSCT. The course of these patients demonstrates the potential long-term risks of persistent post-transplant MC in thalassemia. Although limited to two patients, this experience raises caution regarding the advisability of reduced intensity cytoreductive regimens for the intentional induction of mixed chimerism for the treatment of patients with hemoglobinopathies.
Richard J O’Reilly, MD, Farid Boulad, MD* Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, Bone Marrow Transplant Service, New York New York-Presbyterian Hospital-Weill Cornell Medical College, Department of Pediatrics, New York
Barbara Spitzer, MD Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, Bone Marrow Transplant Service, New York
References
Patricia J Giardina, MD New York-Presbyterian Hospital-Weill Cornell Medical College, Department of Pediatrics, New York
Pediatr Blood Cancer DOI 10.1002/pbc
1. Andreani M, Nesci S, Lucarelli G, Tonucci P, Rapa S, Angelucci E, Persini B, Agostinelli F, Donati M, Manna M. Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation. Bone Marrow Transplant 2000;25: 401–404. 2. Inamoto Y, Yannucci J, Storb RF, Flowers ME. Recurrence of beta-thalassemia major more than 20 years after HLA-identical sibling BMT treated successfully with donor lymphocyte infusion. Bone Marrow Transplant 2011;46: 1037–1038.
