Bone Marrow Transplantation (2014), 1–2 © 2014 Macmillan Publishers Limited All rights reserved 0268-3369/14 www.nature.com/bmt
LETTER TO THE EDITOR
Haploidentical hematopoietic SCT for acquired severe aplastic anemia using post-transplant high-dose CY Bone Marrow Transplantation advance online publication, 6 October 2014; doi:10.1038/bmt.2014.222
Young patients with severe aplastic anemia (SAA) who lack a suitable family donor and fail immunosuppressive therapy (IST) are treated with unrelated donor transplants or a repeat course of IST.1 The outcomes of unrelated allografts have improved in recent years, but are still associated with a high risk of acute and chronic GVHD when compared to matched related donor transplants.2 However, for most of the patients in developing countries matched unrelated donors (MUD) are not available. Other options include cord blood or haploidentical SCT (HaploSCT).3 Cord blood transplantation for acquired SAA has been found to result in high graft failure rates of ~ 50% and chronic GVHD rates of ~ 20%.4 T-cell-replete haploSCT using posttransplant CY (PT/CY) has shown high engraftment rates and very low incidences of GVHD in patients with hematologic malignancies.5,6 This strategy has been used in patients with sickle cell anemia7 and recently in four adults with refractory aplastic anemia.8 This strategy has not yet been reported in children with aplastic anemia. We report herein our experience of PT/CY haploSCT in two pediatric patients with refractory aplastic anemia. An 8-year-old girl was diagnosed with SAA in September 2012. In the absence of a HLA-matched family donor, she was treated with a course of IST (ATGAM 40 mg/kg/day for 4 days and cyclosporine). She did not respond and remained transfusion dependent. She was taken up for haploSCT after 4 months of no response to IST. Patient, donor and transplant characteristics are shown in Table 1. Non-myeloablative conditioning was used as described previously by Luznik et al.:5 fludarabine (30 mg/m2 from day − 6 to − 2), CY (14.5 mg/kg on day − 6 and − 5), and TBI (200 cGy on day − 1). Prophylaxis against GVHD was CY (50 mg/kg on days +3 and +4), tacrolimus (0.06 mg/kg from day +5 through day +180) and mycophenolate mofetil (10 mg/kg q8h from day +5 through day +35). Peripheral blood stem cells (PBSC) from the father were used for transplant. Both the parents and patient were CMV reactive. She developed neutropenic fever during conditioning and was found to have possible pulmonary aspergillosis, which was treated with amphotericin B. CD34+ cell dose infused was 17.6 × 106 per kg of recipient body weight. Neutrophil and platelets engrafted by day +14 and day +9, respectively. On day +18 she developed grade 2 acute GVHD (gut and liver), which was treated with i.v. methylprednisolone 2 mg/kg/day. Complete resolution of GVHD occurred by day +25. She also had elevation in CMV titers by D+21 to 500 copies/mL, which decreased to o150 copies/mL after a week. By day +35 CMV DNA PCR became undetectable without any treatment. The steroid was tapered off in the next one month without any recurrence of GVHD. Postengraftment chimerism was done on unfractionated peripheral blood on day +30, which revealed donor cells to be 97%. Tacrolimus was tapered off after 6 months of therapy without recurrence of GVHD. After 6 months of transplant lymphocyte subset analysis revealed inverse CD4 to CD8 ratio with normal B and natural killer cell numbers. Ig levels were in the normal range. After 18 months of transplant complete blood count (CBC) shows
Hb 10.3 g/dL, WBC 9.3 × 109/L and platelets 150 × 109/L. She continues to be in complete donor chimerism and has not developed any chronic GVHD. The second patient is also an 8-year-old girl, who was taken for haploSCT after 10 months of IST failure. Conditioning chemotherapy and GVHD prophylaxis were the same as for case 1 (Table 1). PBSC from the mother were used as donor cells. Her post-transplant course was complicated by severe sepsis (Chrysobacterium indologens) and primary engraftment failure. On day +27 after first transplant, a rescue transplant with the father as donor was performed. This time TBI was replaced by anti thymocyte globulin (ATG) in conditioning; fludarabine (30 mg/ m2 from day − 8 to day − 4), CY (14.5 mg/kg from day − 6 to day − 5) and horse ATG (30 mg/kg/day from day − 3 to day − 1). GVHD prophylaxis was the same as used before. CD34+ cell dose was 13 × 106/kg. The early post-transplant period was complicated by severe neutropenic sepsis with Klebseilla pneumonia. Neutrophils and platelets engrafted by day 21 and day 22, respectively. She did not develop acute GVHD or CMV reactivation. On day+28, post-engraftment chimerism revealed 98% donor cells. Immunosuppression was successfully tapered off 6 months after transplant. She continues to have sustained complete donor chimerism and her CBC shows Hb 11.4 g/dL, WBC 10.5 × 109/L and platelets 229 × 109/L. She has not developed any GVHD after 13 months of follow-up. Haplo SCT has the advantage of prompt use and donor availability in almost all patients. When using an unmanipulated BM as a graft source, failure rates of 25% and an OS of 30% was reported by EBMT.9 Recently Castagna et al.10 reported 100% engraftment rates after GCSF primed BM or PBSC haploidentical transplants, but a high incidence of chronic GVHD was seen with an OS of 64%. There are few reports of patients transplanted with purified CD34+ cells or recently with selective CD3/CD3 and CD19 depletion.9 PT/CY achieves selective depletion of alloreactive cells, mitigating both graft rejection and GVHD in MHC-matched or MHC-mismatched donor transplants while preserving immunologic memory to past infections.5 Reduced-intensity conditioning haploBMT with PT/CY in patients with hematologic malignancies has been quite successful, with a low rejection rate of 13%, a cumulative incidence of acute grades II–IV GVHD of ~ 30%, and incidences of chronic GVHD and non-relapse mortality of o 15%.6 High engraftment rates and low incidence of GVHD make this strategy a promising option for patients with benign hematologic diseases in which the primary goal is to restore hematopoiesis rather than graft versus tumor effect. Bolaños-Meade et al.7 used this strategy in patients with sickle cell anemia, with 8 out of 16 patients (57%) engrafted and none having developed GVHD. We used PBSC as a graft source as our goal was to prevent rejection by giving a good CD34+ stem cell dose in these heavily pretransfused patients. One of the patients failed to engraft but was salvaged by doing a second transplant with a high CD34+ stem cell dose. In a multicentre study reported by Raj et al.,8 55 patients with different hematologic diseases, including 4 patients with refractory aplastic anemia, underwent PBSC haploSCT using PT/CY regimen. Grade II and III acute GVHD was seen in 53% and 8% patients, respectively, but none developed grade IV acute GVHD. Chronic GVHD was seen in 18% of patients. The authors
Letter to the Editor
2 Table 1.
Donor, recipient and transplant characteristics
Patient
Donor
Conditioning
HLA antibodies
CD34 dose
Neutrophil engraftment
Platelet engraftment
8/F HLA A*1*68B*13*40 DR*15*11
Father, 36/M HLA A*1*24 B*13*40 DR*15*14 Father, 37/M HLA A*24*11 B*40*52 DR*10*15 Mother, 32/F A*68*32 B*18*15 DR*11*11
Flu-Cy-TBI
Negative
17.6 × 106 per kg
Day +14
Day +9
Flu-Cy-TBI
Negative
4.53 × 106 per kg
—
—
Flu-Cy-ATG
Negative
13 × 106 per kg
Day +21
Day +22
8/F HLA A*11*68 B*18*52 DR*15*11
Abbreviations: F = female; M = male.
have concluded that PBSC can safely substitute BM as a graft source for RIC haploSCT. Recently in a retrospective analysis, no detrimental effect of using PBSC instead of BM on GVHD in patients undergoing haploSCT with PT/CY was observed.10 The present report shows that PT/CY HaploSCT is effective and a viable option in patients with refractory aplastic anemia in children for whom MUD are not available. It is especially relevant in developing nations where the cost of MUD transplants is very high (4–5 times of the related donor transplants), making them non-affordable to most of the needy patients. Moreover, there is a need to compare HaploSCT with MUD in a prospective manner to better define the treatment algorithm for SAA. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS NG designed the research and wrote the manuscript; DC designed the research; SKS designed the research and helped in writing the manuscript; VK and MD wrote the manuscript.
N Gupta, D Choudhary, SK Sharma, V Khandelwal and M Dhamija Department of Hematooncology and Bone Marrow Transplant, BLK Super Specialty Hospital, New Delhi, India E-mail: [email protected] REFERENCES 1 Guinan EC. Acquired aplastic anemia in childhood. Hematol Oncol Clin North Am 2009; 23: 171–191.
Bone Marrow Transplantation (2014), 1 – 2
2 Bacigalupo A, Socie' G, Lanino E, Prete A, Locatelli F, Locasciulli A et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica 2010; 95: 976–982. 3 Marsh JC, Kulasekararaj AG. Management of the refractory aplastic anemia patient: what are the options? Blood 2013; 122: 3561–3567. 4 Yoshimi A, Kojima S, Taniguchi S, Hara J, Matsui T, Takahashi Y, Azuma H et al. Unrelated cord blood transplantation for severe aplastic anemia. Biol Blood Marrow Transplant 2008; 14: 1057–1063. 5 Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650. 6 Fuchs EJ. Human leukocyte antigen-haploidentical stem cell transplantation using T-cell-replete bone marrow grafts. Curr Opin Hematol 2012; 19: 440–447. 7 Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ et al. HLA haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 2012; 120: 4285–4291. 8 Raj K, Pagliuca A, Bradstock K, Noriega V, Potter V, Streetly M et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant 2014; 20: 890–895. 9 Ciceri F, Lupo-Stanghellini MT, Korthof ET. Haploidentical transplantation in patients with acquired aplastic anemia. Bone Marrow Transplant 2013; 48: 183–185. 10 Castagna L, Crocchiolo R, Furst S, Bramanti S, El Cheikh J, Sarina B et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2014; 20: 724–729.
© 2014 Macmillan Publishers Limited
LETTER TO THE EDITOR
Haploidentical hematopoietic SCT for acquired severe aplastic anemia using post-transplant high-dose CY Bone Marrow Transplantation advance online publication, 6 October 2014; doi:10.1038/bmt.2014.222
Young patients with severe aplastic anemia (SAA) who lack a suitable family donor and fail immunosuppressive therapy (IST) are treated with unrelated donor transplants or a repeat course of IST.1 The outcomes of unrelated allografts have improved in recent years, but are still associated with a high risk of acute and chronic GVHD when compared to matched related donor transplants.2 However, for most of the patients in developing countries matched unrelated donors (MUD) are not available. Other options include cord blood or haploidentical SCT (HaploSCT).3 Cord blood transplantation for acquired SAA has been found to result in high graft failure rates of ~ 50% and chronic GVHD rates of ~ 20%.4 T-cell-replete haploSCT using posttransplant CY (PT/CY) has shown high engraftment rates and very low incidences of GVHD in patients with hematologic malignancies.5,6 This strategy has been used in patients with sickle cell anemia7 and recently in four adults with refractory aplastic anemia.8 This strategy has not yet been reported in children with aplastic anemia. We report herein our experience of PT/CY haploSCT in two pediatric patients with refractory aplastic anemia. An 8-year-old girl was diagnosed with SAA in September 2012. In the absence of a HLA-matched family donor, she was treated with a course of IST (ATGAM 40 mg/kg/day for 4 days and cyclosporine). She did not respond and remained transfusion dependent. She was taken up for haploSCT after 4 months of no response to IST. Patient, donor and transplant characteristics are shown in Table 1. Non-myeloablative conditioning was used as described previously by Luznik et al.:5 fludarabine (30 mg/m2 from day − 6 to − 2), CY (14.5 mg/kg on day − 6 and − 5), and TBI (200 cGy on day − 1). Prophylaxis against GVHD was CY (50 mg/kg on days +3 and +4), tacrolimus (0.06 mg/kg from day +5 through day +180) and mycophenolate mofetil (10 mg/kg q8h from day +5 through day +35). Peripheral blood stem cells (PBSC) from the father were used for transplant. Both the parents and patient were CMV reactive. She developed neutropenic fever during conditioning and was found to have possible pulmonary aspergillosis, which was treated with amphotericin B. CD34+ cell dose infused was 17.6 × 106 per kg of recipient body weight. Neutrophil and platelets engrafted by day +14 and day +9, respectively. On day +18 she developed grade 2 acute GVHD (gut and liver), which was treated with i.v. methylprednisolone 2 mg/kg/day. Complete resolution of GVHD occurred by day +25. She also had elevation in CMV titers by D+21 to 500 copies/mL, which decreased to o150 copies/mL after a week. By day +35 CMV DNA PCR became undetectable without any treatment. The steroid was tapered off in the next one month without any recurrence of GVHD. Postengraftment chimerism was done on unfractionated peripheral blood on day +30, which revealed donor cells to be 97%. Tacrolimus was tapered off after 6 months of therapy without recurrence of GVHD. After 6 months of transplant lymphocyte subset analysis revealed inverse CD4 to CD8 ratio with normal B and natural killer cell numbers. Ig levels were in the normal range. After 18 months of transplant complete blood count (CBC) shows
Hb 10.3 g/dL, WBC 9.3 × 109/L and platelets 150 × 109/L. She continues to be in complete donor chimerism and has not developed any chronic GVHD. The second patient is also an 8-year-old girl, who was taken for haploSCT after 10 months of IST failure. Conditioning chemotherapy and GVHD prophylaxis were the same as for case 1 (Table 1). PBSC from the mother were used as donor cells. Her post-transplant course was complicated by severe sepsis (Chrysobacterium indologens) and primary engraftment failure. On day +27 after first transplant, a rescue transplant with the father as donor was performed. This time TBI was replaced by anti thymocyte globulin (ATG) in conditioning; fludarabine (30 mg/ m2 from day − 8 to day − 4), CY (14.5 mg/kg from day − 6 to day − 5) and horse ATG (30 mg/kg/day from day − 3 to day − 1). GVHD prophylaxis was the same as used before. CD34+ cell dose was 13 × 106/kg. The early post-transplant period was complicated by severe neutropenic sepsis with Klebseilla pneumonia. Neutrophils and platelets engrafted by day 21 and day 22, respectively. She did not develop acute GVHD or CMV reactivation. On day+28, post-engraftment chimerism revealed 98% donor cells. Immunosuppression was successfully tapered off 6 months after transplant. She continues to have sustained complete donor chimerism and her CBC shows Hb 11.4 g/dL, WBC 10.5 × 109/L and platelets 229 × 109/L. She has not developed any GVHD after 13 months of follow-up. Haplo SCT has the advantage of prompt use and donor availability in almost all patients. When using an unmanipulated BM as a graft source, failure rates of 25% and an OS of 30% was reported by EBMT.9 Recently Castagna et al.10 reported 100% engraftment rates after GCSF primed BM or PBSC haploidentical transplants, but a high incidence of chronic GVHD was seen with an OS of 64%. There are few reports of patients transplanted with purified CD34+ cells or recently with selective CD3/CD3 and CD19 depletion.9 PT/CY achieves selective depletion of alloreactive cells, mitigating both graft rejection and GVHD in MHC-matched or MHC-mismatched donor transplants while preserving immunologic memory to past infections.5 Reduced-intensity conditioning haploBMT with PT/CY in patients with hematologic malignancies has been quite successful, with a low rejection rate of 13%, a cumulative incidence of acute grades II–IV GVHD of ~ 30%, and incidences of chronic GVHD and non-relapse mortality of o 15%.6 High engraftment rates and low incidence of GVHD make this strategy a promising option for patients with benign hematologic diseases in which the primary goal is to restore hematopoiesis rather than graft versus tumor effect. Bolaños-Meade et al.7 used this strategy in patients with sickle cell anemia, with 8 out of 16 patients (57%) engrafted and none having developed GVHD. We used PBSC as a graft source as our goal was to prevent rejection by giving a good CD34+ stem cell dose in these heavily pretransfused patients. One of the patients failed to engraft but was salvaged by doing a second transplant with a high CD34+ stem cell dose. In a multicentre study reported by Raj et al.,8 55 patients with different hematologic diseases, including 4 patients with refractory aplastic anemia, underwent PBSC haploSCT using PT/CY regimen. Grade II and III acute GVHD was seen in 53% and 8% patients, respectively, but none developed grade IV acute GVHD. Chronic GVHD was seen in 18% of patients. The authors
Letter to the Editor
2 Table 1.
Donor, recipient and transplant characteristics
Patient
Donor
Conditioning
HLA antibodies
CD34 dose
Neutrophil engraftment
Platelet engraftment
8/F HLA A*1*68B*13*40 DR*15*11
Father, 36/M HLA A*1*24 B*13*40 DR*15*14 Father, 37/M HLA A*24*11 B*40*52 DR*10*15 Mother, 32/F A*68*32 B*18*15 DR*11*11
Flu-Cy-TBI
Negative
17.6 × 106 per kg
Day +14
Day +9
Flu-Cy-TBI
Negative
4.53 × 106 per kg
—
—
Flu-Cy-ATG
Negative
13 × 106 per kg
Day +21
Day +22
8/F HLA A*11*68 B*18*52 DR*15*11
Abbreviations: F = female; M = male.
have concluded that PBSC can safely substitute BM as a graft source for RIC haploSCT. Recently in a retrospective analysis, no detrimental effect of using PBSC instead of BM on GVHD in patients undergoing haploSCT with PT/CY was observed.10 The present report shows that PT/CY HaploSCT is effective and a viable option in patients with refractory aplastic anemia in children for whom MUD are not available. It is especially relevant in developing nations where the cost of MUD transplants is very high (4–5 times of the related donor transplants), making them non-affordable to most of the needy patients. Moreover, there is a need to compare HaploSCT with MUD in a prospective manner to better define the treatment algorithm for SAA. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS NG designed the research and wrote the manuscript; DC designed the research; SKS designed the research and helped in writing the manuscript; VK and MD wrote the manuscript.
N Gupta, D Choudhary, SK Sharma, V Khandelwal and M Dhamija Department of Hematooncology and Bone Marrow Transplant, BLK Super Specialty Hospital, New Delhi, India E-mail: [email protected] REFERENCES 1 Guinan EC. Acquired aplastic anemia in childhood. Hematol Oncol Clin North Am 2009; 23: 171–191.
Bone Marrow Transplantation (2014), 1 – 2
2 Bacigalupo A, Socie' G, Lanino E, Prete A, Locatelli F, Locasciulli A et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party. Haematologica 2010; 95: 976–982. 3 Marsh JC, Kulasekararaj AG. Management of the refractory aplastic anemia patient: what are the options? Blood 2013; 122: 3561–3567. 4 Yoshimi A, Kojima S, Taniguchi S, Hara J, Matsui T, Takahashi Y, Azuma H et al. Unrelated cord blood transplantation for severe aplastic anemia. Biol Blood Marrow Transplant 2008; 14: 1057–1063. 5 Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650. 6 Fuchs EJ. Human leukocyte antigen-haploidentical stem cell transplantation using T-cell-replete bone marrow grafts. Curr Opin Hematol 2012; 19: 440–447. 7 Bolaños-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ et al. HLA haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood 2012; 120: 4285–4291. 8 Raj K, Pagliuca A, Bradstock K, Noriega V, Potter V, Streetly M et al. Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning. Biol Blood Marrow Transplant 2014; 20: 890–895. 9 Ciceri F, Lupo-Stanghellini MT, Korthof ET. Haploidentical transplantation in patients with acquired aplastic anemia. Bone Marrow Transplant 2013; 48: 183–185. 10 Castagna L, Crocchiolo R, Furst S, Bramanti S, El Cheikh J, Sarina B et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2014; 20: 724–729.
© 2014 Macmillan Publishers Limited
