Bone marrow transplantation for children with severe aplastic anemia: use of donors other than HLA-identical siblings

Abstract Eighty-five percent of untransfused and 70% of transfused patients with severe aplastic anemia (SAA) are cured with bone marrow transplants from histocompatible sibling donors. Use of partially matched family donors or unrelated donors has been relatively unsuccessful because of high incidences of graft rejection and graft-versus-host disease (GVHD). Thirteen children with SAA received marrow grafts from alternative donors (sibling 4, parent 5, unrelated 4). The first three patients were pretreated with cyclophosphamide (CYCLO) +/- irradiation and received methotrexate for GVHD prophylaxis. Subsequent children were pretreated with CYCLO + high-dose cytosine arabinoside + methylprednisolone + total body irradiation, had monoclonal antibody T- cell depletion of the donor marrow, and received cyclosporine for GVHD prophylaxis. Three heavily transfused patients with haploidentical- related donors failed to engraft and died. All 10 patients with more closely matched donors engrafted. Acute GVHD was grade II in only one patient (non-T-depleted); this patient is the only one with severe chronic GVHD. Three engrafted patients died (Pneumocystis pneumonia, systemic parainfluenza, venocclusive disease). Seven children are alive 33+ to 2,692+ days. Donors for the survivors were siblings 3, parent 1, unrelated 3. These data suggest that bone marrow transplantation from closely matched donors other than histocompatible siblings can be effective therapy for SAA if an intensive conditioning regimen is used. These results must be confirmed with larger numbers and longer follow- up.

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Bone marrow transplantation for children with severe aplastic anemia: use of donors other than HLA-identical siblings

Blood ◽

10.1182/blood.v74.5.1852.bloodjournal7451852 ◽

1989 ◽

Vol 74 (5) ◽

pp. 1852-1857

Author(s):

B Camitta ◽

R Ash ◽

J Menitove ◽

K Murray ◽

C Lawton ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Aplastic Anemia ◽

Marrow Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Pneumocystis Pneumonia ◽

Severe Aplastic Anemia ◽

High Dose ◽

Gvhd Prophylaxis

Eighty-five percent of untransfused and 70% of transfused patients with severe aplastic anemia (SAA) are cured with bone marrow transplants from histocompatible sibling donors. Use of partially matched family donors or unrelated donors has been relatively unsuccessful because of high incidences of graft rejection and graft-versus-host disease (GVHD). Thirteen children with SAA received marrow grafts from alternative donors (sibling 4, parent 5, unrelated 4). The first three patients were pretreated with cyclophosphamide (CYCLO) +/- irradiation and received methotrexate for GVHD prophylaxis. Subsequent children were pretreated with CYCLO + high-dose cytosine arabinoside + methylprednisolone + total body irradiation, had monoclonal antibody T- cell depletion of the donor marrow, and received cyclosporine for GVHD prophylaxis. Three heavily transfused patients with haploidentical- related donors failed to engraft and died. All 10 patients with more closely matched donors engrafted. Acute GVHD was grade II in only one patient (non-T-depleted); this patient is the only one with severe chronic GVHD. Three engrafted patients died (Pneumocystis pneumonia, systemic parainfluenza, venocclusive disease). Seven children are alive 33+ to 2,692+ days. Donors for the survivors were siblings 3, parent 1, unrelated 3. These data suggest that bone marrow transplantation from closely matched donors other than histocompatible siblings can be effective therapy for SAA if an intensive conditioning regimen is used. These results must be confirmed with larger numbers and longer follow- up.

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Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia [see comments]

Blood ◽

10.1182/blood.v78.2.277.277 ◽

1991 ◽

Vol 78 (2) ◽

pp. 277-279 ◽

Cited By ~ 109

Author(s):

G Socie ◽

M Henry-Amar ◽

JM Cosset ◽

A Devergie ◽

T Girinsky ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Aplastic Anemia ◽

Marrow Transplantation ◽

Malignant Tumors ◽

Conditioning Regimen ◽

Severe Aplastic Anemia ◽

Male Patients

Abstract From May 1980 to December 1989, 107 consecutive patients with non- constitutional severe aplastic anemia underwent bone marrow transplantation at our institution using cyclophosphamide and thoraco- abdominal irradiation as conditioning regimen. During the same period, 40 patients with Fanconi anemia were also grafted after a similar conditioning, giving a total series of 147 patients. With a mean follow- up of 64 months, four male patients developed a solid malignant tumor, a number that leads to an 8-year cumulative incidence rate of 22% (eg, relative risk to general population = 41, P less than .001). These results should be considered as a warning to clinicians who follow these successfully grafted long-term patients.

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Fludarabine Based Conditioning for Allogeneic Transplantation in Severe Aplastic Anemia.

Blood ◽

10.1182/blood.v106.11.2029.2029 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2029-2029

Author(s):

Mammen Chandy ◽

Biju George ◽

Auro Viswabandya ◽

Vikram Mathews ◽

Ashish Bajel ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Allogeneic Transplantation ◽

Severe Aplastic Anemia ◽

Peripheral Blood Stem Cells ◽

Allogeneic Bmt ◽

Gvhd Prophylaxis ◽

Blood Stem Cells

Abstract Patients with severe aplastic anemia (SAA) who are multiply transfused or septic have a poor outcome after allogeneic stem cell transplantation. Forty three patients (31 males and 12 females) with SAA underwent allogeneic BMT using a fludarabine based conditioning regimen between 1998 and 2005. The median age was 20 years (range: 4–38) with 11 children and 32 adults. All donors were 6 antigen matched HLA identical sibling or family donors. Co morbidities seen included bacterial sepsis in 15 patients, fungal pneumonia in 4 and a recent intracranial bleed in 5 patients. Seven patients had failed Antithymocyte or antilymphocyte globulin (ATG/ALG) and two patients had failed their first transplant. The median time from diagnosis to transplant was 12 months (range: 2 – 96) and the median transfusions prior to BMT was 28 (range: 2 – 380). Conditioning therapy consisted of: Fludarabine (Flu) 180 mg/m2 over 6d + Busulfan (Bu) 8 mg/kg over 2d + ATG 40 mg/kg/day over 4 d in 17 patients, Flu 180 mg/m2 over 6d + Cyclophosphamide (Cy) 120 mg/kg over 2d ± ATG 40 mg/kg/day over 4d in 17 patients, Flu/TBI/OKT3 in 4, and Cy 120 + Flu 150mg/m2 in 5 patients. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and mini methotrexate. Graft source was peripheral blood stem cells in 39 patients and G-CSF stimulated bone marrow in 4. The median cell dose was 5.2 x 108 MNC/kg (range: 2.1 – 13.6) for PBSC and 5.2 x 108 TNC/kg (range: 3.7 – 6.8) for bone marrow. Five patients expired within the first 10 days due to sepsis. Thirty seven patients engrafted with a mean time to ANC > 500 of 11.6 days (range: 8 – 18) and median platelet engraftment time of 13 days (range: 8 – 32). One patient had primary graft failure and expired on day 64 due to fungal pneumonia despite a second transplant. Acute GVHD was seen in 14 patients (38%) with Grade III–IV GVHD in 4 (10.5%). Chronic GVHD was seen in 10 patients with 6 having limited and 4 with extensive GVHD. Two patients had secondary graft rejection on day + 24 and +60 respectively and expired due to fungal pneumonia. At a median follow up of 17 months (range: 5 – 78); 29 patients (67.7%) are alive and well. Among patients treated with Flu/Bu/ATG, 12/17 (70.5%) are alive and well while the DFS is 82% (14/17) in patients treated with Flu/Cy ± ATG. Comparison with patients conditioned with Cy/ATG during 1990–2004 is given in the table. This comparison suggests that a fludarabine based conditioning regimen may be better, with less rejection, than Cy/ATG for allogeneic BMT in sick patients with SAA who are infected and multiply transfused at the time of BMT. Comparative data Fludarabine Cy/ATG Number 43 26 Rejection 3 (7%) 7 (27%) DFS 29(67.7%) 11 (46%)

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Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens

Blood ◽

10.1182/blood-2006-10-052308 ◽

2007 ◽

Vol 109 (10) ◽

pp. 4582-4585 ◽

Cited By ~ 115

Author(s):

Richard E. Champlin ◽

Waleska S. Perez ◽

Jakob R. Passweg ◽

John P. Klein ◽

Bruce M. Camitta ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Aplastic Anemia ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Survival Rates ◽

Severe Aplastic Anemia ◽

Controlled Study ◽

High Dose ◽

Allogeneic Bone

AbstractThe addition of antithymocyte globulin (ATG) to a regimen of high-dose cyclophosphamide has been advocated to enhance engraftment after allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA). In a prospective clinical trial, 134 patients were randomly assigned to receive cyclophosphamide alone or in combination with ATG. All patients received T-cell–replete bone marrow from an HLA-matched sibling. With a median follow-up of 6 years, the 5-year probabilities of survival were 74% for the cyclophosphamide alone group and 80% for the cyclophosphamide plus ATG group (P = .44). Graft failure and graft-versus-host disease (GVHD) rates were similar in both groups. With the survival rates achieved, this study is not adequately powered to detect significant differences between the 2 treatment groups. In conclusion, the results of allogeneic BMT for SAA have improved over time related to advances in supportive care. The addition of ATG to the preparative regimen did not significantly improve the outcome.

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Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia [see comments]

Blood ◽

10.1182/blood.v78.2.277.bloodjournal782277 ◽

1991 ◽

Vol 78 (2) ◽

pp. 277-279 ◽

Cited By ~ 1

Author(s):

G Socie ◽

M Henry-Amar ◽

JM Cosset ◽

A Devergie ◽

T Girinsky ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Aplastic Anemia ◽

Marrow Transplantation ◽

Malignant Tumors ◽

Conditioning Regimen ◽

Severe Aplastic Anemia ◽

Male Patients

From May 1980 to December 1989, 107 consecutive patients with non- constitutional severe aplastic anemia underwent bone marrow transplantation at our institution using cyclophosphamide and thoraco- abdominal irradiation as conditioning regimen. During the same period, 40 patients with Fanconi anemia were also grafted after a similar conditioning, giving a total series of 147 patients. With a mean follow- up of 64 months, four male patients developed a solid malignant tumor, a number that leads to an 8-year cumulative incidence rate of 22% (eg, relative risk to general population = 41, P less than .001). These results should be considered as a warning to clinicians who follow these successfully grafted long-term patients.

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Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation

Blood ◽

10.1182/blood.v87.2.491.bloodjournal872491 ◽

1996 ◽

Vol 87 (2) ◽

pp. 491-494 ◽

Cited By ~ 139

Author(s):

RA Brodsky ◽

LL Sensenbrenner ◽

RJ Jones

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Complete Remission ◽

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Severe Aplastic Anemia ◽

High Dose ◽

Allogeneic Bone

Severe aplastic anemia (SAA) can be successfully treated with allogeneic bone marrow transplantation (BMT) or immunosuppressive therapy. However, the majority of patients with SAA are not eligible for BMT because they lack an HLA-identical sibling. Conventional immunosuppressive therapy also has major limitations; many of its remissions are incomplete and relapse or secondary clonal disease is common. Cyclophosphamide is a potent immunosuppressive agent that is used in all BMT conditioning regimens for patients with SAA. Preliminary evidence suggested that high-dose cyclophosphamide, even without BMT, may be beneficial to patients with SAA. Therefore, 10 patients with SAA and lacking an HLA-identical sibling were treated with high-dose cyclophosphamide (45 mg/kg/d) for 4 consecutive days with or without cyclosporine. A complete response (hemoglobin level, > 13 g/dL; absolute neutrophil count, > 1.5 x 10(9)/L, and platelet count > 125 x 10(9)/L) was achieved in 7 of the 10 patients. One of the complete responders died from the acquired immunodeficiency syndrome 44 months after treatment with high-dose cyclophosphamide. The 6 remaining patients are alive and in continuous complete remission, with a median follow-up of 10.8 years (range, 7.3 to 17.8 years). The median time to last platelet transfusion and time to 0.5 x 10(9) neutrophils/L were 85 and 95 days, respectively. None of the complete responders has relapsed or developed a clonal disease. These results suggest that high-dose cyclophosphamide, even without BMT, may be more effective than conventional immunosuppressive therapy in restoring normal hematopoiesis and preventing relapse or secondary clonal disorders. Hence, further studies confirming the efficacy of this approach in SAA are indicated.

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Reduced-Intensity Bone Marrow Transplantation for Heavily Transfused Patients with Severe Aplastic Anemia - Japanese Single Center Experience.

Blood ◽

10.1182/blood.v108.11.5384.5384 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5384-5384

Author(s):

Teruhiko Kozuka ◽

Kazushi Tanimoto ◽

Koichi Nakase ◽

Yuichiro Nawa ◽

Masamichi Hara

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Aplastic Anemia ◽

Graft Rejection ◽

Marrow Transplantation ◽

Conditioning Regimen ◽

Organ Damage ◽

Severe Aplastic Anemia ◽

Curative Therapy ◽

Reduced Intensity

Abstract Background: Bone marrow transplantation (BMT) is a curative therapy for severe aplastic anemia (SAA). Outcome of BMT can be negatively affected when there is organ damage such as heart failure, liver dysfunction and diabetes mellitus after multiple transfusions in patients with long-standing SAA. Multiple transfusions also sensitize SAA patients with alloantigens and place them at high risk of graft rejection; it is an important problem after BMT for patients with multiply transfused SAA. We investigated the use of the combination of fludarabine monophosphate (FLU), cyclophosphamide (CY) and anti-thymocyte globulin (ATG) as the conditioning regimen in heavily transfused SAA patients. Methods: Four patients with heavily transfused SAA were treated with allogeneic BMT from unrelated and sibling donor. They were treated with a reduced-intensity conditioning regimen that included FLU (120 mg/m2), CY (1,200 mg/m2) and ATG (horse 40 mg/kg, rabbit 15 mg/kg). Results: The regimen was well tolerated, and engraftment rapidly occurred with some therapy-related toxicity encountered. Chimerism analysis on day 30 after transplant showed reconstitution with 100% donor cells in three patients. Among these three patients, two patients showed late graft rejection. At this time of reporting, only one patient is alive with complete donor chimerism. Conclusion: The combination of FLU/CY/ATG was well tolerated also in heavily transfused SAA patients: problems such as graft rejection remain.

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