Improved Outcome of Unrelated Bone Marrow Transplantation for Severe Aplastic Anemia.

Abstract In Japan, unrelated bone marrow transplantations (U-BMT) for severe aplastic anemia (SAA) were first performed in 1993. Transplant regimens and patient selection have changed substantially since then. We aimed to determine the effect of these changes on transplant outcome. We retrospectively analyzed the outcome in patients with SAA who received U-BMT through the Japan Marrow Donor Program between 1993 and 2005. We selected 302 recipient-donor pairs in which molecular analysis of HLA-A, -B, -C, -DRB1, and DQB1 were performed. Patient ages ranged from 1 to 64 years (median, 17 years). Various preconditioning regimens were used by individual centers. Either tacrolimus with methotrexate or cyclosporine with methotrexate was used for the prophylaxis against graft-versus-host disease (GVHD) in 137 (45%) patients and 127 patients (42%), respectively. Of the 302 pairs, 104 (34%) were found to be matched at HLA-A, -B, -C, -DRB1, and DQB1; 97 (32%) were mismatched at a single HLA allele (23 HLA-A or -B, 42 HLA-C, 32 HLA-DRB1 or HLA-DQB1); 83 (28%) were mismatched at two HLA alleles (35 HLA-A or -B and HLA-C, 8 HLA-A or -B and HLA-DRB1 or -DQB1, 40 HLA-C and HLA-DRB1 or -DQB1); and 18 (6%) were mismatched at three HLA alleles. Currently, 210 of the 302 patients are alive with the median follow-up period of 722 days after transplantation. The incidence of graft failure was 2.2%; that of grade II/IV GVHD was 29.0%; that of III/IV acute GVHD was 13.8%; and that of chronic GVHD was 25.2%. Multivariate analysis revealed the following significant risk factors for survival: patients older than 15 years (RR, 1.98; range 1.17–3.35); HLA-A or -B + HLA-C or HLA-DQB1 or -DRB1 (RR 2.18; range 1.29–3.68); three loci mismatching (RR 3.14; range 1.47–6.69); prophylaxis against GVHD with tacrolimus with methotrexate (RR 0.45; range 0.28–0.73), ABO major mismatch (RR 1.67; range 1.05–2.63), and non-ATG-containing CY+TBI regimen (RR 2.17; range 1.16–4.03). Patients were divided into two cohorts based on years of transplantation and we compared patients transplanted within two time periods: 1993–2000 and 2001–2005. Five-year survival increased 55.9+/−4.6% in the 1993–2000 cohort (n=116) and 72.7+/−3.8% in the 2001–2005 cohort (n=186) (p=0.008). Patients and transplant characteristics that differed significantly between the two periods were patients’ age distribution, GVHD prophylaxis, HLA matching, and conditioning regimens. The percentage of patients older than 15 years was significantly larger in the recent period (p<0.001). However, the use of cyclosporine and non-ATG-containing CY+TBI regimen were more frequent in the earlier period (p<0.001). HLA-mismatching between patients and donors was more frequent in 1993–2000 (p<0.001). In conclusion, U-BMT for SAA has improved significantly in the recent 5-years period. Improved HLA matching, avoiding non-ATG-containing CY+TBI regimen, and the use of tacrolimus for GVHD prophylaxis account for this improvement.

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Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome

Blood ◽

10.1182/blood.v79.1.269.bloodjournal791269 ◽

1992 ◽

Vol 79 (1) ◽

pp. 269-275 ◽

Cited By ~ 2

Author(s):

E Gluckman ◽

MM Horowitz ◽

RE Champlin ◽

JM Hows ◽

A Bacigalupo ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Graft Versus Host Disease ◽

Randomized Clinical Trials ◽

Chronic Gvhd ◽

Severe Aplastic Anemia ◽

Term Survival ◽

Host Disease ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Data for 595 patients with severe aplastic anemia receiving HLA- identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

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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.v74.5.1852.1852 ◽

1989 ◽

Vol 74 (5) ◽

pp. 1852-1857 ◽

Cited By ~ 33

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

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 severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome

Blood ◽

10.1182/blood.v79.1.269.269 ◽

1992 ◽

Vol 79 (1) ◽

pp. 269-275 ◽

Cited By ~ 105

Author(s):

E Gluckman ◽

MM Horowitz ◽

RE Champlin ◽

JM Hows ◽

A Bacigalupo ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Graft Versus Host Disease ◽

Randomized Clinical Trials ◽

Chronic Gvhd ◽

Severe Aplastic Anemia ◽

Term Survival ◽

Host Disease ◽

Graft Versus Host ◽

Gvhd Prophylaxis

Abstract Data for 595 patients with severe aplastic anemia receiving HLA- identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.

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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 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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Outcome of Alternative Donor Transplantation for Severe Aplastic Anemia Can Be Comparable to Outcome with Matched Related Donors.

Blood ◽

10.1182/blood.v106.11.2052.2052 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2052-2052

Author(s):

Alana A. Kennedy-Nasser ◽

Kathryn Leung ◽

Steven Gottschalk ◽

Dean A. Lee ◽

George Carrum ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Aplastic Anemia ◽

Pediatric Patients ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Severe Aplastic Anemia ◽

Unrelated Donor ◽

Alternative Donor

Abstract Matched related donor (MRD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia; however, only 25% of patients will have an HLA-identical sibling. Alternative donor transplants may be an option for these patients, but such therapies have been associated with greater incidences of graft failures and graft-versus-host disease (GVHD). We retrospectively analyzed 32 pediatric patients who have undergone either bone marrow or peripheral blood stem cell transplant for severe aplastic anemia at our institution from April 1997 to April 2005. These patients had a total of 34 transplants. One patient had a MRD transplant followed by a matched unrelated donor (MUD) transplant eight years later, while another patient had a HLA-mismatched unrelated donor (MMUD) transplant followed by a transplant from a haplo-identical parent. Of the remaining 30 patients, 12 received MRD transplants, whereas 18 patients received alternative donor transplants - 11 MUD, 3 haplo-identical donors, and 4 MMUD. The median age at transplant was 9 years (range 1.5 to 18.4 yrs). All patients who received alternative donor transplants had previously failed therapy, including antithymocyte globulin (ATG) and cyclosporine. For MRD transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg x 4 days and ATG 30 mg/kg x 3 days. For alternative donor transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg x 4 days, Campath 3–10 mg x 4 days (dependent upon patient’s weight) or ATG 30 mg/kg x 3 days, and TBI (single fraction 200 cGy for MUD; two fractions 200 cGy for MMUD). Alternative donor recipients who received ATG in their preparative regimen were transplanted between December 1997 and March 2001 (n=9), whereas patients who received Campath were treated between November 2001 and April 2005 (n=11). GVHD prophylaxis was either FK506 or cyclosporine +/− mini-methotrexate. The overall survival for MRD patients was 91.7% versus 80% for alternative donor patients at a median follow-up of 47 months (range 3 to 100 months). Of the 32 patients, there were 5 deaths: pulmonary failure with extensive, chronic GVHD (n=1); poor graft function with infection (n=1); and infection (n=3). For patients receiving alternative donor transplants, the overall survival for the Campath group was 81.8% vs. 77.8% in the ATG group. None of the Campath patients developed extensive, chronic GVHD compared to 3/9 ATG patients. In conclusion, alternative donor transplantation using Campath or ATG in the preparatory regimens can establish donor engraftment and offers a curative therapy for pediatric severe aplastic anemia patients with survival similar to that of patients receiving matched sibling transplants. Although follow-up is shorter, Campath may be associated with a reduced incidence of extensive, chronic GVHD and further investigation is warranted.

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Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide

Blood Advances ◽

10.1182/bloodadvances.2020001729 ◽

2020 ◽

Vol 4 (8) ◽

pp. 1770-1779 ◽

Cited By ~ 11

Author(s):

Amy E. DeZern ◽

Marianna L. Zahurak ◽

Heather J. Symons ◽

Kenneth R. Cooke ◽

Gary L. Rosner ◽

...

Keyword(s):

Aplastic Anemia ◽

Total Body Irradiation ◽

Chronic Gvhd ◽

Severe Aplastic Anemia ◽

Gvhd Prophylaxis ◽

Treatment Naïve ◽

Grade Ii ◽

Total Body ◽

Cell Disorder

Abstract Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.

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