Unrelated donor bone marrow transplantation for 100 pediatric patients: a single institute's experience

In all, 100 unrelated donor bone marrow transplantations (UD-BMT) were performed in our institute between October 1993 and January 2003. Of 93 evaluable patients, 73 patients had hematological malignancy, 13 had nonmalignancy and seven had lymphoproliferative disease. The estimated 9-year event-free survival (EFS) rate was 57.1+/-5.5% in all patients. In the following analyses of the patients with hematological malignancy, the standard group had significantly better EFS than the high-risk group (61.5+/-7.0 vs 35.6+/-9.7%, P=0.02), and the EFS rate of the tacrolimus (FK-506)+methotrexate (MTX)+/-methylprednisolone prophylactic group for graft-versus-host disease was superior to that of the FK-506 without MTX group (75.7+/-8.0 vs 55.8+/-7.6%, P=0.02). When we compared the EFS rates of the FK506+MTX+/-methylprednisolone (mPSL) group and the HLA-matched related donor BMT group in our institute, these were almost similar (75.7+/-8.1 vs 68.4+/-9.3%). Therefore, UD-BMT using FK-506+MTX+/-mPSL is a safe and useful method for children with hematological malignancy who require allogeneic BMT.     

Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study

The pharmacokinetics, safety, and efficacy in marrow transplantation of FK506-based immunosuppression for graft-versus-host disease (GVHD) prophylaxis was evaluated in an open label pilot study of 18 patients. Patients more than 12 years of age (median, 35 years; range, 15 to 50 years) with advanced hematologic malignancies receiving HLA-matched sibling marrow grafts were randomized to receive FK506 alone, FK506 and methotrexate (MTX), or FK506 and methyl-prednisolone. Of 17 evaluable patients, all had evidence of sustained marrow engraftment. The median time to an absolute neutrophil count of greater than 500/microL was 15 days for patients receiving FK506 alone or FK506 plus methylprednisolone and 23 days for FK506 plus short MTX. Pharmacokinetic studies did not show any significant difference in clearance of FK506 when administered alone or in combination with methylprednisolone or MTX. The mean bioavailability after oral administration in these same three groups was 0.49 +/- 0.1, 0.27 +/- 0.12, and 0.16 +/- 0.08, respectively (P = .003). The decrease in bioavailability may have resulted from an exacerbation of radiation- induced gastroenteritis by MTX. The most significant adverse effect associated with the administration of FK506 was nephrotoxicity, which occurred in 14 of 18 patients (78%). The mean glomerular filtration rate, determined by clearance of (99MTc)DTPA, decreased to 56% (+/- 18%) of the pretransplant baseline level by week 8 (P = .002). Eight of 18 patients (44%) developed grades II-IV acute GVHD, predominantly of the skin and gastrointestinal tract. The actuarial probability of transplant-related mortality during the first 100 days was 24%. The actuarial probability of 1-year disease-free survival was 39%. In conclusion, although bioavailability of FK506 may be affected in patients receiving MTX, this study suggests that FK506 may have a role in the management of patients after allogeneic marrow transplantation.     

Low incidence of acute graft-versus-host disease by the administration of methotrexate and cyclosporine in Japanese leukemia patients after bone marrow transplantation from human leukocyte antigen compatible siblings; possible role of genetic homogeneity. The Nagoya Bone Marrow Transplantation Group

Japanese patients with leukemia who received bone marrow from human leukocyte antigen (HLA)-compatible siblings had a low incidence of acute graft-versus-host disease (GVHD). Twenty-five (21%) of 120 patients developed moderate (grade II) to severe (grades III to IV) acute GVHD. Severe GVHD was only seen in patients older than 20 years of age. It is also notable that only 2 (5%) of 39 patients who received the combination of methotrexate and cyclosporine (MTX/CSP) for the prevention of GVHD developed grade II acute GVHD, and none developed grades III to IV acute GVHD. Thirteen (30%) of 44 patients receiving MTX alone and 10 (27%) of 37 patients receiving CSP alone developed grades II to IV acute GVHD. Multivariate life-table analysis indicated that the prophylaxis by MTX/CSP was the risk factor for the low incidence of grades II to IV acute GVHD. Compared with the reported incidence of acute GVHD in the patients of the United States, lower incidence of acute GVHD in Japanese BMT patients might be attributable to a lesser degree of genetic diversity in histocompatibility antigens among Japanese.     

FK506 in combination with methotrexate for the prevention of graft- versus-host disease after marrow transplantation from matched unrelated donors

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus- host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno- occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan- Meier estimates of disease-free survival at 2 years for good-risk, poor- risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.     

Successful second transplant from one-locus HLA-mismatched unrelated donor for graft rejection following initial transplant from another unrelated donor in a patient with chronic myelogenous leukemia

We report a patient with chronic myelogenous leukemia who received a second transplant from a one-locus HLA-mismatched unrelated donor after rejection of an initial bone marrow graft. For the first transplant, HLAs were fully matched, conditioning with busulfan + cyclophosphamide (CY) was applied, and cyclosporin A + short-term methotrexate (sMTX) was used for prophylaxis against GVHD. A complete chimera was not obtained, and the graft was rejected on day 122. For the second transplant, there was a one-HLA locus (DR) mismatch, conditioning was done with total body irradiation + cytarabine + CY, and GVHD prophylaxis consisted of FK506 + sMTX. Engraftment was obtained on day 27, and no graft failure was occurred at the time of writing. This case suggests that strong immunosuppression may have prevented rejection of the second bone marrow graft.     

Histocompatible unrelated volunteer donors compared with HLA nonidentical family donors in marrow transplantation for aplastic anemia and leukemia

We treated 14 patients by transplantation of marrow from unrelated volunteer donors. Eight patients had severe aplastic anemia, 3 had chronic granulocytic leukemia, and 3 had Fanconi's anemia. The results are compared with those of a group of 14 similar patients transplanted concurrently from human leukocyte antigen (HLA)-mismatched family members: Sustained engraftment was achieved in 8 of 14 patients in both groups; one additional patient survived with autologous marrow reconstitution following an unrelated donor transplant. In the unrelated donor group, 6 of 9 evaluable patients developed grade III through IV acute graft-v-host disease, as compared with 4 of 9 patients after family-mismatched transplants. Overall survival was similar in the two groups. In the unrelated donor group 4 of 14 (29%) patients survived (median survival 1,299 days) as compared with 5 of 14 (36%) in the mismatched-family donor group (median survival 808 days). In both groups, patients with HLA phenotypically matched donors fared better than those with donors who were mismatched for one or more HLA antigen. Of the patients transplanted from HLA phenotypically matched donors 6 of 12 patients (50%) survived, as compared with 3 of 16 patients (19%) transplanted from HLA-mismatched donors. We conclude that unrelated donor bone marrow transplantation (BMT) should be considered in those cases of leukemia or bone marrow failure in which the chance of cure using conventional therapy is remote and a HLA genotypically or phenotypically matched family donor is not available.     

Methotrexate vs Cyclosporin A as a single agent for graft-versus-host disease prophylaxis in pediatric patients with hematological malignancies undergoing allogeneic bone marrow transplantation from HLA-identical siblings: a single-center analysis in Japan

The efficacy of methotrexate (MTX) as a single graft-versus-host disease (GVHD) prophylaxis agent was compared to that of cyclosporin A (CSA) in 62 pediatric patients (median age: 8 years) with hematological malignancies who had undergone bone marrow transplantation (BMT) from HLA-identical sibling donors at National Kyushu Cancer Center since 1977. In all, 30 patients received MTX by intravenous bolus injection, with a dose of 15 mg/m(2) on day +1, followed by 10 mg/m(2) on days +3, +6, and +11, and then once a week until day +100. A total of 32 patients were treated with CSA, which was given intravenously in the early stages and orally thereafter until day +100, and then gradually tapered and stopped 6 months after BMT. There were no differences between the groups in terms of rates of hematopoietic recovery after BMT. The probabilities of acute GVHD (grades II-IV) and chronic GVHD were 29.6 vs 40.6% (P=0.294) and 19 vs 20% (MTX vs CSA), respectively. Relapse rates and event-free survival were identical. These results suggest that MTX and CSA were equally effective when given after BMT in Japanese pediatric patients with hematological malignancies. Since MTX was given over a shorter time than CSA, it might be more practical in the management of such patients.     

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens

The role of T-cell depletion (TCD) to prevent graft-versus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and VP-16 50 mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8+ T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67% of evaluable patients developed acute GVHD, severe grade III-IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8+ TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8+ TCD for AML is a potentially curative treatment option.     

Allogeneic bone marrow transplantation using partially-matched related donors

Six patients with advanced leukemia and one with severe combined immunodeficiency syndrome received allogeneic bone marrow transplantation (BMT) from HLA haploidentical donors who were compatible for one or two loci on the non-shared chromosome. Methotrexate was used for prophylaxis against acute graft-versus-host disease (GVHD). All patients engrafted but developed moderate to severe acute GVHD, and three patients died. Two leukemic patients relapsed but two others survived and were free of disease 403 and 936 days post-transplant. BMT using related partially matched donors may result in durable engraftment and long-term survivors. The implications of using such donors in expanding the application of BMT are discussed.     

Benefits of mycophenolate mofetil for refractory graft-versus-host disease

We retrospectively evaluated the efficacy of mycophenolate mofetil (MMF) in the treatment of steroid-resistant acute and chronic graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation. Thirteen patients, ten men and three women, consisted of 5 cases of acute myelogenous leukemia, 2 of acute lymphoblastic leukemia, 2 of chronic myelogenous leukemia, 2 of lymphoblastic lymphoma, and 1 case each of adult T-cell leukemia and peripheral T-cell lymphoma. The transfusions consisted of 5 peripheral blood, 7 bone marrow and 1 cord blood from 3 mothers, 4 siblings and 6 unrelated donors with conditioning treatments, including 8 total-body irradiation-based regimens, and 2 busulfan plus cyclophosphamide and 2 reduced-intensity regimens. GVHD prophylaxis included FK506 plus methotrexate (MTX) and/or antithymocyte globulin for 9 patients, and cyclosporine and MTX for 4 patients. All patients were treated with second-line MMF for steroid-refractory acute and/or chronic GVHD, and 11 patients improved. The adverse events were tolerable except for one patient in whom grade 3 neutropenia forced discontinuation of treatment. No case of non-relapse mortality occurred. We consider that MMF is beneficial and well tolerated for treatment of steroid-refractory GVHD.     

Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)     

Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin.

Regimens using cyclosporin (CSP) and either methylprednisolone (MP) or methotrexate (MTX) have been useful in the prophylaxis of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). However, CSP produces a number of side effects, including neurologic toxicity. A retrospective review of recipients of 239 BMTs given CSP-based prophylactic regimens revealed that 10 patients (4.2%, 95% confidence interval 0% to 10.4%) experienced a syndrome characterized by hypertension, severe visual disturbances, seizures and occipital lobe density changes on brain computed tomography (nine patients) or nuclear magnetic resonance imaging (one patient). Neurologic findings were reversible in all cases, usually after temporary discontinuation of CSP. Univariate analysis identified the following risk factors for neurotoxicity: use of unrelated or HLA-mismatched related donors, administration of etoposide (VP-16) or total body irradiation as part of conditioning, use of corticosteroids for prophylaxis or treatment of acute GVHD, or development of either acute GVHD or clinically significant microangiopathic hemolytic anemia (MAHA) post-BMT. In multivariate analysis, the most important predictors were the use of VP-16 (p = 0.008), the use of a continuous infusion CSP plus MP prophylactic regimen for GVHD (p = 0.003) and the development of MAHA after BMT (p less than 0.001). The strong association with MAHA suggests that endothelial damage is related to the development of this complication.     

feasibility and Results of Bone Marrow Transplantation from an HLA-Mismatched Unrelated Donor for Children and Young Adults with Acquired Severe Aplastic Anemia

Treating patients with severe aplastic anemia (SAA) who fail to respond to immunosuppressive therapy (IST) and do not have an HLA-matched donor is challenging. We report favorable outcomes in 11 patients who underwent bone marrow transplantation (BMT) from an HLA-mismatched unrelated donor. The median age was 11 years (range, 3-20 years). The conditioning regimen consisted of cyclophosphamide (200 mg/kg), antithymocyte globulin (10 mg/kg), and total body irradiation (5 Gy). Patients received tacrolimus and methotrexate for prophylaxis against graft-versus-host disease (GVHD). Donorrecipient pairs were mismatched for the HLA-DR antigen in 8 patients by serologic typing. HLA-A and HLA-B antigens were mismatched in 1 and 2 patients, respectively. Ten patients achieved engraftment. One patient who failed to engraft was rescued by a second transplantation from her mother, who was mismatched at 2 HLA antigens. Acute GVHD of grades II to IV occurred in 2 patients. Three patients developed limited chronic GVHD, and 1 patient developed extensive chronic GVHD of the lung. All patients are alive at 9 to 56 months after transplantation (median, 33 months). Considering our encouraging results, HLA-mismatched unrelated-donor BMT for SAA is feasible as a salvage therapy for nonresponders to IST.     

Outcome of bone marrow transplantation from HLA-identical sibling donor in children with hematological malignancies using methotrexate alone as prophylaxis for graft-versus-host disease

Most previous studies of graft-versus-host disease (GVHD) prophylaxis with methotrexate (MTX) alone in patients undergoing HLA-identical sibling donor bone marrow transplantation were performed in adults. With this background, we attempted to analyze the incidence and risk factors of GVHD in bone marrow transplantation (BMT) from an HLA-identical sibling donor in children with hematological malignancies using MTX alone as a prophylaxis for GVHD. Ninety-four patients received MTX by intravenous bolus injection, with a dose of 15 mg/m² on day +1, followed by 10 mg/m² on days +3, +6, and +11, and then weekly until day +60. The probability of developing grade II–IV acute GVHD and chronic GVHD was 19.1 and 31.8%, respectively. Age at transplantation and a female donor to male recipient were identified as risk factors for chronic GVHD in multivariate analysis, but no factors were identified for acute GVHD. The cumulative incidence of transplant-related mortality during the first 100 days was 9.6%. Disease-free survival at 5 years for standard- and high-risk patients was 82.1 and 39.5%, respectively. These results suggest that GVHD prophylaxis with MTX alone is safe and effective in young children under 10 years old at transplantation and in a setting other than female donor to male recipient.     

Feasibility and safety of peripheral blood stem cell transplantation from unrelated donors: results of a single-center study

We compared the outcomes in patients receiving unrelated peripheral blood stem cell transplants (PBSCT) with those receiving bone marrow transplants (BMT) in a matched pair analysis. Seventy-four patients with hematological malignancies with HLA-matched (77%) and mismatched (23%) donors were analyzed in this study. Thirty-four patients (45%) were considered as high risk patients. Sixty-eight patients received standard conditioning regimens with Bu/Cy or TBI/Cy. Six patients received an intensified conditioning regimen with the addition of etoposide, thiotepa or melphalan. GVHD prophylaxis consisted of prednisolone, cyclosporine and methotrexate. Groups were matched for patient, donor, transplant characteristics and HLA compatibility. Peripheral blood stem cell collection led to the collection of a higher number of CD34+ and CD3+ cells in comparison to bone marrow collection. Leukocyte engraftment in the PBSCT group occurred in 14 days (median; range 6-26 days) and in the BMT group in 19 days (range 9-29 days; P < 0.02). The time of platelet engraftment did not differ significantly. The incidence of grades II-lV acute GVHD in the group of HLA-identical patients was 35% in the PBSCT group and 25% in the BMT group (P < 0.33, log-rank). However, there was a significant difference (P < 0.05, log-rank) in incidence and time to onset of acute GVHD II-IV comparing all patients, including the 17 mismatched transplants. Disease-free survival was 51% (19 patients) with a median of 352 days and 59% (21 patients) with a median of 760 days for PBSC and BMT transplants, respectively. In conclusion, our results indicate that allogeneic PBSCT led to significantly faster leukocyte engraftment but is associated with a higher incidence and more rapid onset of severe acute GVHD comparing all patients, including the 17 mismatched transplants. However, the incidence of severe acute GVHD in HLA-identical patients was not different between the PBSCT and BMT groups.     

Dual targeting of Bruton's tyrosine kinase and Janus kinase 3 with rationally designed inhibitors prevents graft-versus-host disease (GVHD) in a murine allogeneic bone marrow transplantation model

The purpose of the present study was to evaluate the effectiveness of targeting Bruton's tyrosine kinase (BTK) with a specific BTK inhibitor, alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13), for prevention of acute fatal graft-versus-host disease (GVHD) in a murine model of allogeneic bone marrow transplantation (BMT). Vehicle-treated control C57BL/6 mice receiving bone marrow/splenocyte grafts from allogeneic BALB/c donors developed severe multi-organ acute GVHD and died after a median survival time (MST) of 40 d. LFM-A13 treatment (25 mg/kg/d) significantly prolonged the MST of the BMT recipients to 47 d. The probability of survival at 2 months after BMT was 2 +/- 2% for vehicle-treated control mice and 22 +/- 6% for mice treated with LFM-A13 (P = 0.0008). Notably, the combination regimen of LFM-A13 plus the standard anti-GVHD drug methotrexate (MTX) (10 mg/m(2)/d) was more effective than LFM-A13 alone, while the combination regimen of LFM-A13 plus the novel anti-GVHD drug JANEX-1 (60 mg/kg/d), targeting Janus kinase 3, was more effective than LFM-A13, JANEX-1 or MTX alone. More than 70% of recipients receiving this most effective GVHD prophylaxis (LFM-A13 + JANEX-1) remained alive throughout the 80-d observation period with an MST of >80 d. Taken together, these results indicate that targeting BTK with the chemical inhibitor LFM-A13 may attenuate the severity of GVHD, especially when it is combined with other anti-GVHD drugs, such as MTX and JANEX-1.     

Prevention of graft-versus-host disease in high risk patients by depletion of CD4+ and reduction of CD8+ lymphocytes in the marrow graft

From March 1994 to September 1997, 30 patients with hematological malignancies (12 ANLL, 10 CML, four ALL and four multiple myeloma) received HLA-identical allogeneic bone marrow transplants with the marrow graft selectively depleted of CD4+ lymphocytes and the CD8+ cell content adjusted to 1x10(6)/kg. Total depletion of CD4+ and partial depletion of CD8+ lymphocytes was carried out by an immunomagnetical method. All patients were considered as having high risk for developing GVHD by at least one of the following criteria: patient age >35 years; donor age >35 years; donor multiparity or marrow from an unrelated donor. Twenty-four cases received marrow from an identical sibling and six from an unrelated donor. In order to assess the role of methotrexate (MTX) in addition to cyclosporin A (CsA) after transplant, patients were randomly assigned to received either CsA alone (n = 15) or CsA plus a short course of MTX (n = 15). No case of primary graft failure was observed, but two patients developed late graft failure. Six patients presented grade II acute GVHD and no case of severe III-IV GVHD was seen. The actuarial probability of developing grade II-IV acute GVHD was 25.9+/-9.6% for the entire population. Patients receiving post-transplant CsA + MTX had significantly less probability of acute GVHD than those receiving CsA exclusively (6.7+/-6.4% vs. 50.5+/-17.8%, P = 0.03) and the schedule of post-transplant immunosuppression was the only factor associated with the incidence of acute GVHD in a multivariate analysis. The actuarial incidence of chronic GVHD for the entire population was 31.8+/-12.5, and there was no significant difference between both groups with additional prophylaxis. Four patients with CML and three with ANLL relapsed: the actuarial probability of remaining in complete remission for all patients was 53.6+/-17.3%. For patients with acute leukemia, the probability of remaining in complete remission did not differ significantly between those transplanted in first complete remission and those receiving a transplant in more advanced phases of the disease (87.5+/-11.6% vs. 72.9+/-16.5%; P = 0.44). The incidence of mixed chimerism assessed by PCR was 34%. Nineteen patients are alive between 2 and 43 months post-transplant, the probability of overall survival being 57.8+/-10.4%. Our data indicate that this method of selective T cell depletion is very effective in preventing acute GVHD in high risk patients, particularly when used in combination with post-transplant CsA + MTX.     

Successful unrelated donor bone marrow transplantation for paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disease of hematopoiesis due to a mutation in the PIG-A gene. Affected patients may demonstrate hemolysis or venous thrombosis, and may develop MDS or aplastic anemia. Successful results may be obtained after conditioning and transplantation from syngeneic or genotypically matched sibling donors. Experience with transplantation from matched unrelated donors (MUD) is limited to eight patients, with only one survivor. We report three patients who underwent successful MUD BMT for PNH. All three patients had severe aplastic anemia (SAA) and PNH at the time of BMT. Unrelated donors were six-antigen HLA-matched (n = 2) or HLA-A mismatched (n = 1). Conditioning consisted of cytarabine, cyclophosphamide, TBI, and ATG. Grafts were T cell-depleted by anti-CD6/CD8 antibodies + complement. Further GVHD prophylaxis consisted of cyclosporine. Patients received 0.7-1.1 x 10(8) nucleated cells/kg and 1.1-2.1 x 10(6) CD34(+) cells/kg. Neutrophil engraftment occurred at 16-21 days. One patient developed grade 1 acute GVHD. Although all three patients experienced significant transplant-related complications, they ultimately resolved and all patients are alive and well 30-62 months after BMT. T cell-depleted MUD BMT is an effective treatment option for PNH-related MDS and SAA.     

Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan

Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSP-based and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60-3.04, P<0.0001 for grade II-IV acute GVHD; HR: 1.81, 95% CI: 1.32-2.48, P=0.0003 for TRM; HR: 1.62, 95% CI: 1.23-2.14, P=0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.