Related Donor Bone Marrow Transplantation Research Articles

173: Outcomes of matched related donor bone marrow transplantation in pediatric patients with myelodysplastic syndrome

Myelodysplastic syndromes (MDS) in children are associated with significant morbidity and risk of leukemic transformation. Allogeneic hematopoietic stem cell transplantation is the only curative therapy. The ideal allogeneic donor is an HLA-identical sibling or relative or Matched Related Donor (MRD). From 1990 to 2005, a total of 12 pediatric or young adult patients with MDS received bone marrow transplant from an HLA matched sibling at our institution. M:F ratio of the study group was 1.4; One patient belonged to ethnic minorities (8%); the median age at transplant was 13.4 years (range 1.1-20.6) and median weight was 54.7 kg (range 10.8-78).

Comparison of Therapeutic Effect between Related Donor and Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) in the Treatment of Leukemia.

Objective : To compare the effect for leukemia between related donor hematopoietic stem cell transplantation (RD-HSCT) and unrelated donor hematopoietic stem cell transplantation (URD-HSCT).Methods: 115 patients received allo-HSCT, of whom 68 received RD-HSCT and 47 received URD-HSCT. All patients are HLA serologically matched. Total body irradiation (TBI) plus cyclophosphamide (CTX) was adopted in 56 cases and modified BuCY conditioning regimen (busulfan, Ara-C, Cyclophosphamide) in 59 cases. T and B cell reconstitution at different time points was assayed by flow cytometer in one year after transplantation. GVHD and nonage infection are observed after transplantation. The diference of haematopoietic and immunological reconstitution between the two groups are estimated with Independent-Samples T test. Kaplan-Meier survival analysis model is used to estimate the overall survival and the disease-free survival (DFS) in two groups.Results: The time in WBC>1.0×109/L are +13.09±2.39 and +16.28±3.01d(P=0.003), the time in BPC>20×109/L are +14.91±6.62 and +20.21±7.29d(P=0.042), respectively, in related donor bone marrow transplantation (RD-BMT) and unrelated donor bone marrow transplantation (URD-BMT). The time in WBC>1.0×109/L are +12.47±2.96 and +13.13±4.09d(P=0.488), the time in BPC>20×109/L are +12.16±4.24 and +15.67±7.12d(P=0.020), respectively, in related donor peripheral blood stem cell transplantation (RD-PBSCT) and unrelated donor peripheral blood stem cell transplantation (URD-PBSCT). The reconstitution of CD4+CD3+ at 1, 3, 6, 9, 12months and CD45RA+CD4+ at 1 month, and CD8+CD3+ at 3 months were different significantly between RD-HSCT and URD-HSCT(P value was 0.001, 0.017, 0.029, 0.041, 0.015, 0.015, 0.043, respectively). The incidence of II~IV°acute GVHD(aGVHD), chronic GVHD(cGVHD) and the lethality of GVHD are 45.45% and 52.27%(P=0.560), 45.31% and 63.16%(P=0.102), 6.06% and 15.91%(P=0.112), respectively, in RD-HSCT and URD-HSCT groups. The relapse rate are 18.18% and 11.36%(P=0.424), respectively, in RD-HSCT and URD-HSCT groups. The incidence of nonage infection are 42.42% and 47.73% (P=0.696), respectively, in RD-HSCT and URD-HSCT groups.The overall survival and the disease-free survival rate at three-year were 67.80±6.90% and 61.60±7.70%(P=0.133), 62.30±6.90% and 56.80±7.90%(P=0.177), respectively, in RD-HSCT and URD-HSCT groups.Conclusion The therapeutic effect for leukemia is not different between RD-HSCT and URD-HSCT.

Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421

Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.

Outcome of alternative donor transplantation for severe aplastic anemia can be comparable to outcome with matched related donors

Matched related donor (MRD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia (SAA); 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 34 hematopoietic stem cell transplants for severe aplastic anemia at our institution from April 1997 to April 2005. One patient had a MRD transplant followed by a matched unrelated donor (MUD) transplant, while another had an HLA-mismatched unrelated donor (MMUD) transplant followed by a transplant from a haplo-identical parent. Twelve patients received MRD transplants, whereas 18 patients received alternative donor transplants—11 MUD, 3 haplo-identical, and 4 MMUD. The median age at transplant was 9 years (range 1.5 to 18.4 yrs). For MRD transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg × 4 days and ATG 30 mg/kg × 3 days. For alternative donor transplants, the conditioning regimen most often utilized cyclophosphamide 50 mg/kg × 4 days, Campath 3-10 mg × 4 days (dependent upon patient weight) or ATG 30 mg/kg × 3 days, and TBI (single fraction 200 cGy for MUD; two fractions 200 cGy for MMUD). Nine alternative donor recipients received ATG in their preparative regimens, whereas 11 received Campath. 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 our 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 offers a curative therapy for pediatric SAA 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.

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

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.

Second hematopoietic stem cell transplant using unrelated donor umbilical cord blood cures 50% of pediatric patients with leukemia relapsing after prior allogeneic transplant from a matched related sibling

Leukemic relapse after allogeneic stem cell transplant is difficult to treat and carries a poor prognosis. Cytotoxic therapy has limited efficacy and subsequent myeloablative transplants are associated with significant treatment related toxicity. We report results of 4 children who relapsed after matched related donor bone marrow transplants (BMT) and then underwent unrelated donor umbilical cord blood transplantation (UCBT) following conditioning with Fludarabine/Melphalan/ATG. Between 7/00 and 5/03 4 children who experienced leukemic relapse after 1 (n = 3) or 2 (n = 1) matched sibling transplants underwent UCBT at Duke University Medical Center. The average age at the time of UCBT was 7 1/3 years (range 5 12 to 15 12 years) old with a median weight of 26 kg (range 20–45 kg). The median time from initial BMT to UCBT was 13 months. Two children had ALL (high risk Pre-B ALL (BMT in CR2, UCBT in CR3); Philadelphia chromosome positive ALL (BMT in CR 1, DLI in CR2, UCBT in CBR3)) and two had AML (M1 AML (BMT in CR1 and CR2, UCBT in relapse); M2 AML (BMT in CR2, DLI × 4 in CR3, UCBT in relapse)). All patients had previously received TBI and were prepared for UCBT with Fludarabine 25mg/m2 qd × 5, Melphalan 45mg/m2 qd × 3 and ATG. Cyclosporine and intermediate dose steroids were given for GVHD prophylaxis. Three children received a 4/6 HLA matched UCB unit, one a 3/6 HLA matched unit, all with at least one mismatch at DRB1. The median nucleated cell dose was 9.8 × 107cells/kg (range 5.6–14.4 × 107cells/kg). All 4 demonstrated complete donor engraftment (absolute neutrophil count greater than 500/μL for three consecutive days) at a median of 24 (range 10–27) days post transplant. Platelet engraftment (untransfused platelet count >50,000/uL) occurred at a median of 55 days post transplant. One patient developed acute GVHD (grade 1 skin) and there was no chronic GVHD seen. The event free survival and overall survival are both 50%. One child died in remission of Legionella pneumonia on day +96 post transplant, and one died of relapse on day + 424 after UCBT. Two of the 4 patients are surviving disease free for a median of 775 (range 362–1189) days post transplant. UCBT after cytoreduction with fludarabine/melphalan/ATG is a viable option as a treatment for leukemic relapse after matched related allogeneic transplant, with low GVHD rate, tolerable treatment related mortality and 50% event free survival.

Early host CD8 T-cell recovery and sensitized anti-donor interleukin-2-producing and cytotoxic T-cell responses associated with marrow graft rejection following nonmyeloablative allogeneic bone marrow transplantation.

We developed a nonmyeloablative conditioning regimen for allogeneic bone marrow transplantation (BMT) followed by donor lymphocyte infusions (DLI) for treatment of chemotherapy refractory malignancies. Although the majority of patients who receive this regimen achieve lasting mixed or full allogeneic chimerism, approximately 30% show initial mixed chimerism followed by loss of the donor graft. These patients recover host hematopoiesis without significant cytopenias. To assess the role of immunologic rejection in graft loss, we compared T-cell recovery and in vitro alloresponses in six patients who lost their marrow graft to that in 16 concurrent patients with sustained donor chimerism. Conditioning included pretransplant cyclophosphamide (150-200 mg/kg), thymic irradiation (700 cGy), and pre- and post-transplant equine antithymocyte globulin (ATG; ATGAM). HLA-identical related donor BMT was followed by DLI at approximately day 35 in patients without graft-vs-host disease. The group with transient chimerism showed significantly increased circulating host T-cell (median 416 cells/mm(3) vs 10 cells/mm(3), p<0.05) and CD8 T-cell numbers (354 cells/mm(3) vs 71 cells/mm(3), p<0.05) compared to the group with stable mixed or full donor chimerism within the first 100 days post-BMT. All DLI recipients who lost chimerism following DLI had greater than 80% recipient T cells at the time of DLI, whereas those with persistent chimerism had <60% host T cells. Graft rejection was associated with the development of a sensitized anti-donor bulk cytotoxic T-lymphocyte (CTL) response in 4 of 6 evaluated patients, compared to only 1 of 10 evaluated patients with sustained chimerism (p<0.05). Additionally, 3 of 5 evaluated transient chimeras showed high anti-donor CTL precursor frequencies in limiting dilution assays, and 3 of 4 evaluated transient chimeras showed high anti-donor interleukin-2 (IL-2)-producing T-helper (T(H)) cell frequencies. High anti-donor T(H) or cytotoxic T-lymphocyte precursors were not detected in sustained chimeras. These data indicate that loss of chimerism in patients receiving this nonmyeloablative regimen is due to immune-mediated rejection. This rejection appears to bemediated by recovering recipient cytolytic CD8(+) cells as well as IL-2-producing recipient T(H) cells. These data are the first to demonstrate sensitization of recipient anti-donor IL-2-producing cells in association with human marrow allograft rejection.

Impact of prophylactic donor leukocyte infusions on mixed chimerism, graft-versus-host disease, and antitumor response in patients with advanced hematologic malignancies treated with nonmyeloablative conditioning and allogeneic bone marrow transplantation

In an attempt to capture graft-versus-tumor effects without graft-versus-host disease (GVHD), the authors initiated a trial of nonmyeloablative allogeneic bone marrow transplantation (BMT) in patients with advanced hematologic malignancies, with the majority of patients having chemotherapy-refractory disease. Forty-two patients received an HLA-matched related donor BMT after a cyclophosphamide and antithymocyte globulin-based conditioning that also included thymic irradiation for patients who had not received prior mediastinal radiotherapy. Prophylactic donor leukocyte infusion (pDLI) at a dose of 1 × 10 7 CD3 + cells per kilogram were given beginning 5 weeks post-BMT to 16 patients with mixed chimerism (MC) but without GVHD, whereas 26 patients did not receive pDLI, either because of GVHD or early relapse. Twelve of 16 patients (75%) receiving pDLI had T cell chimerism at the time of pDLI ≥40%. These patients, by day 100 post-BMT, either converted to full donor chimerism (FDC) (n = 10) or had an increase in or stable donor chimerism (n = 2) after pDLI. Four of 4 patients whose T cell chimerism was ≤20% at the time of pDLI, lost the graft. In contrast, only 5 of 18 evaluable patients (28%) not receiving a pDLI converted to FDC by day 100 post-BMT, 7 maintained MC, and 10 of an evaluable 22 lost the graft. Patients who had undergone a previous autologous stem cell transplant had a higher rate of conversion to FDC (69% v 31%) and higher incidence of GVHD (69% v 34%) compared with those who did not have a previous autologous SCT. Eleven of 16 patients (69%) who received a pDLI achieved a remission with 50% 1-year progression-free survival rate and 44% 3-year overall survival rate. Nineteen of 42 patients (45%) had ≥grade II acute GVHD, including 12 after BMT and 7 after pDLI. Approximately one third of patients, after having initial MC, eventually lost their donor graft. The authors conclude that (1) pDLI has the potential to convert MC to FDC; (2) sustained remissions can be achieved in patients with chemorefractory hematologic malignancies who receive a pDLI, albeit with a significant risk of acute GVHD; and (3) the degree of donor T cell chimerism at the time of pDLI is predictive of the fate of MC, ie, donor T cell chimerism ≥40% or ≤20% at the time of pDLI correlates with conversion of MC or loss of the graft, respectively.

Erratum: Partially mismatched related donor bone marrow transplantation as salvage for patients with AML who failed autologous stem cell transplant

Correction to: Bone Marrow Transplantation (2001) 28, 1031–1036. DOI:10.1038/sj/bmt/1703279 Since the publication of the above paper, an error has been identified in the spelling of one of the authors’ names. J Mehta appeared as ‘J Metha’. Therefore, the authors’ names should appear as follows: KT Godder, J Mehta, KY Chiang, S Adams, F van Rhee, S Singhal, K Higgins-Smith, W O'Neal, S DeRienzo and JP Henslee-Downey.

Unrelated marrow transplantation for children with acute lymphoblastic leukemia in second remission

Allogeneic bone marrow transplantation (BMT) may be curative for more patients than chemotherapy for the child with relapsed acute lymphoblastic leukemia. This study reviewed the outcomes of 363 children with acute lymphoblastic leukemia in second remission who received unrelated donor BMT from 1988 to 2000 in order to define prognostic factors that affect leukemia-free survival (LFS). Median patient age was 9 years (range, 0-19 years), and median follow-up 29 was months (range, 0-125 months). The median duration of first remission was 24 months (range, 0-109 months). Prognostic factors, including age, duration of first remission, HLA matching, and graft-versus-host (GVH) disease, were analyzed using both univariate and multivariate analyses. Overall survival was 38%, and LFS was 36% at 5 years. LFS was significantly worse for patients 15 years or older (log-rank, P =.009). HLA matching was associated with improved LFS. Acute GVH disease developed in 71%, with 29% having grades III-IV. The incidence of chronic GVH disease was 39% for patients who survived more than 80 days and was significantly higher for female patients receiving marrow from female donors (P =.0009). Transplantation-related mortality was 42% and was associated with HLA mismatches, age 15 years and older, and first remission less than 12 months. The 5-year estimate for relapse was 22%, with first remission at least 6 months associated with a lower risk. Results of unrelated donor BMT appear similar to multi-institutional studies of matched related donor BMT, and this approach appears to be curative for many patients. However, innovative approaches are needed for patients with initial remissions of less than 6 months and for older teenagers.

Evaluation of the half-life of intravenous human cytomegalovirus immune globulin in patients receiving partially mismatched related donor bone marrow transplantation.

To evaluate the pharmacokinetics and use of intravenous human cytomegalovirus immune globulin (CytoGam) in allogeneic bone marrow transplantation (BMT). Prospective, nonrandomized, nonblinded, single-center study. University teaching hospital. Five consecutive patients with hematologic malignancies receiving partially mismatched related donor BMT with a uniform conditioning regimen including total body irradiation and chemotherapy. Serum immunoglobulin and cytomegalovirus (CMV) titers were measured before and 24 hours after the first CytoGam infusion on day -6 during the conditioning regimen. These levels were measured every 5 days, and a second dose was administered when the CMV titer returned to 25-50% of the 24-hour level. The half-life of CytoGam was approximately 7 days. We believe this is the first report of CytoGam's half-life in allogeneic BMT. The information may prove vital in a future study in which the agent's potential beneficial effects can be maximized.

Partially mismatched related donor bone marrow transplant for patients with second remission ALL provides long term survival

Godder, K T.; Chiang, K Y.*; van Rhee, F.*; Mehta, J.*; Singhal, S.*; Bridges, K.*; Goon-Johnson, K.*; HensleeDowney, J P. Author Information

One antigen mismatched related donor bone marrow transplant in a patient with acute lymphoblastic leukaemia and β-thalassaemia major: potential cure of both marrow disorders

We report a case of a 34-year-old man with T-ALL and beta-thalassaemia major who underwent a one antigen mismatched related donor bone marrow transplant. Five months post transplant chimeric studies revealed full donor haemopoiesis and the patient remains leukaemia and thalassaemia free at 12 months post transplant. Cumulative risk factors contributing to the increased transplant-related mortality in patients with two different marrow disorders are discussed.

Salvage Therapy for Relapsed Mediastinal B-Cell Lymphoma with Allogeneic HLA-Identical Related Donor Bone Marrow Transplantation, Donor Lymphocyte Infusion and IDEC-C2B8

Primary B-cell lymphoma of the mediastinum is an aggressive non-Hodgkin's lymphoma with distinct clinicopathologic features. Response rates are between 60-80% following intensive chemotherapy regimens. Poor responders or patients with an early relapse usually do not achieve a prolonged second remission with conventional salvage therapy protocols and therefore qualify for intensive or experimental approaches. Here we describe two patients of same age, gender and stage with primary mediastinal B-cell lymphoma and an early relapse after the first courses of combination chemotherapy and irradiation of the mediastinum. One patient relapsed after a salvage therapy with allogeneic donor-related bone marrow transplantation and donor lymphocyte infusion but responded again with a continuing good partial remission after infusion of the chimeric anti-CD20 antibody IDEC-C2B8. For the other patient an allogeneic bone marrow transplantation was not possible. He finally failed to respond to salvage therapy with IDEC-C2B8 and died of progressive disease. The anti-CD20 antibody IDEC-C2B8 induced a partial remission in a patient with primary mediastinal B-cell lymphoma refractory to other therapeutic approaches, including allogeneic bone marrow transplanatation (alloBMT), donor lymphocyte infusion (DLI) and irradiation. The role of IDEC-C2B8 as a component of salvage regimens appears to be worthy for further evaluation in high-risk patients with primary mediastinal B-cell lymphoma

Efficacy and Costs of Granulocyte Colony-Stimulating Factor in Allogeneic T-Cell Depleted Bone Marrow Transplantation

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P < .0001) and time from marrow infusion to discharge (23 days v 17 days,P < .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs.© 1998 by The American Society of Hematology.

Efficacy and Costs of Granulocyte Colony-Stimulating Factor in Allogeneic T-Cell Depleted Bone Marrow Transplantation

Hematopoietic growth factors have shown clinical benefits in patients undergoing chemotherapy and stem cell transplantation, but few studies have been performed to assess whether the benefits are worth the costs. We reviewed 196 patients undergoing T-cell depleted related donor bone marrow transplantation (BMT) between 1990 and 1996 to assess the effect of growth factor use on time to engraftment and costs of hospitalization. Beginning in 1994, based on encouraging results in autologous transplantation, patients (n = 81) were treated with granulocyte colony-stimulating factor (G-CSF) starting at day +1 after marrow infusion until engraftment. Between January 1, 1990 and January 1, 1994, patients (n = 115) did not receive growth factor. CD6 depletion of donor marrow was the only form of prophylaxis against graft-versus-host disease (GVHD). Despite receiving a lower stem cell dose (P = .004), the group receiving G-CSF had a decreased time to engraftment (20 days v 12 days, P &lt; .0001) and time from marrow infusion to discharge (23 days v 17 days,P &lt; .0001). In multivariate modeling, the use of G-CSF was the most significant factor predicting time to engraftment and discharge. Incidence of grades II-IV GVHD, early mortality, percentage of patients who engrafted, and relapse rates did not differ between the groups. Inpatient charges during the first 50 days after marrow infusion (including readmissions) were available on 110 patients and were converted to costs using departmental ratios of costs of charges. Median costs were significantly lower in the group receiving G-CSF ($80,600 v $84,000, P = .0373). Thus, use of G-CSF in this setting allows earlier hospital discharge with lower costs. © 1998 by The American Society of Hematology.

Cytomegalovirus infection in recipients of related and unrelated donor bone marrow transplants: no evidence of increased incidence in patients receiving unrelated donor grafts.

Recent reports suggest an increased incidence of cytomegalovirus (CMV) infection in recipients of unrelated donor (UD) bone marrow transplantation (BMT). In this study we have collated the incidence of CMV infection and disease in sequential UD (n = 119) and related donor (RD; n = 79) BMT performed in a single institution over a 7-year period. Low-risk patients (CMV seronegative recipient and donor) accounted for 51% of UD BMT (n = 61) and 62% of RD BMT (n=49), with CMV excretion documented in one RD BMT only. The remaining high-risk patients received identical prophylaxis regimens with aciclovir and intravenous immunoglobulin (IVIG). Two groups consisting of 58 UD BMT (median age 9.0 years, range 0.7-45.3 years) and 30 RD BMT (median age 13.6 years. range 1.6-47.6 years) were analysed. CMV reactivation/re-infection was documented in 15 UD BMT (26%) and 10 RD BMT (33%) (P = 0.72), and CMV disease in four UD BMT (8%) and four RD BMT (13%) (P = 0.533). In this series the risk of CMV excretion and disease following UD BMT was similar to that following RD BMT.

Hurler Syndrome: II. Outcome of HLA-Genotypically Identical Sibling and HLA-Haploidentical Related Donor Bone Marrow Transplantation in Fifty-Four Children

Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte alpha-L-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = . 0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte alpha-L-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte alpha-L-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.

Hurler Syndrome: II. Outcome of HLA-Genotypically Identical Sibling and HLA-Haploidentical Related Donor Bone Marrow Transplantation in Fifty-Four Children

AbstractUntreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte α-l-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = .0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte α-l-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte α-l-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.

Coagulation abnormalities and thrombotic microangiopathy following bone marrow transplantation from HLA-matched unrelated donors in patients with hematological malignancies.

Thrombotic microangiopathy is a well-known heterogeneous disorder that occurs as a complication of allogenic bone marrow transplantation (BMT). We evaluated 12 consecutive patients receiving HLA-matched unrelated BMT and 12 consecutive recipients of HLA-identical related BMT for the development of bone marrow transplantation-associated thrombotic microangiopathy (BMT-TM) on days 30 and 60 following BMT. A diagnosis was made in four of 12 (33.3%) unrelated compared to none of 12 (0%) HLA-identical cases. Levels of serum lactic dehydrogenase (LDH), fibrin degraded products (FDP) and de novo thrombocytopenia were elevated in eight of 12 patients (66.7%) receiving unrelated donor BMT, and none of the patients receiving related donor BMT. Our findings suggest clinical or subclinical microangiopathic changes may occur frequently in unrelated donor BMT. FDP elevation is possibly an important marker of microangiopathic changes as early complications of BMT.