Unrelated donor bone marrow transplantation for children with acute leukemia.

Summary:Graft-versus-host disease (GVHD) remains a major barrier to successful hematopoietic stem cell transplant for patients who lack a matched related donor. Partial T-cell depletion (TCD) of the graft may decrease the risk of severe GVHD with unrelated donors (URD) and partially matched related donors (PMRD) while retaining an antileukemic effect. We analyzed our experience using URD and PMRD for pediatric patients with leukemias from 1990 to 2001. A subgroup of 'matched' URD donor pairs was retrospectively analyzed for high-resolution class I. Partial TCD was accomplished with monoclonal antibody T10B9 or OKT3 and complement. There were 76 URD (45% matched) and 28 PMRD recipients. Event-free survival (EFS) was 38.3%, and overall survival (OS) 45.1% at 3 years. On multivariate analysis, there was no difference in survival based upon marrow source, but nonrelapse mortality was higher with the use of PMRD. Relapse occurred in 6% of ALL patients, and 22.8% of AML/MDS patients. Grades III-IV GVHD was observed in only 6.7% of patients. Partial TCD allows use of matched or mismatched URD, or PMRD with little mortality from GVHD, durable engraftment, and no increase in relapse risk. Bone Marrow Transplantation (2005) 35, 151-158.

Section: Discussionmentioning

confidence: 99%

Outcomes of transplantation with partial T-cell depletion of matched or mismatched unrelated or partially matched related donor bone marrow in children and adolescents with leukemias

Bunin

Aplenc

Leahey

et al. 2004

“…With HLA-mismatched unrelated donor BMT in children, the incidence of grades 3-4 GVHD has been 30-62%. 24,25 The risk of GVHD could be reduced by T cell depletion, 26,27 but in either case, treatment-related mortality was high and exceeded 50% in some reports. 24 A striking feature of our series is the relatively low early mortality (0% at 100 days post transplant) and 90% survival at 6 months post transplant.…”

Section: Discussionmentioning

confidence: 99%

Tacrolimus for prevention of graft-versus-host disease after mismatched unrelated donor cord blood transplantation

Przepiorka

Petropoulos

Mullen

et al. 1999

Summary:Ten children with hematologic malignancies or a storage disease underwent transplantation using cord blood cells from an unrelated donor mismatched for 1 (n ‫؍‬ 7) or 2 (n ‫؍‬ 3) HLA antigens. The median total nucleated cell dose was 4.0 (range, 2.2-7.1) ؋ 10 7 /kg. GVHD prophylaxis consisted of tacrolimus doseadjusted to maintain a whole blood level of 5-15 ng/ml with or without methotrexate 5 mg/m 2 i.v. on days 1, 3, 6 and 11. Corticosteroids were not administered prophylactically. Median follow-up is 12 months (range, 5-28 months). One patient had autologous recovery and subsequently relapsed 153 days post transplant. For the remainder of the patients, the median time to an ANC Ͼ0.5 ؋ 10 9 /l was 21 days (range, 19-38 days), and the median time to platelets Ͼ20 ؋ 10 9 /l was 39 days (range, 21-97 days). The actuarial risk of grade 2 GVHD was 77% (95% CI, 49-100%), and no patient had grades 3-4 GVHD. Two patients developed chronic GVHD. The survival rate is 90% (95% CI, 81-100%). The combination of tacrolimus and minidose methotrexate is active for the prevention of severe but not moderate acute GVHD after mismatched unrelated donor cord blood transplantation. Keywords: cord blood transplantation; graft-versus-host disease prophylaxis; tacrolimus; unrelated donor Indications for allogeneic transplantation in the pediatric population have increased greatly over the past decade, and now include metabolic storage diseases and hemoglobinopathies in addition to immunodeficiency disorders, marrow failure states and hematologic malignancies. The pool of potential donors has also recently expanded with the introduction of unrelated donor cord blood transplantation (CBT). 1-5 An unexpected advantage of CBT was the lower risk of acute graft-versus-host disease (GVHD) in comparison to marrow or mobilized peripheral blood stem cell transplantation. 6 This is thought to result from the relative immaturity of the T cells in cord blood. and cytokine profile, do not express IL-2 receptors, and have a V␤ chain diversity consistent with lack of prior antigenic stimulation. 7,8 However, the incidence of acute GVHD with CBT from HLA-mismatched unrelated donors remained substantial (38-73%), and the associated treatment-related mortality has limited long-term outcome. [1][2][3][4][5][6] Tacrolimus is an immunosuppressive macrolide lactone that inhibits the effects of calcineurin in the earliest steps of T cell activation, a mechanism of action similar to that of cyclosporine, but the potency of tacrolimus in vitro is more than 100 times that of cyclosporine. 9 This suggested that tacrolimus might be more effective than cyclosporine as GVHD prophylaxis in high-risk settings. We 10,11 and others 12,13 have reported that the combination of tacrolimus and methotrexate (MTX) is active in preventing acute GVHD after alternative donor marrow transplantation (unrelated donor marrow or mismatched related donor marrow transplantation) in adults, and the superiority of tacrolimus over cyclosporine as GVHD prophylaxis was recently de...

“…However, we are encouraged by recent reports of improving outcomes for pediatric ALL patients receiving MUDs with reported results comparable to MFD BMT. [30][31][32] The relative advantage of BMT compared to chemotherapy for patients with relapsed ALL will need continual re-evaluation with further developments in BMT technology and related procedures. The ability to measure MRD status prior to transplantation and modify conditioning, immunosuppression and post-transplant administration of DLI and targeted cellular immunotherapy accordingly promise to improve the outcome of BMT.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic bone marrow transplantation for childhood relapsed acute lymphoblastic leukemia: comparison of outcome in patients with and without a matched family donor

Bleakley

Shaw

Nielsen

2002

Summary:We evaluated the role of BMT in a cohort of 56 children with ALL relapsing after uniform initial treatment protocols in a single institution between 1990 and 1997. The patients were commenced on a single intensive chemotherapy regimen. All patients with a matched family donor (MFD) were recommended to receive BMT. The outcome was significantly better for patients with a MFD. The overall survival at 8 years was 60.0% (95% CI 35.7-77.6%) and 13.5% (95% CI 4.0-28.6%) for patients with and without MFDs (log-rank chi = 7.50 P = 0.0062). The event-free survival at 8 years was 55.0% (95% CI 11.1-31.3%) and 9.2% (95% CI 2.0-23.3%) for patients with and without MFDs (log-rank chi = 8.87 P = 0.0029). Multivariate analysis confirmed the survival advantage of BMT. There was no statistically significant difference in survival for patients initially relapsing within 3 years of first remission compared to children relapsing beyond 3 years. BMT provides a clear survival advantage for children following their first relapse of ALL. We recommend BMT for all children following first relapse of ALL if a MFD is available. Bone Marrow Transplantation (2002) 30, 1-7. doi: 10.1038/sj.bmt.1703601 Keywords: ALL; BMT; pediatric ALL Although the majority of children with ALL can be cured with their initial chemotherapy, the prognosis for those who relapse is guarded. In the past, there have been various reports of improving prognosis for children suffering their first marrow relapse of ALL, with protocols reporting longterm leukemia-free survival rates ranging from under 20% to 31%. [1][2][3][4][5] However, many of these reports do not include patients relapsing after initial treatment with contemporary intensive chemotherapy. With the current intensification of front-line protocols and further improved identification of high risk groups at diagnosis, patients who relapse tend to have resistant disease. Further intensification of chemotherapy, often including BMT is the major option. 6-18 How much advantage BMT in second clinical remission (CR2) offers over intensive chemotherapy alone remains controversial. [8][9][10][11][12][13][14] In particular, it has not been conclusively established whether BMT should be the preferred treatment option for children suffering relapses late after first remission, or at all sites.There have been no randomized trials of chemotherapy vs BMT in CR2 in children. It is unlikely that such trials will be conducted because of the clinical impression that BMT offers a survival advantage and consequent ethical concerns about withholding BMT from children with a suitable BMT donor. Donor vs no donor studies are one form of analysis that offer a relatively unbiased comparison between BMT and alternative treatment options. 19 'Biological randomization' is achieved in donor vs no donor studies by the allocation of all patients with suitable family donors to the BMT group and comparing their outcome to that of children without a suitable donor using intention to treat analysis. We report the outcome of a cohort...