Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission

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...

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

“…[18][19][20] In our study, 32.8% suffered from cGVHD, which was extensive in most cases. Patients with Ͼgr II aGVHD had a significantly higher risk of developing cGVHD.…”

Section: Discussionmentioning

confidence: 99%

Organ toxicity and quality of life after allogeneic bone marrow transplantation in pediatric patients: a single centre retrospective analysis

Matthes‐Martin

Lamche

Ladenstein

et al. 1999

Summary:One hundred and fifty five pediatric patients underwent allogeneic bone marrow transplantation between 1980 and 1996 in the St Anna Children's Hospital in Vienna with an overall survival of 52.3% (81 patients). Seventythree patients with a minimum observation time of 1 year (1-13 years, median: 4.6) were analyzed retrospectively for chronic GVHD, organ toxicity (WHO score), growth and pubertal development. Chronic GVHD was diagnosed in 20 patients (27.3%), being extensive in 17 cases. Maximum organ toxicity was WHO III in two patients (3%) and WHO II in 11 patients (15%) 1 year after BMT and WHO III in one patient (2%) and WHO II in five patients (11%) 3 years after BMT. Impaired growth and pubertal development were detected in more than 30% 3 years after BMT. As all patients presented with a Karnofsky or Lansky score of more than 80%, they were asked to complete a questionnaire comprising 12 questions concerning physical state of health and psychosocial state of health. Restricted contacts were classified as imposing a severe handicap by six patients (8%), restriction in mobility and 'normal life activities' by three patients (4%) and two patients classified themselves as severely physically handicapped. Most patients (75%) reported no physical or psychical impairment.

“…4,5 In contrast to myeloid malignancies, controversial effects of T-cell depletion on relapse rate in ALL have been reported. 1,3,6,7 As normal numbers of NK cells reconstitute from donor progenitors within a few weeks after T-cell depleted SCT, NK cells are possible effectors for a GVL reaction in the early phase post transplant and may be used for immunotherapy. 8 NK cell alloreactivity was found to be associated with a reduced risk of relapse in AML after HLA haplotype-mismatched haematopoietic SCT.…”

Section: Introductionmentioning

confidence: 99%

Cytolytic activity of NK cell clones against acute childhood precursor-B-cell leukaemia is influenced by HLA class I expression on blasts and the differential KIR phenotype of NK clones

Feuchtinger

Pfeiffer

et al. 2009

Relapse after allo-SCT in patients with acute leukaemia remains a major problem. A beneficial impact of alloreactive natural killer (NK) cells has been reported for myeloid malignancies, but has been questionable for B-lineage ALL. We analysed lysis of primary paediatric precursor-B-ALL blasts by 285 NK cell clones to investigate whether HLA class I expression on the blasts and phenotypic killer cell Ig-like receptor (KIR) expression on NK cells affect the lytic activity against ALL blasts. Precursor-B-ALL blasts with low HLA-I expression were lysed by a majority (79%) of NK cell clones, whereas those with high HLA-I expression showed low susceptibility to NK clones independent of their KIR expression patterns. NK cell activity against susceptible blasts was regulated by differential surface expression of the three major KIRs (CD158a, CD158b, CD158e). NK clones with none of these three KIRs or a single KIR that recognized no ligand, were not inhibited by the targets and exerted higher lysis (P ¼ o0.0005) in comparison to NK clones expressing KIRs with a ligand on the ALL blasts. In conclusion, the quantity of HLA-I expression on precursor-B-ALL blast regulates overall NK cell susceptibility; in case of reduced HLA expression, differential surface expression of KIRs affects NK cell alloreactivity against those blasts.