i. MALIGNANT DISORDERS

17. (The following citation includes data on malignant and non-malignant disorders.) Outcomes of unrelated cord blood transplantation in pediatric recipients. Styczynski J, Cheung YK, Garvin J, Savage DG, Billote GB, Harrison L, Skerrett D, Wolownik K, Wischhover C, Hawks R, Bradley MB, Del Toro G, George D, Yamashiro D, van de Ven C, Cairo MS. Bone Marrow Transplant. 2004;34:129-36.

The authors report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center from August 1997 to September 2002, and the risk factors associated with survival. The median age of the patients was 9 years (0.5-20); diagnoses were ALL, AML, CML, HD, HLH, NHL, NBL, B-thal, FA, FEL, Krabbe, WAS, SAA; the median follow-up was 11 months; conditioning was total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9). The median total nucleated cell (TNC) dose was 3.8 x 10(7)/kg (1.1-11); median CD34+: 2.3 x 10(5)/kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/6), 22 (4/6). The cumulative incidence estimate for neutrophil recovery at day +60 was 63%; two patients had neutrophil engraftment after day +60. Two patients had primary graft failure (2/23) (8.7%). Probability of >/=grade II aGVHD by day +60 was 27%, >/=grade III aGVHD was 20% and cGVHD 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and for standard risk patients was 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P=0.024), CD34+/kg (P=0.038) and gender (P=0.048).

The authors comment that their results indicating CD34 cell dose as a significant variable for hematopoietic reconstitution and for OS are complimentary to those of Wagner et al. The probability of aGVHD was strikingly lower than the results of less-HLA-disparate unrelated bone marrow transplants performed in children, and only one patient (cumulative incidence 3%) had extensive cGVHD. In comparison, cGVHD develops in 55-65% of patients receiving HLA-matched BMTs from unrelated donors. The authors suggest that the results should be viewed cautiously because of the small number of patients and events analyzed; the heterogeneity of the diagnoses, methods of conditioning and GVHD prophylaxis; and short follow-up.

18. First report of autologous cord blood transplantation in the treatment of a child with leukemia. Hayani A, Lampeter E, Viswanatha D, Morgan D, Salvi SN. Pediatrics. 2007; 119: e296-300.

The authors present the case of a 3-year-old girl with acute lymphoblastic leukemia who developed isolated central nervous system relapse while receiving chemotherapy 10 months after diagnosis. The child achieved a second remission on retreatment with systemic and intrathecal chemotherapy. She then underwent myeloablative chemotherapy and radiation therapy followed by infusion of her own umbilical cord blood, which the parents had saved after her delivery. Prior to transplantation, the authors used IgH receptor gene and T-γ JG receptor gene loci rearrangements as molecular markers of the leukemia clone. The negative rearrangement signal in UCB, although positive in the leukemic bone marrow, gave the authors some assurance that the cord blood did not contain the leukemia clone. Given the sensitivity limitation of the standard PCR testing, however, one cannot completely rule out the possibility that a low-abundance leukemia clone was present in the UCB.

The patient is now doing well and is in complete remission 20 months after cord blood transplantation.

This report is apparently the first report of autologous CBT for the treatment of childhood leukemia. Autologous UCB transplantation has been reported in 1 patient with neuroblastoma and another with severe aplastic anemia.

In considering the choice of an autologous cord blood unit rather than an allogeneic unit, the authors state that the decision was based on the assessment that the benefits of decreased transplant-related mortality and morbidity (especially the ~30% chance of GVHD) in autologous CBT outweighed the risks of possibly reinfusing the leukemia clone to the patient, and the absence of graft-versus-leukemia effect.

The authors add a disclaimer stating that it is not their intention in this report to advocate private UCB collection and its use but, rather, to report an isolated case and discuss some of the issues and uncertainties surrounding this procedure.

[Comment: The authors do not comment on the fact that the recurrence rate after autologous transplantation for leukemia is significantly higher than the recurrence rate after allogeneic transplantation and, as a result, overall survival is higher after allogeneic HSCT. The authors do not comment on whether a matched allogeneic unit was available but, instead, point out that they considered an autologous unit to be preferable. ]

19. Outcomes of unrelated umbilical cord blood transplantation in pediatric patients with myelodysplastic syndrome. Parikh SH, Martin PL, Szabolcs P, et al. Biol Blood and Marrow Transplant 2005;11(2, Suppl 1);80.

The authors point out that myelodysplastic syndromes (MDS) in children are associated with significant risk of leukemic transformation. Thirty children with MDS were transplanted with unrelated umbilical cord blood. Median age was 9.06 years and median weight was 28.4 kg. Eight patients had secondary MDS and 10 patients had bone marrow blasts >20%. The preparative regimen was TBI-based in 19 and chemotherapy-based in 11 patients. Grafts delivered a median of 4.12 x 10⁷ nucleated cells/kg precryopreservation, and the median CD34+ cell dose infused postthaw was 1.48 x 10⁵/kg. Median time to ANC >500/µL was 24 days and median time to platelet recovery (>50K untransfused) was 72 days. aGVHD grade III-IV occurred in 5 patients; limited cGVHD was seen in 4 patients.

Fifteen patients (50%) died and 15 are surviving in remission from 3.4 to 107 months (median, 50 months) posttransplantation. Six of 8 children with secondary MDS (75%) are alive compared to 13 of 22 (40%) with primary MDS, possibly due to the greater number of patients with >20% blasts in the latter group. These results, especially in patients with <20% blasts pretransplantation, are equivalent to matched allogeneic bone marrow transplantation data.

20. Allogeneic hematopoietic cell transplantation for infants with acute lymphoblastic leukemia. Sanders JE, Im HJ, Hoffmeister PA, Gooley TA, Woolfrey AE, Carpenter PA, Andrews RG, Bryant EM, Appelbaum FR Blood. Blood 2005;105:3749-3756.

The authors state that the role of transplantation in infants with acute lymphoblastic leukemia (ALL) is not defined. Accordingly, they analyzed results of 40 infants diagnosed before age 12 months who received a hematopoietic cell transplant (HCT) between July 1982 and February 2003 in CR1 (n=17), CR2/3 (n=7) or relapse (n=16). Patients were conditioned with cyclophosphamide with total body irradiation (n=39) or busulfan (n=1). Hematopoietic cell grafts included unmanipulated bone marrow from 24 related and 13 unrelated donors, peripheral blood stem cells from 1 unrelated donor and cord blood from 2 unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was methotrexate or cyclosporine (7) or methotrexate plus cyclosporine (33). Thirty-nine engrafted, 20 developed acute GVHD, and 7 chronic GVHD. Sixteen relapsed and seven died of other causes. Patients in CR1 had disease-free survival (DFS) of 76% compared to 45% for CR2/CR3 and 8% for relapse (P=0.0001). Of 33 patients with cytogenetic data, 26 (79%) had MLL gene rearrangement. Fourteen of these 26 were in CR1 and 11 survive in remission. Outcome was associated with phase of disease, but having the MLL gene was not a factor predictive of outcome. Late effects included growth and other hormone deficiencies. The investigators concluded that their data demonstrate that infants with ALL and MLL gene have excellent DFS when transplanted in CR1 and consideration for transplantation in CR1 is warranted.

21. Unrelated cord blood transplantation for children with high risk myelodysplastic syndromes. Alessandra Picardi, Domenico Del Principe, Laura Cudillo, Teresa Dentamaro, Sergio Amadori and Paolo de Fabritiis. Haematologica 2004;89(5):ELT08 (e-letter)

The authors assessed the feasibility and toxicity of unrelated mismatched cord blood transplant in five pediatric patients with high-risk myelodysplastic syndrome. Four patients were at high-risk according to the FAB criteria and one because of age > 2 years, hemoglobin F level greater than 10%, low platelet count, associated immunodeficiency and hemolytic anemia. Before transplantation, two children were treated with chemotherapy: one failed 2 chemotherapy-induction cycles and one had a failure and disease progression after 1 locus mismatched allogeneic transplant from the mother.

Although all patients were considered at high risk of relapse because the proportion of marrow blasts ranged from 12% to 25% at transplant, full donor chimerism was achieved in 4/5 cases on day 28 and two patients are in continuous complete remission more than 5 years after no evidence of cGVHD.

On the basis of their study, the authors state that a search for an unrelated donor, including umbilical cord blood, should be mandatory for patients with MDS who lack an HLA-identical sibling, particularly in pediatric patients who have a longer life expectancy than adults.

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