HSCT remains the only treatment with curative potential for MDS.(1
) UCB as an alternative source of hematopoietic stem cells for unrelated donor transplantation may offer an acceptable option in children without an HLA-matched sibling. While outcomes and risk factors affecting UCBT have been reported in children with acute leukemia,(18
) and the results comparable to that after matched unrelated bone marrow transplantation,(8
) there are few reports detailing risk factors and outcomes after UCBT for MDS. Published reports are limited to very few patients,(4
) and include patients with JMML and/or secondary AML and some reports have included children with adults.(2
) This analysis, in contrast, to other reports, report outcomes after UCBT and prognostic factors associated with this treatment in children with RC, RAEB and RAEB-t.
Neutrophil and platelet recovery were lower than that reported after UCBT for acute leukemia or unrelated donor bone marrow transplantation for MDS in children.(7
) Consistent with reports in children with acute leukemia (9
) transplantation of UCB units containing higher cell doses was associated with faster neutrophil recovery. However, the current analysis observed faster neutrophil with transplantation of UCB units containing 6×107
/kg total nucleated cells or higher. This “cut-off” is almost twice that reported for children with acute leukemia who received UCBT. Lower rates of hematopoietic recovery and the apparent requirement for UCB grafts with higher nucleated cell doses may be explained by abnormalities of bone marrow stroma associated with MDS. In this regard, it is noteworthy that UCB cells co-cultured with bone marrow stroma from patients with MDS exhibit a lower proliferative capacity than when these cells are co-cultured with normal bone marrow stroma.(30
) Given the relatively small number of patients in the current analysis (albeit the largest to-date) the observed optimal cell dose in the current analysis requires validation in a larger cohort. Consistent with other reports, we observed slower hematopoietic recovery with increasing donor-recipient HLA disparity and non-TBI conditioning regimens.(29
) We also observed a marginal advantage for neutrophil recovery in patients with monosomy 7. Most patients with monosomy 7 were transplanted in RC; transplantation prior to the more advanced disease phase (RAEB/RAEB-t) may explain the observed higher likelihood of neutrophil recovery.
Transplantation period and monosomy 7 influenced DFS. Higher failure rates were observed prior to 2001. During the early period UCB units with low cell dose and donor-recipient HLA disparities at 3-loci were selected for transplantation. Whereas UCBT performed during the later period (2001-2005) have generally adhered to selection of units with minimum pre-freeze cell dose >3 × 107
/kg, donor-recipient HLA disparity limited to 1 or 2-loci and selection of patients with disease status in remission (29
). Better unit and patient selection would have enhanced hematopoietic recovery and consequently fewer transplant-related complications and death. Improvements in post-HSCT supportive care, independent of graft source would have also contributed to the success of UCBT in recent years. The waiting period from diagnosis to transplantation was shorter after 2001 and may also have contributed to the observed higher DFS. Shorter waiting times to transplantation included patients with RAEB/RAEB-t and RC with monosomy 7, the groups at highest risk for treatment failure. As with all observational reports, unmeasured and/or unknown factors may have also contributed to the observed improvement after 2001.
DFS rates in patients with monosomy 7 were higher compared to patients with normal or other cytogenetic abnormalities. In a recent EWOG-MDS analysis, complex karyotype defined as 3 or more structural aberrations was an independent prognostic factor, regardless of treatment (C. Niemeyer, personal communication, June 2008). In that analysis, DFS was similar amongst those with normal karyotype, monosomy 7 and karyotypes other than complex. Only 3 patients in the current analysis had complex karyotypes which explain our inability to detect an adverse effect of this karyotype on transplant-outcome. The observed higher DFS with monosomy 7 in the current analysis warrants further examination. However, other two small series of HSCT recipients described similar encouraging results (34
). We explored whether timing of transplantation and chemotherapy prior to UCBT may have influenced DFS. The timing of transplantation in patients with monosomy 7 was not significantly different from those without this abnormality (5 versus 6 months, respectively). We also tested for an effect of treatment prior to transplantation on DFS and found none (univariate analysis; data not shown). Surprisingly, disease status was not associated with DFS. The relatively small sample size may have prevented us from observing a significant effect. Most patients with monosomy 7 had RC and this karyotype might be a surrogate for disease status. . We adhered to the EWOG-MDS classification instead of the WHO or IPSS classification given the former is more appropriate for children.(3
) A separate analysis using the WHO classification (the standard for adults with MDS) was not undertaken. Given the study period, the WHO classification would have had to be assigned retrospectively and the relevant data for retrospective assignment were not available for all patients.
Our report has several limitations. Given the rarity of childhood MDS, we used data reported to two transplant registries to obtain a relatively large sample for a rare disease. As all patients received a myeloablative conditioning regimen we are unable to comment on the use of reduced intensity conditioning regimens especially for children with RC.(36
) UCB grafts are readily available and should be considered when transplantation is required urgently or in the absence of a HLA-matched related or unrelated donor. Recent advances, such as use of double cord blood units may circumvent the cell dose limitation, lead to faster hematopoietic recovery (37
) and lower transplant-related mortality.