In this report we describe the transplant outcomes for children aged ≤18 years with ALL who received RIC before their first allo-HSCT. We found that RIC regimens were associated with myelosuppression in all patients along with high rates of TRM and acute and chronic GVHD. Similarly, leukemia recurrence was also high, resulting in modest DFS rates at 3 years. Several patients reported herein had performance scores of 70 or 80 (Karnofsky or Lansky scale) and/or were in second or subsequent CR at HCT and were thus at significant risk for transplant-related complications and/or leukemia relapse.
An important limitation of this registry study is the lack of information regarding the rationale for the selection of RIC. We speculate patients who received RIC were either treated on an institutional protocol (26% of study population) or judged to be at high risk for transplant-related mortality by the treating physician based on intensity of therapies received prior to HCT even though none of the patients were reported to have renal, cardiac or pulmonary function dysfunction, poor performance score and/or more advanced disease status (beyond second CR) in some patients. There may also be several unmeasured factors that may have contributed to the selection of RIC for allo-HCT in these children. In this context, these data lend support to the notion that RIC regimens can expand HCT options for children and adolescents otherwise unsuitable for dose-intensive myeloablative conditioning who would succumb to their disease with chemotherapeutic regimens alone.
One of the perceived benefits to RIC has been the lower TRM relative to traditional dose-intensive conditioning. We observed TRM rates (19% at day-100 and 32% at 3-years) consistent with other reports describing outcomes for RIC with adult ALL, where TRM ranged from 17–40% (6
). Moreover, in these reports, there appears to be a trend for higher TRM when patients with advanced disease or chemotherapy refractory leukemia are included. The high rate of TRM in our study sharply contrasts with the only other large multicenter pediatric RIC study were TRM was much lower (11%) (14
). This difference might be explained by the use of a uniform conditioning regimen in the report by Pulsipher and colleagues (14
), together with the fact that transplants were carried out in a more contemporary era than this analysis which spanned over a decade. Interestingly, Pulsipher and colleagues report relapse rates of 43% at 2-years which are higher than that observed in the current analysis. This may in part be attributed to the inclusion patients who had failed prior transplantation and at higher risk for recurrent leukemia compared to the population in this analysis. TRM is the competing event for relapse and TRM is expected to be low when recurrence rate is high.
Although RIC regimens are commonly used for adults with chronic leukemia and low to intermediate grade lymphoma (3
), a major concern with using RIC regimens for pediatric ALL is the faster growth kinetic of ALL that might result in higher relapse rates. This concern is, perhaps, magnified by the fact that RIC relies mainly on immunological mechanisms for eradication of disease (i.e., GVL) and yet, post-HCT adoptive immunotherapies designed to exploit GVL, like infusions of donor lymphocytes or NK cells have been disappointing for treating relapsed ALL (4
). However, in the current study, the relapse rate at 3-years was 38% which is comparable to that after dose-intensive myeloablative conditioning regimens in children with ALL (2
) and to that reported after RIC allo-HCT in adults with ALL (6
). Most patients in the current analysis were in second or subsequent CR or had active disease at HCT, and despite the relatively high relapse rate, one third of the patients are alive and disease-free which supports the notion that sustained remission in ALL can also be achieved in children after RIC and allo-HCT. Given the relatively small numbers of patients in the current analysis these findings must be validated in a larger series. Further, the relatively small numbers of patients prevented us from examining for an effect of acute or chronic GVHD on relapse in the current analysis. Nevertheless, a potent effect of acute GVHD in reducing relapse in children with ALL receiving unrelated donor transplants after dose-intensive myeloablative conditioning has been reported, suggesting a role for immune based mediation of relapse risk (20
). Similarly, lower doses of immune suppression (cyclosporine A) after transplantation have been associated with relapse protection in ALL (21
). In some studies adoptive transfer of donor lymphocytes can reverse rising host chimerism associated with minimal residual disease (23
). As well, an association between chronic GVHD and sustained remission following RIC and allo-HCT has been reported for ALL (11
). Taken together, these reports support the assertion that ALL is sensitive to a GVL effect (24
Despite the small numbers of patients and their heterogeneity with respect to performance score, disease status at HCT and donor source, this is the first report on use of RIC regimens for pediatric ALL. All children received RIC and allo-HCT as their first transplant. The observed 3-year DFS rates are comparable to those after dose-intensive myeloablative conditioning regimens and allo-HCT. While our observations must be interpreted with caution, the modest success reported herein offers a potentially life-saving treatment option to children who may otherwise not be eligible for allo-HCT. Only a clinical trial that uses a uniform RIC regimen, GVHD prophylaxis and donor-graft source can further establish the role of RIC allo-HCT for pediatric ALL.