Risk-stratification of newly diagnosed childhood ALL has changed the role of allogeneic HCT for ALL in first remission.(20
) Thus allogeneic HCT for first remission ALL is generally confined to those children who are considered to be at very high risk for relapse.(22
) Children whose ALL relapses within 36 months from diagnosis and achieve a second remission usually undergo allogeneic HCT if a matched sibling donor is available. However, practice variation exists across the country and 50% of the children in our cohort with early (mostly marrow) relapse did not proceed to HCT in second remission, which would have been considered best practice. These patients lack an HLA-matched sibling and the treating physician deferred unrelated donor transplantation. For a child who does not undergo HCT in second remission but relapses and achieves a third remission, alternative donor HCT has been considered the option offering the best chance for cure, despite the limited data available. As ALL therapy continues to be risk-adapted it is reasonable to expect that pediatric referrals for alternative donor HCT to treat ALL in third remission will increase in coming years.
A randomized or prospective therapeutic study of this patient group has never been conducted, and retrospective reviews to date have been limited to small studies.(11
) Borgmann and colleagues reported on a subset of 33 children undergoing BMT for ALL in third remission in Europe from 1983 to 1995.(11
) They found that LFS was approximately 48% and NRM was 30%, with worse outcomes when second relapse occurred within six months from completion of previous therapy. In contrast, patients whose second relapse occurred later had LFS of 61%, comparable to that seen in the same study for patients who underwent HCT for ALL in second remission. Afify and colleagues reported on their single institution experience with a similar group of patients in the UK. (12
) They found that shorter duration of second remission (< 30 months) was associated with lower LFS and higher NRM. Shorter duration of remission and the presence of extramedullary disease were also associated with a higher risk of post-transplant relapse. Most recently, Gassas and colleagues reported on the Canadian experience.(13
) They found that LFS in a group of 22 children was 32% and that most leukemia-free survivors had chronic GVHD, suggesting a role for graft-versus-leukemia effect in survivors.
Our study represents the largest most comprehensive analysis to date of the outcome of children receiving unrelated donor HCT for ALL in third remission. We observed LFS rates of 30% and it was not influenced by disease characteristics, donor or stem cell source, conditioning or graft manipulation. It was of particular interest that only 26% of the cohort had well matched grafts yet HLA matching and graft source did not influence LFS. Assessment of donor-recipient HLA-matching typically requires thousands of patients to efficiently address its impact on transplantation outcomes. Consequently, donor selection practices should follow the recommendations of those reports. One caveat for the current analysis is that information on site of relapse (first and second) was not reported for a substantial number of patients. While it is possible that the relative small numbers did not allow for adequate comparison between subgroups, these results support the recommendation that patients with ALL in third remission, especially those with long intervals between first and second relapse, should proceed to HCT as soon as they achieve third complete remission with the best alternative donor available.
Relapse rates were lowest in the group of children who experienced late first relapse and late second relapse, likely indicative of more sensitive disease compared to other cohorts. We did not observe a survival advantage for patients with chronic GVHD, as suggested by other reports. (13
) However, others have demonstrated graft-versus-leukemia effects after allogeneic HCT for ALL and our inability to demonstrate this phenomenon may be explained by the relatively small sample size of patients experiencing chronic GVHD in this report.
The most sobering observation was perhaps that NRM was high in all patients regardless of time to relapse and in the group of patients with the lowest relapse risk the higher NRM negated any survival advantage. We observed NRM rates higher than those reported for patients with ALL in second remission following matched sibling or unrelated donor HCT.(5
) Forty-two percent of non-relapse deaths were attributable to organ toxicity, suggesting that the cumulative effects of pre-transplant re-induction therapies might mitigate some of the survival benefits provided by allogeneic HCT for third remission ALL. Perhaps another important message from this observation of high NRM rates after HCT in third remission ALL is to preferably transplant as many children as possible in second rather than third complete remission. Our cohort was notable for the 50% in whom first relapse occurred <36 months from diagnosis and assuming that most of these children had marrow relapses they would have met the conventional criteria for transplant in second remission. It is possible that absence of a well-matched donor might have been the reason that some children did not undergo HCT in second remission but this rationale would now be questionable given current outcomes for alternative donor HCT.
Given that reduced intensity conditioning (RIC) has now been explored for children and adults with ALL, such strategies might be considered for heavily pretreated children undergoing HCT for third remission ALL. (23
) A question for the future will be whether LFS can be improved for these children if one attempts to balance the known higher relapse rates associated with reduced intensity conditioning and the expected abrogation of higher NRM rates that follow myeloablative conditioning. Unfortunately, the observation that NRM increased in our study cohort from 19% at day 100 to 45% at 5 years does not clearly support the hypothesis that RIC approaches will necessarily offset NRM and improve survival. The second major cause of NRM in our study was infection without GVHD (18% of NRM) with 9 of the 14 deaths occurring after day 100 and suggests that delayed reconstitution of immunity might be responsible. This is not surprising because at least half of the children had received in vivo or ex vivo T cell depletion and 21% had received both forms of T cell depletion. Taken together this suggests that it will be particularly important in this high risk group to try and minimize peritransplant approaches that impede immune reconstitution and to consider also approaches that might augment infection prophylaxis. Finding the right balance might be challenging because our observation that deaths from GVHD were considerably lower compared to other reports in children with ALL is also readily explained as a benefit of these T cell depletion strategies. (7
We conclude that long-term LFS is achievable in children after unrelated donor HCT for ALL in third remission. However, transplantation in third remission is not an optimal strategy because NRM rates are high which implies that when an HLA-matched sibling is lacking then a more desirable option is transplantation in second remission with the best available alternative donor. When considering transplantation in third remission it is important to consider carefully the impact of one or more T cell depletion approaches on delayed immune reconstitution and at the very least incorporate augmented infection prophylaxis strategies. In addition, post-transplant relapse prevention strategies should be considered, with possible options being use of donor lymphocyte infusions and/or small molecule inhibitors (e.g. tyrosine kinase inhibitors) or other new agents, either prophylactically or pre-emptively triggered by the results of sensitive and specific minimal disease monitoring.