Pediatric Acute Lymphoblastic Leukemia: Is There Still a Role for Transplant?

One of the most extraordinary achievements in the treatment of cancer has been the steady improvement in the survival of children with acute lymphoblastic leukemia (ALL) over the last 40 years. Most children with ALL are now cured, and are cured without the need for transplantation. Success has been achieved by a series of large-scale, multi-center clinical trials demonstrating the value of discipline and cooperation in investigating and treating a rare disease. The key elements of progress in the treatment of ALL have been dose intensification and risk stratification in an attempt to optimize and personalize, to some degree, the administration of therapy in the context of national clinical trials conducted worldwide. Despite these successes, there remains room for improvement. Approximately 460 children (0–14 years of age) died of ALL in the United States in 2009, making ALL the most frequent cause of death for children with cancer.

The question, “Is there a place for transplant in childhood ALL” must be asked often as progress continues. Transplant is clearly only appropriate for children unlikely to be cured with chemotherapy, and identifying these children requires knowledge of current outcomes with chemotherapy, of ALL biology as applied to prognosis, and of likely transplant outcomes. We must use the best and most current data to estimate prognosis to ensure that only the children who will benefit are transplanted. Knowledge of the most current clinical trials and reports and biology should allow us to select the best donor and the best transplant strategy to optimize survival.

The prognosis of newly diagnosed children with ALL has improved such that few children with ALL will now benefit from transplant in their first complete remission (CR1). Age and white count at diagnosis (National Cancer Institute [NCI] criteria) have been used to predict prognosis in ALL for many years, having been identified in early epidemiologic studies as predictors of outcome.¹  Infants were identified early on as having a particularly poor prognosis, and historically have been considered candidates for transplantation at the first remission, because early relapse was a major cause of failure. Chemotherapy has been intensified in recent studies (POG 9407 and CCG 1953), and this strategy improved survival significantly once the need for intensive supportive care and prolonged hospitalization was understood.^2,3  In current US studies, infants under 1 year of age are generally not considered to be candidates for transplantation in CR1—infants with germ-line mixed lineage leukemia (MLL) or those over the age of 90 d with an MLL rearrangement have expected survival in the range of 50% or better—a result unlikely to be bettered by transplantation. In addition, the best transplant results are obtained with the use of radiation, raising concern of late effects in very young children. A small group of babies less than 90 d old at diagnosis and with a rearrangement of MLL continue to have poor survival (event-free survival [EFS] less than 25%), but a great deal of the excess mortality is due to death from early toxicity or very early relapse, and neither of these problems is likely to be improved by transplant. This is an excellent group of patients for the inclusion of novel therapies in front-line treatment, and such studies are ongoing.

Early clinical trials examining the effect of age on prognosis have suggested inferior outcomes for older children and adolescents with ALL, and in particular for young adults 16 to 21 years of age, who fall between the pediatric and internal medicine age groups, leading to some young adults being transplanted in CR1 per typical adult practice. Intensive “pediatric-type” chemotherapy gives this group of patients 5-year EFS in excess of 70%, so transplant can likely be reserved for CR2 in young adults as in most children.⁴ 

Further risk stratification has been achieved using cytogenetic and molecular genetic characterization of leukemia, and has allowed relative therapy reduction in children with leukemia with a good prognosis (e.g., the TEL-AML1 translocation and hyperdiploidy), and the application of novel therapies to those with a poorer prognosis (e.g., Philadelphia- chromosome-positive [Ph+] ALL).⁵  Tyrosine kinase inhibitors have completely changed the landscape of therapy for chronic myeloid lymphoma, and have the potential to do so for Philadelphia positive ALL. Historically, children with Ph+ ALL and a matched sibling donor have been transplanted in CR1. A Children's Oncology Group Study (AALL0031) incorporated an escalating dose of imatinib with chemotherapy before maintenance therapy,⁶  while patients with a matched sibling donor received a transplant. Continuous imatinib exposure improved survival in the children receiving the highest dose of imatinib, with a 3-year EFS of 80%, more than twice that of historical controls (35%). Outcomes in children receiving chemotherapy plus imatinib (3-year EFS of 88%) were not statistically different from those in children receiving imatinib and a matched sibling donor transplant (3-year EFS of 57%) or an alternative donor (off study; EFS of 71%). Imatinib appeared to improve survival by improving the outcomes of children with a higher burden of minimal residual disease (MRD) and also those in the highest-risk group, the small number with induction failure. The follow-up of this study is not yet complete, but no relapses after completion of therapy have been reported. While it remains possible that the addition of imatinib could have delayed but not prevented relapse, these data encourage the hope that the leukemia has been eradicated without the need for transplant, and that remissions will be sustained. Subsequent studies will explore the role of newer tyrosine kinase inhibitors. These data suggest that transplant is no longer routinely needed for Ph+ ALL in CR1.

Risk stratification for ALL using NCI criteria and molecular and cytogenetic markers, which are available in clinical laboratories and have a short turnaround time, plus careful assessment of response to induction therapy, allows risk-adapted therapy to avoid the overtreatment of children with a good prognosis. Despite this, because most children fall into standard- or intermediate-risk groups, the majority of children who relapse do so after assignment to standard risk groups. Additional strategies to identify at diagnosis those destined to relapse would allow for the intensification of chemotherapy or early transplantation to improve outcome. MRD, which is measured using flow cytometry or molecular techniques, clearly identifies children with suboptimal responses to therapy.^7,8  MRD can be used to identify the small subset of children with primary induction failure and a poor prognosis based on MRD who may be candidates for transplantation in CR1.

MRD measurements can also serve as a guide to the effectiveness of chemotherapy prior to transplantation in children in CR1 or beyond, because outcomes of transplantation are clearly improved in those with the lowest disease burden at the time of transplant.^9,10  MRD post-transplantation is clearly undesirable and predicts relapse, and can serve as a trigger for interventions such as reduction or withdrawal of immune suppression or donor-lymphocyte infusion, although the efficacy of these strategies remains suboptimal.

Increased precision in risk assignment at diagnosis might in the future be achieved using array-based analyses. Current data are of great biological interest, but interpretation is somewhat limited by the use of different and evolving platforms for analysis in different studies. Further, it is unclear whether these strategies augment MRD as a prognostic tool rather than identifying the same subset of children with reduced prognosis using a different technology, although it may be hoped that in the future these studies will identify novel subsets with a poor prognosis.^11–15 

Children with B-lineage leukemia who relapse are typically considered for transplant. The median time to relapse in US Children's Oncology Group studies is 36 months, and prognosis depends on time to relapse.¹⁶  Children relapsing early (before 36 months) have a poor prognosis and transplantation should be considered for all of them. Similarly, children with a bone marrow relapse of T-lineage ALL at any time have poor outcomes and should be considered for transplant. The best approach for children with B-lineage disease with a late relapse (beyond 36 months) is less clear-cut, because a significant proportion can be cured with further chemotherapy, in particular those with very late relapse. Some children with ALL will have relapses many years (8 or more) after therapy, and careful consideration should be given to whether this is a true relapse or a second leukemia in a susceptible person who has perhaps retained a premalignant population of cells (e.g., with a TEL-AML translocation), leaving them at risk for a new malignancy with similarities to the initial leukemia.¹⁷  These children will do well with further chemotherapy.¹⁸ 

Conventional advice has suggested that children with relapse beyond 36 months should be transplanted if they have a matched sibling donor but not with an alternative donor. Advances in donor selection and transplantation of cord blood may render this advice obsolete as outcomes with unrelated donor stem-cell sources become similar to those obtained with genoidentical donors; the issue of donor selection is discussed further below. When outcomes are predicted to be equivalent with transplantation and chemotherapy, alternative issues sometimes dictate the choice of therapy; for example, adolescents close to leaving home may prefer transplantation rather than prolonged chemotherapy extending into the college years. Poor tolerance of prior chemotherapy or concerns regarding compliance in children moving beyond parental control will also sometimes drive preference for transplantation.

Transplants performed beyond the second complete remission (CR2) usually involve unrelated donors because children with matched sibling donors are commonly transplanted in CR2. Nemecek et al. reported Center for International Blood and Marrow Transplant Research (CIBMTR) data regarding the outcomes of 155 unrelated donor transplants performed between 1990 and 2005 for children with ALL in the third complete remission (CR3) in abstract form in 2010.¹⁹  The 5-year leukemia-free survival was 33% for the children with a second relapse 26 months beyond the first, and 26% for those with a second relapse less than 26 months after the first. While less than optimal, these data are perhaps better than might be expected, and indicate that in a proportion of children with multiply relapsed ALL, later retrieval is possible. Interestingly, the median time to first relapse of this group was 35 months, very similar to that reported by the CCG 1953 study (36 months), indicating that this is not a physician-selected group of late relapsers with a better prognosis, but may be representative of the population of children with relapsed ALL. Further analysis of the characteristics of the predictors of survival in this group will be instructive in guiding future practice.

Historically, outcomes of unrelated donor transplantation have been inferior to outcomes of sibling donor transplantation, and recommendations for transplant for ALL have differentiated between those with and without a matched sibling donor. However, the outcomes of unrelated donor transplant have improved markedly in the last years, likely due to improvements in HLA-typing, a larger donor pool, and improved supportive care.²⁰  Studies have reported similar survival after unrelated donor transplants (cord blood and adult donors), suggesting that no differentiation need be made and transplant should be offered uniformly to those with a well-matched donor.²¹  One caution regarding this approach is that while survival may be the same, the incidence of acute and chronic graft-versus-host disease (GVHD) may be increased with donors who are phenotypically, not genotypically, matched. Chronic GVHD has an important impact on late quality of life, but the incidence of severe and prolonged chronic GVHD may be less in young children than in older populations.

The impact of increased acute GVHD on relapse risk in ALL remains a controversial topic, because evidence for an important graft-versus-leukemia (GVL) effect has been at best mixed over the years, with generally poor responses to donor lymphocyte infusions.²²  Recent analysis of a large pediatric unrelated donor cohort showed decreased risk of relapse in children who developed acute GVHD, supporting the belief that there is a benefit of GVHD in disease control.²³  Biological studies of 10 patients with ALL receiving T-depleted sibling donor transplants at the National Institutes of Health showed evidence of a CD8+-mediated allogeneic response directed toward the WT1 antigen.²⁴  The possible role of KIR (killer immunoglobulinlike receptor) mismatch in control of ALL has also been controversial. Early studies showed a benefit of KIR mismatch as imputed from HLA typing in acute myeloid leukemia (AML), but not in ALL.²⁵  Additional studies using more direct measurement of KIR genotype and phenotype (a receptor-ligand model) support an important biological effect in vitro and in vivo.^26,27  In contrast, other clinical studies have shown no impact of KIR mismatch, and variability in the methodology used to determine KIR incompatibility and in transplant technique, particularly the degree of T-cell depletion, all contribute to the lack of clarity. Currently, there is insufficient evidence to recommend selection of KIR-mismatched donors in children with ALL.

The increased mismatch associated with unrelated donors might be associated with the hope that it will bring with it more GVL than sibling donors. Unfortunately, a recent CIBMTR analysis does not support this hope for AML or ALL.²⁸  However, this is a separate issue from the hope that GVL might be an alternative method to control leukemia that has already proven itself by virtue of relapse to be resistant to chemotherapy. The effectiveness of GVL after cord blood transplant has been a concern in light of the generally reduced incidence of GVHD, however, clinical studies have not demonstrated increased relapse associated with the use of cord blood compared with sibling or unrelated donor transplants.^21,29  Adding another layer of complexity, a preliminary study comparing single-cord-blood transplant with double-cord-blood transplant suggested reduced relapse with the latter.³⁰  The mechanism of such an effect is unclear, although the incidence of acute GVHD was higher in recipients of double-cord-blood transplants, and these two observations may be related. This initial study included mostly adults in the double-unit group and mostly children in the single-unit group because assignment was based on available cell dose, complicating interpretation of the data. A prospective Blood and Marrow Transplant Clinical Trials Network pediatric study is investigating this question further.

If GVHD improves disease control, then peripheral blood stem cells might be expected to improve survival in those with the most refractory disease. However, any benefit from disease control must be weighed against increased treatment-related mortality, and current data indicate decreased survival associated with the use of peripheral blood stem cells compared with bone marrow in children and adolescents, and no decrease in relapse in a pediatric population with acute leukemia.³¹  In this analysis of registry data, the main cause of increased mortality was increased chronic GVHD, and it is notable that use of peripheral blood stem cells was not associated with an increased risk of acute GVHD.

Available data indicate that the inclusion of radiation in the preparative regimen is a key element in the treatment of ALL, and that, by and large, higher doses are better than lower doses.^16,32,33  In a comparison of children in CR2 treated with chemotherapy or with transplant, outcomes were only improved in the transplant group who received total body irradiation, and there was a trend toward outcomes inferior to those achieved with chemotherapy in children transplanted after a chemotherapy-only preparative regimen.¹⁶  The inclusion of total body irradiation in the preparative regimen is clearly associated with significant late effects, which are accentuated in pediatric populations, increasing the reluctance to transplant very young children in particular because of concerns regarding long-term growth and cognitive function.^34–39  Perkins et al. evaluated 13 children who were transplanted under the age of 3 years (range, 0.58–2.93 years), with follow-up between 3 and 22 years; 11 of these children had received total body irradiation.⁴⁰  All had IQs in the normal range, although other consequences of TBI such as hypothyroidism, hyperlipidemia, second malignancy, growth hormone deficiency, osteochondromata, and decreased bone mineral density were frequent. These data indicate that total body irradiation can be considered for young children with ALL, although careful follow-up and management of remediable late effects is essential. Similarly reassuring data regarding cognitive and academic function and late long-term satisfaction with health come from other studies, and should be helpful to parents for whom decline in cognitive function related to therapy is an understandably daunting prospect.⁴¹ 

The use of reduced-intensity transplant in ALL has lagged behind that in AML, with enthusiasm limited by the mixed evidence for any benefit of allogenicity in disease control in ALL and by concerns of disease progression in the period of establishment of donor hematopoiesis. Reduced intensity transplant is now being explored in adults with ALL, and is clearly feasible, although more detailed analyses of patients likely to benefit are ongoing.^42–44  Pediatric experience of reduced intensity transplant for ALL remains limited, because most children are able to tolerate myeloablative therapy. Verneris et al. have described 38 reduced-intensity pediatric transplants for ALL reported to CIBMTR, with 30% EFS.⁴⁵  However, in registry studies it is hard to ascertain the reason that reduced-intensity conditioning was used and what comorbidities might have been present, so further studies are needed to determine if this is a viable option for disease control.

Outcomes of chemotherapy for pediatric ALL patients are constantly improving. Indications for transplantation change constantly, in particular when novel therapies such as tyrosine kinase inhibitors change the landscape for particular diseases, so it is incumbent upon transplant physicians to follow carefully the data regarding outcomes of chemotherapy. The vast majority of important changes in therapy or in the prediction of prognosis in pediatric ALL patients come from cooperative group studies, and it is important that potentially practice-changing data are shared as early as is safe and as widely as is possible to allow practitioners to remain current in their selection and referral of children for transplantation. The arena of donor selection is also changing rapidly, and very significant improvements have taken place in the last 10 years, both in the size of the donor pool and in methods for selecting the best-matched donor. It is also important that these data are shared and widely known. While incremental improvements in the results of chemotherapy and in donor selection and supportive care are likely to continue, the next big change in the landscape is likely to come from biological studies that will allow us to identify children at diagnosis who are highly unlikely to be cured with chemotherapy alone and need alternative therapy. Whenever high-risk groups are identified, it is then important to demonstrate whether transplant does improve survival, because this cannot be assumed to be true. It is also possible that there is a subgroup of children who will benefit from neither conventional chemotherapy nor allogeneic transplantation, for whom novel therapeutics may offer the best hope for cure.

Conflict-of-interest disclosure: The authors declare no competing financial interests. Off-label drug use: None disclosed.

Stella M. Davies, MBBS, PhD, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45230; Phone: (513) 636-1371; Fax: (513) 636-3459; e-mail: Stella.davies@cchmc.org