Transplantation for adult ALL–typing and timing

Comment on Hunault et al, page 3028

Adults with acute lymphoblastic leukemia (ALL) can enjoy improved survival with sibling marrow transplantation as shown in this issue of Blood. Given the heterogeneous nature of this disease, and advancements in transplantation and nontransplantation strategies, the immediate questions are how to apply these therapies and to whom.

Some of the earliest studies in marrow transplantation showed that adults with ALL could experience improved outcomes relative to conventional chemotherapy, an advantage sometimes disputed by retrospective comparisons.¹  Analogous to large prospective trials in patients with acute myeloid leukemia (AML), several studies have assessed the relative value of matched sibling allogeneic marrow transplantation for adult ALL compared with conventional chemotherapy and/or autologous transplantation.¹  These studies have been somewhat heterogeneous in composition and design, though patients receiving allogeneic transplants typically have the best outcomes.

Against this backdrop, Hunault and colleagues report outcomes from the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) trial initiated in 1994 for adults with high-risk ALL, comparing early consolidation with matched sibling marrow transplantation for those younger than 50 years with delayed salvage with autologous marrow or peripheral blood stem cell (PBSC) grafting at first relapse for those without donors or older than 50 years. They also assessed the utility of interferon maintenance therapy after autologous transplantation. The Groupe Ouest-Est des Leucemies Aigües, Lymphoblastic trial 02 (GOELAL02) study targeted a population previously identified as high risk that included at least non–T-cell phenotype, age older than 35 years, leukocytosis, no complete remission (CR) after a single induction, or the presence of t(9;22), t(4;11), and t(1;19) translocations. Their results show in a convincing fashion that for this particular population, there is significant improvement in both disease-free and overall survivals for patients receiving matched sibling marrow transplants. The trial was well designed and executed with reasonable compliance for a multicenter trial. Induction responses and early mortality appear consistent with other published series in this population. Though intervals from remission to allogeneic transplantation are broad, this is not unexpected and somewhat mitigated by the intent-to-treat analysis. While the sample size of 198 appears adequate for comparing the randomized cohorts, it is probably not substantial enough to assess impact of other clinical or biologic prognostic variables. The number of patients randomized to interferon maintenance after autologous transplantation was small, and disappointingly, but not surprisingly, there was no apparent benefit.

Would the autologous group have done better if patients had undergone transplantation earlier? Data from the earlier French Leucemies Aïgue Lymophoblastique de l'Adulte (LALA87² , LALA94³ ) and the Bordeaux-Grenoble-Marseilles-Toulouse (BGMT⁴ ) cooperative studies suggest that this is not the case, with patients receiving early autologous transplants doing worse than those who underwent matched sibling transplantation.^2-4  This is also the second prospective trial showing no benefit with available immune modulators such as interferon or interleukin-2 after autologous transplantation,⁴  so that identification of effective maintenance for those patients without an allogeneic donor remains an important area of future study.

The relevance of clinical trials designed and performed years earlier must be viewed within the context of contemporary prognostic variables and treatment strategies. Despite the obvious clinical differences observed in the GOELAL02, we should be careful applying those results to current standards. For patients with Philadelphia chromosome–positive (Ph⁺) adult ALL, the availability of imatinib mesylate as adjunctive therapy as well as the ability to assess levels of minimal disease has potential to significantly alter therapeutic strategies. With this is mind, it is uncertain whether removing Ph⁺ patients from the GOELAL02 population would enhance or dilute the early allogeneic effect. It also remains unclear if there is any role for autologous transplantation in patients with Ph⁺ disease. Nonetheless, given the GOELAL02 patient mix, the most relevant questions are whether the allogeneic effect of matched sibling marrow can be duplicated with other allogeneic sources such as unrelated marrow,^5,6  PBSCs, or umbilical cord blood and whether older patients would derive similar benefit from reduced-intensity allogeneic transplantation strategies. The latter is especially relevant given the observed adverse impact of increasing age.

Ultimately, without pretransplantation identification and stratification of current prognostic indicators, it is unclear which patients will benefit most from allogeneic transplantation. Results of the French Cooperative Group for Research on Adult Acute Lymphoblastic Leukemia and substantially larger transatlantic Medical Research Council–Eastern Cooperative Oncology Group⁷  trials are eagerly anticipated and should help answer some of these questions. ▪