The Rules of the Road Have Changed: What's the Best Route to Curing ALL?

Allogeneic hematopoeitic cell transplantation (allo-HCT) historically has been the recommended course of postremission treatment for adult patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1).¹  Large prospective clinical trials (donor vs. no donor comparisons) conducted during the 1980s through early 2000s demonstrated that young adult patients with standard-risk ALL in CR1 benefited more from allo-HCT using matched sibling or matched unrelated donors following a myeloablative allo-HCT as compared to the standard adult postremission chemotherapy protocols.^2–5  This data set was bolstered further by a systematic review and meta-analysis performed using individual patient data from 13 trials representing 2,962 older adolescents and adult patients (age, 15-59 years) and compared the outcomes of allo-HCT, autologous HCT, and postremission chemotherapy.^6–7  The analysis showed a survival benefit for having a matched sibling donor for patients younger than 35 years, but not for patients older than 35 years with standard-risk and high-risk ALL, with an absolute benefit of approximately 10 percent at five years.⁶  Survival at five years for patients younger than 35 years who underwent HCT was 53.7 percent compared to 45.6 percent with postremission chemotherapy, and for patients age at least 35 years of age the five-year survival was 36.6 percent for allo-HCT versus 35 percent for post-remission chemotherapy. Since these reports were published, however, the treatment of adult patients with Philadelphia chromosome negative (Ph^-) ALL has changed in three significant ways: 1) Pediatric chemotherapy regimens not represented in the studies mentioned here are now being used for older adolescents and young adult patients up to age 40 to 50 years and may improve leukemia-free survival without allo-HCT, whereas all the studies that have contributed to the above recommendation for allo-HCT in CR1 utilized standard adult regimens (which were lower in intensity as compared to pediatric-inspired regimens) as the comparator arm of the analysis with transplant; 2) Minimal residual disease (MRD) testing is now incorporated into the risk stratification system, and it was not used in any of the trials in the 1980 to 2000 study period; 3) Novel immunotherapy has been developed to eradicate MRD and is now routinely being incorporated into front-line regimens. Therefore, with the advancement of the chemotherapy protocols and utilization of MRD assessments to predict the risk of relapse, the role of allo-HCT is now less clear and reevaluation of the criteria for allo-HCT in CR1 is an area of ongoing investigation.

Three retrospective analyses have compared the outcomes of young adult patients treated with post-remission allo-HCT or post-remission pediatric-inspired chemotherapy regimens.^8–10  Dr. Matthew D. Seftel and colleagues compared the outcomes of 422 young adult patients (18-50 years) with Ph^- ALL who underwent a matched sibling or unrelated donor allo-HCT in CR1 in the United States or Canada and reported the data to the Center for International Blood and Marrow Transplant Research (CIBMTR) to a cohort of 108 young adult patients with Ph^- ALL who received pediatric-inspired chemotherapy regimen and no allo-HCT through the Dana Farber Cancer Institute Adult ALL Consortium.⁸  Dr. Matthew J. Wieduwilt and colleagues compared the outcomes of 217 patients from an age-matched cohort who underwent an allo-HCT (matched sibling or unrelated donor) in CR1 and whose data was reported to the CIBMTR to a cohort of 263 young adult patients (16-39 years) with Ph^- ALL who received post-remission pediatric style chemotherapy on CALGB 10403 trial.⁹  Both analyses revealed that pediatric inspired chemotherapy regimens without HCT were associated with superior outcomes in terms of disease-free survival (DFS), overall survival (OS), and treatment-related mortality (Table). MRD was not used widely for the adults in the United States during the study period of 2001 to 2012, and thus did not inform either of the reported comparisons. Specifically, the role of allo-HCT versus chemotherapy in high-risk ALL patients (i.e., those with detectable MRD) could not be explored. Dr. Nathalie Dhédin and colleagues on behalf of The Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) reported their retrospective analysis of the role of HCT in 522 patients with high-risk ALL in CR1 treated on the pediatric-inspired GRAALL-2003/2005 trials, which included MRD assessments.¹⁰  Their analysis revealed no significant difference in relapse-free survival (RFS) between the HCT cohort and the chemotherapy cohorts for patients who had undetectable MRD following induction therapy. For patients with detectable MRD after induction therapy, however, RFS and OS were better for patients in the HCT cohort, suggesting allo-HCT may improve the outcomes for this subset of high-risk ALL patients.

Yet, prospective data were lacking. Dr. Josep-Maria Ribera and colleagues on behalf of the Programa Español de Tratamientos en Hematología (PETHEMA) Group conducted a prospective trial (ALL-AR-03) for adolescent and adult patients with high-risk features at diagnosis (defined as age >30 years, white blood cell count [WBC] > 30K/µL, t(4;11) or other MLL rearrangements) and used two response assessments for treatment stratification: early bone marrow response (day 14) and MRD evaluation (assessed with 4-color flow cytometry) following three cycles of intensive consolidation therapy.¹¹  Patients with a good morphologic response at day 14 of induction and end of consolidation MRD level lower than 5 × 10^-4 were assigned to chemotherapy and no allo-HCT, and patients with poor early morphologic response on day 14 and/or MRD level higher than 5 × 10^-4 were assigned to allo-HCT. Poor MRD clearance was the sole prognostic factor for survival outcomes: five-year DFS and OS were 32 percent and 37 percent, respectively, for patients assigned to allo-HCT and 55 percent and 59 percent, respectively, for patients assigned to continued postremission chemotherapy.

In the current article, Dr. Ribera and colleagues report the results of their follow-up trial, PETHEMA ALL-HR-11, which further investigates the role of HCT in high-risk ALL based on MRD response. The trial was a single-arm study conducted at 51 Spanish hospitals and enrolled 348 young adult patients (age, 15-60 years) with newly diagnosed ALL and included more stringent criteria for high-risk patients (defined as age 30-60 years, WBC > 30 × 10⁹/L for B-lineage ALL, or > 100 × 10⁹/L for T-lineage ALL, hypodiploid ALL, t(v;11q23), or KMT2A rearrangements and complex karyotype) as compared to ALL-AR-03. Another difference in this trial as compared to ALL-AR-03 was that post-remission therapy was based only on MRD assessments (utilizing 8-color flow cytometry) on day 14, as well as at the end of induction (week 5-6) and consolidation (week 16-18). The chemotherapy regimen was intensified slightly for patients who did not achieve CR or had detectable MRD, and for patients with T-ALL. as compared to ALL-AR-03. Patients who achieved CR and had MRD levels lower than 0.1 percent at the end of induction were continued on chemotherapy, whereas patients who did not achieve CR at the end of the first induction, or had an MRD of at least 0.1 percent, were assigned to receive a second cycle of induction chemotherapy, followed by allogeneic HSCT. The results of ALL-HR-11 were similar to that of ALL-AR-03: Patients assigned to chemotherapy and no transplant (i.e., those with MRD levels < 0.1%) had a five-year OS of 59 percent, while patients who were MRD-positive and underwent transplant had an inferior five-year OS of 38 percent. The five-year cumulative incidence of relapse was similar in the MRD-negative chemotherapy cohort and MRD-positive allo-HCT cohort (45% vs. 40%, respectively). Thus, the differences in survival between the chemotherapy and transplant patients were attributed to the treatment-related mortality associated with HSCT. Interestingly, there was a subset of patients (18%) who were MRD negative (<0.01%) at day 14 of induction and those patients had particularly good outcomes, with a five-year OS of 82 percent.