Although current chemotherapy regimens successfully cure 80% of children with newly diagnosed ALL, substantial numbers of patients experience relapse and have poor outcomes. Though most patients experiencing relapse achieve remission, a definitive cure continues to be elusive. As reported previously, the most important factors in survival after relapse are the site of and time to relapse.10
Of patients experiencing first relapse, 85% ± 3% achieved CR after their next treatment attempt (). For early first relapse (< 36 months from diagnosis), the CR rate was 83% ± 4% (n = 110) and for late first relapse (≥ 36 months from diagnosis), the CR rate was 93% ± 3% (n = 59). Breaking down early relapse into very early relapse (< 18 months from diagnosis) and intermediate (18 to 36 months from diagnosis), we found CR rates of 78% ± 6% and 86% ± 5%, respectively. This is generally in keeping with the reported literature in which remission rates for patients in first relapse ranged from 71% to 93%, but it is important to note that some of these data also include isolated extramedullary relapses.5,8,20,21
When further examined, the CR rate for very early and intermediate first marrow relapse also seems better in our series than those reported by Raetz et al.22
In that report, CR2 was 68% ± 6% (n = 69) for overall early relapse events, with 45% ± 11% for very early (< 18 months) relapse (n = 24) and 79% ± 6% for intermediate (18 to 36 months) relapse (n = 45).22
We were also able to assess the efficacy of subsequent therapeutic attempts and observed that there was a significant decrease in those achieving remission, with rates of 44%, 27%, and 12% for third, fourth, and further therapeutic attempts, respectively (). New agents and combinations might be assessed against this benchmark.
In this analysis, we were also able to observe patients over time through multiple relapses to assess factors contributing to subsequent outcomes. Not surprisingly, patients who did not obtain a CR with the prior therapeutic attempt had a much lower likelihood of obtaining a CR with a subsequent therapeutic attempt ( and Fig A1 [online only]). (It should be noted in Fig A1 [online only] that patients in < CR who had a high rate of achieving CR with a second therapy includes those patients with primary refractory ALL.) The duration of the prior remission remained a significant factor in predicting subsequent response ( and Fig A2 [online only]).
We found DFS for patients in CR2 to be 27% ± 4% at 5 years. These results are similar to those found in the literature, though exact comparisons are difficult as a result of different cohorts of patients analyzed with different end points (Appendix Table A2
[online only]). DFS rates ranges from 16% to 39% ± 5% depending on the study, time to end point, and the patient population.5–8,20,23,24
Though slightly different variables were measured, all the results show similar poor outcomes for patients in CR2.
Few data appear for DFS rates in CR3 and beyond. We found rates of 15% ± 7% at 5 years, whereas Chessels et al8
showed those in CR3 had survival of roughly 20% for HSCT from transplantation and 10% for chemotherapy in patients with relapse of any site. Saarinen-Pihkala et al24
found that patients in CR3 had rates (overall survival, not disease-free) of 36% for those receiving stem-cell transplantation and 15% for those receiving chemotherapy. They also showed that for patients in CR3, 10-year EFS was 28% ± 2% for patients receiving chemotherapy only. Einsiedel et al20
reported that only 12% of patients experiencing a second relapse remained in continuous CR.
We also attempted to assess the utility of HSCT. We examined HSCT as a time-dependent variable and corrected for waiting time bias. We found increased survival (hazard ratio = 0.58; P
= .003 in multivariate analysis) for patients undergoing HSCT, regardless of time to relapse or the number of prior relapses. However, we acknowledge that our study is retrospective and selection bias remains. In a small, randomized study, Gaynon et al23
found no advantage for HSCT in early relapse. Eapen et al25
found an advantage for matched sibling donor total-body irradiation–based transplantation for early marrow relapse, but not for late marrow relapse in a large registry study. Malempati et al6
examined the cohort of standard-risk patients experiencing relapse from CCG-1952 and found no advantage for HSCT for patients experiencing early or late relapse.
Historically, more than 90% of candidate new agents that enter the clinic fail to earn licensure. Those that succeed may benefit some cancers, but not others. Validated preclinical models are lacking, and unfortunately, single-agent response rates provide little guidance. One agent may have striking single-agent activity (eg, ifosfamide in rhabdomyosarcoma), yet fail to displace an older agent, namely, cyclophosphamide. Conversely, an agent may have no anticancer activity (eg, leucovorin), yet provide benefit in the proper combination, namely, sequential leucovorin followed by fluorouracil. Agents identified through the Pediatric Preclinical Tumor Panel as showing activity against specific tumors are now entering clinical trials. Hopefully, in the future, we will have a better understanding of the usefulness of the Pediatric Preclinical Tumor Panel for predicting clinical activity.26
Another potential challenge in evaluating the utility of such therapies is how to optimally assess efficacy at an earlier time point other than survival. This would allow a more rapid selection of potentially effective agents. Efficient drug development requires early recognition of winners and losers. A variety of multidrug regimens provide a 40% CR rate in second and subsequent relapse.27
Review of TACL data support this surprisingly uniform benchmark. We hypothesize that candidate agents are best tested in combination, and successful combinations should have CR rates surpassing the 40% benchmark.
Minimal residual disease (MRD), measured either by flow cytometry or polymerase chain reaction, may supplement morphologic response. Recently, Raetz et al22
showed the impact of MRD on outcomes for patients with relapsed ALL. Patients who were MRD negative at the end of the first block of chemotherapy had improved survival compared with those who were MRD positive. MRD positivity was also correlated strongly with the duration of initial remission; those patients experiencing relapse at less than 18 months from initial diagnosis had the highest proportion of MRD positivity. Furthermore, in a follow-up study evaluating the potential benefit of adding a monoclonal CD22 antibody (epratuzumab) to the reinduction platform, a greater proportion of patients experiencing early relapse were MRD negative at the end reinduction compared with historical controls, thus highlighting the possible utility of such measurements in assessing relapse therapy.28
However, MRD remains an unvalidated surrogate at present for patients with relapsed ALL who are treated with novel agents.
The TACL consortium was created to develop novel agents and regimens and bring those deserving forward quickly for testing in larger venues. We propose that agents and regimens that show no improvement over our baseline CR and DFS rates need no further study. Promising agents might be restudied with alternative partners. Response rates depend on the population actually treated. On the basis of our data, we plan to construct a model that will provide us with an expected response rate for any patient population with relapsed or refractory ALL. Future analysis of our data may yield valuable information regarding different chemotherapeutic regimens used and may identify particular regimens that have been more successful than others.