Despite the success in treating the majority of children with newly diagnosed ALL, effective treatment strategies for marrow relapse have been elusive. The challenges begin early in therapy with a significant number of reinduction failures, particularly when disease recurs early. Moreover, when remissions are achieved, they are less durable as evidenced by reports of subsequent relapses in up to one third of patients within the median time to alloSCT.2
The primary objective of the AALL01P2 study was to develop a reinduction regimen for marrow relapse that was safe and feasible with the intention of later using this regimen as a platform to combine with promising new agents. Because second remissions are frequently short lived, the study used three nonoverlapping blocks of chemotherapy in an effort to achieve deeper remissions. The chemotherapy combinations used in these blocks had previously been defined to be active in the relapse setting.14,18,19
This study was also designed to monitor MRD sequentially after each treatment block to help assess the relative efficacy of individual blocks.
Patients on this study were randomly assigned upfront to two different block orders to determine if the sequence of therapy influenced outcomes. There were no significant differences in outcome between arms A and B and because of greater toxicity associated with blocks 1 and 3 compared with block 2, we have elected to use the 1, 2, 3 block order going forward. Protocol therapy consisted of the three-block reinduction only. Postinduction therapy varied and was at the discretion of the treating physician, precluding any comparisons between ongoing chemotherapy and alloSCT.
When this study first opened, toxicity in block 1 was too high, prompting substitution of doxorubicin and prednisone for idarubicin and dexamethasone (as in the POG-9310 regimen).3
After this modification, the toxic death rate of 4.0% was similar to the 3% to 8% rates seen with other regimens.1,3,5,12,23
Other toxicities were manageable with infectious complications occurring most commonly. The incidence of fever and neutropenia and documented infections was highest during blocks 1 and 3, and similar to the incidence observed with other regimens of similar intensity.12
Despite the toxicities, the median time for completion of each block of therapy was very close to the scheduled 36 days.
Remission reinduction rates with this regimen were 68% for ER and 96% for LR. Patients with very early relapse (< 18 months) fared exceptionally poorly with CR2 rates of only 45%. These results are very similar to what has been consistently reported in the literature: 66% to 82% for ER and 90% to 95% for LR. 2-8,10,11,15,23-25
Even when intensive salvage strategies including alloSCT are employed, longer-term EFS rates for ER are only 10% to 20%, compared with 40% to 50% for LR.2,5
It is striking that these outcomes have been remarkably consistent over recent decades, irrespective of differences in the components of salvage regimens.
In addition to timing of relapse, blast immunophenotype and site of relapse are both important prognostic variables. Historically, patients with T-cell relapse have fared poorly.2,5,26,27
In a recent report by St Jude Children's Research Hospital, CR2 rates for this population were 60%, with a 5-year EFS of only 5%.25
Although the number of T-cell patients on this study was very small, this therapy was ineffective for this group: five of seven patients experience reinduction failure and there were no survivors.
Isolated marrow relapses are the most challenging to treat, whereas isolated extramedullary relapses have more favorable outcomes and combined relapses have an intermediate prognosis.24,28
Patients with combined relapses on this study had CR2 rates and a 12-month EFS probability which were similar to patients with isolated marrow relapses. However, there were only 14 patients with combined relapses on this study, limiting comparisons in outcomes.
Our results highlight several important points about MRD in trials of relapsed ALL. First, the rates of MRD positivity are much higher than observed in first-line ALL clinical trials. Using the same methodologies, 26% of children with newly diagnosed high-risk ALL that received a four-drug induction regimen were MRD positive at end induction, versus 62% of relapsed ALL patients in this trial.29
Second, as previously demonstrated in the relapse setting,30,31
early MRD response was a strong predictor of outcome. The absence of MRD at the end of the first month of reinduction therapy portended better outcomes in all patients, and separately in ER and LR patients. The combination of timing of relapse and MRD appeared to identify three groups of patients. ER patients who were MRD positive had a dismal outcome, while LR patients who were MRD negative had an excellent outcome, approaching that seen in newly diagnosed patients. MRD-negative ER patients and MRD-positive LR patients appeared to form an intermediate group. These data suggest that MRD may be helpful in stratifying salvage therapy in the near future.
The kinetic pattern of MRD in patients showed continued regression in disease burden with subsequent blocks of therapy in 40 (71%) of 56 of patients who had measurable disease at the end of the first block. These results suggest that the additional blocks of therapy are effective and contribute to the durability of the remission. Also supporting this contention is the finding that 4-month EFS probabilities on this study, which is a time point approximating time to SCT, were very similar to the CR2 rates observed at the end of block 1. Despite further reduction in MRD burden with ongoing block therapy in the majority of patients, and more durable responses during the initial 4 months, later failures occurred, suggesting that alternative postinduction therapy may be needed. Subsequent blocks of therapy appeared less effective for patients who did not achieve a morphologic CR after block 1, as those patients had dismal outcomes. These findings agree with those recently reported by Gaynon and colleagues2
where none of the nine patients with M2 marrows at the end of reinduction survived.
Taken together, several conclusions about early response and MRD can be drawn. First, three-block reinduction chemotherapy appears effective for those patients who achieve a morphological remission and are MRD-negative at the end of the first month of treatment. Second, approximately 70% of patients who achieve CR2, but have detectable MRD at the end of block 1, will have sustained remissions and further reductions in MRD with ongoing chemotherapy. Finally, patients who fail to achieve CR2 at the end of block 1, or who have persistent MRD at the end of three blocks, have exceptionally poor outcomes and may benefit from novel treatment strategies.
In summary, the AALL01P2 study established a reinduction regimen for initial marrow relapse which was feasible to administer, with acceptable toxicity and comparable remission reinduction rates to other contemporary salvage regimens. Extending the duration of reinduction to three blocks appeared to be beneficial for the group of patients with initial favorable morphologic responses. The inferior reinduction rates and the persistence of MRD at the end of block 1 in the majority of patients highlight the urgent need for the integration of new agents into salvage regimens to reduce early disease burden more effectively. A COG phase I/II study using the anti-CD22 monoclonal antibody epratuzumab with this platform is presently underway.32
Ongoing laboratory initiatives are also seeking to define mechanisms of relapse and targeted agents of promise for incorporation into future salvage treatment strategies for this challenging group of patients.33