There are many incredible studies presented at this year’s annual meeting, but few are truly impactful enough to change practice and make us question our preconceived notions about fundamental principles we have been taught. The plenary presentation on the ASAP trial in acute myeloid leukemia (AML) does just that.
Funded by a non-profit group, this pivotal study questioned the utility of salvage chemotherapy prior to allogeneic transplantation in patients with AML. Do patients with AML that are relapsed/refractory following initial induction therapy need to achieve complete remission (CR) prior to proceeding with allogeneic stem cell transplant? The prerequisite of CR prior to transplant was established based on studies reporting inferior outcomes with transplant in the presence of active disease. For patients with relapsed/refractory AML, we all know that the only chance of a cure is an allogeneic transplant. However, there remained an open question on the necessity of inducing CR through intensive salvage chemotherapy before allogeneic transplant. Many of us have witnessed firsthand the toxicity that salvage-intensive chemotherapy regimens engender, and indeed this was a pivotal question worth asking!
To answer this question the non-inferiority randomized ASAP trial included patients with AML (n= 281) with either relapsed disease(~1/3 patients) or patients not in CR (~2/3 patients) following their first cycle of induction chemotherapy. Patients were randomized to either an intensive approach, consisting of salvage chemotherapy with high-dose cytarabine (3 g/m2) and mitoxantrone, or bridging chemotherapy, such as low dose cytarabine and single doses of mitoxantrone if necessary (a less intensive approach). The primary end point of this trial was “success of treatment,” defined as the number of patients in CR at day 56 after an allogeneic transplant. Overall survival was a key secondary outcome for this study.
The investigators themselves were surprised by their findings (we had the fortune of hearing this firsthand from the principal investigator, Dr. Stelljes). They found that the primary end point was similar between the two cohorts, meeting the pre-specified noninferiority margin (81% and 84% of patients met the end point in the intensive and less intensive approach, respectively). Patients with the less intensive approach proceeded with allogeneic transplant more rapidly (4 weeks) than those receiving the more intensive approach (8 weeks). Furthermore, the three-year overall survival in both cohorts (51% and 54% in the disease control and remission induction strategy, respectively) was superior to what has historically been reported for relapsed/refractory AML.
This study challenges our notion that CR (or at least attempts to induce it) are necessary prior to proceeding to transplant for patients with relapsed/refractory AML. Indeed, many of us can think of patients who might theoretically have been cured with a transplant but never received it, either because they never achieved a CR or they succumbed to treatment-related toxicities. The results of this study indicate that patients with relapsed or primary refractory AML should get to transplant ASAP!
No study is perfect, and one of the limitations of this study is its inclusion of patients who did not achieve CR after a single cycle of induction therapy, since a subset may still achieve CR after a second induction cycle. There is also a possibility that patients with florid disease were filtered out of this trial as investigators may have felt uncomfortable with patients being enrolled on a control arm with less intense therapy while awaiting transplantation. In addition, these findings only apply to a developed country with a robust transplant network, where workup for transplants is initiated right away and donor searches are deployed early. Although a variety of conditioning regimens were used (including reduced intensity), most patients received myeloablative conditioning, and hence these findings may be less relevant for less-intense regimens. The salvage regimens used did not incorporate novel agents such as venetoclax, which may also affect the generalizability of results. Although overall survival was similar between both cohorts, the trial was not formally powered for overall survival, and the primary end point was CR rate at day 56 post-allogeneic transplantation. Longer-term follow-up is required to reliably compare overall survival between the two cohorts.
Despite these caveats, we truly have a practice-changing study on our hands, and we can commend these investigators enough for the realization of this important trial. Look forward to more insightful, practice-changing studies from this group in the future, as well as secondary analyses from this work (such as financial implications and genomic subgroups that benefit the most). This will be a tough act to follow for future plenary sessions, so job well done to these investigators.
Dr. Vardell and Dr. Mohyuddin indicated no relevant conflicts of interest.
