Jun 20, 2021
Venetoclax in combination with FLAG-IDA chemotherapy shows safety and promising efficacy in both untreated and relapsed/refractory AML in this phase 1b/2 study, providing a strong rationale for phase 3 trials incorporating this agent in patients fit for intensive therapy.
TRANSCRIPT
This JCO Podcast provides observations and commentary on the JCO article “Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia” by DiNardo et al. My name is Richard Dillon, and I am a Clinical Senior Lecturer in Cancer Genetics at King’s College London and Consultant Hematologist at Guy’s Hospital, London, UK. My oncologic specialty is Adult Acute Myeloid Leukaemia. I'd like to note that my institution receives research funding support from Abbvie.
The recently published VIALE-A and VIALE-C trials demonstrated significant efficacy of venetoclax when added to low dose chemotherapy in patients with newly diagnosed AML who cannot receive intensive chemotherapy due to their age or comorbidities. Venetoclax has now become the standard of care for these patients, and there is growing interest in investigating how the potent anti-leukemic efficacy of this agent can be exploited in younger patients, who are fit to receive intensive treatment with curative intent. To date, only a small number of studies have addressed this important question.
In the front-line setting, a phase 1b study performed in Australia by Chua and colleagues tested the addition of 14 days of venetoclax to a regimen consisting of 7 days of infusional cytarabine and two doses of idarubicin for patients aged over 65 with previously untreated AML. This was well tolerated, and the overall response rate was 72%: 97% in patients with de-novo and 43% in patients with secondary AML.
Karol and colleagues from St. Jude’s Children’s Hospital performed a phase 1 study testing the combination of 28 days of venetoclax with varying doses of cytarabine and idarubicin in children with relapsed or refractory AML. At the recommended phase 2 dose, which was 600mg of venetoclax and eight doses of 1000mg per square meter cytarabine, with or without idarubicin, the overall response rate was 70%. Importantly, for children who received a lower dose of cytarabine (20 doses of 100mg per meter square), the response rate was markedly lower at 33%.
In the study referred to in this podcast, DiNardo and colleagues combined venetoclax with the FLAG-IDA regimen. FLAG-IDA is an intensive chemotherapy schedule incorporating high-dose cytarabine, typically used for patients with refractory or relapsed AML. And in this setting, overall response rates between 50 and 60% have been reported. FLAG-IDA has also been used in patients with newly diagnosed AML—for example, in the UK NCRI AML15 study, where the overall response rate was 86% and 5-year overall survival was 44%.
The current study comprised a phase 1b dose escalation in patients with relapsed or refractory disease, followed by a phase 2 dose expansion in both newly diagnosed and relapsed or refractory patient cohorts. In total, 68 patients were treated with the venetoclax FLAG-IDA combination. As expected, this combination was severely myelosuppressive, and during the dose-escalation phase, a number of alterations were made to the schedule to mitigate this toxicity, including reductions in the cytarabine dose to 1.5g per meter square and the length of venetoclax treatment to two weeks in induction and one week in consolidation. With these modifications, hematological toxicity at the recommended phase 2 dose was manageable. The time to count recovery was 31 days for previously untreated patients and 37 days for patients with relapsed or refractory disease and was not prolonged in patients who had undergone previous allogeneic stem cell transplantation. Haematological toxicity was more severe in the second cycle of treatment with 59% of patients experiencing delayed count recovery beyond day 45. Nevertheless, day 60 mortality was low at 4.4%.
The response rates observed in this study were impressive. At the recommended phase 2 dose, 97% of newly diagnosed and 70% of relapsed or refractory patients had achieved a composite complete remission, which included CR, CRi and CR with partial hematological recovery, CRh. CR or CRi was achieved in 72% and 48%, and MRD negativity by flow cytometry was achieved in 89% and 48% of patients with newly diagnosed and relapsed or refractory disease, respectively.
Although the number of patients was too small to reliably identify molecular and cytogenetic groups with a differential response, patients with relapsed or refractory AML with genotypes previously reported to be particularly sensitive to venetoclax containing regimens, which are NPM1, IDH1 and IDH2, appeared to have a particularly high rate of response with a composite CR rate of 100% and 12-month overall survival rate of 83%. In addition, the 7 patients with MLL rearrangements appeared to do particularly well, with a composite CR rate of 100% and 80% of patients testing negative for MLL fusion transcripts by PCR. One-year overall survival in this group was 80%, possibly highlighting MLL-rearranged leukemias as an additional group with particular sensitivity to BCL2 inhibition. This signal was not apparent in earlier trials using low doses of chemotherapy, perhaps because MLL rearrangements are much less frequent in older adults, or alternatively perhaps because this lesion requires higher doses of chemotherapy to synergise with BCL2 inhibition to overcome the apoptotic threshold.
On the other hand, there appeared to be some groups with less favorable responses. Patients with core-binding factor leukemias appeared to do less well than expected, with a median overall survival time of 7.6 months. Patients with these leukemias were excluded from the earlier phase 2 and 3 studies of venetoclax, so there is no prior clinical data regarding their sensitivity to BCL2 inhibition; however, this finding does concur with in vitro data suggesting a lack of sensitivity.
The outcomes for patients with TP53 mutations were disappointing with a median overall survival time of 9 months for newly diagnosed and 7 months for relapsed patients. Interestingly, even in the four TP53-mutated patients who tested MRD negative by flow cytometry, the TP53 mutation was still detectable by next-generation sequencing after treatment. The number of patients in these groups were small and will require confirmation in larger studies; however, alternative treatment strategies might be required for these patients.
Overall, these results appear extremely promising and suggest that venetoclax may have significant activity when used with intensive induction or salvage chemotherapy schedules in younger adults. This now needs to be confirmed in randomized trials comparing intensive chemotherapy with and without venetoclax in both the front-line and salvage settings. If these trials are positive, further comparative studies will be needed to define the best chemotherapy schedule to combine with venetoclax. While limited data indicate that standard doses of cytarabine are likely inadequate, the optimal dose of cytarabine, and the additional value of fludarabine and anthracyclines remains to be defined. Nevertheless, the study by DiNardo and colleagues represents a significant step forward in the deployment of venetoclax in young fit adults, with the hope that this will increase the rate of long-term cures from this aggressive and frequently fatal hematological malignancy.
This concludes this JCO Podcast. Thank you for listening.