Venetoclax Improves Upon Survival of FLAG-IDA in Patients With AML

Curtis Lachoweiz, MD

Historic research has shown that the combination of fludarabine, cytarabine, granulocyte-colony stimulating factor, and idarubicin (FLAG-ID) is an effective regimen for many young and fit patients with acute myeloid leukemia (AML), achieving composite complete response CR rates of 85% in de novo AML. FLAG-IDA may also be an effective treatment for secondary AML (sAML) or relapsed/refractory AML, which has composite CR rates of 63% and 21%, respectively.

Newer research presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition suggested that the addition of a BCL-2 inhibitor venetoclax to the FLAG-ID regimen could improve responses in the sAML or R/R populations.

The phase 1b dose-escalation study enrolled patients aged 18 years old and older with treatment naïve/newly diagnosed or R/R AML were eligible. In the phase 2 dose-expansion cohort, patients were split into 2 arms: a treatment naïve/newly diagnosed arm, and a R/R AML arm. The median ages of the cohorts were 51, 44, and 47 respectively.

At the time of the update, 62 patients had completed 1 or more cycles of treatment. Of those patients, 18% had sAML. Additionally, 66% of patients received 1-2 cycles of treatment while 34% received 3 or more cycles. Prior to therapy, 50% of phase 1b patients and 32% of phase 2b patients underwent prior allogeneic stem cell transplantation (ASCT).

In an interview with Targeted Oncology, Curtis Lachowiez, MD, a hematology and medical oncology fellow at the University of Texas MD Anderson Cancer Center, discussed the findings from the study of venetoclax added to the FLAG-ID regimen for the treatment of patients with secondary or R/R AML.

TARGETED ONCOLOGY: What set the stage for this research?

LACHOWIEZ: I think the stage was set for FLAG-IDA based on previous studies that combined venetoclax, the BCL-2 inhibitor with more od what we called low-intensity therapies like azacitidine (Vidaza) and decitabine (Dacogen) in the elderly or unfit patient population. What we saw with that combination is that the addition of venetoclax to 1 of the hypo-methylating agents led to improvements in overall survival (OS). Naturally, the next question was whether or not that improvement could also be seen in the intensive induction and consolidation arena in the patients wih newly diagnosed and R/R AML who were fit enough to receive intensive chemotherapy and potentially proceed to consolidative transplantation.

There were some early data for this, with the recently reported CAVEAT study, which was the phase 1b study that looked at venetoclax in combination with the 5+2 schedule of either idarubicin or cytarabine and it did show improvement in OS. So, I think these were some of the groundwork studies that led to the current study in its present state.

TARGETED ONCOLOGY: What were the primary objectives of the study and what methods were used to assess them?

LACHOWIEZ: The primary objectives of the study were to determine the safety and tolerability of the combination of venetoclax with FLAG-IDA induction and consolidation. We know that FLAG-IDA induction and consolidation is a very effective regimen but at the same time, it causes a significant amount of myelosuppression. It was definitely important to see whether or not we saw prolonged myelosuppression when venetoclax was added to this regimen, or if there were other toxicities that were unanticipated. The second primary objective was to determine the overall efficacy of FLAG-IDA with venetoclax in both newly-diagnosed and R/R AML populations.

There were 2 separate cohorts studied independently here. The initial study enrolled 25 in each arm, and because of favorable results, we've expanded that to enroll 50 in each arm. The phase 1b portion of the study, the safety and efficacy portion, used a 3 x 3 dose escalation and de-escalation design, which is a standard approach to safety and efficacy study. The phase 2 portion of the study used a Bayesian approach to determine efficacy and futility.

TARGETED ONCOLOGY: What did the results show?

LACHOWIEZ: First of all, for the phase 1b portion did show us that FLAG-IDA is a tolerable regimen and does have a safety profile that is acceptable. There was profound myelosuppression with the combination so, it's a regimen that must be used carefully. Part of FLAG-IDA is the administration of growth factor support. Judicious use of growth factor supports as well as surveillance for infections and monitoring of peripheral blood counts are necessary.

The most common adverse events that we saw were those that are anticipated in patients with myeloid malignancies who receive intensive induction regimens. So, it included febrile neutropenia, pneumonia, bacteremia, and sepsis. There was a protocol amendment that reduced the duration of venetoclax in induction from days 1 through 21, to days 1 through 14, and it also reduced the dose of cytarabine from 2 grams per meter squared to 1.5 grams per meter squared. This was because a number of the phase 1b patients that were initially enrolled had infectious grade 3 or 4 infectious complications.

After the protocol amendment, reducing the venetoclax duration and the dosing of cytarabine, we still saw infectious complications, albeit at a lower rate. This demonstrates to us that this is a safe combination and is tolerable. Then in the efficacy portion of the study, we saw very favorable response rates both in newly-diagnosed and R/R groups. We saw an overall response rate of 97% in the newly-diagnosed population with a composite CR rate of 90% in the R/R population as a whole. This included several cohorts. This was the phase 1b dose-finding cohort and then a phase 2b cohort that was treated at what we considered the recommended phase 2 dosing after protocol amendment.

We saw composite CR rate of 67% in that population which is very favorable for patients with R/R AML. Even more exciting, we saw MRD negative CRs as measured by multiparameter, flow cytometry in 96% of the newly-diagnosed patients and 69% of the R/R population.

We know more and more that MRD is a good surrogate marker of relapse risk both pre and post-transplant. The regimen was very effective at bridging patients to transplant, so about 70% of newly diagnosed patients are able to successfully bridge to an ASCT with this regimen, and 46% of R/R patients were as well. To us, this suggests that this regimen could be an optimal regimen in the adverse risk newly-diagnosed population where transplant is indicated and in the R/R population to allow people to transition successfully to transplant and safely. A significant number of patients transitioned without what we considered full count recovery, which was an area under the curve greater than 500, with a platelet count greater than 50,000. But despite this, we did not see any adverse outcomes.

TARGETED ONCOLOGY: How did those numbers compare to historical rates?

LACHOWIEZ: One of the issues with the newly-diagnosed population is that we do see high CR rates, maybe anywhere between 60% to 80%. It depends what regimen you look at. But we know that about 30% to 40% of these patients will relapse. So, I think longer follow-up is warranted to determine the role of this regimen in the newly-diagnosed patienst who do not proceed to transplant or procees to transplant for that matter. And I think that what will be interesting is how MRD plays into that equation.

We saw nice response rates in the newly-diagnosed population and we were able to take patients to transplant effectively with it. I think the question remains, though, and will probably need to be evaluated in prospective randomized trials determining whether or not this regimen is superior to other regimens that are out there at the present for the newly-diagnosed patients with AML.

In the R/R population, there's really no standard of care for a salvage regimen. There was a phase 3 study where FLAG-IDA was included as one of the investigator’s choice of regimens that they could use in the salvage setting. Here we saw a fairly unfavorable responses with it. And although this was a fairly small population of patients that received it, the responses were around 25% to 30%, with a median OS of about 3 to 4 months. Compared to that historic cohort, this is a marked improvement in OS.

I think there's been other retrospective analyses in the R/R setting that have shown more favorable outcomes with intensive chemotherapy than the ones I just mentioned. But still, we see survival that is usually less than a year in the R/R AML patient and is difficult to achieve any meaningful composite or CR rate at all. With this regimen, we saw a composite CR of 67%. I think we're seeing maybe a 10% increase in CR rates here. But I think this will need longer follow-up, certainly to follow forward and see how this ultimately plays out.

TARGETED ONCOLOGY: In terms of efficacy, was there comparable activity across subgroups?

LACHOWIEZ: Most subgroups have fared well with FLAG-IDA. I will say that unfortunately, the 1 subgroup that still appears to have adverse outcomes, and we were not able to see improvements in OS with FLAG-IDA or an induction intensification by adding venetoclax to FLAG-IDA was the TP53-mutated population. These patients continued to have inferior response rates. There were 10 patients that had TP53 mutations at the time of study enrollment. Unfortunately, in both the newly-diagnosed and R/R population, the duration of response was short, and these patients had a median duration of response of approximately 3 months and inferior OS of less than a year. So, I think this is a population where new therapeutics are definitely still needed. There's hope for the anti-CD-47 antibody magrolimab as well as APR-246, which I think is still trying to find its place in this setting.

Whether or not there's a role for FLAG-IDA for patients with TP53 mutations, I don't know. But I think at this time, I can certainly say that these patients appear to do worse than other subgroups, secondary AML, older AML patients, they all appear to have favorable response rates with this regimen. But again, the numbers are small here. There were only 11 patients with secondary AML. So, someone who had an antecedent hematologic disorder, like MDS that received a prior therapy, maybe azacitidine or decitabine, and then progressed to AML. So, this was a small subset of patients that were included in this trial. So, I think these responses are definitely encouraging. And I'm optimistic about them. But I think they have to be taken with a little bit of a tempered view because of the small sample size.

TARGETED ONCOLOGY: Was there anything about the analysis that surprised you?

LACHOWIEZ: I think the responses and especially the MRD-negative responses in the R/R population, were maybe a bit of a surprise, because of the historical outcomes that we had seen. Salvaging these patients and finding a window of opportunity to both get these patients into a CR and then take them to transplant is challenging. I think it was a pleasant surprise.

Another thing that was a little interesting was that we had a population of R/R patients that actually had favorable cytogenetic findings.. Interestingly, in our population, these patients appeared to do a little bit worse than the other relapsed/refractory patients as a whole. I don't know why, at this point in time, there's some nice biologic plausibility there that actually core binding factor mutations may contribute to a degree of resistance to this regimen. But much more work will be needed to be done to confirm that.

TARGETED ONCOLOGY: What are you key takeaways from this research?

LACHOWIEZ: I think the important thing for people to remember is that this is an effective regimen. Hopefully, we will have this data published sometime soon. So, if someone is interested in using this regimen, it is available to them to do so. But I think it's also a regimen that needs great care taken with the administration of it, because it is not without its own AE profile.

_REFERENCE:

_{Lachowiez, C., Konopleva, M., Kadia, T., et al. Interim analysis of the phase 1b/2 study of the BCL-2 inhibitor venetoclax in combination with standard intensive AML induction/consolidation therapy with FLAG-IDA in patients with newly diagnosed or relapsed/refractory AML. ASH. December 6, 2020. Accessed March 31, 2021. https://bit.ly/3cEtDTZ}