Venetoclax combined with AML induction/consolidation therapy with FLAG-IDA in newly diagnosed or R/R AML

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Published: 7 Dec 2020
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Dr Curtis Lachowiez - University of Texas MD Anderson Cancer Center, USA

Dr Curtis Lachowiez speaks to ecancer about the interim results of a phase 1b/2 study he presented at the virtual ASH 2020 meeting on the use of venetoclax combined with AML induction/consolidation therapy with FLAG-IDA in newly diagnosed or relapsed/refractory AML.

He explains that there is more and more data that suggests incorporating venetoclax into treatment regimens can lead to more robust responses.

Dr Lachowiez reports from the phase 1b safety portion of the trial that there was a prolonged myelosuppression which led to the dose being altered to a safer level.

He explains that the outcomes were favourable with newly diagnosed patients seeing a composite complete response rate of around 90%.

This program is funded in part via an independent grant from AbbVie. ecancer is editorially independent and there is no influence over content.

 

The logical rationale behind this study is that we now have more and more data, including randomised phase III data, from the primary investigator on this study, Dr DiNardo, incorporating venetoclax into treatment regimens using what we consider low-intensity therapies for AML treatment, predominantly the hypomethylating agents decitabine and azacytidine. We see really robust responses and synergistic leukemic cell killing when we use venetoclax combined with either of those agents.

Similarly there is the recently published phase Ib CAVEAT trial where they used an attenuated schedule of the 5 2 regimen of idarubicin in combination with cytarabine, so cytotoxic chemotherapy, and added venetoclax to that regimen, in an older AML patient population. Similarly to the HMA therapy venetoclax combinations, we see improved outcomes in elderly patients with AML who traditionally have done quite poorly with intensive chemotherapy. The next step is to say can we further improve outcomes in a younger, fitter population with newly diagnosed AML as well as patients with relapsed and refractory AML by intensifying induction and consolidation with FLAG-IDA based induction and consolidation chemotherapy combined with venetoclax?

The methods used in this study were standard three by three dose escalation cohort study for the phase Ib portion, the safety portion of the study, to determine both the maximal tolerated dose and identify any dose-limiting toxicities and the phase II portion where we assessed response and efficacy where dose expansion cohorts in both the newly diagnosed AML patients as well as relapsed and refractory AML patients with each arm, enrolling up to fifty patients planned for each arm. We’re currently at 68 patients out of the 100 total expected enrolled patients.

The main finding from the phase Ib safety portion was not unanticipated, which is that when we add venetoclax to intensive chemotherapy we see that we have prolonged myelosuppression. From a safety standpoint we initially amended the protocol and reduced the dose of the cytarabine and the duration of the venetoclax in the phase Ib portion of the study because we saw an increased rate of myelosuppression and infectious complications. However, I think the takeaway is that with dose optimisation we were able to safely combine FLAG-IDA induction and consolidation with venetoclax. We saw quite favourable outcomes both in the newly diagnosed and the relapsed and refractory AML populations. In the newly diagnosed AML population we saw a composite complete response rate of approximately 90%, including 96% of patients achieving measurable residual disease negative composite CR as assessed by multiparameter flow cytometry. This shows us that FLAG-IDA venetoclax in the newly diagnosed AML population is able to achieve durable and deep – the responses have been durable to date as well, but deep responses – when we add venetoclax to FLAG-IDA.

Similarly in the relapsed and refractory population, which continues to be a very adverse-risk population, has poor outcomes and is in need of new therapies, we saw that we had a composite CR rate of about 67% in the relapsed and refractory cohort combined. When we looked at the outcomes in these patients what we saw is that 69% of these patients achieved an MRD negative composite CR. So these were very, very promising results in the relapsed and refractory cohorts.

As far as survival outcomes are concerned, the newly diagnosed cohort has demonstrated very favourable overall survival to date, a median event free and overall survival that has not been reached at the time of data analysis, although I will say in the newly diagnosed population follow-up is maybe a little bit on the early side to have any firm, definitive conclusions as far as the impact of this regimen on overall survival. The median study follow-up is twelve months, so I think the study follow-up is mature to discuss the survival impact in the relapsed and refractory AML population. What we see in the relapsed and refractory population is that particularly those patients in the phase IIb cohort, which is the optimised venetoclax dose in addition to the optimised cytarabine dose for induction and consolidation, we see a median event free survival of approximately 11 months and a median overall survival that hasn’t been reached. The one-year overall survival in these relapsed and refractory patients, 23 patients in this cohort to date, was 68%, which is definitely an improvement compared to historical outcomes in this patient population.

Were there any adverse events?

Grade 3 or 4 adverse events that occurred in two or more study participants were predominantly infectious and not necessarily unanticipated, particularly in the myelosuppressed patient population and the relapsed/refractory patients in particular. The most common adverse events that we saw in two or more patients were febrile neutropenia, bacteraemia and pneumonia. Febrile neutropenia and pneumonia were fairly evenly distributed both between the newly diagnosed and the relapsed and refractory populations.

We did see a higher incidence of bacteraemia in the relapsed and refractory cohorts. This was driven predominantly by an increased number of patients in the phase Ib portion of the study developing bacteraemia or sepsis prior to the protocol amendment and the dose adjustments of the cytarabine and venetoclax like I spoke to previously.

What could be the clinical impact of this study?

I think that the main clinical impact of this study is twofold. I think in the newly diagnosed AML population we do see that this is a very effective regimen that produced deep responses, particularly in adverse risk AML patients by ELN risk stratification. This regimen could be used as an induction and consolidation in those intermediate patients that maybe between the patient provider decide not to proceed to transplant, but I think really where it stands out is as a regimen that achieves deep remissions and appears to be an effective bridge, at least thus far, to transfer these patients to transplant.

The same is true in the relapsed and refractory population. Like I mentioned before, we’re still looking for effective regimens in these patients and I think to date that these are probably some of the best response rates we’ve seen in a prospective setting in the relapsed and refractory AML population. This regimen has suggested that based on our results so far that FLAG-IDA venetoclax could be an optimal regimen, or effective regimen nonetheless, to bridge patients to transplant.

I think probably the only other piece to add is that we are still learning that AML treatment is not a one size fits all approach, and we are exploring our biomarkers that determine whether or not a patient is going to be sensitive or responsive to FLAG-IDA venetoclax and identify those patients that will be resistant. This is something that we’ll have to continue looking at in our translational analyses. We see that unfortunately patients with p53 mutations, similar to prior studies, continue to have inferior outcomes compared to patients without p53 mutations, despite induction intensification with FLAG-IDA venetoclax. This shows us that we still have a ways to go to optimise treatment, not just based on the clinical diagnosis of either the frontline setting for newly diagnosed AML versus salvage therapy for relapsed and refractory disease, for really defining those molecular characteristics, or the molecular phenotype if you will, that will predict whether or not a patient will be responsive to this therapy.

Lastly, I just want to take a second to thank the MD Anderson leukaemia department and then in particular my mentor and PI Dr Courtney DiNardo for allowing me to analyse and present this data at ASH. I think much of the credit goes to her and co-PI Dr Marina Konopleva as well for their work in this field.