Phase 2 Trial Results Showed Venetoclax Added to CLAD/LDAC Is Highly Active as Frontline Therapy in Older Patients With Newly Diagnosed AML

Pharmacy Times® interviewed Patrick K. Reville, MD, MPH, hematology/oncology fellow, Department of Leukemia, the University of Texas MD Anderson Cancer Center, on the poster presentation titled “Venetoclax [Venclexta; AbbVie and Genentech] Added to Cladribine [Mavenclad; Merck] (CLAD) + Low Dose AraC (LDAC) Alternating with Azacitidine [Onureg; Bristol Myer Squibb] (AZA) Is Highly Active As Frontline Therapy in Older Patients with Newly Diagnosed Acute Myeloid Leukemia in a Phase 2 Study” at the 64th American Society of Hematology (ASH) Annual Meeting and Exhibition in New Orleans, Louisiana.

Pharmacy Times®: What did the longer-term follow up results from the phase 2 clinical trial of venetoclax added to cladribine plus low-dose araC alternating with azacytidine show regarding regimen durability and safety?

Patrick K. Reville: Two things are happening in this update. One is we've enrolled more patients, and we have longer follow up for those patients that had been enrolled earlier.

So we had published the initial results in the Journal of Clinical Oncology last year. At that update, we had 60 patients. Now we've enrolled 93 patients. So we've enrolled an additional 33 patients.

Again, we're seeing really similar activity. So the response rates and how deep the responses are, which we've measured by measurable residual disease by flow cytometry, seem to be holding up with this further accrual of patients.

Then again, the longer term follow ups continue to show really good long term outcomes. And so where we had more limited follow up for some of those patients at our initial publication, with a longer follow up again, we're not seeing many late relapses that would change sort of the long term trajectory of these patients.

On this study, the patients are older, so everybody that's enrolled is either 60 or older, or there was one patient that was under 60, that was ineligible for intensive chemotherapy. And so the duration of response and the long term outcomes here are very impressive for this older group of patients.

Pharmacy Times®: What did the study show regarding efficacy of this lower-intensity regimen win older patients with newly diagnosed AML?

Patrick K. Reville: In this regimen, cladribine with low-dose araC added to venetoclax, and it alternates with 5 azacitidine and venetoclax. So in this regimen, again, we're seeing very high response rate. So the overall response rate on this study was 92%. Again, showing very good deep responses as measured by flow cytometry, so we're looking at measurable residual disease rates in the 85% range, which is really unprecedented for this older cohort of patients with AML.

So with the additional patients and a longer follow up, we confirmed the activity continued to be high. Those rates of response and MRD negativity were similar to what we had presented earlier.

So the long-term outcomes continued to be really good. So we looked at the disease-free survival in the patients that responded to treatment and the 2 year disease free survival was 63%, and the overall survival of that group was 68%. At 2 years, both of those numbers were higher than what we would have expected if they had received a standard lower intensity therapy.

Especially compared to intensive chemotherapy, we're seeing lower rates of high grade adverse events. So, patients with AML, especially older patients with AML, are prone to infectious complications, especially as we treat them initially. But even with that our rates of serious infectious adverse events were relatively low in the study. So the rates of febrile neutropenia were under 50%, and we didn't see any limiting infectious complications.

The other big complication that we worry about when we add venetoclax is tumor lysis syndrome, we only saw one case of tumor lysis syndrome. That was a grade 4 event, but overall about a 1% rate of tumor lysis syndrome on the study. The other side effects of the regimen were well managed.

Pharmacy Times®: What were the rates of disease-free survival and overall survival on this regimen?

Patrick K. Reville: So the 2-year disease free survival rate was 63%, and the overall survival rate was 68%.

Pharmacy Times®: What are the next steps following these phase 2 results?

Patrick K. Reville: So we've confirmed that the regimen is highly active in older patients. The study really enrolls 2 different types of patients, one is an older patient that is or would otherwise be eligible for intensive chemotherapy. So there's a group of patients, in particular those patients that are between 60 and 75, that are eligible to have received intensive chemotherapy.

There's another group of patients that we’re enrolling, and this could have been younger patients as well, but patients that are ineligible for intensive chemotherapy. And I think that as we think about how do we validate these findings, especially in like a randomized phase 3 setting, you think about doing 2 different types of studies for those patients. The standard treatment right now for patients that are older but fit for intensive chemotherapy is to give them intensive chemotherapy.

So one potential option would be to do a study where we compare this regimen of chemotherapy and cladribine plus low-dose araC and venetoclax to intensive chemotherapy in older patients that are fit for intensive chemotherapy.

The other study could be, in the patients that are ineligible for intensive chemotherapy, compare what is the standard of care, which would be the azacytidine and venetoclax to the cladribine and low-dose araC and venetoclax.

So I think that as we continue to refine the regimen, we need to think about how we validate these findings so that we can confirm that this regimen is highly active and potentially could be a new standard of care.