Early Study Results Show Novel Therapy Safe and Effective in Relapsed/Refractory Acute Myeloid Leukemia

Results of a phase 1 clinical trial demonstrated that a novel inhibitor — ABBV-075 (mivebresib) — showed a tolerable safety profile and induced some antileukemic effects as a single-agent treatment, as well as in combination with Venclexta (venetoclax), in patients with relapsed/refractory acute myeloid leukemia (AML).

Although there has been growth in the understanding of AML, the study authors noted, five-year overall survival rates remain relatively low. In fact, according to the authors, approximately 40% of newly diagnosed patients aged younger than 60 years and less than 20% of patients aged 60 years or older are alive at five years.

There is, however, recent research to indicate that certain genetic alterations that accumulate with age may shed light on the low survival rates among elderly patients with the disease, according to the authors.

Moreover, a certain set of proteins (bromodomain and extraterminal [BET]) have been shown to drive the expression of cancer-causing genes.

The BRD4 protein, for example, is necessary for a tumor to maintain its life in AML, the authors noted. Importantly, BET inhibitors can limit the development of cytokines and chemokines, which help maintain a tumor’s environment.

“Previous preclinical studies demonstrated that (BET inhibitors, of which ABBV-075 is) have broad antiproliferative activities across cancer cell lines and are highly effective in tumor models,” the authors wrote in the study, which was published in Cancer.

To assess the safety profile and efficacy of ABBV-075 as a single-agent therapy or in combination with Venclexta in the relapsed/refractory AML setting, the study authors enrolled 44 patients (median age, 68 years; range, 29 to 84 years) who either failed to respond to standard-of-care therapy or no standard of care exists.

Nineteen patients initially received the single-agent treatment, of which five, however, experienced disease progression or relapse and were switched to the ABBV-075 and Venclexta group. In total, 30 patients received the combination. Half the patient population (22 patients) had received at least three previous lines of treatment.

Each patient reported a treatment-emergent side effect. For patients who received the single-agent treatment, the most common side effects included an impaired sense of taste (79%), fatigue (68%), decreased appetite (58%), nausea and diarrhea (47%, respectively). Seventy-four percent of patients who received single-agent treatment and 88% of those who received the combination experienced a serious side effect, regardless of if it was related to ABBV-075. Seventeen patients experienced a side effect which led them to discontinue treatment. Additionally, 35% of patients died while on the study.

The study authors were able to assess leukemia burden change from start of trial among 36 patients. A measurable reduction of bone marrow blasts (a bone marrow blast of at least 20% is indicative of AML, whereas 5% or less constitutes a normal bone marrow blast count) occurred in 44% of patients who received ABBV-075 alone and 80% who received the combination. Three patients who switched from the single-agent treatment to the ABBV-075 and Venclexta combo also experienced a bone marrow blast count reduction.

“This is the first-in-human study to describe the safety, tolerability … (and) efficacy of the BET (inhibitor ABBV-075) as monotherapy or in combination with (Venclexta) in patients with (relapsed/refractory) AML,” the authors wrote. “The safety profile of (ABBV-075) in this study is consistent with previous findings, with the most common (treatment-emergent side effects) being fatigue, nausea, decreased appetite, diarrhea and dysgeusia.”

The authors noted there is another study evaluating BET inhibitors with the chemotherapy azacitidine in this particular population and that overall, more research is necessary to confirm ABBV-075’s use in patients with AML.

“Further exploration of BET (inhibitor) combinations for synergy and to overcome potential resistance mechanisms against targeted therapies in patients with hematologic malignancies are needed,” they concluded.

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