Venetoclax monotherapy appears to improve outcomes in some patients with acute
myelogenous leukemia (AML), according to a phase 2, single-arm study.
"This study included patients that
were in categories that are difficult to treat - relapsed, refractory, and/or
elderly and deemed medically unfit to receive induction therapy," Dr.
Anthony Letai from Dana-Farber Cancer Institute in Boston told Reuters Health
"The fact that some of these
patients had leukemias that were relapsed or refractory to very tough regimens,
including regimens that require multi-week inpatient hospital stays, but
nonetheless responded to an oral outpatient therapy taken once a day was a very
interesting result," he said.
Venetoclax, a highly selective, oral
small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor, received FDA
approval for chronic lymphocytic leukemia (CLL) earlier this year.
Dr. Letai and colleagues
investigated the efficacy and biological correlates of response in the first
clinical study of venetoclax monotherapy in 32 patients with
relapsed/refractory AML or untreated AML unfit for intensive therapy.
The objective response rate was 19%
(six of 32), with two patients achieving a complete response and four achieving
a complete response with incomplete blood count recovery. All objective
responses were achieved by the week-4 assessment.
An additional 19% had antileukemic
activity demonstrated by partial bone marrow response and incomplete
The six-month leukemia-free survival
rate was 10% (median leukemia-free survival, 2.3 months), and the six-month
overall survival estimate was 36% (median overall survival, 4.7 months), the
researchers report in Cancer Discovery, online August 12.
At the time of this report, all
patients had discontinued venetoclax: 29 due to progressive disease, one due to
adverse event, one withdrew consent, and one proceeded to allogeneic
hematopoietic stem cell transplant after achieving stable disease.
"Our data provide evidence that
AML with IDH1/2 mutations exhibits BCL2 dependence and validates preclinical
data that suggest suppression of cytochrome c oxidase activity in IDH1/2 mutant
AML lowers the mitochondrial threshold to trigger apoptosis upon BCL2
inhibition," the researchers note. "However, activity observed in
patients with wild-type IDH1/2 suggests targeting BCL2 with venetoclax should
not be restricted to patients with mutations in IDH1/2."
Venetoclax monotherapy was generally
well tolerated, although treatment-emergent adverse events were reported for
all patients. Nausea, diarrhea, hypokalemia, vomiting, and headache were the
most commonly reported adverse events.
"This study was the first
report of venetoclax in AML, and as such was a single-agent study," Dr.
Letai said. "However, I do not think single-agent use will be common in
AML for this drug. I think that venetoclax will be incorporated into
combinations with many other agents active in AML."
"Right now, in the elderly setting,
it is being combined with either hypomethylating agents (vidaza or decitabine)
or low-dose cytarabine, both commonly used in the elderly in AML," he
said. "The response rates have been fantastic, around 70%, as reported in
abstracts at ASH and ASCO. There will likely be clinical testing of
combinations including venetoclax at all stages of AML therapy, including
induction, consolidation, salvage. Indeed, some of these trials are already
starting. Who knows, perhaps even maintenance? It is well tolerated, so lends
itself to combination."
"Genomics and genetics are
often equated with personalized medicine, the job of which is to match the
right patient with the right drugs," Dr. Letai added. "Venetoclax has
so far demonstrated activity in CLL, mantle cell lymphoma, AML. There are no
related to BCL-2 that would indicate activity in these cancers. If we relied on
genetics alone, these would have missed."
"Instead, we and others took a
functional approach to identifying BCL-2 dependence in cancers, and thus
identifying good targets for venetoclax," he said. "I think that
these functional precision-medicine approaches are going to be vital to taking
advantage of all the new drugs that are appearing in cancer. If we rely on genomics
alone, we will probably miss most of our therapeutic opportunities."
Dr. Fernando Ramos from the
University of Leon in Spain, who recently reviewed AML in older adults, told
Reuters Health by email, "Venetoclax may be an interesting option for
rescue therapy in this patient subset."
"Precision medicine has come a
long way," added Dr. Ramos, who was not involved in the study.
"Venetoclax may be an interesting partner to azanucleosides in unfit AML
Currently, venetoclax is in phase 2
testing for AML, diffuse large B-cell lymphoma, and non-Hodgkin lymphoma and in
phase 3 testing for multiple myeloma.
AbbVie and Genentech funded the
study, employed 13 of the 22 authors, and had various relationships with four
other authors, including Dr. Letai.