CLINICAL NEWS
Written in
Featured research from recent issues of Blood
PAPER SPOTLIGHT
Venetoclax Plus Obinutuzumab Confers
High MRD-Negative Rates in CLL
is very important to patients,” Dr.
Flinn noted.
With this study, investigators
evaluated the toxicity and preli-
minary efficacy of venetoclax-
obinutuzumab in adults with CLL
who had an Eastern Cooperative
Oncology Group performance
status of 0-1 and adequate hema-
tologic and organ function.
The study was conducted in
two phases: a dose-finding phase
and a safety-expansion phase.
Fixed-dose obinutuzumab was ad-
ministered at the following doses
in six 28-day cycles: cycle 1: 100 mg
on day 1, 900 mg on day 2, 1,000
mg on days 8 and 15; cycle 2-6:
1,000 mg on day 1. The venetoclax
dose was initially escalated from
100 mg to 400 mg in a 3+3 design
to determine the maximum toler-
ated dose when combined with
standard-dose obinutuzumab.
Treatment was administered
according to one of two schedules
during the
first cycle:
TABLE 1. Response Rates
In schedule
A, patients
Efficacy Population,
N (%)
received a
Relapsed/refractory population
43
venetoclax
ramp up
ORR
41 (95)
(from 100
CR/CRi
16 (37)
to 400 mg),
PR
25 (58)
followed by
SD
2 (5)
fixed-dose
Firstline population
32
obinutu-
ORR
32 (100)
zumab; in
schedule
CR/CRi
25 (78)
B,
patients
PR
7 (22)
received
a
ORR = overall response rate; CR = complete response; CRi = CR with incom-
loading dose
plete marrow recovery; PR = partial response; SD = stable disease
Results from a phase Ib study
demonstrated that the com-
bination of the BCL2 inhibitor
venetoclax with the anti-CD20
monoclonal antibody obinutu-
zumab was safe and induced high
rates of minimal residual disease
(MRD)–negativity in patients with
previously untreated and relapsed/
refractory chronic lymphocytic
leukemia (CLL). The study was
published in Blood.
“The combination of veneto-
clax and obinutuzumab produces
deep, durable remissions with
MRD negativity in both the blood
and the marrow,” lead author Ian
W. Flinn, MD , of Sarah Cannon
Research Institute/Tennessee
Oncology told ASH Clinical News.
“As a consequence, many pa-
tients treated with this regimen
in the frontline setting can dis-
continue therapy after one year.
The ability to come off of treat-
ment with time-limited therapy
of obinutuzumab over 21 days,
followed by venetoclax. After
receiving the obinutuzumab-
venetoclax combination for six
cycles, participants then received
venetoclax as a single agent until
disease progression (in relapsed/
refractory patients) or venetoclax
for 12 months (in previously un-
treated patients).
A total of 78 patients were
enrolled: 50 with relapsed/refrac-
tory disease and 32 with previously
untreated disease. Three patients
discontinued treatment: one who
did not meet study inclusion criteria
and two who experienced adverse
events (AEs) prior to completing
two cycles of the combination
treatment.
Overall, the safety and efficacy
populations comprised 45 and 43
patients with relapsed/refractory
CLL, respectively; all 32 patients
with previously untreated CLL
were evaluable.
Most patients in each cohort
received venetoclax at the recom-
mended phase II dose of 400 mg/
day and completed six cycles of
combination treatment.
No dose-limiting toxicities were
observed during the dose-finding
phase, and there were no differences
in safety between dosing schedules.
Incidence of tumor lysis syndrome
(TLS) were similar, with two grade 3
TLS events in each of the schedules.
For the expansion study, patients
received venetoclax at a fixed dose
of 400 mg on schedule B.
All 77 safety-evaluable patients
experienced at least one AE, most
of which (87%) were grade 1 or 2.
The most commonly reported any-
grade AEs were infection, diarrhea,
infusion-related reactions, nausea,
and neutropenia.
The most common grade 3-4
AEs in the safety-expansion phase
included:
• neutropenia: 58% in the
relapsed/refractory cohort
and 53% in the firstline
cohort
• infections: 29% and 13%
• thrombocytopenia: 22%
and 22%
All infusion-related reactions were
grades 1-2, except for two grade
3 AEs in the relapsed/refractory
cohort. No deaths were reported
in the firstline cohort, while three
patients in the relapsed/refractory
cohort had a fatal AE (including
two instances of pneumonia and
one of acute respiratory failure).
Seven of 45 relapsed/refrac-
tory patients (16%) and one of
32 previously untreated patients
(3%) discontinued venetoclax due
to AEs – most of which occurred
after one year of treatment – while
obinutuzumab was discontinued
due to AEs in 2 patients (4%) and
no patients, respectively.
After a median follow-up of
29.3 months (range = 3-55 months)
in the relapsed/refractory cohort
and 26.7 months (range = 16-39
months) in the firstline cohort,
the overall response rates were
Continued on page 30
PERSPECTIVES
“The use of novel single-agent therapy, such as ibrutinib, has changed the face of
therapy for both upfront and relapsed/refractory CLL, inducing high overall response
rates and dramatic increases in progression-free survival. However, lower CR rates and
the need to reach MRD-negative status have led to the testing of ‘novel-novel’ drug
combinations in CLL.
The BCL2 inhibitor venetoclax used in tandem with the anti-CD20 monoclonal
antibody obinutuzumab takes advantage of two drugs with nonoverlapping mecha-
nisms of action, and this phase I study in both relapsed/refractory and upfront CLL
adds to our understanding of the safety and efficacy of so-called ‘doublet’ therapy.
While each agent is known in its own right to induce reductions in leukemic burden,
28
ASH Clinical News
their combination use has also raised questions about safety and toxicity.
In this study, the venetoclax-obinutuzumab combination resulted in undetect-
able MRD and concordance between MRD data for blood and marrow – which can be
predictive of superior clinical outcomes. In total, the results for both safety and clini-
cal responses are reassuring for future use and testing of this combination in both
upfront and relapsed/refractory cohorts of CLL.”
Neil E. Kay, MD
Mayo Clinic
Rochester, MN
May 2019