CLINICAL NEWS
Venetoclax Combined with Rituximab
in Patients with Relapsed/Refractory CLL
PI3K Inhibitors Safe and
Effective in CLL Patients
An early-phase study of the combination of
venetoclax, an investigational B-cell lymphoma 2 (BCL-2) selective inhibitor, with
rituximab showed response rates of 80 percent
in patients with relapsed/refractory chronic
lymphocytic leukemia (CLL), in a phase Ib
study presented at the European Hematology
Association Congress.
Venetoclax is a novel, once-daily oral treatment that works by preventing apoptosis of
some cells – including lymphocytes – that can be
expressed in certain types of cancer.
The cause of CLL is unknown, and there
are few safe and effective treatments for it, the
authors wrote, but the combination of venetoclax
with rituximab is “encouraging.” The study was
presented by Andrew W. Roberts, MBBS, PhD,
of the Royal Melbourne Hospital Department of
Clinical Hematology and Bone Marrow Transplant Service in Australia, and head of Clinical
Translation at the Walter and Eliza Hall Institute
of Medical Research.
Eligible patients began treatment with 20 or
50 mg of venetoclax daily, which was increased
weekly to final doses of 200 to 600 mg. After the
weekly lead-in phase, monthly rituximab was
added (at 375 mg/m2 and then 500 mg/m2) for
a total of six doses. All patients had previously
been treated with a median of two therapies.
Response to treatment was assessed using the International Workshop on Chronic Lymphocytic
Leukemia (IWCLL) criteria. Minimal residual
disease (MRD) was assessed in local laboratories
using ≥4 color flow cytometry on cells in bone
marrow (BM) and blood.
A total of 49 patients were enrolled in five
dose-escalation cohorts (n=41) and a safety ex-
Updated data on the safety and effectiveness of three different phosphoinositide 3-kinase inhibitors (PI3K inhibitors)
presented at the European Hematology Association (EHA)
Congress show that these agents are safe and effective for
patients with chronic lymphocytic leukemia (CLL).
The PI3K inhibitors target one or more of the phosphoinositide 3-kinase enzymes, which are part of an
important signaling pathway for many cellular functions,
including growth control, metabolism, and translation
initiation. Idelalisib, TGR-1202, and duvelisib demonstrated high response rates that were durable – offering
a promising treatment option for patients with CLL,
particularly those with relapsed/refractory disease.
pansion cohort at 400 mg/day (n=8). Forty-five
patients (92%) had prior rituximab therapy, and
14 (29%) were rituximab-refractory.
Dr. Roberts and colleagues reported that
patients with CLL taking the venetoclax combination had an overall response rate (ORR) of 84
percent (n=41/49), with 41 percent of patients
achieving either a complete response (CR) or CR
with incomplete marrow recovery (CRi; TABLE
1). Response rates were similar in patients with
the del(17p) karyotypic abnormality. Only 3 of
41 (7%) responders had progressive disease (at 5,
8, and 12 months). Eleven patients discontinued
the study: six due to progressive disease, two
due to adverse events (AEs), and three patients
withdrew consent.
Additionally, six patients stopped venetoclax
after achieving CR/CRi. Three patients maintained a response after a median of 12 months
(0-21). “Potentially, the most interesting part of
these initial results is the data regarding the patients who have been able to come off treatment
and who continue to maintain their complete
response,” Dr. Roberts said
Minimal residual disease (MRD) was evaluable in 40 patients. MRD-negativity in BM was
achieved in 13 out of 20 (65%) patients with CR/
CRi and in 24 out of 49 (49%) patients overall
(TABLE 2).
In terms of safety, the most common overall
treatment-emergent AEs seen in >25 percent of
patients were neutropenia (53%), diarrhea and
nausea (47%), upper respiratory tract infection
(41%), pyrexia (37%), and fatigue, headache, and
cough (each 33%). There was one treatmentemergent AE that led to death due to tumor
lysis syndrome, and there were two treatmentemergent deaths that
occurred in patients
with progressive
TABLE 1. Best Response
disease.
“The combinaAll pts, n=49
del17p, n=9
tion of venetoclax
ORR, n (%)
41 (84)
7 (78)
and rituximab has
a
3b (33)
CR/CRi
20 (41)
a tolerable safety
PR
20 (41)
4 (44)
profile and induces
deep and durable
nodular PR (nPR)
1 (2)
0 (0)
responses,” Dr. Robc
4 (8)
1 (11)
PR unconfirmed
erts and colleagues
Stable disease (SD)
1 (2)
0 (0)
concluded, adding
Progressive deisease (PD)
2 (4)
0 (0)
that a randomized clinical trial is
1 (2)
1 (11)
Discontinued prior to assessmentd
underway to further
a
b
c
6/20 CRi; 2/3 CRi; 1 awaiting next scan to confirm PR, 1 withdrew consent, 1 withdrew due to neutest for safety and
ropathy; 1 had PD shortly after PR; dFatal TLS event; No other fatal TLS events occurred after protocol
modification
efficacy of this combination. ●
TABLE 2.
Bone Marrow MRD Status, n (%)
MRD-negative
MRD-positive
Not evaluable
CR/CRi
13
5
2
PR/nPR
10
10
1
Other
e
1
f
1
6g
24/49 (49)
16/49 (33)
9/49 (18)
Total
PR unconfirmed; SD; No sample
e
REFERENCE
f
g
ASHClinicalNews.org
Roberts A, Ma S, Brander D.
Venetoclax (ABT-199/GDC-0199)
combined with rituximab induces
deep responses in patients with
relapsed/refractory chronic
lymphocytic leukemia. Abstract
#S431. Presented at the 2015
European Hematology Association,
Vienna, Austria, June 13, 2015.
Idelalisib
Two presentations at this year’s EHA Congress characterized
the impact of idelalisib treatment on patient safety and quality-of-life (QoL). Idelalisib was recently approved by the U.S.
Food and Drug Administration for the treatment of relapsed
CLL in combination with rituximab. The first study, presented by Rodolphe Perard, MD, of Merck Serono Ltd. in
the United Kingdom, examined the drug’s impact on healthrelated QoL, analyzing data from the phase III randomized
controlled trial comparing idelalisib plus rituximab with
rituximab-alone in patients with previously-treated CLL
unsuitable for cytotoxic therapy.1 Dr. Perard [