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Drug sequencing strategy needed for CLL
Blood
Take-home message
•
This retrospective study compared patients with chronic lymphocytic leukaemia (n= 683)
treated with kinase inhibitors (ibrutinib and idelalisib) and venetoclax. Patients treated
with ibrutinib had improved progression-free survival when it was used as front-line
therapy and when it was used in the treatment of relapsed/refractory, del(17p), and
complex karyotype leukaemias.
•
Ibrutinib is superior to idelalisib, and, in the event of ibrutinib treatment failure,
venetoclax appeared superior to idelalisib and chemoimmunotherapy. Studies are needed
to confirm and optimise the ordering of treatment with kinase inhibitors and venetoclax
in this patient population.
Abstract
BACKGROUND
Ibrutinib, idelalisib, and venetoclax
are approved for treating CLL patients in the US.
However, there is no guidance as to their opti-
mal sequence.
PATIENTS AND METHODS
We conducted a multi-
center, retrospective analysis of CLL patients
treated with kinase inhibitors (KIs) or venetoclax.
We examined demographics, discontinuation
reasons, overall response rates (ORR), survival,
and post-KI salvage strategies. Primary endpoint
was progression-free survival (PFS).
RESULTS
A total of 683 patients were identified.
Baseline characteristics were similar in the ibru-
tinib and idelalisib groups. ORR to ibrutinib and
idelalisib as first KI was 69% and 81% respec-
tively. With a median follow up of 17 months
(range 1–60), median PFS and OS for the entire
cohort were 35 months and not reached.
Patients treated with ibrutinib (vs idelalisib)
as first KI had a significantly better PFS in all
settings; front-line (HR 2.8, CI1.3–6.3 p=0.01),
relapsed-refractory (HR 2.8, CI 1.9–4.1 p<0.001),
del17p (HR 2.0, CI 1.2–3.4 p=0.008), and com-
plex karyotype (HR 2.5, CI 1.2–5.2 p=0.02). At
the time of initial KI failure, use of an alternate KI
or venetoclax had a superior PFS as compared
to chemoimmunotherapy (CIT). Furthermore,
patients who discontinued ibrutinib due to pro-
gression or toxicity had marginally improved
outcomes if they received venetoclax (ORR
79%) versus idelalisib (ORR 46%) (PFS HR .6,
CI.3–1.0, p=0.06).
CONCLUSIONS
In the largest real-world experi-
ence of novel agents in CLL, ibrutinib appears
superior to idelalisib as first KI. Further, in the
setting of KI failure, alternate KI or venetoclax
therapy appear superior to CIT combinations.
The use of venetoclax upon ibrutinib failure
might be superior to idelalisib. These data
support the need for trials testing sequencing
strategies to optimise treatment algorithms.
Optimal sequencing of ibrutinib, idelalisib,
and venetoclax in chronic lymphocytic leu-
kemia: results from a multi-center study of 683
patients.
Blood
2016 Dec 01;128(22)4400, AR
Mato, BT Hill, N Lamanna, et al.
Idelalisibwith bendamustine and rituximab
improves outcomes of relapsed/refractory CLL
The Lancet Oncology
Take-home message
•
This was a multicentre, placebo-controlled, double-blinded phase III study evaluating
safety and efficacy of adding idelalisib to bendamustine plus rituximab in 416 patients
with relapsed/refractory chronic lymphocytic leukaemia (rrCLL). Median progression-free
survival (PFS) was 20.8 months and 11.1 months in the treatment and placebo groups,
respectively (P < 0.0001). Rates of febrile neutropenia were higher in the treatment
group (23% vs 13%).
•
The addition of idelalisib to bendamustine plus rituximab improved PFS in rrCLL, with
increased toxicity rates.
Abstract
BACKGROUND
Bendamustine plus rituximab
is a standard of care for the management of
patients with relapsed or refractory chronic lym-
phocytic leukaemia. New therapies are needed
to improve clinically relevant outcomes in these
patients. We assessed the efficacy and safety
of adding idelalisib, a first-in-class targeted
phosphoinositide-3-kinase δ inhibitor, to ben-
damustine plus rituximab in this population.
METHODS
For this international, multicentre,
double-blind, placebo-controlled trial, adult
patients (≥18 years) with relapsed or refractory
chronic lymphocytic leukaemia requiring treat-
ment who had measurable lymphadenopathy
by CT or MRI and disease progression within 36
months since their last previous therapy were
enrolled. Patients were randomly assigned (1:1)
by a central interactive web response system
to receive bendamustine plus rituximab for a
maximum of six cycles (bendamustine: 70 mg/
m
2
intravenously on days 1 and 2 for six 28-day
cycles; rituximab: 375 mg/m
2
on day 1 of cycle
1, and 500 mg/m
2
on day 1 of cycles 2–6) in
addition to either twice-daily oral idelalisib
(150 mg) or placebo until disease progression
or intolerable study drug-related toxicity. Ran-
domisation was stratified by high-risk features
(IGHV, del[17p], or TP53 mutation) and refractory
versus relapsed disease. The primary endpoint
was progression-free survival assessed by an
independent review committee in the intention-
to-treat population.
FINDINGS
Between June 26, 2012, and Aug 21,
2014, 416 patients were enrolled and randomly
assigned to the idelalisib (n=207) and placebo
(n=209) groups. At a median follow-up of 14
months (IQR 7-18), median progression-free sur-
vival was 20.8 months (95% CI 16.6-26.4) in the
idelalisib group and 11.1 months (8.9-11.1) in the
placebo group (hazard ratio [HR] 0.33, 95% CI
0.25-0.44; p<0.0001). The most frequent grade 3
or worse adverse events in the idelalisib group
were neutropenia (124 [60%] of 207 patients)
and febrile neutropenia (48 [23%]), whereas in
the placebo group they were neutropenia (99
[47%] of 209) and thrombocytopenia (27 [13%]).
An increased risk of infection was reported in
the idelalisib group compared with the placebo
group (grade ≥3 infections and infestations:
80 [39%] of 207 vs 52 [25%] of 209). Serious
adverse events, including febrile neutropenia,
pneumonia, and pyrexia, were more com-
mon in the idelalisib group (140 [68%] of 207
patients) than in the placebo group (92 [44%]
of 209). Treatment-emergent adverse events
leading to death occurred in 23 (11%) patients in
the idelalisib group and 15 (7%) in the placebo
group, including six deaths from infections in
the idelalisib group and three from infections in
the placebo group.
INTERPRETATION
Idelalisib in combination with
bendamustine plus rituximab improved progres-
sion-free survival compared with bendamustine
plus rituximab alone in patients with relapsed
or refractory chronic lymphocytic leukaemia.
However, careful attention needs to be paid
to management of serious adverse events and
infections associated with this regimen during
treatment selection.
Idelalisib or placebo in combination with benda-
mustine and rituximab in patients with relapsed
or refractory chronic lymphocytic leukaemia:
interim results from a phase 3, randomised,
double-blind, placebo-controlled trial.
Lancet
Oncol
2017 Jan 27;[EPub Ahead of Print], AD
Zelenetz, JC Barrientos, JR Brown, et al.
LEUKAEMIA
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PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY