CLINICAL NEWS
Written in Blood
Patients with MEF2 tumor mutations
(representing 15.4% of patients tested) were
more likely to respond to panobinostat, with
a likelihood ratio of 3.67 for achieving a CR
or PR (95% CI 1.46-9.19). The authors noted
that this raises “the possibility that these mutations are associated with greater sensitivity
to HDI.”
Early changes in ctDNA levels (measured
in 25 patients via lymphoma-related genesequencing and digital polymerase chain
reaction) appeared to be a strong predictor
of changes in tumor burden. Levels differed
substantially from baseline to day 15 of panobinostat treatment in the majority of patients
(n=20/25), and 10 patients had increased
ctDNA levels at this time.
“Changes in ctDNA after only 15 days of
therapy [demonstrated a] very high specificity and positive predictive value,” the authors
explained. “No patients with an increase in
ctDNA at 15 days responded to treatment,
while all patients who eventually responded
had a significant drop in ctDNA after 15 days
of therapy. Overall survival and PFS were
also significantly associated with a decrease
in ctDNA.”
Though the study was limited by its small
sample size and unblinded design, the results
“promote sequence-based analysis of ctDNA
as a powerful and promising tool for gleaning early signals of response, while possibly
affording opportunity to detect ongoing
clonal evolution, a known feature of DLBCL,”
the authors concluded. ●
Among the 11 responding patients, a
median of six treatment cycles were administered (range = 4-50 cycles). Five responding
patients had progressed at the time of study
analysis.
“The response rate observed [in this
study] was appreciably higher than previous
studies of HDI in DLBCL, which may be due
to the purported greater potency of panobinostat relative to other HDIs,” the authors
wrote. See TABLE 3 for a complete comparison
of treatment efficacy.
The most common grade ≥3 adverse
events associated with panobinostat with
or without rituximab were thrombocytopenia and neutropenia. Toxicity-related dose
reductions and dose interruptions or delays
were required in 58 percent (n=23) and 55
percent of patients (n=22), respectively. “As
expected, panobinostat was associated with
thrombocytopenia and neutropenia, which
required dose reductions in a large number
of patients,” Dr. Assouline and authors wrote.
“Overall, a lower dose of panobinostat, such
as 20 mg three times per week, and possibly
a two-week-on/one-week-off regimen should
be considered in subsequent trials to allow
more continuous therapy.”
To help identify patients who are most
likely to respond to HDI treatment, the
authors compared circulating tumor DNA
(ctDNA) analysis and tissue biopsies before
treatment and at day 15 of panobinostat
treatment. Biopsy samples were assessed
for mutations commonly associated with
DLBCL (including HME genes) and for
COO, MYC, and BCL2 expression.
Twenty-three biopsies were obtained prior
to panobinostat treatment; the remaining
patients underwent targeted gene sequencing.
TABLE 3.
REFERENCE
Assouline SE, Nielsen TH, Yu S, et al. Phase 2 study of panobinostat
+/- rituximab in relapsed diffuse large B cell lymphoma and biomarkers
predictive of response. Blood. 2016 May 10. [Epub ahead of print]
Comparison of Treatment Efficacy
Panobinostat plus
Rituximab
(n=19)
Panobinostat
(n=21)
n
Percentage
(95% CI)
n
Percentage
(95% CI)
n
Percentage
(95% CI)
ORR (CR + PR)
6
29%
(95% CI 11.352.2)
5
26%
(95% CI 9.251.2)
11
28%
(95% CI 14.643.9)
CR
5
24%
2
11%
7
18%
PR
1
5%
3
16%
4
10%
SD
0
0%
1
5%
1
3%
PD
15
71%
13
68%
28
70%
Time to response
Median days
73
21
42
Range (days)
23-209
21-231
21-231
Not reached
9.4
(95% CI 4.3-not
reached)
14.5
(95% CI 9.4-not
reached)
6.2-43.2
1.6-40.5
1.6-43.2
2
3
5
Duration of response
Median months
Range
(months)
Number
progressed
ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease; PD =
progressive disease
32
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