On Location 2015 ASH Annual Meeting
M-protein levels also decreased to undetectable levels two
months after treatment. Fourteen weeks after treatment,
the patient remains in stringent CR, according to Dr.
Kochenderfer. “This is the first example of CAR T cells,
or any kind of T-cell therapy, completely eradicating or
decreasing measurable multiple myeloma,” he said. “For
the first time, we have demonstrated that CAR T cells can
eradicate large burdens of multiple myeloma.”
However, four hours after infusion, the patient showed
signs of cytokine release syndrome, including fever, tachycardia, dyspnea, acute kidney injury, coagulopathy, hypotension requiring vasopressor support, and muscle damage.
The second patient in the highest dose level had 80 percent of his bone marrow composed of plasma cells prior to
treatment; again, this patient experienced toxicities, including signs of cytokine release syndrome, fever, tachycardia,
hypotension, delirium, hypoxia, and coagulopathy. This
patient also experienced a drop in M-protein after treatment, from 3.6 g/dL to 0.8 g/dL four weeks after infusion,
and bone marrow plasma cells were undetectable.
“The findings [of the current study] suggest that
CAR-BCMA is a promising option for advanced multiple myeloma patients who have failed several previous
therapies,” Dr. Kochenderfer said. Since the patient who
had the best response to the CAR-BCMA therapy also
experienced the most toxicities, further investigation into
how to predict and avoid these toxicities is needed. However, he added, “toxicity was substantial, but reversible,
and similar to that seen in previous CAR T-cell trials.”
REFERENCE
Ali SA, Shi V, Wang M, et al. Remissions of multiple myeloma during a first-in-humans clinical trial
of T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor. Abstract #LBA-1.
Presented at the 2015 ASH Annual Meeting, December 8, 2015; Orlando, Florida.
James Kochenderfer, MD
Adding Idelalisib to Treatment Regimen Lengthens Survival in Relapsed/
Refractory Chronic Lymphocytic Leukemia
The triplet combination of idelalisib,
bendamustine, and rituximab (BR) improved overall survival (OS) and progression-free survival (PFS) compared with
BR alone in patients with relapsed and/or
refractory chronic lymphocytic leukemia
(CLL), according to results from a recent
phase III, randomized, double-blind,
placebo-controlled study presented as a
late-breaking abstract at the 2015 ASH
Annual Meeting.
“The combination of idelalisib plus
BR was superior to BR alone,” said
Andrew D. Zelenetz, MD, PhD, from
the Department of Medicine, Lymphoma
Service at Memorial Sloan Kettering
Cancer Center in New York, during his
discussion of the results. “Idelalisib plus
BR represents an important new option
over a standard of care. If your plan is
to use a chemotherapy regimen, then
chemotherapy with idelalisib clearly has
important benefits for the patients, in
terms of progression-free and overall
survival.” Idelalisib is a first-in-class
phosphoinositide 3-kinase (PI3k) delta
inhibitor that has been approved by the
U.S. Food and Drug Administration for
use in combination with rituximab for
patients with relapsed CLL and as a firstline treatment in patients with del17p or
TP53 mutation who are not eligible for
chemoimmunotherapy.
The study enrolled 416 patients
between June 2012 and August 2014.
Patients were eligible for the study if they
had received prior therapy containing
a purine analog or bendamustine, prior
treatment with an anti-CD20 antibody,
CLL progression within 36 months of the
completion of the last prior therapy, and
were “fit” to receive cytotoxic therapy. The
median time from prior therapy was 16
months, and the median number of prior
therapies was two (range = 1-13).
40
ASH Clinical News
Patients were randomized to receive:
• Idelalisib 150 mg plus bendamustine
70 mg/m2 and rituximab 375 mg/m2
during cycle 1 and 500 mg/m2 during
cycles 2-6 (n=207)
Results of a Phase 3 Double-Blind Placebo-Controlled
Study
TABLE 2.
• Bendamustine 70 mg/m2 and
rituximab 375 mg/m2 during cycle
1 and 500 mg/m2 during cycles 2-6
plus placebo (n=209)
Treatment was continued until disease
progression, death, intolerable toxicity,
or withdrawal of consent. Computed tomography imaging was performed every
12 weeks to assess patients for disease
progression.
After 12 months of follow-up, the
median PFS in patients treated with
idelalisib plus BR was more than double
the median PFS in patients treated
with BR alone: 23.1 months versus 11.1
months, respectively (hazard ratio [HR]
= 0.33; 95% CI 0.24-0.45; p<0.0001).
Additionally, though the median OS
had not been reached in either cohort
at the time of reporting, there was a 45
percent reduction in the risk of death
when idelalisib was added to treatment
(HR=0.55; 95% CI; 0.36-0.86). As seen
in the TABLE, the results were consistent across all patients, regardless of
the presence of high-risk features (i.e.,
del17p, TP53, unmutated IGHV, and
refractory disease).
At the pre-specified interim analysis
(once 67% of events had occurred), an
independent review committee recommended stopping the study early to
allow patients in the control arm to
receive idelalisib and unblinding the
results. “It was recommended that the
study should be stopped and that the
results should be made public, because
of an overwhelming benefit for the addition of idelalisib to the conventional
arm,” Dr. Zelenetz explained.
However, Dr. Zelenetz added, “this
was not without toxicity, and virtually
all patients in both arms experienced
treatment-related toxicity.”
Ninety-three percent of patients
in the idelalisib arm experienced a
grade ≥3 adverse event (AE), while 76
percent of those in the BR-alone arm
experienced a grade ≥3 AE. Serious
AEs were seen in 66 percent of patients
treated with idelalisib, compared with
44 percent of those in the control arm.
Rates of dose reductions or treatment
discontinuation due to AEs were 11
percent and 26 percent, respectively, in
the idelalisib-treated arm. These rates
were nearly double what was seen in
the control arm, at 6 percent and 13 percent, respectively.
The most common treatment-related
AEs for those receiving idelalisib plus
BR were neutropenia (63.3%) and
pyrexia (41.5%). Neutropenia was also
the most common treatment-related adverse event for those receiving BR alone
(53.6%), followed by nausea (34.4%).
“This safety profile is consistent with
what we know for idelalisib, bendamustine, and rituximab,” he noted. ●
REFERENCE
Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib plus
bendamustine and rituximab (BR) is superior to BR alone in
patients with relapsed/refractory chronic lymphocytic leukemia:
results of a phase 3 randomized double-blind placebo-controlled
study. Abstract #LBA-5 from the 2015 ASH Annual Meeting,
December 8, 2015; Orlando, Florida.
January 2016