Literature Scan
“Anti-CD19 CAR T cells can cause
lasting remissions in a subset of patients
with progressive B-cell malignancies after
allogeneic stem cell transplantation,” James
Kochenderfer, MD, investigator in the
Experimental Transplantation and Immunology Branch of the National Institutes of
Health and corresponding author on the
study, told ASH Clinical News. “The fact that
the CAR T cells caused remissions without
chemotherapy clearly demonstrates the antimalignancy activity of the CAR T cells.”
The phase I dose-escalation study included 20 patients treated between August 2010
and February 2015. Patients had measurable
CD19+ B-cell malignancies including:
• chronic lymphocytic leukemia (CLL;
n=5)
• diffuse large B-cell lymphoma
(DLBCL; n=4)
• mantle cell lymphoma (MCL; n=5)
• Philadelphia chromosome (Ph)negative ALL (n=4)
• Ph-positive ALL (n=1)
• follicular lymphoma (FL) that had
transformed to DLBCL (n=1)
Patients had previously undergone human
leukocyte antigen-matched sibling (n=13) or
unrelated donor alloHCT (n=7). Chemotherapy and antibody therapies had to be
stopped two weeks prior to CAR19 T-cell infusion. Disease stage was determined at least
two weeks after the last therapy before CAR
T-cell infusions, and patients were excluded if
they had evidence of acute GVHD > grade 1
or moderate or severe chronic GVHD.
Patients received a median of four
post-transplant lines of therapy prior to
enrollment (range = 1-24), and at least two
months elapsed between the most recent
DLI and CAR19 T-cell infusion.
Subjects received a single infusion of
CAR19 T cells obtained from the alloHCT
donor’s T cells, and dose-escalation followed
a standard, phase I, 3+3 design. Patients did
not receive conditioning with chemotherapy
prior to infusion.
Following CAR19 T-cell therapy, the
overall response rate (ORR) was 40 percent,
with eight patients achieving remission: six
CRs and two partial remissions. Patients
with acute lymphocytic leukemia (ALL)
experienced the highest response rate, with
four of five patients obtaining minimal
residual disease-negative CR. The longest
ongoing CR was reached in a patient with
chronic lymphocytic leukemia (30 months),
and, of the two partial remissions, one
Ibrutinib Plus Bendamustine
and Rituximab Yields Positive Results for Patients
With CLL/SLL
Adding ibrutinib to a standard treatment regimen of bendamustine and rituximab for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic
lymphoma (SLL) led to significant improvements in progression-free survival (PFS) and
overall response rate (ORR), according to a study led by Asher Chanan-Khan, MD, from
the Mayo Clinic Cancer Center in Jacksonville, Florida, and published in Lancet Oncology. Safety profiles were similar between the three-drug regimen and the control arm, the
authors noted, without added toxicities.
“The results of this trial demonstrate that ibrutinib has added benefit beyond the current standard-of-care chemoimmunotherapy in previously treated patients with CLL or
SLL,” Dr. Chanan-Khan and colleagues wrote. “Ibrutinib can be administered safely with
bendamustine plus rituximab and represents an alternative option to traditional chemoimmunotherapy.”
The international, double-blind, placebo-controlled, randomized, cross-over, phase
III HELIOS trial included 578 adult patients enrolled at 133 sites in 21 countries in North
America, Europe, Latin America, and Asia between September 2012 and January 2014.
Patients were eligible for the study if they had:
• Relapsed/refractory CLL or SLL following at least one previous line of therapy
consisting of at least two cycles of a regimen containing chemotherapy
• An Eastern Cooperative Oncology group performance status of 0-1
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ASH Clinical News
persisted for longer than 18 months. Eight
patients had stable disease, with the longest
duration of stable disease persisting for longer than 31 months following infusion.
“Many of the patients who obtained
remission after CAR19 T-cell infusions did
not obtain remission after standard DLIs
that contained higher T-cell doses, which
demonstrates that in some cases, CAR19
T-cell infusion is superior to standard DLI
at eradicating malignancy,” Dr. Brudno and
colleagues observed.
Peak blood CAR T-cell levels (measured
by quantitative polymerase chain reaction)
were higher among those who achieved
remission compared with those who did not
(p=0.001), “indicating that increasing the
peak blood levels of CAR19 T cells in vivo is
an important goal for future research,” the
authors explained. Programmed cell death
protein-1 (PD-1) expression, an inhibitory
receptor expressed on T cells, was significantly elevated on CAR T cells after infusion, suggesting that administering PD-1
antagonists after CAR19 T-cell infusion
might improve the rates of remission.
The researchers reported no findings
of new-onset acute GVHD following CAR
T-cell infusion, despite 14 patients (70%)
having had a history of GVHD sometime
after alloHCT and prior to enrollment.
GVHD occurred in only two patients on the
trial: A case of mild chronic ocular GVHD
developed approximately two years after
CAR19 T-cell infusion and a case of slowly
worsening chronic mild GVHD.
The most commonly reported adverse
events (AEs) included fever, tachycardia,
and hypotension, which was similar to other
trials assessing CAR T cells, the authors
noted. Sixty percent of patients experienced
grade 3/4 AEs, including an increase in serum creatine kinase in two patients that was
associated with mu scle pain and weakness.
Though the study is limited by its small
sample size, Dr. Brudno and co-authors
concluded that the findings “point toward a
promising future when CAR T-cell therapy
will be commonly used in transplant regimens to specifically target malignancy-associated antigens. CAR T cells could be
administered as planned infusions along
with or soon after stem cell infusions. Genetically targeted T cells will be an integral
part of allogeneic transplant protocols to
separate graft-versus-malignancy activity
from GVHD.” Follow-up is also limited, and
the study had no comparison group.
REFERENCE
Brudno JN, Somerville RP, Shi V, et al. Allogeneic T cells that express
an anti-CD19 chimeric antigen receptor induce remissions of B-cell
malignancies that progress after allogeneic hematopoietic stem-cell
transplantation without causing graft-versus-host disease. J Clin Oncol.
2016;34:1112-21.
• Lymph node disease >1.5 cm as measured by a computerized tomography (CT) scan
• Absolute neutrophil count >1 x 109/L
• Platelet count >50 x 109/L
• Adequate liver and kidney function
Patients were excluded from the study if they had del17p13 CLL or SLL; had received previous treatment with ibrutinib or other Bruton tyrosine kinase inhibitors; were refractory
or relapsed within 24 months with a previous regimen containing bendamustine; received
hematopoietic cell transplant; or had a history of a stroke, intracranial hemorrhage, or
clinically significant cardiovascular disease within six months prior to the study.
Eligible patients were randomized 1:1 to receive a four-week treatment regimen of:
• bendamustine: 70 mg/m2 intravenously on days 2 and 3 in cycle 1 and days 1 and 2 in
cycles 2-6
• rituximab: 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2-6
• ibrutinib: 420 mg orally once daily (n=289) or placebo (n=289)
“A large proportion of [these patients had] high-risk features such as unmutated IGHV
status (81% of 519 patients), del11q (26%), and bulky disease (56%),” the authors added.
“The median time between previous treatment and study treatment was 24 months or less
in both treatment groups, indicating a population with poor prognosis.”
Patients receiving placebo were allowed to crossover to the ibrutinib arm if disease progression was confirmed.
In addition to PFS (the study’s primary endpoint), secondary endpoints of the study
included overall survival (OS), ORR, proportion of patients with a negative response for
minimal residual disease (MRD), and safety.
The majority of patients in both the ibrutinib and placebo cohorts received the maximum six cycles of treatment (81% [n=235] and 77% [n=222], respectively). Patients in the
ibrutinib cohort had a median of 14.7 months of treatment exposure compared with 12.8
May 2016