CLINICAL NEWS
However, she noted, progress in cell manufac-
turing suggests that CAR products could be gener-
ated for nearly all patients who need them. At the
National Cancer Institute, for example, 94 percent
of patients were able to receive manufactured cell
products. “We will find a time where, at least from
a technical standpoint, this product could be made
for every child who would need it. The economics
of it, I think, will still need to be demonstrated,” Dr.
Mackall said.
Inotuzumab Ozogamicin
Inotuzumab ozogamicin, a CD22-directed antibody-
drug conjugate, was approved as the first antibody-
drug conjugate for adult patients with CD22-positive
relapsed or refractory ALL. The decision was based
on results from the phase III INO-VATE 1022 trial,
reported Tanya Wroblewski, MD, clinical reviewer
at the FDA. The CR rate in the inotuzumab arm
was 36 percent, versus 17 percent in the investigator
choice of chemotherapy arm. Duration of CR also
was longer in the inotuzumab arm, at 8.0 months
versus 4.9 months in the control arm.
However, overall survival in the total number of
patients enrolled and treated in the INO-VATE ALL
study did not reach statistical significance, “which
is surprising given the CR rate, MRD-negativity
rate, and the number of patients who proceeded to
subsequent transplantation in the inotuzumab arm,”
Dr. Wroblewski added.
“The antibody drug conjugate class of thera-
peutics embodies the principle of Ehrlich’s magic
bullet – something that cancer researchers have been
working toward for many, many years,” Dr. Mackall
said during her discussion of this anti-CD22 therapy.
“There have been substantial technological improve-
ments in engineering antibodies and in refining the
chemistry needed to link the chemotherapy agent to
the antibody,” she noted, which is resulting in more of
these agents entering clinical trials.
While inotuzumab ozogamicin showed “im-
pressive” remission rates in adults with relapsed or
refractory B-cell ALL, Dr. Mackall mentioned that
her excitement over the new agent is tempered by
toxicity concerns. The drug carries a boxed warning
for hepatotoxicity, including hepatic veno-occlusive
disease (VOD). In patients who received inotuzumab
ozogamicin in the INO-VATE trial, 14 percent devel-
oped VOD overall, and 23 percent who underwent
subsequent allogeneic hematopoietic cell transplanta-
tion (alloHCT) developed VOD.
Previous experiences with a related compound,
gemtuzumab ozogamicin, also raise concerns,
she said. “[Gemtuzumab ozogamicin] previously
similarly demonstrated activity in acute myeloid
leukemia, but clinical benefit was diminished by the
risk of VOD in those patients, many of whom go on
to get alloHCT,” she said.
NHL
Axicabtagene Ciloleucel
Axicabtagene ciloleucel was the second CAR T-cell
therapy approved by the FDA in 2017, and it is
indicated for the treatment of adult patients with
relapsed or refractory large B-cell lymphoma after
two or more lines of systemic therapy. This includes
adults with diffuse large B-cell lymphoma (DLBCL)
not otherwise specified, primary mediastinal large
B-cell lymphoma, high-grade B-cell lymphoma, and
DLBCL arising from FL, but is not indicated for
ASHClinicalNews.org
primary central nervous system (CNS) lymphoma,
said Yvette Kasamon, MD, clinical reviewer at the
FDA.
Approval was based on results from the single-
arm, multicenter ZUMA-1 trial, which enrolled more
than 100 adult patients with aggressive B-cell NHL.
Following conditioning with low-dose cytarabine
and fludarabine, 72 percent of patients responded to
axicabtagene ciloleucel, with a CR rate of 51 percent.
“Only patients who achieved CR tended to have
durable remissions. In patients with the best overall
response of CR, the median duration of response
was not reached after approximately eight months
of follow-up,” Dr. Kasamon said. “In contrast, in
patients who achieved only partial remission, the
median duration of response was two months.”
The overall risk-benefit ratio is favorable in the
approved population, she added. However, as with
tisagenlecleucel, this CAR T-cell therapy carries
boxed warnings for CRS and CNS neurotoxicity,
and is only available through a REMs. In ZUMA-1,
52 percent of patients experienced a serious AE, the
most common of which (occurring in ≥10% of pa-
tients) included febrile neutropenia CRS, encepha-
lopathy, and infections.
“This is a ‘living drug’ with significant side ef-
fects,” noted Helen Heslop, MD, DSc (Hon), Dan
L. Duncan Ch