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Ipilimumab for patients with relapse after allogeneic transplantation
Comment by
Isabel Cunningham, MD
F
rom a phase 1 investigator-
initiated study using an agent
effective in the most malignant
skin cancer, comes exciting news of
the success of ipilimumab in leukae-
mic skin tumours, among the most
resistant forms of AML. When leu-
kaemia relapses in extramedullary
sites after allogeneic transplant, mar-
row is not in simultaneous relapse in
most cases initially, remaining 100%
donor. Tumours typically progress
autonomously to involve other sites
and may kill the patient even before
contaminating the marrow.
Effective treatments of non-skin
leukaemic tumours, standard for
those in testis and meninges, centre
on combined local tumour treatment
and systemic chemotherapy to pro-
tect the marrow. Immunologic ap-
proaches such as donor lymphocyte
infusions and second transplants
have rarely ablated leukaemic tu-
mours permanently. Leukaemic
tumours in skin have unique biol-
ogy in repeatedly recurring through-
out the skin. They are resistant to
most treatment. Electron beam
radiotherapy may produce transient,
but rarely durable, response.
The remarkable complete remis-
sions produced by ipilimumab in
3 cases (that presumably occurred
without concurrent marrow relapse),
with 2 lasting over a year, suggest the
first breakthrough in treating and
understanding this lethal problem.
The site-specificity is highlighted
in this report by the lack of remis-
sions among AML cases treated
for marrow relapse. It is notewor-
thy that ipilimumab was begun
a median of 3 months after skin
relapse, after failures with other
therapies. In view of how quickly
extramedullary leukaemia grows,
immediate treatment upfront will
likely produce even more durable
remissions.
Dr Cunningham is Adjunct
Associate
Research
Scientist,
Division of
Hematology
Oncology,
Columbia
University
College
of Physicians and
Surgeons in New York.
Ipilimumab for patients with relapse after
allogeneic transplantation
The New England Journal of Medicine
Take-home message
•
The safety and efficacy of ipilimumab (3 or 10 mg per kilogram of body
weight) in 28 patients with relapsed haematologic cancer after allogeneic
HSCT was examined in a multicentre phase 1/1B study. Among patients
who received the lower dose, no responses were observed that met the
formal response criteria. Complete and partial response rates in patients
who received a dose of 10 mg per kilogram were 23% and 9%, respec-
tively. A durable response lasting more than 1 year was achieved in 4
patients. The rate of immune-related toxicity was 21% (6 patients) and
included 1 death. Treatment with ipilimumab was suspended in 4 patients
(14%) who experienced graft-versus-host disease (GVHD).
•
Ipilimumab is active in patients with relapse of haematologic cancers after
allogeneic HSCT, but some patients experience GVHD or immune-related
adverse events.
Abstract
BACKGROUND
Loss of donor-mediated immune antitumour activity after allogeneic
haematopoietic stem-cell transplantation (HSCT) permits relapse of haematologic
cancers. We hypothesized that immune checkpoint blockade established by
targeting cytotoxic T-lymphocyte-associated protein 4 with ipilimumab could
restore antitumour reactivity through a graft-versus-tumour effect.
METHODS
We conducted a phase 1/1b multicentre, investigator-initiated study
to determine the safety and efficacy of ipilimumab in patients with relapsed
haematologic cancer after allogeneic HSCT. Patients received induction therapy
with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3
weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60
weeks in patients who had a clinical benefit.
RESULTS
A total of 28 patients were enrolled. Immune-related adverse events,
including one death, were observed in 6 patients (21%), and graft-versus-host
disease (GVHD) that precluded further administration of ipilimumab was observed
in 4 patients (14%). No responses that met formal response criteria occurred in
patients who received a dose of 3 mg per kilogram. Among 22 patients who
received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%)
had a partial response, and 6 (27%) had decreased tumour burden. Complete
responses occurred in 4 patients with extramedullary acute myeloid leukaemia
and 1 patient with the myelodysplastic syndrome developing into acute myeloid
leukaemia. Four patients had a durable response for more than 1 year. Responses
were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased
activation of regulatory T cells, and expansion of subpopulations of effector T
cells in the blood.
CONCLUSIONS
Our early-phase data showed that administration of ipilimumab was
feasible in patients with recurrent haematologic cancers after allogeneic HSCT,
although immune-mediated toxic effects and GVHD occurred. Durable responses
were observed in association with several histologic subtypes of these cancers,
including extramedullary acute myeloid leukaemia.
N Engl J Med
2016;375:143-153, Davids MS, Kim HT, Bachireddy P, et al.
JOURNAL SCAN
Nivolumab results in high rate of response in refractory classical
Hodgkin’s lymphoma
The Lancet Oncology
Take-home message
•
In this single-arm, phase 2 study, the authors evaluated the efficacy and safety of nivolumab monotherapy in 80
adults with recurrent classical Hodgkin’s lymphoma following failure of autologous stem-cell transplantation and
brentuximab vedotin. After a median of 8.9 months of follow-up, 66.3% of patients achieved an IRRC-assessed
objective response. Common adverse effects included fatigue (25%), reaction to the infusion (20%), and rash (16%).
The most common grade ≥3 adverse events were neutropenia (5%) and increased lipase concentrations (5%).
There were 3 deaths during the study period but none was thought to be related to therapy.
•
Treatment with nivolumab results in a response in the majority of patients with refractory Hodgkin’s lymphoma, and
the safety profile is acceptable. Nivolumab may represent a novel treatment option for this population.
Abstract
BACKGROUND
Malignant cells of classical Hodgkin’s lymphoma
are characterised by genetic alterations at the 9p24.1 locus,
leading to overexpression of PD-1 ligands and evasion of
immune surveillance. In a phase 1b study, nivolumab, a PD-
1-blocking antibody, produced a high response in patients
with relapsed and refractory classical Hodgkin’s lymphoma,
with an acceptable safety profile. We aimed to assess the
clinical benefit and safety of nivolumab monotherapy in
patients with classical Hodgkin’s lymphoma after failure of
both autologous stem-cell transplantation and brentuximab
vedotin.
METHODS
In this ongoing, single-arm phase 2 study, adult
patients (aged ≥18 years) with recurrent classical Hodgkin’s
lymphoma who had failed to respond to autologous stem-
cell transplantation and had either relapsed after or failed to
respond to brentuximab vedotin, and with an Eastern Coop-
erative Oncology Group performance status score of 0 or 1,
were enrolled from 34 hospitals and academic centres across
Europe and North America. Patients were given nivolumab
intravenously over 60 min at 3 mg/kg every 2 weeks until
progression, death, unacceptable toxicity, or withdrawal from
study. The primary endpoint was objective response follow-
ing a prespecified minimum follow-up period of 6 months,
assessed by an independent radiological review commit-
tee (IRRC). All patients who received at least one dose of
nivolumab were included in the primary and safety analyses.
FINDINGS
Among 80 treated patients recruited between Aug
26, 2014, and Feb 20, 2015, the median number of previous
therapies was four (IQR 4–7). At a median follow-up of 8.9
months (IQR 7.8–9.9), 53 (66.3%, 95% CI 54.8–76.4) of 80
patients achieved an IRRC-assessed objective response.
The most common drug-related adverse events (those that
occurred in ≥15% of patients) included fatigue (20 [25%]
patients), infusion-related reaction (16 [20%]), and rash (13
[16%]). The most common drug-related grade 3 or 4 adverse
events were neutropenia (four [5%] patients) and increased
lipase concentrations (four [5%]). The most common serious
adverse event (any grade) was pyrexia (three [4%] patients).
Three patients died during the study; none of these deaths
were judged to be treatment related.
INTERPRETATION
Nivolumab resulted in frequent responses
with an acceptable safety profile in patients with classical
Hodgkin’s lymphoma who progressed after autologous stem-
cell transplantation and brentuximab vedotin. Therefore,
nivolumab might be a new treatment option for a patient
population with a high unmet need. Ongoing follow-up will
help to assess the durability of response.
Nivolumab for classical Hodgkin’s lymphoma after failure of
both autologous stem-cell transplantation and brentuximab
vedotin: a multicentre, multicohort, single-arm phase 2 trial
.
Lancet Oncol
2016 Jul 20;[Epub ahead of print], Younes A,
Santoro A, Shipp M, et al.
Haematology practice implications: New
adult T-Cell lymphoma research
INTERVIEW WITH ANDRE GOY, MD
Dr Andre Goy, Chairman, and Direc-
tor, and Chief of Lymphoma at John
Theurer Cancer Center at the Hack-
ensack University Medical Center,
speaks with
PracticeUpdate
’s
Dr Farzanna Haffizulla on the anti-
CCR4 monoclonal
antibody mogam-
ulizumab for the
treatment of adult
T-cell lymphoma.
The remarkable complete remissions produced by ipilimumab in 3 cases (that presumably
occurred without concurrent marrow relapse), with 2 lasting over a year, suggest the first
breakthrough in treating and understanding this lethal problem.
HAEMATOLOGY
PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY
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