TRAINING and EDUCATION
in transplant-naïve patients.
In addition to risks of myelosuppression, combination
chemotherapy regimens also increase the risk of secondary
malignancy in cHL long-term survivors. Myelodysplastic
syndromes (MDS) or therapy-related acute myeloid leuke-
mia (AML) typically occur in a dose-dependent manner,
two to eight years after initial treatment of HL with alkylat-
ing agents and topoisomerase inhibitors. Salvage chemother-
apy and conditioning regimens for AHCT also contribute to
the increased risk of AML/MDS in these patients.
For this reason, we favor use of combination therapies
for a limited duration (maximum 4-6 cycles) and only
in specific circumstances in which a rapid and significant
response is necessary; that is, in patients with organ
involvement, symptoms, or to achieve best response prior
to alloHCT. Furthermore, cumulative anthracycline dose
must be limited, and pretreatment ejection fraction as-
sessed if anthracycline-containing regimens are used in
the relapsed setting.
Checkpoint Inhibitors and Immunomodulatory Therapy
Over the last few years, there has been a growing interest
in modulating the extensive, but ineffective, inflammatory
and immune cell infiltrate surrounding Reed-Sternberg
(RS) cells. RS cells express high levels of programmed
death receptor-1 ligands (PD-L1), and by engaging PD-1–
positive immune effector cells, tumors can evade the
immune response.
In May 2016, the FDA approved the PD-1 inhibitor
nivolumab for the treatment of patients with cHL who have
relapsed or progressed after AHCT and post-transplant
brentuximab vedotin. The drug carries a warning for
patients who have undergone alloHCT, based on reports of
transplant-related deaths and hyper-acute and severe-acute
graft-versus-host disease (GVHD) following nivolumab
treatment. The FDA also required that the drug’s manufac-
turers conduct a post-marketing study to assess the safety of
nivolumab in these patients.
In March 2017, pembrolizumab became the second
PD-1 inhibitor approved for cHL, for a slightly different
population: adults and children whose disease is refractory
to treatment or has relapsed after receiving three or more
prior lines of therapy. In a phase II study evaluating the
safety and efficacy of pembrolizumab, response rates ranged
from 70 to 74 percent in patients who had undergone
AHCT, with or without subsequent brentuximab vedotin.
Confirmatory studies are under way with checkpoint
inhibitors in cHL. If the promising response rates in multi-
center studies of these agents hold up, this approach should
probably be offered after brentuximab.
Novel Agents in Clinical Trials
Several biologic agents are under development and
TABLE.
Selected Combination Regimens
have shown activity in
Fast Facts
this setting, including
✓ ✓ Patients with cHL who relapse after AHCT represent a population
lenalidomide, everoli-
with a median OS of one to two years.
mus, panobinostat, and
the immune checkpoint
✓ ✓ Brentuximab vedotin should be the first choice for patients who
inhibitors nivolumab and
relapse following AHCT.
pembrolizumab.
✓ ✓ Following brentuximab vedotin, recommendations are participation
Response rates with
in a clinical trial, checkpoint inhibitors, single-agent chemotherapy,
everolimus and histone
IFRT, or observation in select cases.
deacetylase inhibitors
✓ ✓ Combination chemotherapy strategies should be reserved for
rival those observed with
symptomatic patients with either a large disease burden or
lenalidomide in patients
extranodal disease, or those who are alloHCT candidates, given the
with relapsed cHL. Given
risks for toxicity and subsequent malignancies.
the associated risks of
✓ ✓ Many biologic agents are under development and have shown
grade 3/4 toxicities and
activity in this setting, including lenalidomide, everolimus, and
pulmonary toxicity, we
panobinostat.
recommend exercising
caution if considering
the use of everol