Drugs that activate the immune system to
fight cancer have brought remarkable recoveries to many people in recent years.
But one of those drugs seems to have had
the opposite effect on three patients with an uncommon blood cancer who were
taking part in a study. After a single treatment, their disease quickly became
much worse, doctors reported in a letter to The New England Journal of
The cases are a sobering reminder that
immunotherapy is still in its early days, and can unleash powerful forces that
are not fully understood. Patients and doctors are eager to try the treatments
when other options have run out, even for cancers in which they haven’t yet
been tested. Sometimes those hail-Mary efforts work. But they can backfire.
The patients, treated last year at
different hospitals, had adult T-cell leukemia-lymphoma, which is caused by a
virus. The drug was nivolumab, or Opdivo, which belongs to a class called
checkpoint inhibitors. The drugs cost more than $100,000 a year. Nivolumab has
been approved to treat eight types of cancer, but not this type of lymphoma.
The virus linked to the lymphoma — HTLV-1 —
infects millions of people around the world, with the highest known prevalence
in Japan, Africa, South America, the Caribbean and parts of Australia. But only
5 percent or fewer of those infected develop adult T-cell leukemia lymphoma;
the reason is not known. The virus can be transmitted through sex,
breast-feeding, needle-sharing, transfusions and transplants.
In the United States, lymphoma from the
virus is seen most commonly in immigrants from affected regions.
The patients described in the journal were
the first three in a nationwide clinical trial meant to test the drug in 20
people with the lymphoma. But after the third got worse instead of better,
researchers shut down the study, which was funded by the National Cancer
Institute. They wrote to the journal to alert other doctors to the potential
risk of giving the drug, a form of immunotherapy, to patients with that type of
“I don’t think we should use nivolumab in
this disease at all, considering our experience,” said Dr. Murali Janakiram, an
author of the letter, who treated a patient at Montefiore Medical Center in the
Bronx, N.Y. “That’s why we wanted to get this publication out. With other
T-cell lymphomas, we should be cautious that this could potentially happen, but
continue with the clinical trials.”
“We really were quite shocked by the
results with all three of these patients,” said Dr. Lee Ratner, of Washington
University School of Medicine in St. Louis, who designed and organized the trial.
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This type of lymphoma has four subtypes,
including two that are often fatal less than a year after being diagnosed.
People with the other two can survive longer.
The first patient, who joined the study in
February 2017 and was treated at the National Institutes of Health, had an
indolent form called “smoldering,” and had survived, with various treatments,
for more than 20 years, according to Dr. Thomas A. Waldmann, a physician and
“She lived through the time from where she
had infants to where she had kids in college,” Dr. Waldmann said.
But she had painful skin lesions and other
signs that the disease was worsening. The doctors had run out of treatment
Trying a checkpoint inhibitor seemed to
make sense. The cancerous cells in this type of lymphoma have a lot of
mutations, and the drugs had been found to work best in that situation.
“We thought this approach in this patient
would be beneficial,” Dr. Waldmann said. “What we observed was just the
opposite. All the aspects of smoldering were replaced by the characteristics of
the very aggressive, acute T-cell malignancy.”
Less than a week after one nivolumab
infusion, the patient’s skin lesions turned swollen and warm. Her spleen became
massively enlarged and painful, and there was a 63-fold increase in her levels
of DNA from the cancer-causing virus.
“If one has been studying and working with
a patient for 20 years, one develops a relationship,” Dr. Waldmann said. “It
was very disconcerting to see this.”
Doctors used radiation treatments to shrink
the patient’s spleen and skin lesions. They did not know if the nivolumab was
to blame, but they gave her no more of it. She seemed to return to the
condition she’d been in before receiving the drug, with worsening disease. She
died a few months later.
At the time, Dr. Waldmann suspected that
the drug might have made the disease progress. Checkpoint inhibitors work by
activating white blood cells called T-cells, a part of the immune system that
should attack tumors. But in patients with this type of lymphoma, the drugs
might mobilize diseased T-cells as well as healthy ones.
Still, the researchers could not be sure if
the patient’s decline had just been an unfortunate coincidence.
Then, a few months later, something similar
happened at Ohio State University. Just days after being treated, a patient
with smoldering disease developed flulike symptoms, and within a few weeks,
“the leukemia had just massively progressed into the bones and bone marrow and
everywhere,” said Dr. Jonathan E. Brammer, an oncologist there.
She had to be taken off the study and
treated with chemotherapy. Dr. Brammer said he did not know how she is now,
because she had traveled to Ohio State for the study, and then went back home
and continued treatment with local doctors.
“In science, when you administer a drug,
you expect one outcome, but until you actually do it you don’t know what the
outcome is going to be,” Dr. Brammer said.
The third patient, treated at Montefiore
last November, had an acute form of the disease and had already been through
several types of chemotherapy. The disease becomes very resistant to chemo, so
the nivolumab study seemed like a better option than more chemo, Dr. Janakiram
“We gave him the first dose, and within 15
days, by the time he was ready to receive the next dose, his disease was just
taking off,” Dr. Janakiram said. “It was even more aggressive.”
The patient was switched back to chemo, and
stabilized. He had gone to Montefiore to join the study, and then went back to
his original doctors. Dr. Janakiram said he did not know how the patient
Researchers at the three centers, along
with Dr. Ratner, compared notes and decided to call off the study.
“This is a disease that can worsen at any
point of time,” Dr. Janakiram said. “But then it’s just so soon after the drug
that we cannot rule out that it’s the drug causing the problem.”
Dr. Jedd D. Wolchok, an immunotherapy
expert at Memorial Sloan Kettering Cancer Center who was not involved in the
study, said the information was important, and he agreed that patients with any
type of T-cell lymphoma — and there are many — should be carefully monitored if
given a checkpoint inhibitor.
“This is a time of very rapid learning,” he
The original version of this article appeared here.