Mr. Unger’s experience, 30 years ago
According to Mr. Unger, the initial treatment for his stage IIIB Hodgkin lymphoma was MOPP (mechlorethamine hydrochloride, vincristine sulfate, procarbazine hydrochloride, and prednisone) plus ABVD (doxorubicin hydrochloride, bleomycin sulfate, vinblastine sulfate, and dacarbazine).
“They wanted to give me two chemo programs at once because they said I was very sick,” Mr. Unger recalled. “I wound up staying in the hospital quite a bit because every time I got these [treatments] I’d get a fever. This went on for month after month after month. Finally, they said: ‘The tumors are starting to shrink. ... I want you to meet Dr. Gulati.’ ”
Mr. Unger said that Dr. Gulati told him: “There is another procedure called the bone marrow transplant which we’ve been doing. This would be like hitting it with a nuclear weapon. We would really wipe it out and make sure that you never come back.”
The alternative was high-dose radiotherapy. However, Dr. Gulati shared MSKCC’s hard-won knowledge that an autologous transplant was less successful after radiation. Dr. Gulati also told Mr. Unger that surgery was needed before the transplant: a laparotomy to restage his tumors.
After discussing the situation with his father, Mr. Unger decided to undergo the transplant.
The night before treatment started, he was laughing and joking with a friend in his room at MSKCC. The next day, the laughing stopped. The conditioning, he said, “was harrowing beyond belief ... 100 times worse than the chemo.”
Chemotherapy came first, followed 2 days later by radiation, presumably TNI. Mr. Unger experienced constant vomiting, intraocular bleeding and high fevers; the soft tissue of his throat “fell apart,” he said.
“I couldn’t move. It was like being dead,” he said. “Finally, maybe after a month or so, I could finally have a little water.” Mr. Unger said his immune system took 6-8 weeks to recover. He concluded, with heroic understatement, “it was rough.”
The battle against Hodgkin was over, but fallout from the chemotherapy lingered. Although Mr. Unger was able to return to his family and the job he loved, in the following years he was never entirely well. He contracted shingles soon after his transplant, then diabetes within 15 years. A heart attack followed in 2008 then, in 2015, an autoimmune disease that still affects his mobility.
However, Mr. Unger remains grateful: “The fact that we did these cutting-edge techniques with me got me to the point where – although I had some problems afterward, and I have problems now – it gave me well over 30 years of a really great life.”
“There are a lot of good doctors out there,” he added. “Some of them go to extraordinary lengths to help people. I try to do the same with the extra 30 years I’ve been given, try to be nice to people and make people feel good. I don’t really see any other reason to be on earth.”
Treatment for Hodgkin lymphoma: 2022
For a comparison of Mr. Unger’s experience with the current approach to Hodgkin lymphoma, this news organization spoke to Miguel-Angel Perales, MD, current chief of the adult bone marrow transplant service at MSKCC. Although Dr. Perales could not comment specifically on Mr. Unger’s case without his records, Dr. Perales was able to review the revolutions in treatment for all patients over the past 30 years.
Courtesy MSKCC
Dr. Miguel-Angel Perales
Certainly, physicians no longer need to inflict a laparotomy on patients just to stage the disease, Dr. Perales said. “This sounds barbaric today. Nowadays we have PET scans.”
Another key change, Dr. Perales said, is in the up-front management of the disease.
For example, MOPP “is going back to the prehistory of chemotherapy,” Dr. Perales said. He was not surprised to learn that Mr. Unger later developed complications such as diabetes and heart disease.
“We’ve completely revolutionized the treatment,” Dr. Perales said. “We [now] use combinations that are much less toxic than MOPP, [and] we’re curing more patients up front.” Treatment is tailored by stage and the likelihood of response to therapy. Aggressive approaches are reserved for patients more likely to fail treatment.
Pretransplant conditioning has also changed for the better, with less toxicity and fewer long-term complications. Total body irradiation has “fallen by the wayside,” said Dr. Perales. Instead, patients get BEAM, a combination of carmustine, etoposide, cytarabine (Cytosar-U, Ara-C), and melphalan (Alkeran), 1 week before the transplant.
Perhaps the most profound change, which began in the 1990s shortly after Larry’s transplant, was that peripheral-blood stem cells gradually replaced bone marrow for both autologous and allogeneic transplant. In 2022, nearly all autologous transplants use peripheral-blood stem cells.
Instead of onerous bone-marrow aspiration in the operating room, the stem cells are collected from the patient’s blood. First, the patient’s bone marrow is hyperstimulated with high doses of filgrastim (G-CSF, Neupogen, Granix) for several days. Stem cells spill into the patient’s blood. Once blood is collected from the patient, the stem cells are separated and stored ready for the transplant. (In theory, stem cell products are “cancer free”; in practice there may be some contaminating cells, said Dr. Perales.)
Nowadays “transplanting” the stem cells back into the body bears no relation to what happened in 1992. The stem-cell infusion is typically an outpatient procedure, and one-third of patients may never be admitted to the hospital at all.
In contrast to Mr. Unger’s excruciating 8-week hospital stay, immune recovery currently takes 12-14 days, often entirely in the patient’s own home, with the option of extra filgrastim to speed things up.
Despite these profound changes, said Dr. Perales, the real quantum leap has occurred post transplant.
In 2015, a multinational team led by MSKCC’s Dr. Craig Moskowitz published a trial in the Lancet showing that brentuximab vedotin halved the risk of relapse after autologous transplantation in high-risk Hodgkin lymphoma patients versus placebo (hazard ratio, 0.57; P = .0013; n = 329). The CD30-directed antibody-drug conjugate was so successful that the placebo patients were encouraged to cross over into the treatment group; many of them were salvaged.
As a result, Dr. Perales said, brentuximab vedotin has now become the standard in high-risk Hodgkin patients following a transplant.
The checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) have also been “transformational” in Hodgkin lymphoma, Dr. Perales said. He explained that Hodgkin lymphoma is “exquisitely sensitive” to these therapies because the disease expresses high levels of the binding proteins for these drugs. This allows the immunotherapies to hit both the immune system and the disease.
Most cancers have response rates for checkpoint inhibitors below 40%, according to a recent analysis by Anas Younes, former chief of lymphoma at MSKCC, and his colleague Eri Matsuki, then a visiting fellow. By contrast, in Hodgkin lymphoma response to these drugs is 66%-87%.
Dr. Perales said: “It tells you how effective these drugs are, that we could move from somebody getting MOPP, which is like throwing a nuclear bomb at somebody, to a combination of two drugs that can easily be given out-patient and that have very little, if any, side effects.”
The future: No chemo, no transplants?
“One of the holy grails in Hodgkin would be if we could treat patients with the combination of a checkpoint inhibitor and brentuximab and what is being termed the ‘chemotherapy-free’ approach to Hodgkin disease,” said Dr. Perales.
What else remains to be done in the world of transplants for Hodgkin lymphoma?
Dr. Perales didn’t hesitate: “To eliminate the need for them. If we can have better targeted therapy up front that cures more patients, then we never even have to consider transplant. Basically, to put me out of work. I’m sure I’ll find other things to do.”
The current treatment of Hodgkin lymphoma “is really what we all consider one of the successes in oncology,” said Dr. Perales. “It’s a beautiful story.”
Dr. Perales reported receiving honoraria from numerous pharmaceutical companies; serves on data and safety monitoring boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; and serves on the scientific advisory board of NexImmune. He has ownership interests in NexImmune and Omeros, and has received institutional research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.