When I say ‘cancer,’ you probably picture a specific type of cancer that you have read about or even had a personal experience with. Indeed, while there are many hundreds of different cancer types that afflict humans, there are a few standouts which have so deeply penetrated our culture that their names are recognizable even to those outside of the medical profession—think lung or breast adenocarcinomas, leukemias, melanomas, or glioblastomas. While these diseases have earned their places at the top of ‘Cancer’s Most Familiar’ list (often through their sheer prevalence or particularly dismal prognoses), their ubiquity hides a dark underbelly of cancer, a world bathed in uncertainty: the world of rare cancers.
You probably haven’t heard of the type of cancer we will discuss today. It’s a type of lymphoma—cancer of immune cells—and more specifically, it is a cancer of T-cells. T-cells come in different types, among which are the ‘cytotoxic’ T-cells which are responsible for engaging and killing infected or cancerous cells. When these T-cells transform into cancerous cells themselves, they comprise a malignancy termed cytotoxic T-cell lymphomas. These lymphomas also come in multiple types, depending on the location and specific subtypes of T-cells involved: those that originate from cytotoxic T-cells in the skin are called cytotoxic cutaneous T-cell lymphomas, or cytotoxic CTCLs. If all of these different names strike you as confusing and complicated, suffice to say that many cytotoxic CTCLs are 1.) generally aggressive and debilitating tumors, and 2.) exceedingly rare among cancers.
“We may see at most a few dozen patients with cytotoxic CTCL in our clinics over the course of an entire year,” notes Dr. Ajay Gopal, a physician-scientist in the Clinical Research Division at Fred Hutch and Hematology-Oncology Division at the University of Washington whose group studies hematological malignancies including CTCLs. “This rarity makes treating and studying these tumors very difficult.”
Your conception of modern cancer research may include armies of hardworking scientists toiling in labs, studying cancer cells in dishes and treating mice with arrays of potential therapeutics, before the most promising candidates are tested in large, randomized, placebo-controlled clinical trials. But what if there were no mouse models, no culturable cancer cells in which to develop and test potential cures? What if there were not enough patients to enroll in clinical trials, even if potential therapies were discovered? This is the reality faced by clinicians encountering cytotoxic CTCL and numerous other types of rare cancers, even in today’s world of rapid medical and technological advancement.
“When we get a patient with a rare cancer like cytotoxic CTCL, we’re really limited to a handful of therapeutics which have been approved for similar—but not identical—tumor types,” says Gopal. “From this small handful of potential treatments and lacking a ‘standard of care,’ individual clinicians must make judgement calls about how to treat their patients, using whatever scant information is available in the literature or from their own experience treating the disease.”
One of these clinicians was Dr. Christina Poh, a colleague of Dr. Gopal’s who began to notice a pattern among the cytotoxic CTCL patients that she was treating—over time, it seemed that the patients given a specific chemotherapeutic called pralatrexate (which shows efficacy in other types of T-cell lymphoma) seemed to respond better than patients given other therapies. To test whether this perceived trend was real, Poh and Gopal teamed up with Dr. Michi Shinohara at the University of Washington and other colleagues and conducted a retrospective study—basically, a systematic review of patient records to determine if there were any differences in outcome between patients who received pralatrexate and those who did not. Reporting their results in Blood Advances, the team find promising results that this chemotherapy is effective for treating cytotoxic CTCL. Of the 18 patients they studied, those who received pralatrexate exhibited significantly higher overall survival (OS) and progression-free survival (PFS) than those who did not, and 12/18 showed a ‘complete response,’ whereby all detectable signs of cancer were absent in a period following administration of the therapy. Furthermore, their analysis suggests that the doses of pralatrexate that elicited these responses were tolerable, with only a single patient discontinuing the therapy due to intolerable side effects.
So, mission accomplished—should we be treating every cytotoxic CTCL patient with pralatrexate now? “Not so fast,” says Gopal. “It’s important to recognize the limitations of this study; 18 patients is an incredibly small sample size to generalize from, and since the study was retrospective, any associations we found are suggestive of an effect but cannot account for other factors which may influence the outcome.” It’s also worth noting that pralatrexate isn’t a cure—most of the patients in the study had progression-free survival (PFS) measured in months, and a significant fraction ultimately relapsed after treatment and succumbed to the disease. Gopal continues, “This study is small and imperfect, but it’s also the best we have, and it’s a whole lot better than doing nothing, or choosing therapies with the hope that they work. For cancers this rare, even small studies like these have the potential to meaningfully impact clinical practice.” The team is hopeful that these promising results might form a foundation on which to build larger, multi-center retrospective or even prospective studies to further evaluate pralatrexate as a therapy for cytotoxic CTCL.
How effective is pralatrexate in treating cytotoxic CTCL compared to other chemotherapies? Why does pralatrexate work where other chemotherapies that work through a similar mechanism do not? How does pralatrexate efficacy interact with other therapies that cytotoxic CTCL patients have received, and could combining pralatrexate with some of these other therapies improve efficacy? These questions await a future in which we better understand cytotoxic CTCL—a future which we are approaching every day, thanks to the careful work of physician scientists and clinician scholars like Drs. Poh, Shinohara, and Gopal.
The spotlighted work was funded by philanthropic donations.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Dr. Ajay Gopal, Michi Shinohara, Qian Wu, Stephen Smith, Mengyang Di, Chaitra Ujjani, Brian Till, Edus Warren, Ryan Lynch, and Mazyar Shadman contributed to this research.
Poh, C., Voutsinas, J. M., Shadman, M., Lynch, R. C., Warren, E. H., Crimp, C. A., Till, B. G., Ujjani, C. S., Di, M., Raghunathan, V., Smith, S. D., Wu, Q. V., Shinohara, M. M., & Gopal, A. K. (2025). Pralatrexate is effective in cytotoxic cutaneous T-cell lymphomas. Blood Advances, 9(15), 4037–4042.
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.
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