The lymphomas are an incredibly complex assemblage of neoplastic diseases. They are not one disease, and, at least based on the World Health Organization (WHO) Classification of Tumors published in 2017, they represent a collection of approximately 80 different malignancies, a number that will certainly increase with the next iteration. This diversity in disease is a reflection of the diverse normal cells that give rise to these malignancies. Although oncologists are used to thinking about malignant disease based on the cell of origin, only a minority of us can appreciate the vast repertoire of cells that comprise our immune system; even fewer of us can imagine how those cells spawn a unique malignant signature, rendering them distinct from their normal cellular counterpart, and other subtypes of peripheral T-cell lymphoma (PTCL).
Helen Ma, MD
Enrica Marchi, MD, PhD
Owen A. O’Connor, MD, PhD
Appreciating the complexities of the lymphomas requires one to appreciate the development of normal lymphocytes and their distinct ontogeny, as they mature from naive immature cells to more mature, card-carrying members of a complex immune system. Our immune system comprises three basic types of lymphocytes, including B, T, and natural killer (NK) cells, each playing its own role. Uniquely, however, these cells don’t live a solitary existence; in fact, they mandatorily require interaction with other types of lymphocytes, as well as their stromal surroundings, the microenvironment. ‘Social distancing’ among lymphocytes is tantamount to having severe combined immunodeficiency syndrome.
It is because the underlying biology of the normal cell counterpart is itself so complex that lymphoma classification has become the fodder for endless classification jokes. Our understanding of the disease is inextricably linked to appreciating the function of normal lymphocytes.
Many Challenges of T-Cell Lymphomas
Of the approximately 85,000 cases per year of lymphoma in the United States, it is estimated that just between 10,000 and 15,000 of them are T-cell lymphomas.1,2 The most common of these lymphomas is an entity known as PTCL–not otherwise specified, which has an incidence of about 2,500 cases per year in the United States.
ASCO has estimated that there are fewer than 15,000 medical oncologists in the United States.3 If we assume that all cases are spread evenly over all practices, it implies that each medical oncologist would expect to see one case of PTCL per year. Assuming the same for the most common PTCL entity, each medical oncologist might expect to see one case every 6 years. The rarity is daunting. How can any one physician, or city for that matter, ever see enough cases to be called an expert? It’s easy to neglect and ignore what one never sees—only one of the many challenges with T-cell lymphoma.
“‘Social distancing’ among lymphocytes is tantamount to having severe combined immunodeficiency syndrome.”— Helen Ma, MD; Enrica Marchi, MD, PhD; and Owen A. O’Connor, MD, PhD
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Treating Patients Based on Few Data
And so, it comes as no surprise, and no one’s fault, that decisions on how best to treat these patients are often made with essentially no data. Researchers and clinicians in T-cell lymphoma have become incredibly adept at extrapolating and interpreting small data sets to try to draw meaningful generalizations.
The standard front-line treatment is based on chemotherapy regimens predicated around CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), a program extrapolated from a different disease, namely B-cell lymphoma. And, as one might expect, it doesn’t work very well, with just 20% of patients alive after 2 years.
Treatment of patients with relapsed or refractory disease routinely follows these same B-cell treatment algorithms, often using ifosfamide/carboplatin/etoposide with or without autologous stem cell transplantation, despite the absence of any prospective data. The use of CHOEP, which integrates etoposide into the CHOP backbone, has become a “standard of care,” based on a retrospective German study; the trial evaluated its merits in a massive database of German clinical trial data, which demonstrated no statistical benefit, compared with CHOP, in patients with PTCL.4 Yes, a commonly used standard of care in PTCL is derived from a retrospective study that failed to show any statistical benefit of adding etoposide to the CHOP backbone. These have been desperate years, and even a small cohort of 13 patients in an unplanned subset analysis of selected trials has led to recommendations of one drug over another in that setting—a practice discouraged by most regulatory bodies around the world.
Therapeutic Progress of Late
However, despite the daunting heterogeneity, the stunning rarity, our general lack of understanding about disease biology, and the neglect, we have somehow muddled through the mess. The past 10 years have seen more progress in PTCL than the prior 50 years. As of 2020, the U.S. Food and Drug Administration has approved three drugs (pralatrexate, and two histone deacetylase [HDAC] inhibitors: romidepsin and belinostat) for the broader category of diseases we call PTCL as well as one drug (brentuximab vedotin) for anaplastic large T-cell lymphoma (ALCL). Although none of these agents are perfect, they are no worse than the drugs used to transform the natural history of multiple myeloma.
“The past 10 years have seen more progress in PTCL than the prior 50 years.”— Helen Ma, MD; Enrica Marchi, MD, PhD; and Owen A. O’Connor, MD, PhD
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These drugs are changing how we think, the paradigms of care, and are now daring us to think well outside the box. Several of these drugs have now been approved in many countries around the world, with pralatrexate approved by more than 35 international Healthcare Ministries. In fact, on the heels of the U.S. approvals, China has approved chidamide, an HDAC inhibitor similar to belinostat and vorinostat, and Japan has approved pralatrexate, romidepsin, brentuximab vedotin, mogamulizumab, and the purine nucleoside phosphorylase inhibitor forodesine. Small incremental steps over time can bring newfound attention to even the most ignored of lymphomas.
Although we have yet to discover any singular unifying mechanism of T-cell lymphomagenesis across the 30 PTCL entities, several lines of evidence have begun to suggest themes worthy of our attention. The first builds on the empiric observation that PTCLs appear to be uniquely vulnerable to epigenetic drugs and are the only disease for which there are four HDAC inhibitors approved, all producing eerily similar activity (overall response rates of 25%, with durations of response lasting about a year).
Why do PTCLs exhibit such a susceptibility to these epigenetic drugs? Although preliminary, recent data have suggested that at least one of these PTCL subtypes, angioimmunoblastic T-cell lymphoma, exhibits a susceptibility to the hypomethylating agent azacitidine. Second, as in acute myeloid leukemia and glioblastoma multiforme, select PTCL subtypes appear to be enriched for a host of mutations that govern DNA methylation, including genes such as TET2, IDH2, and DNMT3.
These two developments beg the following question: Do these patterns of mutation influence the disease’s vulnerability to our available epigenetic drugs? Perhaps most compelling, three independent research groups have reported that coupling a recurring mutation found in PTCL—the RHOA G17V mutation with a TET2-mutated gene—in various genetically engineered mouse models can produce spontaneous angioimmunoblastic T-cell lymphoma! The tumor-bearing mice that develop these T-cell malignancies have shown marked sensitivity to HDAC inhibitors and other drugs active in the disease, apparently recapitulating the experiences in patients.
Is it possible to recapitulate complex PTCL in engineered murine models as a means to screen novel drug or drug-drug combinations? Do these findings, and plenty more we can’t share here, all emerging over the past 10 years or so, poise us to finally make an impact to help patients suffering from this challenging malignancy?
Building Novel Treatment Platforms Based on Data
These rapidly have captured the imagination, and it seems that the early experiences are paving a more hopeful path for patients and researchers alike. Although few studies were dedicated to PTCL more than a decade ago, there are now more than 250 studies focusing on the disease, at least based on what is reported in ClinicalTrials.gov. These trials are producing data on the potential merits of many new classes of drugs, but it does look like combinations of drugs active in the disease, and in particular combinations that might address some of the underlying biologic dysregulation, are producing unprecedented activity. Along the way, these new combination experiences are providing a platform upon which we can squarely add new drugs in a rational way, to fashion new, and hopefully, chemotherapy-free programs.
Many of these examples are building off the synergy seen with various drugs in combination with HDAC inhibitors such as romidepsin. To date, a host of drugs have been studied in doublets with romidepsin,5,6 including bortezomib, pralatrexate, PI3K inhibitors, alisertib, and hypomethylating agents such as azacitidine. Although the results are early, combinations such as azacitidine and romidepsin are producing high overall and complete response rates, with a progression-free survival in PTCL that is, to date, superior to anything seen in the past and superior even to the experience in B-cell lymphomas—a first for this neglected disease.7
“Although the T-cell malignancies are far from having their own version of rituximab, there are now several immunologic drugs proving to be active in PTCL.”— Helen Ma, MD; Enrica Marchi, MD, PhD; and Owen A. O’Connor, MD, PhD
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The strategy of building novel drug platforms that might inform a logic for combining rational agents is one most research oncologists have been dedicated to for decades. And although the T-cell malignancies are far from having their own version of rituximab, there are now several immunologic drugs proving to be active in PTCL; one is now firmly established to improve the outcome of CD30-positive T-cell lymphomas, mostly ALCL, in combination with chemotherapy (brentuximab vedotin plus cyclophosphamide, doxorubicin, prednisone). The established merits of combining brentuximab vedotin with chemotherapy sets the stage to explore this drug in combination with newer doublets, perhaps breaking the addiction to relatively ineffective chemotherapy.
In addition, new biologics are targeting programmed cell death protein 1/programmed cell death ligand 1; NK-cell engagers are targeting CD30/16a; the ‘Do Not Eat Me’ signals inhibited by the anti-CD47 monoclonal antibody; antibodies such as mogamulizumab targeting CCR4; and a host of others offer new opportunities to build highly disease-specific platforms. These agents are producing a nearly infinite number of opportunities, as long as we are willing to continue to think outside the box.
Grassroots Movement in PTCL
The past decade has witnessed nothing short of a grassroots movement in PTCL. The establishment of several international registries, a global consortium of collaborating trialists, two major international meetings focused solely on the disease, new drugs and novel drug platforms, recent animal models that recapitulate select subtypes of PTCL, deeper insights into the use of gene-expression profiling to refine our understanding molecular classification, and modern global collaborations, all offer the prospect of hope. For a disease long neglected, forgotten, and ignored, it’s refreshing to see, at long last, it’s now become T time.
Drs. Ma and Marchi both work at the Center for Lymphoid Malignancies at Columbia University Medical Center, College of Physicians and Surgeons, New York. Dr. O’Connor is the American Cancer Society Research Professor at the Center for Lymphoid Malignancies at Columbia University Medical Center, New York.
DISCLOSURE: Dr. Ma reported no conflicts of interest. Dr. Marchi has received research support from Merck, Celgene, and Spectrum, and is a scientific advisor to Spectrum and Mundipharma, Myeloid Therapeutics. Dr. O’Connor has received research support from Celgene, Merck, Affimed, Kymera, Denovo, Spectrum, and TG Therapeutics, and is a scientific advisor to Mundipharma.
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7. O’Connor OA, Falchi L, Lue JK, et al: Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: A multicenter phase 1 study. Blood 134:1395-1405, 2019.