New Hope for T-cell Lymphoma

Until recently, patients with T-cell lymphoma have been treated with the same treatments used for B-cell lymphoma. Unfortunately, this approach has not resulted in enduring remissions for those with T-cell lymphoma.

However, major inroads into understanding the molecular basis of T-cell lymphomas are now being made leading to the development of treatments that specifically target the different T-cell lymphomas. This was one of the key outcomes from the fifth annual T-cell Lymphoma Forum held recently in San Francisco.

What is the T-cell Forum?

The forum was started five years ago by Dr. Francine Foss with the goal of gathering scientists and clinicians from around the world working in the area of either T-cell biology or T-cell lymphoma to try and understand why patients with T-cell lymphoma did so poorly on treatment. Dr. Foss was one of the co-chairs for this year’s forum. Dr. Foss is a professor of medical oncology at Yale Cancer Center, New Haven, Connecticut, USA.

“This meeting was to get the basic science folks, the translational research folks and the clinicians who are seeing the patients together in one room to discuss the needs, and to try to strategise how we could move forward in an area where there is tremendous unmet medical needs and also where there is a tremendous lack of evidence because we haven’t done the tumour profiling, the gene array studies and we don’t understand the biology as well as we do with the B-cell lymphomas,” she said.

At the 2013 meeting, efforts were made to explore whether there were potential animal model systems that could be used to help in the development of drugs. As well, focus was placed on what was known about existing transduction pathways and other pathways that can be targeted with available treatments.

Molecular basis for T-cell lymphomas

The understanding of the molecular basis for T-cell lymphomas has improved greatly in the last few years and at this year’s forum, presenters provided new insights into the possible mechanisms of T-cell lymphoma genesis.

“We know a lot about the molecular pathology that underlies the pathology of many B-cell malignancies but for years we’ve really been limited by a remarkable paucity of information regarding the underlying mechanisms of T-cell lymphoma genesis,” said Dr. Owen O’Connor, co-chair of the T-cell Lymphoma Forum. Dr. O’Connor is chief of the Lymphoma Service at NewYork-Presbyterian/Columbia and associate professor of medicine at Columbia College of Physicians and Surgeons.

As a result of these new insights, there is a greater understanding of the biological basis of T-cell lymphoma.

“We’ve learned that not all T-cell lymphomas are alike and they can derive from different precursor T cells which should dictate a potentially different treatment approach,” said Dr. Foss.

Uniqueness of T-cell lymphoma

T-cell lymphomas are unique for a number of reasons. In the classification system, there are at least 20 subtypes and they are not all alike. T-cell lymphomas tend to be more extranodal than B-cell lymphomas, and they are much harder to diagnose than B-cell lymphomas because of the myriad of clinical presentations.

Under the broad category of lymphocytes, they come in in three broad categories: B, T and NK. All these cells play remarkably different roles in the immune system.

“So, it makes sense that biologically these cells are not the same, they are actually very different,” said Dr. O’Connor.

From a clinical perspective, for many years there was no deep insight that aggressive T-cell lymphomas were all that different from B-cell lymphomas. Consequently, treatment paradigms used for B-cell lymphomas were applied to the treatment of T-cell lymphomas.

“Unfortunately that experience taught us that T-cell lymphoma patients often experience early relapse or refractory disease to the conventional chemotherapy regimens used to treat B-cell lymphoma. Therein, we established that T-cell lymphomas are markedly different from B-cell lymphomas with regard to their response and curability with chemotherapy,” said Dr. O’Connor.

Importance of distinguishing between B- and T-cell lymphomas

The overwhelming majority of lymphoma diagnoses are B-cell lymphomas (85%), with the remaining 15% being T-cell lymphomas.

“The first distinction is to identify if you have a lymphoma whether it’s a T or B. But a more important thing for a T-cell lymphoma patient is getting the initial diagnosis of lymphoma because many of these patients will present with symptoms or syndromes like, for instance, an autoimmune syndrome or a fever of unknown origin and it will be difficult to get the diagnosis,” said Dr. Foss.

To help in making the diagnosis, Dr. O’Connor noted that it’s critical that diagnostic biopsies be obtained and that the pathologist undertake a variety of immunohistochemical stains so the clinician can differentiate whether the tumour is derived from B, T or natural killer (NK) cells.

Treatment options for T-cell lymphoma

Progress has also been made on the clinical front with many new drugs and potential ideas on how to use them to advance the upfront treatment outcomes for patients with T-cell lymphoma.

“Nothing short of a plethora of new drugs are emerging with their own unique activity in T-cell lymphoma. There is also exciting new data that seems to suggest that we might be combining these drugs in efforts to make new platforms that could potentially challenge CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in the future,” said Dr. O’Connor.

Dr. Foss added that “an important part of the meeting was going back and looking at what the potential effective therapies are and helping to elucidate what patients may benefit…and make some sense of how to administer these therapies, and what group of patients should get what agents.”

The agents currently approved for use in some countries for the treatment of T-cell lymphoma are brentuximab vedotin, pralatrexate, romidepsin and vorinostat.

Challenge of undertaking clinical trials in T-cell lymphoma

T-cell lymphomas are rare diseases which presents a number of challenges, one of which is not having enough patients to enrol into clinical trials. Dr. Foss indicated that perhaps there are too many clinical trials being undertaken at various clinical institutions as well as pharmaceutical companies competing with each other over a small number of patients.

“We as a community need to start prioritising these studies to get any meaningful information and get enough patients on a study to be able to draw a conclusion,” said Dr. Foss. She also added that translational components need to be part of clinical trials.

“We need to be doing some profiling of the tumours to try to look for markers or predictors of which patients are going to respond to that therapy,” she said. However, Dr. Foss explained that these kinds of studies are expensive and obtaining funding from other sources is challenging in light of budget cuts.

Another issue is that given the rarity of the diseases, many medical oncologists are likely to only see a patient with T-cell lymphoma every few years.

“Given the way these diseases concentrate, many medical oncologists never even see most of the different subtypes of PTCL (peripheral T-cell lymphoma), so it makes it very difficult for any one doctor to develop sufficient expertise to be able to manage these diseases based upon experience,” he said.

Marked geographic variations with regard to the distribution of the different T-cell lymphomas is also a challenge. For example, in the British Isles, enteropathy-associated T-cell lymphoma is more common than elsewhere. In Asia, there is a very high incidence of HTLV-1-associated adult T-cell leukemic lymphoma.

“So, there are marked variations in the distribution of the different subtypes of the disease as well as across countries and, as a general feature in North America and Europe, these diseases are remarkably rare,” said Dr. O’Connor.

The current regulatory climate also presents a challenge as Europe and North America, and potentially Asia, require very large randomised trials be conducted in this patient population.

“While we’re in a relative time richness and wealth with these new drugs, it does present challenges with how we’re going to prioritise our patients for these various trials so we can get the answers as fast as possible,” said Dr. O’Connor.

Role of transplant in T-cell lymphoma

The use of transplant was also discussed at the forum. Based on the National Comprehensive Cancer Network (NCCN) guidelines, transplant should be considered in first remission even though there is no proven benefit in this approach. Dr. Foss explained that NCCN can set up a guideline for a treatment approach without proven benefit by looking at multiple levels of evidence. If there is a large enough number of patients to support the safety and potential benefit of the approach, it is appropriate to put it in the guidelines.

Dr. Foss noted that autologous transplant has become a practice standard. However, while the benefit is unclear, if it is not done, then the patient may be deprived of a potentially curative modality; on the other hand, if it is undertaken, the patient may be exposed to a morbid procedure that may not necessarily translate into a benefit.

“The discussion at the meeting was that we need to do some kind of randomised trial. It is probably going to have to be an international study. The Europeans are ahead of us on that, they already have those kinds of trials underway,” said Dr. Foss. Results from these trials are not expected for another two years.

Role of patient groups

Education about the role of clinical trials is key as many patients have a number of misconceptions about the true value of a clinical trial and believe clinical trials will render them experimental animals or that they will be placed in the placebo arm of a randomised trial.

“We need to educate patients about the marked importance of using clinical trials as a form of therapy for their disease and to discuss with their doctors some of their preconceived myths about clinical trials rather than establishing those myths as ingrained truths and being misled about the right therapy for their disease,” said Dr. O’Connor.

Physician education is also key. A patient with relapsed T-cell lymphoma following CHOP, should not be treated with the same paradigms used to treat B-cell lymphoma.

“I think we need to change the physician, how they think about the treatment of this disease and really break away from the paradigms that we’ve been using for decades for B-cell lymphoma,” said Dr. O’Connor.

Patients can also play a role in advocating for continued research in these rare diseases. “It’s always useful to us to have that advocacy at the level of the FDA (Food and Drug Administration) whenever one of the new drugs is being considered, because a lot of the time they need to be reminded of the unmet medical need given that we don’t have the randomised trials with the large numbers of patients that the solid tumours have,” said Dr. Foss.

Moving forward

As a next step, Dr. Foss says physicians and scientists need to come together to pool their data on gene array analysis on tumours and prognostic markers that have been identified in T-cell lymphoma. In addition, efforts need to be made to compile clinicians’ treatment experience on some of the newer treatments to help identify patients who will benefit.

Role of the Lymphoma Coalition

Dr. O’Connor sees the Lymphoma Coalition playing a role in increasing awareness about the importance of clinical trials. He feels that the T-cell lymphoma community needs to be targeted and efforts made to work with key opinion leaders (KOLs) in T-cell lymphoma to help educate community physicians about the best way to treat the disease.

“I think the biggest thing is to potentially work with the KOLs in T-cell lymphoma to see what clinical trials they are enrolling and to maybe suggest to patients, who may be treated in the community, that it may be in their better interest to go to a local academic university where they can get access to a half dozen clinical trials looking at new drugs in T-cell lymphoma, rather than staying in a community practice where all they are going to get is the standard fare in terms of paradigms we’ve been using for 30 years,” said Dr. O’Connor.

 

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