Hope for Peripheral T-cell Lymphoma

Peripheral T-cell lymphomas (PTCL) are rare and heterogeneous lymphomas comprising numerous histologies.

Given the rarity and number of these lymphomas, the tendency has been to group them as one entity. For decades they have been treated in much the same way as B-cell lymphomas using conventional chemotherapy resulting in poor long-term survival.

“Until the recent advent of brentuximab vedotin (Adcetris) for CD30+ anaplastic large cell lymphoma (ALCL) and potentially other CD30+ lymphomas, we haven’t had much joy,” said Dr. Judith Trotman. Dr. Trotman is Associate Professor at the University of Sydney, Australia. She is also Senior Staff Specialist and Director of the Clinical Research Unit at the Haematology Department at the Concord Hospital in New South Wales.

Brentuximab vedotin is directed against the CD30 antigen, a protein expressed on the surface of some T-cell lymphomas. The antibody delivers a linked toxin to the tumour cell. In B-cell non-Hodgkin lymphomas, nearly 90% express CD20 making it an attractive therapeutic target for a monoclonal antibody that targets the CD20 antigen. Until the advent of brentuximab vedotin, however, no such antibodies had been identified that acted against T-cell lymphomas.

Results from a clinical trial that examined the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory ALCL, showed that brentuximab vedotin was very effective with an overall response rate of 85% in patients with CD30+ ALCL with more than half of these patients achieving a complete response. The median duration of response was 13 months in patients achieving a partial or complete remission.1

The current standard front-line treatment for PTCL has not resulted in the outcomes necessary for long-term remission for most types of PTCL. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the current standard front-line treatment.

“CHOP is a very poor standard and I think for any patient diagnosed with T-cell lymphoma, even at diagnosis, the best treatment option is to enrol the patient in an approved quality clinical trial,” Dr. Trotman said. Until recently, however, there have been few clinical trials given the rarity and broad spectrum of PTCL.

Diagnostic Challenges

When a patient is diagnosed with T-cell lymphoma, it can be very challenging for the clinician to recognise the likely diagnosis and the pathologist to identify the histological type.

“Finding haematologists and pathologists with extensive PTCL experience is a challenge because it is such a rare disease,” said Dr. Trotman.

For this reason, extremely rare T-cell lymphomas, such as hepatosplenic T-cell lymphoma, are often diagnosed very late in the disease.

“One haematologist might only see a single hepatosplenic T-cell lymphoma in his or her career. Not seeing the volume of T-cell diseases makes it harder to firstly recognise and secondly to diagnose which subtype the patient may have,” said Dr. Trotman.

PTCL Prevalence

Certain PTCLs are more common in Asia than other parts of the world. This may be a result of exposure to specific viruses, such as the Epstein-Barr virus and the human T-cell leukaemia virus-1, in Asian countries.2

“Of the PTCLs diagnosed in Europe, approximately 4% cent will be nasal, natural killer (NK) T-cell lymphoma; whereas in parts of Asia, such as Hong Kong, 40% will be nasal NK T-cell lymphoma,” said Dr. Trotman.

A study undertaken by the International T-Cell Lymphoma Project showed the marked variability in the distribution of T-cell lymphomas.2 For example, the prevalence of PTCL-not otherwise specified is higher in North America (34.4%) and Europe (34.3%) compared with Asia (22.4%) but adult T-cell acute lymphoblastic lymphoma or leukaemia is more prevalent in Asia (25.0%) compared with North America (2.0%) and Europe (1.0%).

In Australia, Dr. Trotman noted that NK T-cell lymphoma is not uncommonly seen.

“We have a big Asian population so we see a reasonable amount of NK T-cell lymphoma such that we might make the diagnosis every one to two years instead of every 10 years,” she said.

Importance of Distinguishing between T-cell and B-cell Lymphomas

Distinguishing between T-cell and B-cell lymphomas is key for two reasons. One reason is to do with prognostication as patients with PTCL do not do as well as those with other types of lymphoma. “On average, 30% of patients will be alive in five years’ time following diagnosis. While some histologies do a lot better than this, such as ALK+ ALCL, others do a lot worse,” said Dr. Trotman.

The second reason for distinguishing between T-cell and B-cell lymphomas is because of the therapeutic approach. While there are antibodies such as rituximab that are directed against B-cell antigens on the surface of malignant B-cell lymphomas, there are no such antibodies against T-cell lymphomas, with the recent exception of brentuximab vedotin which is directed against the CD30 antigen expressed in some T-cell lymphomas. Although effective, brentuximab vedotin is associated with toxicity with sensory neuropathy a particular issue often requiring a dose reduction. In the clinical trial undertaken by Pro et al., peripheral sensory neuropathy was one of the most common adverse events.1 There is a current randomised trial being conducted in many countries assessing the efficacy of substituting brentuximab vedotin for vincristine – the “O” in CHOP – in the front-line treatment of CD30+ PTCLs.

Treatment Options in the Relapsed Setting

In the relapsed setting as in the front-line setting, the best option, where available, for patients is to enrol in a clinical trial. If that is not an option other treatments include using the same approaches as used for relapsed B-cell lymphomas.

“People will often try using DHAP (dexamethasone, high-dose Ara C, cisplatin), ICE (ifosfamide, carboplatin, etoposide) or GDP (gemcitabine, dexamethasone, cisplatin) for two to three cycles to try and get patients to autologous or even allogeneic stem cell transplantation, but the ability to tolerate all the treatments and the ability to control the disease to get the patient to transplant gets more and more difficult,” she said.

Newer therapies for use in the relapsed setting that are targeted towards PTCL are romidepsin (Istodax) and pralatrexate (Folotyn), both approved in the USA and Europe. In a clinical trial in which patients with relapsed or refractory PTCL received single-agent romidepsin, the response rate was 25% and median duration of response was 17 months.3

Pralatrexate has also been shown to be effective in patients with relapsed or refractory PTCL. Results from the PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) study showed patients had a response rate of 29% and median duration of response for 10.1 months following treatment with pralatrexate.4 Both therapies are not available worldwide and LC strongly suggests that you review access to these therapies nationally for this cohort of patients.

New Therapy under Investigation

In the ongoing quest to find more effective therapies for patients with relapsed and refractory PTCL, a phase III, randomised clinical trial is currently underway. In this trial – the LUMIERE study – patients are randomised to receive either alisertib or one of the following: gemcitabine, pralatrexate or romidepsin. Twenty-five countries are enrolling patients with 161 sites participating. The primary outcome measures of the trial are overall response rate (ORR) and progression-free survival (PFS).

If the results show improved ORR and PFS then Dr. Trotman said the next step may be to see if it’s safe to combine alisertib with chemotherapy agents. Alisertib is an oral aurora kinase inhibitor. Aurora kinases have been identified as being potential targets in anticancer therapy.

Overcoming Clinical Trial Enrolment Challenges

One of the challenges with clinical trials is patient enrolment. In an effort to overcome this challenge, haematologists in New South Wales developed an app called ClinTrial Refer. This app allows haematologists in New South Wales to scroll through and identify all currently recruiting clinical trials that are available in that state. The ClinTrial Refer app is also available in Victoria, the second largest state in Australia after New South Wales and is being developed for the State of South Australia.

“The app is a fantastic tool that has resulted in a 300% increase in cross referrals in the last nine months,” said Dr. Trotman.

Prior to the app, one to three patients would be referred each month, now 11 patients are being cross referred each month.

“The 300% increase in cross-referrals has been sustained and is being translated into increased recruitment to our lymphoma portfolio not just at our hospital but across hospitals throughout New South Wales,” she said.

“For example, statewide collegiality has supported Concord’s recruitment to the LUMIERE study. Haematologists have the app on their smart phones in the clinic or multidisciplinary team meetings. This enables a quick check of available trials and better access to emerging therapies through clinical trial participation for patients across the state,” she said.

Dr. Trotman said she is aware that patients with lymphoma, in particular those with follicular and mantle cell lymphomas and other commonly relapsing blood cancers, download the app to keep track of currently recruiting trials.

The following images show how the app works.

                 

ClinTrial Refer search screen     T-cell lymphoma studies           ECHELON-2 trial details

 

Role of Patient Organisations

“A lot more needs to be done in clinical research to improve the outcomes of patients with PTCL. The Lymphoma Coalition needs to trumpet loud and clear the importance of clinical trial participation for T-cell lymphomas if we are to ever improve on the poor prognosis for these patients, far more than just about any other histology,” said Dr. Trotman.

Like other T-cell lymphomas, PTCL needs ongoing research and attention to better understand the disease given that it is not like B-cell lymphomas and, for this reason, investigation and clinical trials need to be undertaken in the T-cell environment.

References

  1. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012;30:2190-6.
  2. International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008;26:4124-30.
  3. Coiffier B, Pro B, Prince H, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 2012;30:631-6.
  4. O’Connor O, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011;29:1182-9.

 

July 28, 2014

 

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