Highlights from the 2015 T-Cell Lymphoma Forum
The seventh annual T-Cell Lymphoma Forum was held in San Francisco at the end of January. It provided a forum for researchers, scientists and clinicians from around the world to come together to provide updates and latest findings in molecular pathogenesis as well as potential treatment options for patients with peripheral T-cell lymphomas (PTCLs), cutaneous T-cell lymphomas (CTCLs) and natural killer (NK) T-cell lymphomas (TCLs).
The last meeting we had the opportunity to attend was in 2013 and we noted that major inroads were being made into understanding the molecular basis of T-cell lymphomas, knowledge that is essential to helping ensure that new drugs being developed specifically target the different types of T-cell lymphomas. As evidenced in the presentations at the 2015 T-Cell Lymphoma Forum, this research is ongoing.
Presently, the current standard first-line treatment for patients with PTCLs continues to be CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone). Unfortunately, patients do not achieve long-term remissions. While there are therapies available for use in the refractory/relapsed setting in T-cell lymphoma that have shown some benefit, they have not resulted in long-term remissions either. Currently, in the USA five therapies have been approved by the Food and Drug Administration (FDA) for use in refractory/relapsed PTCLs; namely, belinostat, brentuximab vedotin, pralatrexate, romidepsin and vorinostat. Belinostat is also approved in Lymphoma Coalition European Union member countries as well as Switzerland. Brentuximab vedotin is approved in Australia, Canada, Israel, Singapore and Switzerland. In addition to being approved in the USA, pralatrexate is approved in Israel, Singapore and Switzerland. Romidepsin has received regulatory approval in Australia and Canada. Vorinostat is approved in Argentina, Australia, Canada, Colombia and Japan. For information on therapies available for T-cell lymphomas go to the Global Database Search on the Lymphoma Coalition website. Belinostat, romidepsin and vorinostat are histone deacetylase (HDAC) inhibitors, brentuximab vedotin is a CD30-directed antibody-drug conjugate and pralatrexate is a folate analogue metabolic inhibitor. Efforts are ongoing to determine how the effects of these therapies can be potentiated.
The following is a summary of the presentations given at the T-Cell Lymphoma Forum covering novel drug combinations, global epidemiology, findings from clinical research being undertaken in Japan as well as challenges in the management of PTCLs.
Novel Drug Combinations in T-cell Lymphomas
Six presentations were given in this session that examined the use of novel drug combinations in T-cell lymphomas. Highlights from the presentations were:
- Although three HDAC inhibitors (belinostat, romidepsin and vorinostat) have been approved in the USA for the treatment of refractory or relapsed PTCLs, a better understanding of the mechanisms of action are needed in order to improve responses to treatment. Results from complementary deoxyribonucleic acid (cDNA) studies undertaken to better understand the sensitivity and resistance of HDAC inhibitors have shown no consistent gene expression signature. Some evidence suggests that HDAC inhibitors can cause DNA damage. Based on results from trials undertaken in cell lines, it would appear that clinical and laboratory data are not consistent with the canonical explanation of how HDAC inhibitors work. (Presenter: Susan E. Bates, MD)
- Data on the effectiveness of combining romidepsin and alisertib were reviewed. Alisertib is an inhibitor of the serine/threonine protein kinase Aurora A kinase. Both romidepsin and alisertib have demonstrated efficacy in the treatment of T-cell lymphomas as single agents although durations of remission are short (nine to 10 months) with romidepsin. Consequently, studies are underway to determine if combining these two agents would improve outcomes. In a study presented at the American Society of Hematology annual meeting in 2014, the combination of these two agents was shown to be highly synergistic in T-cell lymphoma cell lines but other subtype studies indicate that there was no synergy in diffuse large B-cell or mantle cell lymphoma cell lines. (Presenter: Michelle A. Fanale, MD)
- A retrospective analysis of the cutaneous lymphoma database in Australia was undertaken to determine the efficacy of treatments used to treat patients with mycosis fungoides (MF) and Sézary syndrome (SS). Findings showed that no chemotherapy regimen was superior to another with the median time to next treatment (TNTT) being 3.9 months. The use of interferon alpha (IFN-a) provided a median TNTT of 8.7 months and HDAC inhibitors a median TNTT of 4.5 months. IFN-a achieved a superior TNTT compared with chemotherapy for all disease stages and HDAC inhibitors were as effective as chemotherapy and likely less toxic. (Presenter: H. Miles Prince, MD, PhD)
- Treatment in the relapsed or refractory setting for PTCLs needs to be optimised as results from the current front-line treatment (CHOP) are disappointing. More data on the biology and particularly the rationale for combining two to three of the new agents are needed. A number of phase II trials are ongoing looking at different combinations such as romidepsin plus lenalidomide, romidepsin plus bortezomib and pralatrexate plus romidepsin. (Presenter: Pier Luigi Zinzani, MD, PhD)
- Brentuximab vedotin has demonstrated efficacy as a single agent in patients with T-cell lymphomas including anaplastic large cell lymphoma (ALCL). Efforts are underway to determine if its effectiveness can be potentiated through combination with other agents. Agents that have been studied in combination with brentuximab vedotin include CHOP, bendamustine, ICE (ifosfamide, carboplatin, etoposide) and gemcitabine. Studies have also examined brentuximab vedotin’s use in combination with belinostat, pralatrexate, mogamulizumab and alisertib. Other possible therapy combinations include brentuximab vedotin plus programmed death (PD)-1 inhibitors, brentuximab vedotin plus anaplastic lymphoma kinase (ALK) inhibitors and brentuximab vedotin plus P13 kinase inhibitors. While study results are promising, toxicities need to be monitored to ensure they do not increase. (Presenter: Stephen M. Ansell, MD, PhD)
- The use of bendamustine for the treatment of PTCLs has also been studied but results from studies have shown that it did not lead to a long duration of response. (Presenter: Bertrand Coiffier, MD, PhD)
Conundrums in PTCL Management
The three presentations in this session looked at when to consider allogeneic stem cell transplantation (allo-SCT), cytotoxic and gamma-delta subtypes of PTCL, and whether central nervous system (CNS) prophylaxis should be routinely used in PTCLs. Highlights from the session were:
- While autologous-SCT (auto-SCT) may appear to be considered better than no transplant at all, some patients are not well served by this approach. Patients who do best with this approach are those with ALCL while those with other histologies such as PTCL have inferior outcomes. To achieve a good outcome, patients need a complete or partial response, and a low International Prognostic Index (IPI) score or prognostic index for T-cell lymphoma (PIT) score. With allo-SCT, results in the relapsed setting are not nearly as good as those seen in the upfront setting. Allo-SCT does have a role in first remission but only in a highly selected population. However, there are patients with high risk scores at presentation who have donors, understand the risks and benefits who may benefit from allo-SCT but not auto-SCT. (Presenter: Sonali M. Smith, MD)
- PTCLs that express gamma-delta T-cell receptors are not only very aggressive and rare (less than 1% of lymphoid neoplasms) but also very difficult to treat. Primary cutaneous gamma-delta T-cell lymphoma (PCDG-TCL) and CD8+ T-cell lymphomas of the skin have progressive clinical courses. They express cytotoxic markers and have similar clinical features. There is no consensus on best treatment but allo-SCT is an option. A less aggressive form of PCGD-TCL has recently been identified. One of the markers that may predict for it is the expression of CD30. Consequently, in the future, patients could receive brentuximab vedotin as it targets CD30. (Presenter: Francine M. Foss, MD)
- The use of CNS prophylaxis is uncertain in PTCLs as CNS relapse is rare. The highest incidence of CNS relapse is seen in ALCL and lowest incidence in angioimmunoblastic T-cell lymphoma (AITL). Lactic dehydrogenase and involvement of the paranasal sinus are important risk factors for CNS relapse in NK/TCL. (Presenter: Barbara Pro, MD)
Improving Treatment Strategies in PTCLs and CTCLs
In this session, an update was provided on the T-Cell Project. The T-Cell Project is a prospective collection of data on patients with PTCLs. Through the collection of these data, it is hoped that a more accurate prognostic index can be developed for the most common types of PTCLs and that the clinical characteristics and outcomes of the less common ones will be better defined.
Other topics presented in this session were the use of denileukin diftitox in CTCL, data from the British Columbia registry on the survival of patients with refractory or relapsed PTCLs, a review of how new therapies should be incorporated into a treatment algorithm for PTCLs, use of watch and wait in adult T-cell leukaemia/lymphoma (ATL) and current issues and trends in the use of allo-SCT for ATL. Highlights from the session were:
- Of the 1,000 patients in the T-Cell Project registry, 943 could be analysed. With the exception of those with ALK+ disease, no improvements were seen in overall survival (OS). These results demonstrate the need for new therapies. The analysis also identified many potential prognostic factors for which confirmation studies are needed. Registration in the T-Cell Project (click here) needs to continue with the inclusion of more centres (currently 67 centres are part of the project) and more samples collected. (Presenter: Massimo R. Federico, MD)
- Denileukin diftitox was originally approved as a treatment option for patients with persistent or recurrent CD25+ CTCL in 1999 and available as a treatment option until 2011 when it was removed from the market because of impurity issues. Denileukin diftitox has been reformulated and is currently being tested in clinical trials. (Presenter: Youn H. Kim, MD)
- Findings from the British Columbia database of patients with refractory or relapsed PTCLs showed that the median OS following relapse was 5.5 months and median progression-free survival (PFS) following relapse was 3.1 months. Patients with a good performance status at relapse had slightly better outcomes: median OS 13.7 months; median PFS 6.1 months. (Presenter: Kerry J. Savage, MD)
- While the availability of new agents such as belinostat, brentuximab vedotin, pralatrexate and romidepsin has improved outcomes, patients will likely relapse within three to six months and be in need of another therapy option. New agents are under investigation in phase I and II trials but the challenge is to determine how to take these novel agents forward. (Presenter: Steven M. Horwitz, MD)
- The clinical course of ATL is very heterogeneous within the four types of ATL; namely, acute, smouldering, chronic and lymphoma. While the standard of treatment in Japan is watch and wait, results from two retrospective analyses showed that with smouldering ATL, five-year OS was between 40% and 50%. However, when patients with chronic and smouldering ATL received IFN-a plus zidovudine (AZT), five-year OS was 100% and 42%, respectively. (Presenter: Kenji Ishitsuka, MD, PhD)
- The use of allo-SCT has been explored as a treatment alternative in Japan in patients with aggressive ATL. A phase II trial is currently underway examining the use of VCAP (vincristine, cyclophosphamide, doxorubicin and prednisone), AMP (doxorubicin, ranimustine and prednisone), and VECP (vincristine, etoposide, carboplatin and prednisone) (VECP) (VACP-AMP-VECP) followed by allo-SCT with myeloablative conditioning and reduced-intensity conditioning to determine if patient outcomes can be further improved. (Presenter: Takuya Fukushima, MD, PhD)
Biological Therapies for T-cell Lymphomas
A number of biological therapeutic approaches were examined in this session. Highlights from these presentations were:
- Findings from the use of epigenetic therapy in Epstein-Barr virus (EBV)-associated NK/TCL were reviewed. New agents that target as well as inhibit the enzymes responsible for epigenetic changes have been developed. They include HDAC inhibitors, in particular vorinostat. The use of vorinostat inhibited the proliferation of cell lines in both T-cell and NK cell lines. It also induced apoptosis and reduced the expression of EBV latent genes while increasing the expression of EBV-lytic genes. Another therapy that has potential for the treatment of EBV NK/TCL is mogamulizumab, a humanised monoclonal antibody that targets CC chemokine receptor 4 (CCR4). To date, its use has been examined in various cell lines as well as patient lymphocytes with results showing that mogamulizumab induced antibody-dependent cellular cytotoxicity activity against CCR4. (Presenter: Hiroshi Kimura, PhD)
- Immunotherapeutic approaches in the treatment of CTCL through the blockade of PD-1 and PD-ligand 1 (PD-L1) were reviewed. The expression of PD-1 and PD-L1 in MF and SS provides a possible therapeutic target. An open label, nonrandomised, phase II trial – sponsored by the Cancer Immunotherapy Trials Network – is currently underway examining the use of MK-3475 (pembrolizumab), an anti-PD-1 monotherapy in patients with MF/SS. The goal of the trial is to demonstrate that with treatment, it is possible to modulate the microenvironment of patients. Ideally, both PD-1 expression and T-cell infiltrate will increase over time. It is also hoped the trial will determine why some patients do not respond to therapy. (Presenter: Holbrook Kohrt, MD, PhD)
- Data on the use of antiviral approaches as a potential therapeutic approach in the management of ATL were reviewed. Therapies that have been studied include IFN-a plus AZT and arsenic plus AZT and IFN-a. Based on study findings, antiviral therapy may be an efficacious treatment option for ATL. (Presenter: Olivier Hermine, MD)
- ATL is a highly aggressive CD4+ T-cell lymphoma caused by human T-cell lymphotropic virus type 1 (HTLV-1). Patients have an extremely poor prognosis primarily because they are resistant to cytotoxic agents. Consequently, allogeneic haematopoietic stem cell transplantation (allo-HCT) is widely used in Japan for the treatment of ATL. (Presenter: Atsuhiko Hasegawa, DVM, PhD)
- Chidamide, an oral subtype-selective HDAC inhibitor, was recently approved in China for the treatment of refractory or relapsed PTCLs. The agents that are currently available in the USA (brentuximab vedotin, belinostat, romidepsin, pralatrexate and vorinostat) are not available in China. Results from clinical trials showed that as a single agent, chidamide was efficacious and had a well-tolerated safety profile. (Presenter: Yuankai Shi, MD, PhD)
Clinical Research on T-cell Lymphomas in Japan
In the keynote presentation, clinical research undertaken in Japan in T-cell lymphomas was reviewed. Highlights were:
- OS for ATL and extranodal NK/TCL is the worst of all the PTCL subtypes in Japan. Most patients with ATL cannot be cured with current therapy options while cure is possible for a small number of patients with NK/TCL.
- Results from clinical trials have shown that SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide) is an effective therapy for refractory/relapsed NK-TCL.
- Treating ATL is challenging. Associated with HTLV-1, it is estimated that in Japan 1.2 million people are HTLV-1 carriers of which 1,200 will develop ATL. HTLV-1 can be transmitted through breast milk, semen and blood with the onset of disease usually occurring when patients are aged 60 years. For those with aggressive disease, treatment with VCAP-AMP-VECP was recommended. Another possible therapy option is AZT plus IFN-a.
- Mogamulizumab has recently been approved in Japan for use in patients with ATL, CTCL and PTCL. A worldwide development programme examining the use of mogamulizumab is currently underway in the European Union and the USA in patients with previously treated ATL. (Presenter: Kensei Tobinai, MD)
This session comprised five presentations that examined treatment options for MF and SS, emerging trends in the treatment of nasal NK/TCL, the significance of circulating EBV DNA in NK/TCL, the role of positron emission tomography-computed tomography (PET-CT) in the management of NK/TCL and extranodal variants of ATL. Highlights from the session were:
- Skin-directed therapy for SS and MF is limited although new topical agents such as vorinostat, resiquimod, sirolimus and hypericin (used with light) offer new approaches. Treatments are needed to improve the outcomes in patients with advanced disease. Studies have examined the combination of belinostat plus panobinostat which was shown to be effective. Pralatrexate has also demonstrated a very active role in CTCL. Other targeted therapies that have been studied include bevacizumab, ogamulizumab, alemtuzumab and zanolimumab. (Presenter: Madeleine Duvic, MD)
- Long-term survival of extranodal NK/TCL has improved as a result of changes in treatment approaches that include not using anthracycline-based regimens but rather L-asparaginase-containing chemotherapy regimens such as SMILE followed by auto-HCT, and using radiation therapy earlier. Issues that still need to be addressed are the roles of PET-CT and EBV DNA in the monitoring and staging of the disease. A new prognostic model is needed to better reflect patient outcomes as a result of receiving the newer treatments. A proposed model – Prognostic Index of NK-cell lymphoma, PINK – should be considered. (Presenter: Won Seog Kim, MD, PhD)
- All cases of NK/TCL are infected with EBV. To diagnose NK/TCL, EBV must be present; if not present the disease should be classified as PTCL-not otherwise specified (NOS). (Presenter: Yok-Lam Kwong, MD)
- PET-CT is a useful tool in the management of NK/TCL. It helps with the initial staging of NK/TCL. However, additional clinical trials are needed in order to standardise PET-CT protocols. (Presenter: Huiqiang Huang, MD, PhD)
- ATL has four clinical subtypes: acute, lymphoma, chronic and smouldering. Extranodal variants of the lymphoma subtype have also been identified. (Presenter: Kunihiro Tsukasaki, MD, PhD)
Global Epidemiology of T-cell Lymphomas
Presentations were given that examined issues relating to the epidemiology of T-cell lymphomas. Highlights from these presentations were:
- Patients (n = 230) from Latin America (Argentina, Brazil, Chile and Uruguay) have been included in the T-Cell Lymphoma Project. The most frequent subtypes seen are PTCL-NOS (42.4%), AITL (24.4%), ALK- ALCL (24.4%), ALK+ ALCL (7%) and NK/TCL (11%). In addition to participating in the T-Cell Lymphoma Project, Brazil is setting up its own registry to prospectively analyse patients with T-cell lymphomas. (Presenter: Carlos Chiattone, MD, PhD)
- The incidence and frequency of T-cell lymphoma subtypes among American Indian and Alaskan Native people were reviewed. Findings showed that the incidence is low compared with other ethnic groups. Most reported cases among American Indians and Alaskan Natives are from the West coast which is not surprising as that is where the majority of this population lives. (Presenter: Andrei Shustov, MD)
- The incidence of T-cell lymphomas is higher in Japan compared with the USA. However, the incidence of specific subtypes of T-cell lymphoma, namely PTCL-NOS and AITL, were similar between the two countries. The only two subtypes where incidence was higher in Japan compared with the US were NK/TCL and ATL although their incidence is increasing in the USA. (Presenter: Dai Chihara, MD, PhD)
Five presentations examining issues in molecular pathogenesis in T-cell lymphomas were given. While highlights from these presentations are very scientific, they are interesting as they indicate the degree of information and understanding researchers are gaining. This understanding is evident in the discussion presented by Dr. Elaine Jaffe on the anticipated changes the World Health Organisation will be making to the classification of T-cell lymphomas. Dr. Jaffe is Head, Hematopathology Section and Senior Investigator, Laboratory of Pathology at the National Cancer Institute in Bethseda, USA. The revised classification is expected to be published in 2016. Highlights from the presentations on molecular pathogenesis were:
- Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) mutations are commonly seen in glioma, acute myeloid leukaemia, chondrosarcoma, cholangiocarcincoma and, to a smaller extent, prostate, melanoma and colon cancers. IDH2 mutations have also been found in approximately 30% of AITLs making it a possible target of treatment for AITL and other T-cell lymphomas. Two inhibitors are currently in development: AG-221 which will target IDH2 and AG-I20 which will target IDH1. (Presenter: Tak W. Mak, PhD)
- SS is a disease of immune dysregulation that can be related to the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and other protein receptors. SS cells express high levels of CTLA4 which may explain why the microenvironment of the disease is immunosuppressive. Corynebacterium glutamicum (CATA3) is also overexpressed. The accumulation of CATA3 leads to activation of CTLA4 and may be an important regulatory loop. The overexpression of certain genes in SS could be helpful from both a diagnostic and prognostic standpoint. Cytokines, particularly IL-15, play a significant role in the genesis of T-cell lymphomas. (Presenter: Pierluigi Porcu, MD)
- DNA methyltransferase 3A (DNMT3A) mutations are seen in 20% to 30% of AITL cases and 15% to 25% of PTCL-NOS cases. They are also associated with Ten-Eleven Translocation 2 (TET2) mutations. Possible targeted therapies for patients with DNMT3A mutations are hypermethylating agents, agents that target haematopoietic stem cells and inhibitors of histone markers. However, it’s unclear which type of agent should be used and the consequences of DNMT3 mutations are not fully understood. (Presenter: Lucile Couronne, MD, PhD)
- The gene mutations of AITL are being analysed in an attempt to further clarify the gene structure of AITL. G17V RHOA mutations coexist with TET2 mutations and may play a role in the clonal evolution of premalignant cells into tumour cells. (Presenter: Mamiko Sakata-Yanagimoto, MD, PhD)
- DUSP22-IRF4 locus on 6p25.3 (DUSP22) and TP63 on 3q38 are two chromosomal rearrangements seen in ALK- ALCL. ALK- ALCL with DUSP22 rearrangements have demonstrated a five-year OS of 90% following receipt of conventional chemotherapy, similar to what is seen in ALK+ ALCL cases. However, patients with ALK- ALCL with TP63 rearrangements did not do well with median OS being approximately 17 months. Triple negative cases, i.e., those not expressing DUSP22, TP63 and neither ALK- nor ALK+, had an intermediate prognosis. Questions that need to be answered include determining the genetics of triple negative ALCL, determining if DUSP22 fluorescence in situ hybridization would be a useful marker for both prognosis and diagnosis, and whether the rearrangements suggest targets for potential therapy. (Presenter: Andrew L. Feldman, MD)
The T-Cell Lymphoma Forum provided an ideal venue for the exchange of information. While progress in the development of new and effective therapies for T-cell lymphomas may seem slow, great strides are being made in gaining a better understanding of what is happening at the molecular level that will, in turn, lead to better and more targeted therapies resulting in longer remissions.
If you believe you may have a T-cell lymphoma, please see a haematologist immediately. This article is not to be used as a guideline for patient treatment. Please see your doctor for further information.
Author: Leonie Bedford, Medical Writer, Lymphoma Coalition
March 30, 2015