Therapy for Peripheral T-Cell Lymphomas: Where We Are and Where We Hope to Be

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous, often aggressive, group of non-Hodgkin lymphomas (NHL) comprising about 10% to 15% of all new NHL diagnoses.[1,2] The most common subtypes are peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large-cell lymphoma (ALCL). Historically the therapeutic approaches for PTCL have been derived from standard treatments for various subtypes of aggressive B-cell lymphoma. However, outcomes remain poor when these strategies are used in the management of PTCL, with 5-year overall survival ranging from 30% to 50% for the most common subtypes.[3]

Four drugs have been approved by the US Food and Drug Administration (FDA) for treatment of relapsed PTCL: pralatrexate, romidepsin, brentuximab vedotin (approved for ALCL only), and belinostat. In the relapsed/refractory setting, rates of response to single-agent therapy with these drugs (other than use of brentuximab vedotin for ALCL) range from 20% to 35%.[4-7]

In his review, Dr. Lunning outlines the evidence supporting current management of PTCL.[8] As he describes, studies suggest that the addition of etoposide to frontline chemotherapy regimens and consolidation with autologous stem cell transplant may improve outcomes in this group of diseases. The need for improvements in treatment of these lymphomas remains significant. In our emerging era of molecularly based therapy, however, there is hope for better treatment of PTCL.

Dr. Lunning reviews the use of histone deacetylase inhibitors and brentuximab vedotin in this setting, as well as a number of novel therapies now under investigation, particularly for patients with relapsed/refractory disease. For many of our current therapies, the mechanism of action in T-cell lymphomas specifically is not well defined. However, there are other agents in use or under investigation that seem to have more targeted action or understandable mechanisms: crizotinib, an oral small-molecule tyrosine kinase inhibitor of the anaplastic lymphoma kinase (ALK) and several other kinases; and AG-221, an isocitrate dehydrogenase 2 (IDH2) inhibitor. As we can see from Dr. Lunning’s review, current therapies for PTCL have moved the field forward incrementally in the relapsed setting, and there is hope of further advances with the investigation of novel agents as part of initial treatment. It is possible that with an improved understanding of mechanistically targeted agents, we will be able to tailor therapy better to individual subtypes or tumor-specific factors, with the goal of better long-term results for our patients.[7,9-12]

Several of these more mechanistically based therapies are currently in clinical trials for T-cell lymphoma. In patients with ALK-positive ALCL, there are efforts to study the use of crizotinib, which has been approved for treatment of lung cancer harboring a translocation in the ALK gene. As ALK is constitutively expressed in a subset of patients with ALCL, this is an attractive therapeutic target. In small series of relapsed patients, response rates of 60% to 100% to crizotinib have been seen, including one study of 11 patients (9 with ALCL) showing an overall response rate (ORR) of 91%.[13] Several other ALK inhibitors are also in development but are being studied primarily in lung cancer.

IDH2 is an enzyme that normally catalyzes the conversion of isocitrate to alpha-ketoglutarate (α-KG) in the Krebs cycle. Mutations in the IDH2 gene are seen in several malignancies, including acute myeloid leukemia (AML), gliomas and glioblastoma, chondrosarcoma, and cholangiocarcinoma. Recently a phase I study of the oral IDH2 inhibitor AG-221 in patients with AML and myelodysplastic syndrome showed an ORR of 56% in 45 subjects, including complete and durable responses.[14] Gain-of-function mutations in IDH2 are seen in 20% to 45% of cases of AITL and rarely in PTCL-NOS.[15,16] Early-phase studies of AG-221 in malignancies harboring an IDH2 mutation, including disease-specific cohorts of AITL, are underway (ClinicalTrials.gov ID: NCT02273739).

Phosphatidylinositol 3-kinase (PI3K) inhibitors and their downstream targets (eg, AKT, mammalian target of rapamycin [mTOR]) are important in cell differentiation, metabolism, survival, and proliferation. Idelalisib, a PI3K-delta inhibitor, is currently approved for chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma; many other PI3K inhibitors are being developed and investigated.[17,18] With regard to T-cell lymphoma, the PI3K-delta/gamma inhibitor duvelisib (IPI-145) has demonstrated an ORR of 53% in PTCL.[19] Further studies of IPI-145 as part of a combination strategy for T-cell lymphoma are in development.

Another pathway of therapeutic interest in PTCL is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway; this is because mutations in JAK3 have been seen in natural killer (NK)-cell/T-cell lymphomas, and activation of the JAK/STAT signaling pathway has also been described in PTCL.[15,16] Ruxolitinib, approved for treatment of myelodysplastic syndrome and myeloproliferative neoplasms, is being investigated in relapsed lymphoma, including PTCL (ClinicalTrials.gov ID: NCT01431209).

As Dr. Lunning clearly explains, our standard therapies for PTCL may cure a subset of patients, and thus far novel agents have not changed the outcomes for the majority. Studies incorporating those novel agents as part of upfront treatment regimens are underway, and there is hope for improved responses. However, most of those studies are aimed at patients with PTCLs as a whole rather than a specific disease subgroup. It may be that we will need to stratify different patients for different therapies. Recent efforts at targeted re-sequencing have identified several recurrent mutations that are promising in the development of new therapies for T-cell lymphomas. The use of emerging molecularly based therapy presents an opportunity to understand the mechanisms of action of these newer agents in T-cell lymphomas, which in turn could lead to identification of predictive biomarkers and better-tailored regimens for our patients.

Financial Disclosure:Dr. Horwitz receives grant/research support, and is a consultant to, Celgene, Millennium, Seattle Genetics, and Spectrum; he also receives grant/research support from (but is not a consultant to) Kyowa HakkoKirin. Dr. Mehta-Shah has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89:3909-18.

2. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: International Agency for Research on Cancer; 2008.

3. Vose J, Armitage J, Weisenburger D; 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.

4. O’Connor OA, 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.

5. O’Connor OA, Masszi T, Savage KJ, et al. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): results from the BELIEF trial. J Clin Oncol. 2013;31(suppl):abstr 8507.

6. Coiffier B, Pro B, Prince HM, 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.

7. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30:2190-6.

8. Lunning M. Treatment of peripheral T-cell lymphoma: many shades of gray. Oncology (Williston Park). 2015;29:545-50.

9. Pro B, Advani R, Brice P, et al. Four-year survival data from an ongoing pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood. 2014;124:abstr 3095.

10. Horwitz SM, Advani RH, Bartlett NL, et al. Objective responses in relapsed T-cell lymphomas with single-agent brentuximab vedotin. Blood. 2014;123:3095-100.

11. Kim YH, Tavallaee M, Rozati S, et al. Phase II investigator-initiated study of brentuximab vedotin in mycosis fungoides or Sezary syndrome: final results show significant clinical activity and suggest correlation with CD30 expression. Blood. 2014;124:abstr 804.

12. Fanale MA, Horwitz SM, Forero-Torres A, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014;32:3137-43.

13. Gambacorti Passerini C, Farina F, Stasia A, et al. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst. 2014;106:djt378.

14. Stein E, Tallman M, Pollyea DA, et al. Clinical safety and activity in a phase I trial of AG-221, a first in class, potent inhibitor of the IDH2-mutant protein, in patients with IDH2 mutant positive advanced hematologic malignancies. Cancer Res. 2014;74:abstr CT103.

15. Odejide O, Weigert O, Lane AA, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood. 2014;123:1293-6.

16. Schatz JH, Horwitz SM, Teruya-Feldstein J, et al. Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia. 2015;29:237-41.

17. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123:3390-7.

18. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-delta, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood. 2014;123:3406-13.

19. Horwitz SM, Porcu P, Flinn I, et al. Duvelisib (IPI-145), a phosphoinositide-3-kinase-δ,γ inhibitor, shows activity in patients with relapsed/refractory T-cell lymphoma. Blood. 2014;124:803.