Novel therapies for peripheral T-cell lymphomas

Abstract

Peripheral T-cell lymphomas (PTCLs) are a diverse family of lymphoid neoplasms with poor prognosis. They represent approximately 6-10% of non-Hodgkin lymphomas with significant geographic variation. The median age at diagnosis varies with histology, however the majority of patients with PTCL are in their fifth or sixth decade of life. Until recently clinical development of new agents for PTCL was slow due to difficulties in making the correct diagnosis, lack of uniform classification and combination of rarity and biologic diversity of the group. In the last 5 years, significant advances were made to overcome these obstacles, leading to the approval of three new agents for relapsed and refractory PTCL by the Food and Drug Administration, based on well conducted prospective studies. Pralatrexate, a unique antifol, was the first agent granted approval, followed by romidepsin, a histone deacetylase inhibitor, and brentuximab vedotin, an immunoconjugate. Owing to the unique nature of these agents, durable responses were seen in patients with highly refractory disease, and some of these responses are long lasting after discontinuation of therapy. Accumulating data indicate that these novel agents have little cumulative toxicity and can be administered continuously to patients who are not candidates for consolidative stem-cell transplantation (SCT), with little impact on quality of life. They might also provide a new salvage option for patients eligible for SCT with no impact on autologous stem-cell collection or subsequent engraftment. New studies are underway to evaluate efficacy and safety of new agents in combination regimens for both newly diagnosed and relapsed/refractory PTCL. Several other investigational drugs showed promise in recent trials. This review focuses on novel therapies for T-cell lymphomas, their place in current treatment paradigms and future directions.

Keywords: T-cell lymphoma; brentuximab vedotin; pralatrexate; romidepsin; therapy.

Figure 1.

Mechanism of action of pralatrexate. Pralatrexate is transported into the tumor cell via reduced folate carrier type 1 (RFC-1) membrane transporter; inside the cell pralatrexate is polyglutamated by FPGS; pralatrexate-Glu metabolite accumulates inside the cell with ensuing blockade of DHFR and DNA synthesis. Illustration courtesy of Alessandro Baliani© (2013).ADP, adenosine diphosphate; AMP, adenosine monophosphate; AICARFT, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase; ATP, adenosine triphosphate; DHFR, dihyfdrofolate reductase; dTMP, de-oxy-thymidine monophosphate; dUMP, de-oxy-uridine monophosphate; FPGS, folylpolyglutamyl synthase; GARFT, glycinamide ribonucleotide formyltransferase; GMP, guanosine monophosphate; G, glutamate; IMP, imidazole phosphate; PRPP, phosphoribosyl pyrophosphate; THF, tetrahydropholate; TS, thymidine synthase.

Figure 2.

Mechanism of action of romidepsin. Binding of romidepsin to intracellular and intranuclear histone deacetylase (HDAC) leads to hyperacetylation of histones and DNA unfolding. Increase in DNA accessibility facilitates binding of the transcription factors and changes the activity of numerous genes affecting cell growth, proliferation and apoptosis, resulting in cell death in sensitive tumors. Illustration courtesy of Alessandro Baliani© (2013).

Figure 3.

Mechanism of action of brentuximab vedotin (BV). BV binds to surface CD30 leading to endocytosis; incorporation of BV–CD30 into the lysosomal complex leads to cleavage of the peptide linker and release of monomethyl auristatin E (MMAE) inside the cell; binding of the MMAE to the tubulin network leads to cell cycle arrest in the G2/M phase and apoptosis. Illustration courtesy of Alessandro Baliani© (2013).