Forodesine in the treatment of relapsed/refractory peripheral T-cell lymphoma: an evidence-based review

Abstract

T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma (PTCL) generally have a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy; once relapse occurs, it is mostly regarded as an incurable disease. To overcome the chemorefractoriness of PTCL, several novel agents have been developed. Since the first approval of pralatrexate, a dihydrofolate reductase inhibitor, for relapsed/refractory PTCL by the US Food and Drug Administration, several new agents, such as romidepsin (histone deacetylase inhibitor), brentuximab vedotin (antibody-drug conjugate targeting CD30), chidamide (histone deacetylase inhibitor), and mogamulizumab (anti-CC chemokine receptor 4 monoclonal antibody), have been approved as a therapeutic option for relapsed/refractory PTCL in several countries, including the US, Europe, China, and Japan. Forodesine is a novel, potent purine nucleoside phosphorylase inhibitor that is effective against T-cell malignancies. Although the clinical development of forodesine was discontinued in the US and Europe, a multicenter Phase I/II study of oral forodesine for relapsed PTCL was recently completed in Japan. The overall response rate was 24% (10 of 41 patients), which included four patients with complete response. In general, the toxicity of forodesine is manageable. As the study met the primary end point, forodesine was approved for the treatment of relapsed/refractory PTCL in Japan in March 2017, which was the first approval of forodesine in the world. As forodesine is an oral formulation, it is more convenient than other novel intravenous agents approved for PTCL. However, it is necessary to appropriately manage opportunistic infections and secondary lymphomas possibly associated with long-lasting lymphocytopenia caused by forodesine. In this manuscript, we have summarized the currently available evidence for forodesine and discussed the clinical implications for PTCL treatment.

Keywords: PNP; PTCL; T-cell lymphoma; forodesine; lymphoma; new agents; non-Hodgkin lymphoma; purine nucleoside phosphorylase.

Figure 1

Selected novel agents for PTCL. Abbreviations: ADC, antibody–drug conjugate; ADCC, antibody-dependent cell-mediated cytotoxicity; CCR4, CC chemokine receptor 4; DHF, dihydrofolate; DHFR, dehydrofolate reductase; FPGS, folylpolyglutamate synthase; HDAC, histone deacetylase; IMP, inosine monophosphate; PDX, pralatrexate; PDX-G, polyglutamylated pralatrexate; PNP, purine nucleoside phosphorylase; PRPP, 5-phosphoribosyl-1-pyrophosphate; PTCL, peripheral T-cell lymphoma; THF, tetrahydrofolate; TS, thymidylate synthase.

Figure 2

Structures of purine nucleoside analogs. Notes: Forodesine is a member of purine nucleoside analogs. Unlike the other purine nucleoside analogs, forodesine contains nitrogen in the ring of D-ribofuranose (red arrow) and C-glycosidic bond (red ring).

Figure 3

Epstein–Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) developed during forodesine therapy. Notes: A 68-year-old female was diagnosed with anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Lymph node biopsy at the initial diagnosis revealed the disseminated presentation of large atypical lymphocytes (A, hematoxylin and eosin, ×600). Immunohistochemical staining revealed that the tumor cells were positive for CD3 (B, ×600) and CD30 (C, ×600). The patient received eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) and achieved complete remission. Six months after the completion of CHOP chemotherapy, the first relapse was confirmed and the patient joined the Phase I study of oral forodesine. After 4 years of forodesine administration (100 mg, once daily), the patient experienced epigastric pain. Endoscopic examination revealed gastric ulcer lesions and a biopsy demonstrated the diffuse growth of large atypical lymphocytes (D, hematoxylin and eosin, ×400). Immunohistochemical staining revealed that the tumor cells were positive for CD20 (E, ×400). EBV early RNA 1 (EBER1) expression was detected in tumor cells by in situ hybridization (F, ×400). The patient was diagnosed with EBV-positive DLBCL. The patient received cyclophosphamide, vincristine, procarbazine, and prednisolone (C-MOPP) in combination with rituximab, and subsequently achieved complete remission.