In this issue of Blood, Ishida and colleagues report the latest update on their nationwide retrospective study of allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia in Japan.1
In this large cohort of patients they found a median overall survival (OS) of 9.9 months and 3-year OS of 36% in 586 transplanted ATL patients.1 Allogeneic hematopoietic stem cell transplantation (HSCT) was instrumental in attaining meaningful long-term survival in a some patients with immune reconstitution and eradication of virus-laden cells after reduced intensity conditioning (RIC) or myeloablative conditioning (MAC). Considering the short survival after conventional chemotherapy and antiviral therapy, allogeneic HSCT for ATL is a good starting point to improve the therapy of this recalcitrant T-cell malignancy. High rates of infections and acute graft-versus-host disease (GVHD) were still evident despite the use of RIC allogeneic HSCT.
Adult T-cell leukemia/lymphoma (ATL/ATLL) caused by human T-cell lymphotropic virus type I (HTLV-1) infection manifests itself in 2% to 10% of infected individuals after a long period of latency and is characterized by the proliferation and accumulation of activated CD4+ T cells.2 ATL is an intractable aggressive malignancy with unique features: (1) resistance to conventional chemotherapy including high-dose therapy and autologous stem cell transplantation; (2) hypercalcemia with or without bone lesions in one-third of patients at presentation and more than 70% during the entire course of the disease (associated with elevated macrophage colony stimulating factor I [CSF-1/M-CSF] and osteoclast differentiation via expression of RANKL [receptor activator of nuclear factor kB ligand] on the surface of hematopoietic precursors); (3) severe T-cell immunodeficiency with recurrent opportunistic infections that complicate effective treatments such as allogeneic stem cell transplantation; and (4) ATL cells can migrate into sanctuary sites such as the skin (20%-40%; via Chemokine receptor 4 CCR4 and leukemic cell expression of cutaneous lymphocyte antigen [CLA]), gastrointestinal tract (via Chemokine receptor 9 CCR9), and central nervous system (10%).
Recently, HTLV-1 bZIP factor (HBZ), a viral gene encoded on the minus strand, has been shown to impair cell-mediated immunity by suppressing transcription from the interferon γ gene promoter in CD4 T cells, thereby suppressing Th1 cytokines and explaining the multiple opportunistic infections these patients encounter that impact overall survival in the postinduction and allogeneic HSCT settings.3 In addition, Macaire et al showed that Tax protein induces the expression of antiapoptotic Bcl-2 proteins like Bfl-1 and Bcl-xL, which contribute to the survival of HTLV-1–infected T cells, yet another reason for early relapse and failure to eradicate tumor cells after induction chemotherapy.4
ATL cells expressing viral proteins like Tax display constitutive NF-kB activation as well as JAK/STAT pathway activation, the sum of autocrine and paracrine signaling within the microenvironment, further promoting cell survival and resistance to chemotherapy.5 Furthermore, newly described gain-of-function mutations of JAK3 have been reported in the FERM domain of JAK3 in ATL6 as well as in non–HTLV-1–expressing T-cell acute lymphoblastic leukemia.7 Given that Jak3 activation is associated with a poor outcome, an early relapse-targeted inhibition of that pathway may become a high priority in ATL therapy.8 Further research is needed to determine the timing and role of antiviral therapy, and Jak3 inhibition in the allogeneic HSCT setting.
Additional targeted therapies to eradicate minimal residual disease and prevent early relapse after allogeneic HSCT include a humanized anti-CCR4 monoclonal antibody that has shown activity in a phase 2 setting in relapsed ATL patients9 and the use of histone methylation inhibitors to reverse tumor-suppressor gene silencing. Sasaki et al showed that ATL cells have a deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog.10 Ultimately, a combined treatment strategy will be required to boost overall survival and complete remission rates in ATL. Thus, we may retain antileukemia T-cell activity while preventing severe acute GVHD by inhibiting JAK3 signaling and/or using epigenetic therapy in ATL after allogeneic HSCT.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■