PD-1 Inhibitor Therapy in Adult T-Cell Leukemia-Lymphoma

THE AUTHOR REPLIES:

The three patients (one each with smoldering, chronic, and acute ATLL) whom my colleagues and I described had disease progression that was temporally related to nivolumab administration. Ishitsuka et al. describe their experience involving eight patients with aggressive lymphoma, who did not have such rapid disease acceleration. Even though the numbers of patients in these trials are very small, there is sufficient evidence to be concerned about safety with PD-1 inhibition in patients with ATLL. The possibility of intrinsic immunologic or environmental differences in patients with ATLL in different geographic regions cannot be ruled out. However, my colleagues and I agree with Ishitsuka et al. that the key difference is more likely to be due to differences in disease status.

Expression of the T-cell receptor is maintained in most patients with T-cell lymphoma, and PD-1 signaling or loss may play an important role in ATLL proliferation. In the chronic subtype, the presence of induction of the signal transducer and activator of transcription (STAT)¹ and upregulation of PD-1² may be important mechanisms of tumor progression, whereas in aggressive ATLL, PD-1 expression and function may depend more on the presence or absence of PD-1 deletion.³ My colleagues and I postulate that our patients had ATLL cells under a negative suppressor control involving PD-1 or PD-L1. The administration of nivolumab then released them from this suppressor control, revealing their intrinsic acute ATLL features. In contrast, the patients in the Japanese study were in the aggressive, acute phase or unfavorable, chronic phase, either of which may have already bypassed control by PD-1– or PD-L1–dependent suppressor cells. My colleagues and I agree with Kataoka and Ogawa that further exploration of the PD-1–PD-L1 axis in ATLL will be valuable. The importance of ascertaining the determinants of response or progression before the use of PD-1 or PD-L1 inhibitors in patients with ATLL is an issue that requires further study.