Rapid Progression of Adult T-Cell Leukemia/Lymphoma During PD-1 Inhibitor Therapy
In a letter to the editor in The New England Journal of Medicine, Ratner et al describe rapid progression of adult T-cell leukemia/lymphoma (ATLL) in three consecutive patients receiving programmed cell death protein 1 (PD-1) inhibitor therapy with nivolumab (Opdivo). As stated by the authors, ATLL, an aggressive clonal T-cell cancer caused by human T-cell leukemia virus type 1 (HTLV-1), exhibits a higher mutation rate than other hematopoietic cancers; alterations include changes in the T-cell receptor, nuclear factor κB, and immune surveillance pathways, including overexpression of the programmed cell death-ligand 1 (PD-L1) gene.
Patient Histories
The patients were the first three enrolled as part of a phase II trial of nivolumab undertaken in patients with ATLL with increased mutational burden and overexpression of PD-L1. The patients had chronic, smoldering, and acute subtypes of ATLL. The first two had disease that progressed slowly over several months, and the third had stable disease. All had normal blood counts and laboratory values at baseline. The first patient had negative positron emission tomography findings and the second had negative computed tomography findings apart from skin tumors.
Rapid Disease Progression
All three patients exhibited rapid progression of disease following a single dose of nivolumab. The first patient had warmth and swelling of skin lesions within the first week. All three patients developed leukocytosis, hypercalcemia, renal insufficiency, and increased lactate dehydrogenase. Two patients had 24% and 30% atypical lymphocytes in the blood and developed hyperbilirubinemia and progressive splenomegaly. The third patient exhibited worsening of nodal and splenic disease. HTLV-1 proviral load was assessed in two patients and showed increases by a factor of 63.0 and 2.4. One patient received radiotherapy for skin lesions and spleen and the other 2 patients received salvage chemotherapy.
As noted by the authors, other investigators recently have found that PD-1 acted as a tumor suppressor in a mouse model of T-cell lymphoma. They stated, “The consistent and rapid amplification of cancer in all three patients after a single dose of nivolumab…provides support for the probable role of PD-1 functioning as a tumor suppressor in humans. It is unclear whether this finding is specific to ATLL….[D]espite the recent recommendation to consider the use of PD-1 inhibitor therapy for ATLL, our clinical experience provides examples of cases in which this treatment may have led to rapid disease progression.”
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