Successful implementation of genomically based treatment of chemotherapy refractory peripheral T-cell lymphoma (PTCL).

Background: The treatment of peripheral T-cell lymphoma (PTCL) after failure of standard therapy represents a significant clinical challenge as the best approach has not been defined. The outcomes of patients with peripheral T-cell lymphoma (PTCL) after relapse, in the absence of hematopoietic stem-cell transplantation, are poor with median overall survival is less than six months. Thus, relapsed/refractory PTCL presents an area of unmet medical need.

Case Presentation: Herein, we report an 84-year old woman with stage IV PTCL with extensive involvement of the bowel and abdominal pain. She was treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy which was complicated by prolonged pancytopenia, without response. Disease progression was manifested by small bowel obstruction, for which she received palliative radiation therapy, further complicated by cardiac arrhythmia and sepsis. In the meantime, clinical-grade next generation sequencing of a lymph node (406 gene panel) showed six genomic alterations: NRAS Q61R, PTEN Q17*, CREBBP R768*, EP300 R1529*, SETD2 loss exons 19-21, along with an intermediate tumor mutational burden. Tissue PD-L1 staining was low positive by immunohistochemistry. The patient was discussed in Molecular Tumor Board with consensus opinion favoring a combination of the MEK inhibitor trametinib (for the NRAS alteration) and the checkpoint inhibitor nivolumab for the elevated mutational burden and PD-L1 positivity. Her abdominal pain resolved and she achieved a complete remission ongoing at 5+ months. Side effects at five months included only low-grade rash and peripheral edema.

Conclusions: Our observations suggest that matching patients with hematologic malignancies with customized combinations based on genomic sequencing warrants further study as a way to achieve and/or deepen responses, including in patients who are elderly and/or have refractory disease and significant disease-related complications.