Bortezomib, Ifosfamide, Carboplatin, and Etoposide in a Patient with HIV-Negative Relapsed Plasmablastic Lymphoma

Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B cell lymphoma (DLBCL), often associated with HIV infection. We present a case of a 53-year-old HIV-negative man with untreated hepatitis C viral infection who presented with abdominal pain and lymphadenopathy. Lymph node and bone marrow biopsies were consistent with plasmablastic lymphoma. He had partial response (PR) to 6 cycles of EPOCH but disease progressed seven weeks later. Repeat biopsy was consistent with plasmablastic lymphoma. Three cycles of bortezomib, ifosfamide, carboplatin, and etoposide (B-ICE) chemotherapy resulted in a partial response (PR). Five months later, he presented with widespread lymphadenopathy and tumor lysis syndrome with circulating blasts. Flow cytometry revealed a different population of lymphoma cells, this time positive for CD5, CD19, CD20, and CD22, with dim expression of CD45 and CD38. The patient died on the first day of ESHAP chemotherapy. There are no treatment recommendations or standard of care for plasmablastic lymphoma. A literature search yielded 10 cases in which bortezomib was administered in either HIV-positive or HIV-negative PBL. Six reported a partial response, 3 reported a complete response, and 1 was a near-complete response. Bortezomib, in combination with chemotherapy, may be an effective treatment option in PBL as reported here

Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer

Background Preclinical studies showed metformin reduces exhaustion of tumor-infiltrating lymphocytes and potentiates programmed cell death protein-1 (PD-1) blockade. We hypothesized that metformin with nivolumab would elicit potent antitumor and immune modulatory activity in metastatic microsatellite stable (MSS) colorectal cancer (CRC). We evaluated this hypothesis in a phase II study.Methods Nivolumab (480 mg) was administered intravenously every 4 weeks while metformin (1000 mg) was given orally, two times per day following a 14-day metformin only lead-in phase. Patients ≥18 years of age, with previously treated, stage IV MSS CRC, and Eastern Cooperative Oncology Group 0–1, having received no prior anti-PD-1 agent were eligible. The primary endpoint was overall response rate with secondary endpoints of overall survival (OS) and progression-free survival (PFS). Correlative studies using paired pretreatment/on-treatment biopsies and peripheral blood evaluated a series of immune biomarkers in the tumor microenvironment and systemic circulation using ChipCytometry and flow cytometry.Results A total of 24 patients were enrolled, 6 patients were replaced per protocol, 18 patients had evaluable disease. Of the 18 evaluable patients, 11/18 (61%) were women and the median age was 58 (IQR 50–67). Two patients had stable disease, but no patients had objective response, hence the study was stopped for futility. Median OS and PFS was 5.2 months (95% CI (3.2 to 11.7)) and 2.3 months (95% CI (1.7 to 2.3)). Most common grade 3/4 toxicities: Anemia (n=2), diarrhea (n=2), and fever (n=2). Metformin alone failed to increase the infiltration of T-cell subsets in the tumor, but combined metformin and nivolumab increased percentages of tumor-infiltrating leukocytes (p=0.031). Dual treatment also increased Tim3+ levels in patient tissues and decreased naïve CD8+T cells (p=0.0475).Conclusions Nivolumab and metformin were well tolerated in patients with MSS CRC but had no evidence of efficacy. Correlative studies did not reveal an appreciable degree of immune modulation from metformin alone, but showed trends in tumorous T-cell infiltration as a result of dual metformin and PD-1 blockade despite progression in a majority of patients