The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma

Abstract

This is a phase 2 study to assess the role of tumor histogenesis (subtype), fluorodeoxyglucose positron emission tomography (FDG-PET), and short-course etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with dose-dense rituximab (SC-EPOCH-RR) in newly diagnosed HIV-associated CD20(+) diffuse large B-cell lymphoma. Patients received a minimum of 3 and a maximum of 6 cycles with 1 cycle beyond stable radiographic and FDG-PET scans. Overall, 79% of patients received 3 cycles. Combination antiretroviral therapy was suspended before and resumed after therapy. Thirty-three enrolled patients had a median age of 42 years (range, 9-61 years), and 76% had a high-intermediate or high age-adjusted international prognostic index. At 5 years median follow-up, progression-free and overall survival were 84% and 68%, respectively. There were no treatment-related deaths or new opportunistic infections during treatment, and patients had sustained CD4 cell count recovery and HIV viral control after treatment. FDG-PET after 2 cycles had an excellent negative but poor positive predictive value. Tumor histogenesis was the only characteristic associated with lymphoma-specific outcome with 95% of germinal center B-cell (GCB) versus 44% of non-GCB diffuse large B-cell lymphoma (DLBCL) progression-free at 5 years. SC-EPOCH-RR is highly effective and less immunosuppressive with shorter duration therapy compared with standard strategies. However, new therapeutic advances are needed for non-GCB DLBCL, which remains the important cause of lymphoma-specific death. This trial was registered at www.clinicaltrials.gov as NCT000019253.

Trial registration: ClinicalTrials.gov NCT00019253 NCT00019253.

Figures

Figure 1

Treatment paradigm for SC-EPOCH-RR. Thirty-three patients with DLBCL received 2 cycles of EPOCH-RR after which time CT and FDG-PET scans were performed. Response was based on serial CT body and FDG-PET scans, beginning at cycle 3 day 1 and performed after each cycle thereafter until treatment completion. Patients who had “negative” studies, as defined in “Evaluation and treatment,” received 1 additional cycle (minimum of 3) of therapy. Patients who had a “positive” CT and/or FDG-PET study received additional cycles until they were negative, for a maximum of 6 cycles. Two patients with progressive disease on treatment did not complete their initial therapy.

Figure 2

PFS and OS Kaplan-Meier curves. PFS (A) is 84% and OS (B) is 68% at the median follow-up of 5 years. PFS (C) and OS (D) for patients with GCB versus non-GCB DLBCL. PFS (E) and OS (F) for EBV-negative versus EBV-positive DLBCL, and PFS (G) and OS (H) for CD4 cell count greater than 100 cells/μL (100 cells/mm3) versus less than 100 cells/μL (100 cells/mm3) at diagnosis.

Figure 3

HIV viral load and T-cell dynamics. (A) Median change in plasma mRNA HIV viral loads in 28 patients without early deaths. Viral loads increased with the peak shown at the end of therapy and declined below baseline at 3 months after completion of therapy and reinstitution of cART. cART-naive patients (♦) compared with patients with prior exposure (■) had slightly higher viral loads at presentation. (B) Median changes in CD4 cells in 28 patients without early deaths. CD4 cells declined to a nadir at end of therapy but recovered to baseline 6 to 12 months later. cART-naive patients (♦) compared with patients with prior exposure (■) had lower CD4 cells at baseline but equivalent CD4 cells 6 to 12 months after therapy. Medians with 95% CIs calculated by bootstrapping are shown.

Figure 4

Association of tumor histogenesis (cell of origin), EBV expression, immune status (CD4 cell count at diagnosis), and outcome. Outcome: progression/relapse (▲) or PFS (○). EBV status: positive (red), negative (blue), or unknown (black).