In a pooled analysis of sequentially performed trials for HIV-associated aggressive B-cell NHL, we found improved clinical outcomes for patients treated with rituximab plus infusional EPOCH compared rituximab with standard CHOP chemotherapy, including significantly improved EFS and OS. This benefit was likewise observed after adjustment for baseline covariates associated with inferior clinical outcomes, including at least two poor risk IPI features (stage III–IV disease, elevated LDH, or poor performance status) and low CD4 count </100/uL) at the time of lymphoma diagnosis. The studies were performed by the same clinical trials organization and group of clinical investigators. Antiretroviral therapy was at the discretion of the treating physician in AMC034 and was used concurrently with chemotherapy in 70% of the patients, whereas it was mandatory in AMC010. Antibacterial and antifungal prophylaxis was not required in AMC010, but was mandatory in AMC034. Other guidelines for supportive care were similar between the two studies. These similarities should mitigate the impact of unknown or unmeasured factors on the improved outcomes we observed. Moreover, in AMC034 the EPOCH arm followed sequentially by rituximab did not meet the prespecified efficacy endpoint that was met for patients randomized to concurrent R-EPOCH, providing additional evidence that the benefits for concurrent R-EPOCH were indeed attributable to that specific therapeutic regimen. Similar benefits for R-EPOCH were seen in both low and high risk aaIPI groups. We also found that patients treated with R-CHOP or R-EPOCH who had a CD4 count below 50/μl experienced a 35–40% rate of treatment related mortality, suggesting that alternative therapeutic approaches should be considered in this population. For patients with a CD4 count of 50/uL or higher, both regimens were associated with similar treatment-associated mortality rates of about 5–6%, indicating a more favorable therapeutic index for R-EPOCH.
The efficacy of R-EPOCH observed in the multi-institutional AMC034 is also consistent with results reported in other trials performed a single centers. Little and colleagues21
demonstrated a CR rate of 74% with a progression-free survival (PFS) and OS of 73% and 60% at 53 months in patients with HIV associated NHL treated with dose-adjusted EPOCH (DA EPOCH); the addition of rituximab improved these outcomes in a study performed by Dunleavy and colleagues18, 22, 23
with a reported CR rate of 92% and a 4 year PFS/OS of 86% and 70% for patients treated with EPOCH-RR (rituximab on days 1 and 5 of each cycle).
We adjusted our clinical outcome estimates for the two strongest predictors of outcome in HIV associated lymphomas, the IPI score and CD4 cell count. The age-adjusted international prognostic index is a validated and commonly used index to predict outcomes in immunocompetent patients with aggressive NHL,24
and has also been validated in patients with HIV-associated NHL.25–28
Low CD4 counts have consistently been associated with poor outcomes in the pre-cART and cART era.5, 27–29
When considered together in the same patient population, Bower and colleagues found that the IPI and the CD4 cell count remained the only independent predictors for mortality in patients diagnosed with HIV associated NHL in the cART era,30
supporting our strategy of including only these two baseline covariates in addition to treatment in our analysis.
The main limitations of our analysis are that patients were not concurrently randomized to R-CHOP versus R-EPOCH, and the analysis was conducted in a post-hoc manner. Although we controlled for the most important prognostic factors (CD4 count and aaIPI score), the association of R-EPOCH with improved clinical outcomes compared to R-CHOP might still be secondary to unaccounted confounding factors.
In summary, our finding that treatment of HIV-associated lymphomas with R-EPOCH results in superior outcomes when compared to R-CHOP is consistent with the results of other trials assessing the efficacy of these regimens. These results provide level 2 evidence supporting the use of R-EPOCH for selected patients HIV-associated B-cell NHL and a CD4 count of 50/uL or higher. Benefits were seen in both high and low risk patients, but were more pronounced in the high risk IPI group. Based upon these findings, the ongoing AMC075 trial includes R-EPOCH as the control arm patients with HIV-associated DLBCL and high aaIPI risk or other poor risk features (i.e., high Ki67 proliferation rate) by comparing R-EPOCH alone or in combination with the histone deacetylase inhibitor vorinostat. Additional confirmation is required in prospective, randomized clinical trials, however. This is currently the objective of an ongoing effort led by the CALGB, where immunocompetent patients with DLBCL are randomized in a 1:1 fashion to receive either R-CHOP or R-EPOCH (CALGB 50303; NCT0118209). The results of this trial will eventually provide level 1 evidence that may define a role for infusional R-EPOCH therapy in DLBCL.