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Improved outcomes have recently been reported for rituximab (R) plus infusional EPOCH chemotherapy in HIV-associated, aggressive B-cell non-Hodgkin’s lymphoma (NHL). The objective of this analysis was to assess whether patient selection or other factors contributed to this improvement and to identify subjects at greatest risk for lethal toxicity.
We performed a pooled analysis of two consecutive trials including 150 patients with HIV-associated NHL who received either R-CHOP (n=99; AMC010) or R-EPOCH (n=51; AMC034). Age-adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (< 100/μl vs. ≥ 100/μl), and treatment (R-CHOP vs. R-EPOCH) were included as variables in a multivariate logistic regression model (for CR) and Cox-proportional hazard regression models (for event-free survival [EFS] and overall survival [OS]).
Features significantly associated with improved CR rate, EFS and OS included low aaIPI score and baseline CD4 count of at least 100/μl. When adjusted for aaIPI and CD4 count, patients treated with concurrent R-EPOCH showed improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI] 0.23, 0.69; p<0.001) and OS (HR 0.38; 95% CI 0.21, 0.69; p<0.01). Treatment-associated death occurred significantly more often in patients with a CD4 count of less than 50/uL (37% vs. 6%; p< 0.01).
This analysis provides additional level 2 evidence supporting the use of concurrent R-EPOCH in patients with HIV-associated lymphoma and a CD4 count of >50/uL, and supports the design of an ongoing phase III trial comparing concurrent R-EPOCH with R-CHOP in immunocompetent patients with diffuse, large B-cell lymphoma (NCT00118209).
The incidence of aggressive non-Hodgkin lymphomas (NHL) is up to about 600 fold higher in individuals with human immunodefiency virus (HIV) infection. Despite a decrease in the incidence of HIV-associated NHL since the advent of combination antiretroviral therapy (cART), NHL remains the most common HIV-associated malignancy in the United States.1, 2, 4, 5
Rituximab (Rituxan®, Genentech, Inc., San Francisco, CA, USA) is a monoclonal antibody directed against the CD20 antigen present on malignant and normal B lymphocytes. Rituximab (R) is a highly effective treatment for immunocompetent patients with B-cell lymphoma, whether used alone in selected patients with low-grade B-cell lymphoma, or in combination with chemotherapy in patients with low-grade and aggressive B-cell lymphoma.6, 7 It is FDA approved for the treatment of CD20 positive Non-Hodgkin lymphomas (NHL). The addition of rituximab to standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens has been shown to significantly improve complete response (CR) and overall survival (OS) rates in patients with diffuse large B-cell lymphoma (DLBCL) in several trials.8–10 For HIV-associated lymphoma only one phase III study with rituximab has been reported. The AIDS Malignancy Consortium (AMC) compared R-CHOP with CHOP alone and found that the addition of rituximab resulted in fewer deaths due to lymphoma (14% vs. 29%; p<0.05) offset by a higher infectious death rate (14% vs. 2%; p<0.05) in the R-CHOP arm, resulting in comparable CR rates and OS (AMC010).11 Other phase II trials in HIV-associated lymphoma have documented safety and efficacy for R-CHOP,12, 13 suggesting that addition of rituximab to chemotherapy should be considered standard of care for most HIV-infected patients with B-cell lymphomas.14
Several phase II trials have suggested that infusional cytotoxic therapy may be more effective than CHOP in patients with aggressive B-cell NHL, including immunocompetent15, 16 and HIV-positive16–18 patients, whether or not rituximab was given concurrently with chemotherapy. In AMC034, patients with HIV-associated aggressive B-cell NHL were randomized to receive infusional EPOCH chemotherapy (etoposide, prednisone, vincristine, Cyclophosphamide, and doxorubicin) concurrently with rituximab or followed sequentially by rituximab given weekly for 6 weeks after the completion of chemotherapy.19 The CR rate was 69% in the concurrent arm (95% confidence intervals [CI] 56%, 79%) and 53% in the sequential arm (95% CI 41%, 64%). In this randomized “pick the winner” phase II trial design, the null hypothesis that the CR rate is 50% versus the alternative of 75% was rejected for the concurrent arm in favor of the alternative (P=0.005) and accepted for the sequential arm (P=0.39), suggesting that concurrent R-EPOCH is more effective than sequential therapy. The objectives of the current pooled analysis including patients treated with concurrent rituximab plus chemotherapy in AMC010 (R-CHOP) and AMC034 (R-EPOCH) was to determine whether the apparent benefit of infusional therapy persisted after adjustment of known prognostic covariates, and to identify subjects at high risk of lethal toxicity when treated with rituximab plus chemotherapy.
We pooled data from the 2 consecutively performed AMC trials, including AMC01011 and AMC03419. The characteristics of the trials are shown in Table 1, including the time periods the studies were performed, lymphoma therapy, antiretroviral therapy, and supportive care. Both trials included the same AMC sites and the same group of investigators. Both trials had similar eligibility criteria. HIV positive patients ≥18 years with an ECOG performance status of 0–2 and adequate organ function were eligible if they had previously untreated aggressive CD20-positive B-cell non-Hodgkin lymphoma of stages II or higher (or stage I with elevated LDH). Both protocols included Pneumocystis jirovecii prophylaxis and the use of myeloid growth factors. Meningeal prophylaxis was administered at the discretion of the treating physician and recommended for patients at high risk of CNS relapse as defined previously.11, 19 No antibiotic prophylaxis for neutropenia was recommended in AMC010, whereas fluoroquinolones and fluconazole were added in AMC034. Antiretroviral therapy was mandatory for patients in AMC010, but left at the treating investigator’s discretion in AMC034.
We pooled the data of 99 patients treated with R-CHOP in AMC010 and 51 patients treated with concurrent R-EPOCH in AMC034. Normally distributed data was presented as mean ± standard deviation. For univariate associations of variables, means were compared using the student’s t-test for normally distributed data and alternatively, the non-parametric Mann-Whitney U test. Proportions were assessed for associations using the Pearson Chi-square test or the non-parametric Fisher’s exact test. Actuarial graphs for the outcomes event-free survival (EFS; defined as time between registration and either relapse or progression of lymphoma or death from any cause) and overall survival were plotted according to the Kaplan-Meier method. The log-rank test was used to compare the treatment arms with respect to EFS and OS. A multivariate logistic regression model was used to estimate the odds ratio (OR) for the outcome complete response (defined as confirmed or unconfirmed complete response (CR/CRu) per International Response Criteria20). Other variables included were age-adjusted international prognostic index (aaIPI; low risk defined as scores 0–1, or high risk as scores 2–3), CD4 count (< or ≥100/μl) and treatment (R-CHOP or R-EPOCH). A Cox-proportional hazard regression model was used to estimate the hazard ratio for the outcomes EFS and OS. Test assumptions for all statistical tests were evaluated and found not to be violated. A p-value <0.05 was considered statistically significant and resulted in rejection of the null-hypothesis; all statistical tests were two-sided. 95% confidence intervals (95% CI) were quoted whenever applicable. Statistical analysis was performed using SAS software, version 9.2 (SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513, USA).
The characteristics of the patients included from both trials in this analysis are shown in Table 2. There were no significant differences in age, sex, CD4 count at lymphoma diagnosis, or histology between the study groups, although patients treated in AMC034 tended to have a higher median CD4 count. The most common histological lymphoma subtype in both trials was DLBCL.
We evaluated the relationship between treatment with clinical outcomes without adjustment for CD4 count or aaIPI. For all patients, R-EPOCH was significantly favored over R-CHOP for OS (Figure 1a; p<0.01) and EFS (Figure 1b; p<0.001). When stratified by aaIPI, similar benefits were seen for R-EPOCH in patients with low aaIPI risk (Figures 1c–d) and high aaIPI risk (Figure 1e–f).
The results of the multivariate analyses are shown in Table 3. The odds ratio for complete response was significantly higher in patients with low risk aaIPI scores (OR 4.6, p<0.001) and a CD4 count ≥100/μl (OR 2.7, p=0.01). There was a trend toward improved CR rate for R-EPOCH that was not statistically significant (OR 1.9; p=0.12). With regard to EFS, features associated with a significantly lower hazard rate (HR) for 2-year EFS included both aaIPI (HR 0.30, p<0.001) and CD4 count ≥ 100/uL (HR 0.42, p<0.001). Low risk aaIPI and high CD4 count were also associated with significantly improved 2-year OS rates. When adjusted for these covariates, treatment with R-EPOCH was associated with significant improvement in the EFS rate (HR 0.4, p<0.001) and OS rate (HR 0.38, p< 0.001). In other words, patients with R-EPOCH had a 60% lower likelihood of a death or progressive lymphoma and 62% lower risk of death compared with R-CHOP after adjustment for the baseline covariates aaIPI and CD4 count. If the analysis is restricted to DLBCL, similar benefits with respect to CR, EFS and OS were observed (Table 4).
The rate of treatment-associated deaths in both trials is summarized in Table 5. The treatment-associated mortality rate for R-CHOP was 14% in AMC010 and 9% for R-EPOCH in AMC034.11, 19 Treatment-associated death occurred significantly more often in patients with a CD4 count of less than 50/uL when the results of both trials were combined (37% vs. 6%; p< 0.01), and individually for patients treated with either R-CHOP (36% vs. 6%, P<0.001) or R-EPOCH (38% vs. 5%, p=0.02). The cause of treatment-related death for patients with a CD4 count <50/ul was cryptosporidiosis, sepsis, and JC virus infection in AMC034 (n=3), and sepsis syndromes in AMC010 (n=8).
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.
DETAILS OF ALL FUNDING SOURCES FOR THE WORK IN QUESTION:
Supported by The ASCO Cancer Foundation 2010 Young Investigator Award and by the CTSA Grant UL1 RR025750 and KL2 RR025749 and TL1 RR025748 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH roadmap for Medical Research, and the AIDS Malignancies Consortium Grant U01CA121947. Its contents are solely the responsibility of the authors and do not necessary represent the official view of the NCRR, NIH or ASCO.
ALL FINANCIAL DISCLOSURES:
Stefan K. Barta: no disclosures
Jeannette Lee: no disclosures
Lawrence D. Kaplan: no disclosures
Ariela Noy: no disclosures
Joseph A. Sparano: no disclosures