Although the clinical outcomes of HIV-positive patients with NHL have improved since the advent of cART, management remains challenging in those with BL. Because of the rarity of this disease, no comparative study of modified CODOX-M/IVAC-R versus DA-R-EPOCH has been performed. This prospective study was designed to compare these regimens, which are recommended by the present NCCN guidelines, in Chinese patients with HIV-associated BL. DA-R-EPOCH may be an alternative to the modified CODOX-M/IVAC-R regimen for treating Chinese patients with HIV-associated BL, with better efficacy as demonstrated by the median OS of 18.0 (95% CI, 14.0–22.0 months) versus 7.9 months (95% CI, 4.8–11.0 months; P = 0.032). Particularly, no treatment-related deaths were reported in the DA-R-EPOCH group; however, one patient died of septic shock in the modified CODOX-M/IVAC-R group. Hematologic toxicities were manageable in the DA-R-EPOCH group, and the incidence of febrile neutropenia was much more frequent in the modified CODOX-M/IVAC-R group than in the DA-R-EPOCH group (90% [n = 9] vs 22.2% [n = 4]; P = 0.001).
We found a one-year PFS rate of 47.5% (95% CI, 51–82%), one-year OS rate (primary endpoint) of 52.1% (95% CI, 53–85%), and two-year OS rate of 26.1% (95% CI, 50–82%) in 28 Chinese patients with HIV-associated BL. The survival rates with the CODOX-M/IVAC ± R treatment regimen were contradictory for HIV-associated BL. In one retrospective study of CODOX-M/IVAC with or without rituximab in 80 HIV-positive patients with BL, the 3-year PFS and 3-year OS rates were 68% and 68%, respectively [6]. Another retrospective study of 42 patients with HIV-associated BL treated with CODOX-M/IVAC-R showed a two-year OS rate of 72% and event-free survival (EFS) rate of 81% [7]. Additionally, one study of 34 patients with HIV-associated BL treated with CODOX-M/IVAC-R reported a one-year PFS rate of 69% and one-year OS rate of 72% [5]. However, a study of 35 patients with HIV-associated BL and BL/DLBCL in a South African public hospital reported a two-year OS rate of 38% and two-year EFS rate of 23% [2]. Similarly, our results were very inferior to those of a previous study by Dunleavy, which showed 100% EFS and 90% OS rates in 11 patients with HIV-associated BL treated with SC-EPOCH-RR [17]. Despite the potential differences in the underlying patient populations, the average age (40 years) and median CD4 + cell count (243.5 cells/µL) are similar to those of international studies of HIV-associated BL [2–7, 17, 21]. It appears that the prognosis for Chinese patients with HIV-associated BL was worse than that found in previous studies. The reason is unclear, but the ratio of bulky disease was higher than that in previous studies [2–7, 17, 21]. The tumors in Chinese patients with HIV-associated BL may be less differentiated and much more invasive. Therefore, a clinical trial of a more efficacious regimen for Chinese patients with HIV-associated BL is needed.
The present prospective study showed that DA-R-EPOCH significantly prolonged the median OS compared with modified CODOX-M/IVAC-R (18.0 vs. 7.9 months; P = 0.032). DA-R-EPOCH yielded a longer median PFS, but this increase was not significant (14.0 vs. 4.6 months; P = 0.078). However, the objective response rate (ORR) was similar between the two groups (94.4% for DA-R-EPOCH and 90.0% for modified CODOX-M/IVAC-R). These results are similar to those of a study by Tan et al. on DA-R-EPOCH in 106 cases of HIV-related lymphoma, which showed that the ORR was 78.3% [14]. The results were also consistent with the ORR of SC-RR-EPOCH, which was 100%, as reported by Dunleavy et al., in 11 patients with HIV-related BL [17]. There was no difference between SC-RR-EPOCH and DA-R-EPOCH according to Dunleavy et al., and their ORR was higher than that of 49% in the report by Sissolak et al. on HIV-associated BL treated with mainly intensive chemotherapy regimens: cytoreduction with low-dose cyclophosphamide, vincristine, and prednisone followed by induction with vincristine, methotrexate, cyclophosphamide, doxorubicin and prednisone (LMB-86); or cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone [2]. Additionally, SC-RR-EPOCH had a higher OS rate of 90% compared with OS rates of approximately 70% in studies by Noy et al. and Barnes et al. on CODOX-M/IVAC-R for HIV-associated BL [5, 6, 17]. One study of 30 patients with HIV-associated BL treated with CODOX-M/IVAC showed a three-year OS rate of 52% [22]. Thus, addition of rituximab to traditional chemotherapy is effective and significantly improves ORR and OS [7]. In addition to the stronger anti-tumor activity of DA-R-EPOCH, another potential reason for the improved efficacy of DA-R-EPOCH or SC-RR-EPOCH is the lower toxicity compared with that of the intensive chemotherapy CODOX-M/IVAC-R regimen, which caused grade 3–5 AEs in 80% of patients [5–7, 17].
Approximately 88% of the SC-EPOCH-RR/EPOCH-R cycles were administered to outpatients, whereas the modified CODOX-M/IVAC-R required hospitalization for both high-dose methotrexate and IVAC [5–7]. In our study, all patients were hospitalized. Neutropenic fever was significantly higher in the modified CODOX-M/IVAC-R group than in the DA-R-EPOCH group (90.0% vs. 22.2%; P = 0.001). The high toxicity was consistent with that reported previously. In a retrospective study, Xiao et al. found that, of 15 Chinese patients with HIV-associated BL, 12 (80.0%) developed neutropenia, and 7 (46.6%) died of treatment-related causes (septic shock [n = 4], hemorrhage [n = 1], severe arrhythmia [n = 1], and renal failure [n = 1]) [8]. Furthermore, in the AMC 048 trial, the frequency of neutropenic fever was 24% [5], and in a study by Dunleavy et al., the frequency was 22% after treatment with DA-R-EPOCH, which required hospitalization [17]. Because of the decreased hematologic toxicity, the rate of infection necessitating hospital admission was significantly decreased in the DA-R-EPOCH group compared with that in the modified CODOX-M/IVAC-R group (16.7 vs. 90%; P = 0.001). Additionally, thrombocytopenia of grades 3 and 4 was significantly decreased in the DA-R-EPOCH group compared with that in the modified CODOX-M/IVAC-R group (16.7% vs. 80%; P = 0.002). Particularly, we eliminated grades 3 and 4 mucositis toxicities. Compared with that of modified CODOX-M/IVAC-R, the toxicity of DA-R-EPOCH was tolerable and had less fatal treatment-related AEs.
Finally, for prognostic factors of Chinese patients with HIV-associated BL, the primary extra-nodal organ was identified as a significant adverse factor for OS (HR: 28.78 [95% CI: 4.00–207.08]; P = 0.001). This suggests that the tumor characteristic at the time of clinical presentation is an important determinant of clinical outcomes. Numerous studies have identified IPI and CD4 + cell counts as important predictors of HIV-associated BL outcomes in the post-cART era [3, 13, 14]. Unlike other studies, the present study found that no clinical disease prognostic characteristics, including IPI and CD4 + cell counts, were associated with PFS or OS. CD4 + cell count was not identified as an important predictor of HIV-associated BL outcome in a retrospective study by Sissolak et al. [2]. Treatment with R-EPOCH was a significant favorable prognostic factor for OS (HR: 0.19 [95% CI: 0.05–0.68]; P = 0.011). This finding may account for the potential superiority of DA-EPOCH over modified CODOX-M/IVAC-R among Chinese patients with HIV-associated high-risk BL, including the higher efficacy and lower toxicity. There are challenging questions regarding the role of HAART during treatment of cART [3]. The scientific consensus states that HAART is necessary to prevent uncontrolled HIV replication and loss of immune function during chemotherapy; therefore, 100% of patients were administered HAART before chemotherapy. This may explain why CD4 + cell counts were not associated with the clinical outcomes of chemotherapy plus rituximab.
Our study had some limitations. As this was a prospective single-center study, investigator bias and selection bias could not be avoided. The use of concurrent cART was not uniformly prescribed. Prior WHO guidelines recommended that cART should not be initiated if the CD4 + cell count was > 350 cells/µL. However, based on Chinese guidelines for HIV [20], all patients were administered cART before chemotherapy regardless of the baseline CD4 + cell count. Finally, our analysis maybe underpowered and could not detect subtle differences in outcomes given the small number of patients in each group.
In summary, the data from our study suggest there is no longer a need for high-intensity, high-toxicity chemotherapy treatment for high-risk BL. We aggressively treated HIV-infected patients with BL and improved OS rates by using DA-R-EPOCH. This regimen minimized drug-related toxicity compared with modified CODOX-M/IVAC-R. Thus, given the severe toxicity associated with previous chemotherapy regimens for BL, the results of this uncontrolled retrospective clinical trial are particularly promising. Confirmatory prospective trials of patients with HIV and BL are warranted.