After the discovery and widespread use of cART in resource-rich countries, overall survival in HIV-associated lymphoma improved, in one study from an average of 6 months to 20 months [6
], and more aggressive treatment regimens were once again considered. With the additional immunological support enabled with cART, the next major trial of chemotherapy in HIV-associated lymphoma compared CHOP to rituximab-CHOP combination therapy and was reported by Kaplan and authors as part of the AIDS Malignancy Consortium trial 010. This study found a trend towards increased efficacy (CR rate of 58% versus 47%) in the rituximab plus chemotherapy arm, however, also noted a significantly increased risk of treatment-related death in the combination arm of 14% compared to 2%. This increased risk of death was attributed to increased infectious complications during the treatment course and, on additional analysis, seemed to predominate in patients with CD4 counts <50
L. This finding supports the importance of risk stratification by CD4 count, even in patients on cART at the start of chemotherapy [38
For a time, this report led to decreased use of rituximab therapy in patients with HIV-associated lymphoma. However, additional data was recently provided by Dunleavy and colleagues [39
] and Sparano and colleagues [40
] in a pair of articles published in 2010. In these studies, rituximab therapy was used to treat HIV-positive patients with DLBCL and NHL, respectively. There were no treatment-associated infectious deaths noted in the study by Dunleavy, supporting the safety of rituximab in this setting. Additionally, this study demonstrated other methods aimed at decreasing the duration of associated immunosuppression and myelotoxicity with chemotherapy regimens. The authors utilized a decreased number of cycles of infusional EPOCH in combination with “dose-dense” rituximab (given on days 1 and 5). The EPOCH was dose adjusted based on hematological parameters per protocol prior to each cycle of therapy, thereby regulating the average neutrophil nadir. Second, the study utilized interim FDG-PET scans to guide the number of chemotherapy cycles, with one cycle given after the first negative PET-CT. By using this strategy, about 80% of the patients received only three cycles of therapy with the highest number of received cycles being 5, delivered in 12% of the subjects. The CR rate was 91% with 5-year PFS and OS of 84% and 68%, respectively. Of the 10 deaths on study, half were due to lymphoma and 5 occurred while subjects remained in remission. 3 of these deaths were due to opportunistic infection and 1 developed a secondary Burkitt lymphoma. The immediate application of this treatment regimen in resource-limited settings is prevented for multiple reasons. First, a lack of hospital beds and hospital staff relative to the large numbers of patients in need of treatment prevents delivery of five days of infusional EPOCH. Second, while this regimen is dose adjusted for hematological parameters, it is delivered with G-CSF support, a therapy that is not available in most resource-poor settings. Third, PET scans, and even CT scans, are not available in routine clinical practice at the present time to rationally select patients that may safely receive fewer cycles of chemotherapy.
Even with these limitations, however, several principles can be incorporated to improve care in resource-poor settings. Dose adjustment has been investigated in trials of chemotherapy in sub-Saharan Africa with some success. One such study, and the first prospective trial investigating chemotherapy for HIV-associated lymphomas in Africa, was performed by Mwanda and colleagues, reported in 2009 [26
]. This study utilized a dose-modified oral chemotherapy regimen based on a United States trial that was completed before the availability of antiretroviral therapy [41
]. The dose-modified regimen included lomustine (50
day 1, cycle 1 only), etoposide (100
days 1–3), cyclophosphamide (100
days 22–26), and procarbazine (100
days 22–26). As the initial regimen required G-CSF support, doses were decreased in the protocol to prevent this requirement. Additional modifications during therapy were also outlined, in a manner similar to the infusional EPOCH regimen. These adjustments led to a 50% dose reduction in all medications for an absolute WBC count less than 3,000
L or a platelet count under 100,000
L. For WBC count less than 1,500
L or platelets under 50,000
L doses were held until counts improved. If counts did not improve within three weeks, subjects were removed from the protocol—though this did not occur in any subjects on protocol. Median CD4 count in the 49-patient cohort was 198
L, 37% of patients were on antiretroviral therapy, and most had a history of previous opportunistic infection. 65% of the patients completed the two cycles determined by the protocol and a 6% treatment-related mortality was noted during the study, a significant improvement from previous studies. The reported CR rate was 58% with 78% having an objective response, numbers that are comparable to pre-cART studies in resource-rich nations. Median overall survival was 12 months, though a large variance was noted in patients on cART compared to no retroviral therapy with a median overall survival in the latter group of about 6 months.
This study serves as an example that prospective chemotherapy trials can be completed in resource-limited settings. It also identifies additional benefits from such studies, which may aid the management of HIV-associated lymphoma in resource-rich nations. First, this study by Mwanda and colleagues in East Africa is notable for its inclusion of female participants. In contrast to the >85% male composition of many of the other major trials in the field [6
] this cohort was composed of 60% women. Second, the chemotherapy regimen was composed of some medications that are known to cross the blood-brain barrier (lomustine, procarbazine) and without additional intrathecal therapy the rate of CNS relapse (6%) was similar compared to other trials performed prior to widespread availability of cART. Further investigation of the use of CNS-active agents in HIV-associated lymphoma therapy may be warranted, especially in situations where delivery of intrathecal therapy is difficult.