We recommend that patients should be entered into clinical trials, if available (GPP). We recommend that first-line treatment of DLBCL in HIV-positive individuals includes chemotherapy regimens used in HIV-negative patients, such as CHOP or infusional Pirfenidone concentration therapies such as EPOCH. No randomized studies have been published in the era of ART and hence there is no optimal ‘gold-standard therapy’ (level of evidence

1B). We recommend that chemotherapy regimens should be combined with HAART therapy (level of evidence 1B). We recommend the concomitant administration of rituximab (level of evidence IB). Patients with CD4 cell counts <50 cells/μL may require closer surveillance (GPP). Until recently, patients with HIV-associated BL have been treated similarly to HIV-positive patients with DLBCL. However, in a large retrospective study the

survival of patients with BL was very poor when treated with CHOP or M-BACOD (methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), despite adjunctive HAART [54]. This was corroborated by the results of a Phase II prospective study involving 74 patients with HIV-NHL and HIV-BL treated with rituximab and the CDE infusional regimen (R-CDE). In multivariate analysis, a diagnosis of HIV-BL was significantly associated with a worse outcome in comparison to HIV-NHL patients [50]. In the HIV-negative setting, BL is a highly curable malignancy if intensive chemotherapy regimens of short duration are combined with CNS-penetrating therapy 17-AAG [62–64]. In the UK, the most widely used regimen is CODOX-M/IVAC (cyclophosphamide, Dimethyl sulfoxide vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, cytarabine) and the two MRC/NCRI studies (LY6 and LY10) have stratified patients into low-risk and high-risk (Table 4.6). In low-risk disease, patients receive 3 cycles of CODOX-M and those with high-risk disease receive 4 cycles of chemotherapy alternating between CODOX-M and IVAC. Grade

3/4 haematological toxicity is universal with this regimen with a high incidence of neutropenic fever and mucositis. The reported treatment-related death rate is around 8–14% [62,63]. In the LY6 study, the main toxicity was from the use of high-dose methotrexate at a dose of 6.7 g/m2 [63] and thus in the LY10 study, the dose was reduced to 3 g/m2 [62] without compromising outcomes. In the LY10 study, the 2-year PFS and OS for low-risk disease was 85% and 88%, respectively, and for high risk, 49% and 52%, respectively [62]. Two small retrospective studies and one prospective comparative study [65–67] have demonstrated the feasibility of administering more intensive chemotherapy regimens, such as CODOX-M/IVAC [65] and hyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) to HIV-positive patients with BL [66].