To be or not to be HIV+, that is no longer the question

In this issue of Blood, Noy et al report the outcomes of HIV-infected patients with Burkitt lymphoma (BL) treated with a modified cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC)-rituximab regimen that rival outcomes seen in HIV-uninfected patients.¹ 

BL is the second most common AIDS-related lymphoma and occurs even in patients with relatively preserved CD4 counts and immune function. Although the risk of developing non-Hodgkin lymphoma (NHL) in people living with HIV (PLWH) has decreased substantially since the introduction of highly active antiretroviral therapy (HAART) in 1996, the risk remains greatly elevated compared with the general population. Notably, the risk for BL has not decreased substantially, especially compared with the more common diffuse large B-cell lymphoma (DLBCL) (standardized incidence ratio, 33.7 vs 17.6, respectively).² 

In the pre-HAART era, survival for PLWH diagnosed with lymphoma was dismal, and treatment was mainly palliative. Although survival for HIV-infected patients with DLBCL started to improve significantly in the early HAART era, similar improvement lagged behind for BL.³  The persistent suboptimal outcomes for AIDS-related BL in the early HAART era were based in the continued use of nonintensive regimens in PLWH out of concern for intolerable toxicities, specifically hematologic, infectious, and neurologic, that are associated with intensive regimens. However, with the more recent use of intensive and infusional regimens for AIDS-related BL, survival rates have caught up, and most patients today can achieve long-term survival.⁴ 

One such intensive regimen is CODOX-M/IVAC as first described by Magrath et al.⁵  Noy et al, on behalf of the AIDS Malignancy Consortium (AMC), modified the Magrath regimen in the AMC 048 trial mainly to reduce mucositis and hematologic and neurologic toxicity. Furthermore, they added the CD20-directed monoclonal antibody rituximab and intensified treatment of leptomeningeal disease if present at diagnosis.

Patients enrolled in AMC 048 had characteristics that were largely representative of PLWH diagnosed with NHL in the United States. Most patients had high-risk disease, and 12% (n = 4) had leptomeningeal involvement at diagnosis. Notably, 23% (n = 7) had a Karnofsky performance status <70%.

The modified CODOX-M/IVAC-rituximab regimen resulted in a 1-year progression-free survival (PFS) of 69.3%, as well as a 1- and 2-year overall survival (OS) of 72.2% and 69%, respectively. Of the 34 enrolled patients, only 59% (n = 27) experienced grade 3 or 4 hematologic toxicities, and only 24% (n = 8) developed neutropenic fever, which is markedly lower compared to the original Magrath regimen, where grade 3 or 4 hematologic toxicities are nearly universally seen.⁵  In AMC 048, grade 3 and 4 neurotoxicity occurred in 21% (n = 7) of patients compared with 27% of patients who developed painful disabling neuropathy with the original Magrath regimen. No patient had grade 3 or 4 mucositis. Taking into account that most patients (84%) received HAART concurrently with antineoplastic therapy, considered by many a risk factor for additive toxicity, the modifications in AMC 048 seem to be successful in curbing the above side effects. Of the 11 patients who died, only 1 died of treatment-related complications, whereas 8 died of disease progression, and 1 died in remission of a nonmalignant complication of HIV. Nevertheless, 12% of patients terminated protocol treatment early because of toxicities.

It should be noted that, of 25 cases for whom central pathology review was available, only 76% (n = 19) were confirmed as BL, whereas others were reclassified as DLBCL (n = 3), high-grade lymphoma with features intermediate between BL and DLBCL (n = 2), and high-grade lymphoma, not otherwise specified (n = 1). However, even when the analysis was restricted to the 19 patients with centrally confirmed BL, PFS and OS remained largely unchanged (72.2% and 78%, respectively). The survival rates in AMC 048 rival outcomes in immunocompetent patients with BL treated with CODOX-M-IVAC⁶  or other similarly dose-intense regimens commonly used to treat BL, such as a hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone/cytarabine/methotrexate plus rituximab regimen.⁷  This confirms the observation by other authors, such as Oriol et al, who found that survival can be similar between HIV-positive and HIV-negative patients with BL treated with the same intensive regimen.⁸ 

Although the results of AMC 048 are very encouraging and demonstrate that intensive regimens for AIDS-related BL are both tolerable and efficacious, the question whether multiagent dose intense regimens are needed in the treatment of BL remains unanswered. Using a short course (SC) of the infusional regimen EPOCH (infusional etoposide, oral prednisone, infusional vincristine, bolus cyclophosphamide, and infusional doxorubicin) with a double dose of rituximab (SC-EPOCH-RR) to treat 11 patients with AIDS-related BL, Dunleavy et al, from the National Cancer Institute (NCI), observed a PFS of 100% and 90% OS after a median follow-up of 73 months.⁹  This regimen omits systemic ifosfamide and high-dose methotrexate. Although both agents are thought to be important for disease control in BL, especially to treat and/or prevent lymphomatous central nervous system (CNS) involvement, they also have substantial toxicities. In the NCI study by Dunleavy et al, only 1 patient had CNS involvement at baseline and was successfully treated with intrathecal methotrexate alone. No patient relapsed in the CNS. However, given the small number of patients enrolled in this single institution study, there remains significant concern that omission of these agents will jeopardize disease control, specifically in high-risk patients. It will be interesting to see whether the results of Dunleavy et al will be maintained in the ongoing larger cooperative group trial that currently evaluates dose-adjusted EPOCH-R in patients with BL (ClinicalTrials.gov identifier #NCT01092182).

Nonetheless, Noy et al provide further evidence to settle the controversy of whether intensive lymphoma therapy for PLWH is possible. Long-term survival for PLWH and lymphoma today can be achieved for the majority of patients, similar to non–HIV-infected patients, when treated with appropriate regimens by physicians with expertise in the management of HIV-associated malignancies. Although it might appear that a milestone in the care of PLWH and cancer has been reached, many issues still need to be addressed. For one, PLWH are still less likely to receive cancer treatment compared with HIV-negative persons with a similar cancer diagnosis.¹⁰  The results of AMC 048 will hopefully go a long way in reducing the hesitancy in the medical community to allow HIV-infected patients with hematologic malignancies access to adequate care.