While rates of certain HIV-associated non-Hodgkin lymphomas have declined since the introduction of antiretroviral therapy (ART), the incidence of Burkitt lymphoma (BL) has remained steady among patients with HIV. The lifetime risk of developing BL is approximately 10% to 20% in this patient population regardless of ART status, and BL comprises up to 40% of HIV-associated lymphomas.1 Treatment strategies are similar for HIV-positive and HIV-negative patients, and recent findings have shown promise for dose-adjusted regimens conferring lower toxicity than the traditional dose-intensive chemotherapy paradigms that were modeled after pediatric leukemia regimens.
In research published in the Journal of Clinical Oncology, comparable outcomes were observed in BL patients (113 patients; median age, 49 years) with and without HIV following dose-adjusted treatment with etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R). Event-free survival (EFS) was 84.5% and overall survival was 87.0% at a median follow-up of 58.7 months, with similar results noted regardless of HIV status or age.1,2
Clarification of the role of HIV infection in lymphomagenesis may further advance the development of lower toxicity treatment regimens for HIV-associated BL (HIV-BL). In a review published in the Lancet Haematology, one of the investigators of the DA-EPOCH-R study explored this topic along with colleagues from Springfield Medical Center and the University of Massachusetts.2
“[Because] patients with HIV-BL tend to have higher CD4 counts and still develop BL, the exact role of HIV is not just reduction of CD4 cells,” according to Ariela Noy, MD, a medical oncologist and hematologist at Memorial Sloan Kettering Cancer Center in New York, and chair of the Lymphoma Working Group of the AIDS Malignancy Consortium. “Our paper elucidates the many possible mechanisms including B-cell dysregulation and theoretical effects of HIV proteins, like Tat. Those with Epstein-Barr virus and BL also have a distinct mechanism.”
Additionally, the authors discussed current treatment considerations and remaining gaps in this area, including the poor outcomes of patients with relapsed or refractory disease, as well as those with involvement of the marrow, peripheral blood, or central nervous system at diagnosis. “We need better treatments for these patients, including drugs that cross the blood brain barrier,” she said.
To learn more about treatment approaches and ongoing needs in HIV-BL, we interviewed Lawrence D. Kaplan, MD, clinical professor of medicine and director of the Adult Lymphoma Program in the division of hematology-oncology at the University of California, San Francisco, and Erin Reid, MD, clinical professor of medicine in the divisions of hematology-oncology and blood and marrow transplantation at the University of California, San Diego, and vice-chair of the Lymphoma Working Group of the AIDS Malignancy Consortium.
What are some recent developments and ongoing challenges in treating HIV-associated Burkitt lymphoma?
Dr Kaplan: The first thing to recognize is that treatment of BL in patients with HIV disease is, in general, very successful. For the most part, such patients are treated in the same way as their HIV-negative counterparts and have comparable treatment outcomes. This has been true for a number of years now, and we can say the same for other types of aggressive lymphomas that are seen in HIV patients.
For many years, the standard of care for BL has been the use of short-course intensive therapies like [cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC)] and modifications of the original regimen to make it more tolerable. Hyper-[cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (CVAD)] has sometimes been used, but it is intensive and not short. Regimens like CODOX-M/IVAC have had excellent outcomes in both HIV-positive and HIV-negative patients but are more toxic in older patients.
The addition of rituximab to these chemotherapy regimens (R-CODOX-M/IVAC) is generally considered to be beneficial based on some phase 2 and retrospective data, and a randomized phase 3 French trial studied the use of the LMB chemotherapy regimen (an intensive French chemotherapy regimen) with or without rituximab in non-HIV-positive patients, finding that the addition of rituximab was associated with improved progression-free and overall survival.3 The AIDS Malignancy Consortium studied a modified R-CODOX-M/IVAC regimen in 34 patients in the AMC 048 trial. Outcomes were good and comparable to studies of this regimen in non-HIV patients.4
The more recent study was an [National Cancer Institute (NCI)]-sponsored multicenter phase 2 trial of the large cell lymphoma regimen, dose-adjusted EPOCH-R. The results of this trial demonstrated excellent outcomes with less toxicity than might be expected with the more intensive regimens noted above.1 It is notable that in this trial about 25% of patients (28 total) were HIV-positive. There was no difference in event-free survival between HIV-positive and -negative patients; the 4-year EFS in both groups was about 84%. Hematologic toxicity and febrile-neutropenia incidence were comparable to those seen in AMC 048.
My preference is generally for R-CODOX-M/IVAC for patients with CNS or leptomeningeal involvement.
One of the challenges in BL is CNS involvement. Patients with CNS involvement represent the highest risk group in this disease, whether HIV-positive or not. I generally select the R-CODOX-M/IVAC regimen for such patients due to the inclusion of CNS-penetrating agents that are used in the regimen. But this group remains problematic.
In addition, it is very difficult to treat patients who relapse or respond poorly to initial therapy, and there is little clinical data regarding what to do with such patients. We usually try to get them to autotransplant, but few will make it to transplant due to lack of response to second-line chemotherapy. Little data exists on any type of targeted therapy at this point, and the disease is uncommon and thus difficult to study.
Dr Reid: In 2015, the AIDS Malignancy Consortium published a multicenter prospective phase 2 trial demonstrating the feasibility and efficacy of treating HIV-BL with modifications to CODOX-M-IVAC.4 Rituximab was added, cyclophosphamide and methotrexate doses and/or timing were modified, vincristine was capped, and combination intrathecal therapy was employed. The primary endpoint was 1-year overall survival, which was 72% (95% CI, 53%-85%) and 2-year OS was 69% (95% CI, 50%-82%).
The NCI reported promising outcomes of using short-course (3 cycles) EPOCH-R in a single-center study which included 11 patients with HIV-BL, with 100% survival at 2 years.5 None of the patients in the HIV-BL group the NCI study had CNS involvement and only 10% had high-risk disease, while 4 of the 34 patients in the AMC study had CNS involvement and all had high-risk disease. Due to this and small sample size leading to overlapping confidence intervals for the 2 studies, direct comparisons are difficult.
Dose-adjusted EPOCH-R for BL was recently reported in a multiinstitutional setting involving 113 patients, 98 (87%) of whom had high-risk disease, 10% had involvement of the cerebrospinal fluid, and 25% were HIV-seropositive.1 Four-year event free survival was 85% for HIV-seropositive patients, which was similar to EFS in HIV-seronegative patients. The most important clinical variable associated with survival was CSF status, with 46% 4-year EFS compared to 90% in those with and without involvement.