HIV‐associated Burkitt lymphoma in the combination antiretroviral therapy era: Real‐world outcomes and prognostication

Abstract We performed a retrospective study to analyze the clinical characteristics and outcomes of human immunodeficiency virus–associated Burkitt's lymphoma in Chongqing University Cancer Hospital, southwest China, from March 2012 to February 2022. In the entire cohort, the median age was 36 years (range, 28–60 years), and more patients were male (82.4%). The median CD4+ T cell count was 214/μl (range, 54–601), of whom 47.1% had a CD4+ T cell count below 200/μl. Most patients had elevated lactate dehydrogenase (LDH), elevated β2‐MG, extranodal involvement and advanced Ann Arbor stage at diagnosis. With a median follow‐up of 11.5 months (range, 1.6–94.9 months), the overall 1‐year progression‐free survival and overall survival (OS) rates were 27.6% and 47.6%, respectively. The 1‐year OS times in the LDH < 3 upper limit of normal and LDH ≥ 3 upper limit of normal groups were 62.5% and 31.3%, respectively (p = 0.008). The 1‐year OS times in the received <4 cycles and ≥4 cycles groups were 0% and 77.8%, respectively (p < 0.001). These results demonstrated that LDH < 3 upper limit of normal and received ≥4 cycles of chemotherapy were significantly associated with improved outcomes. However, rituximab administration was not significantly associated with improved outcomes.

Besides, the incidence of positive Epstein-Barr virus (EBV)-encoded RNA (EBER) was 25%-40% in the HIV-positive BL, and it was only 3%-5% in the HIV-negative BL [10,11]. China that treats HIV-associated lymphoma patients. Herein, we conducted a retrospective analysis to identify clinical characteristics and prognostic factors in HIV-associated BL.

Patients
All

Statistical analysis
Progression-free survival (PFS) was defined as the time from lymphoma diagnosis to disease progression, relapse, or death from any cause. Overall survival (OS) was defined as the time from lymphoma diagnosis to last follow-up or death from any cause. All statistical data were analyzed with SPSS version 26 or GraphPad Prism 9. Survival was estimated using Kaplan-Meier curves and compared by the log-rank test. p < 0.05 was considered statistically significant.

Patient characteristics
The baseline clinical features of these patients are summarized in Tables 1 and 2. There were no significant differences in each of the parameters between patients on EPOCH or R-EPOCH besides β 2 -MG. All the 17 patients had HIV before lymphoma was diagnosed. In addition, all the patients were on cART at diagnosis.

Treatment-related mortality
The most common toxicities during treatment were myelosuppression, which included neutropenia and thrombocytopenia. Compared with HIV-negative patients in our center, there was no significant increase in infection. In the R-EPOCH cohort, three patients died of PD. In the EPOCH, total eight patients died, which included two patients died of infection and six died of PD. Besides the patient along with CNS disease present at diagnosis, the other patients had no CNS relapse.   Figure 1C). The 1-year OS times in the LDH < 3 upper limit of normal and LDH ≥ 3 upper limit of normal groups were 62.5% and 31.3%, respectively (p = 0.008) ( Figure 1D).

Treatment efficacy and outcomes
The 1-year PFS times in the received <4 cycles and ≥4 cycles groups were 0% and 44.4%, respectively (p = 0.002) (Figure 2A). The 1-year OS times in the received <4 cycles and ≥4 cycles groups were 0% and 77.8%, respectively (p < 0.001) ( Figure 2B). These results demonstrated that LDH < 3 upper limit of normal and received ≥4 cycles of chemotherapy were significantly associated with improved outcomes.

Rituximab administration and patient outcome
Of these patients with complete follow-up data, 11 patients (64.7%) received EPOCH regimen, and 6 patients (35.3%) received R-EPOCH regime. The overall 1-year PFS rates for EPOCH and R-EPOCH were 20.2% and 41.7%, respectively (p = 0.121) ( Figure 2C); the overall 1-year OS rates were 30.3% and 62.5%, respectively (p = 0.297) ( Figure 2D). These data suggested that HIV-associated Burkitt lymphoma patients receiving rituximab had higher OS, but more observations of HIV-associated Burkitt lymphoma cases are needed to make a conclusive statement.

DISCUSSION
Little is known about the incidence and clinical features of HIVassociated BL as these are less common than BL in the general population. These retrospective studies try to explain the prognostic factors and outcomes in HIV-associated BL. Alderuccio [12]    In this study, we also found that LDH ≥ 3 upper limit of normal at diagnosis and received <4 cycles of chemotherapy were identified as poor prognostic factors associated with a higher risk of treatment failure, and HIV features no longer influence prognosis in HIV-associated BL. The mechanism may be related to gluconeogenesis and DNA metabolism, as an LDH level serves as an important checkpoint of gluconeogenesis and DNA metabolism. Besides, we also found that HIV-associated features, which include CD4 cell count did not affect prognosis of HIV-associated BL. Habbous et al. [21] also found that HIV status did not affect prognosis for patients with DLBCL receiving R-CHOP in a general population.
In summary, we found that HIV-associated features no longer influence outcomes in HIV-associated BL and also found that LDH ≥ 3 upper limit of normal at diagnosis and received <4 cycles of chemotherapy were the two prognostic factors associated with inferior survival.
Currently, people with HIV positive are mostly excluded from clinical trials precluding the evaluation of novel agents. Hope more prospective clinical studies toward incorporating HIV-positive BL in the future. Moreover, more prospective clinical studies are needed to establish a prognostic risk assessment system for HIV-associated BL.

AUTHOR CONTRIBUTIONS
Conceived and designed the study; analyzed the data; and drafted and revised the paper: Chaoyu Wang, Shunsi Liang, Jieping Li. Conceptualized and designed the study: Yao Liu. All authors provided critical comments to the manuscript. All authors contributed to the article and approved the submitted version.