HIV-associated Burkitt Lymphoma Research Articles

Long-Term Survival Rates and Treatment Trends of Burkitt Lymphoma in Patients with HIV-A National Cancer Database (NCDB) Study.

Burkitt lymphoma (BL) accounts for 10-35% of AIDS-defining lymphoma in people with HIV (PWH). Previous research consisting of smaller cohorts has shown decreased survival for HIV-associated BL. This study aims to compare overall mortality in BL patients with and without HIV, while investigating impact of treatment modalities in HIV-associated BL. Using the 2004-2019 NCDB, we identified 4312 patients with stage 3 or 4 BL who had a known HIV status and received either chemotherapy alone or chemotherapy and immunotherapy. Time to death was evaluated using Kaplan-Meier survival estimates. Risk of death was evaluated using an extended multivariable Cox model adjusted for multiple factors and with a Heaviside function for HIV status by time period (0-3 month vs. 3-60 month). Of the 4312 patients included, 1514 (35%) had HIV. For months 0-3 from time of diagnosis, HIV status was not associated with a statistically significant increase in risk of death (HR = 1.04, 95% CI: 0.86, 1.26, p = 0.6648). From month 3to 60, positive HIV status was associated with a 55% increase in risk of death compared to those without HIV (95% CI: 1.38, 1.75, p < 0.0001). Further, this difference in hazard rates (0-3 vs. 3-60) was statistically significant (HR = 1.49, 95% CI: 1.22-1.82, p < 0.001). There is an increased mortality rate from months 3 to 60 in BL patients with HIV compared to patients without HIV. Additionally, risk of death in the first 3 months is significantly decreased by 45% in patients with HIV treated with combination chemotherapy and immunotherapy compared to patients without HIV receiving combination chemotherapy and immunotherapy, providing valuable clinical insight into treatment decision making in the care of HIV-associated BL.

Clinical characteristics and outcomes of newly diagnosed patients with human immunodeficiency virus-associated Burkitt lymphoma: the Central and Western China AIDS lymphoma league 002 study (CALL-002 study)

BackgroundDespite the introduction of combined antiretroviral therapy, the clinical outcomes of HIV-associated Burkitt lymphoma (BL) remain poor.MethodsTo evaluate the clinical characteristics, prognostic factors, and outcomes of HIV-associated BL, we conducted a retrospective analysis of patients from multiple centers in China.ResultsThe study included 41 patients from 8 medical centers. Among the included population, male patients accounted for 87.8%, with 75.6% in advanced stages. Notably, 46.3% of cases involved bone marrow, while 19.5% involved the central nervous system (CNS). The most commonly used chemotherapy regimen was DA-EPOCH ± R, accounting for 53.6% of cases. The overall response rates for patients receiving DA-EPOCH ± R and R-Hyper-CVAD were 59% and 58.2%, respectively. Interestingly, patients receiving regimens containing rituximab had similar complete remission rates (25% vs. 23.5%) and overall survival time (45.69 ± 11.58 vs. 47.79 ± 11.72 months, P = 0.907) compared to those without rituximab, but differed in progression rates (33.3% vs. 47.1%). For the entire cohort, the 1-year progression-free survival (PFS) and overall survival (OS) rates were 52% and 67%, respectively. CNS involvement was independent risk factors for survival, with 1-year PFS and OS rates of 0% and 38% for patients with CNS involvement, and PFS and OS rates of 66% and 75% for patients without CNS involvement.ConclusionsHIV-associated BL patients in China have poor prognosis and show limited response to current treatment regimens. The absence of CNS involvement significantly improves clinical outcomes. The use of rituximab is not significantly associated with improved outcomes but can reduce disease progression.

Outpatient administration of high-dose methotrexate in adults without drug monitoring – a case-control study of risk factors for acute kidney injury

IntroductionHigh-dose methotrexate (HDMTX) is an essential part of chemotherapy regimens for hematologic neoplasms. The incidence of acute kidney injury (AKI) after HDMTX in unmonitored outpatient infusion had not been reported in adults yet. In this study, we evaluated toxicity data after outpatient administration of HDMTX without drug monitoring. MethodsPatients 16 years old or over with acute lymphoblastic leukemia and non-Hodgkin lymphoma who received at least one outpatient infusion of HDMTX without drug level monitoring were included. This is a retrospective, nested case-control study, in which the cases comprised patients who developed AKI after HDMTX. ResultsOverall, 302 patients were included, encompassing 840 infusions. Hospitalization occurred in 8.6 %. A total of 25 patients presented AKI after HDMTX administration, corresponding to 3 % of the methotrexate (MTX) infusions and 8.3 % of the patients. HIV-associated Burkitt lymphoma was more common in patients who presented AKI (18 vs. 6.8 %, p = 0.03). Baseline factors related to AKI after HDMTX were age > 44 y, body surface area ≥ 1.76 m2, body mass index (BMI) ≥ 23.8 kg/m2, glomerular filtration rate, and thrombocytopenia (< 150×109/L). Multivariable analysis for adjusting such factors found that BMI was independently related to AKI after HDMTX (OR 3.8). Death after AKI occurred in 56 %. ConclusionOur data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fared worse than expected, with more hospitalizations and death. A higher BMI was associated with the MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients.

Prognostic Factors in Hospitalized Patients with HIV-Associated Burkitt's Lymphoma - Real World Data Analysis

Introduction Burkitt Lymphoma (BL) is a highly aggressive and rare B-cell non-Hodgkin Lymphoma, characterized by translocation and dysregulation of the MYC gene. BL comes in three distinct forms: endemic, sporadic, and immunodeficiency related, which is most commonly secondary to HIV. Despite improvements in antiretroviral therapy (ART), the reported incidence of BL has remained stable over time. BL is a highly curable disease in patients able to tolerate aggressive therapies. However, little is known about real-world outcomes in United States patients with HIV- related BL. Our study highlights multiple factors associated with inpatient mortality and morbidity. Methods The National Inpatient Sample database was queried from October 2015 to December 2020. Adults aged &amp;gt;= 18 with a primary diagnosis of BL were identified and stratified into those with and without HIV. Complications included were queried using ICD codes most found in the secondary diagnosis variables. Baseline characteristics, inpatient complications, and outcomes were compared using chi-squared and Wilcoxon rank-sum tests. Logistic regression analysis was performed to assess the risk of death before and after adjusting for multiple risk factors. Results We found 3,650 admissions with a primary diagnosis of BL, 400 (11%) of whom had HIV. Patients with HIV were younger, 49% were younger than 40 years old as compared to 29% in patients with no HIV. There was a higher percentage of black patients 115 (29%), and most had Medicaid 170 (44%), there was no difference between income, hospital bed size or geographical region. Interestingly, in multivariable analysis, there were no significant differences in length of stay, race, or mortality between patients with and without HIV. The factors associated with mortality in HIV patients included acute renal failure OR 11.4 (1.22 to 107) and Sepsis OR 38.6 (1.62 to 921) Conclusion BL is an increasingly important disease in HIV-infected patients given that the incidence remains high despite advances in ART. This nationwide data analysis demonstrates the demographic characteristics of patients with HIV-associated BL in the US and the encouraging findings that outcomes are not significantly different between patients with and without HIV. Yet our study demonstrates the disproportionate distribution of HIV-BL in females and black patients. Further studies are needed to examine gender and racial disparities.

Readmission rates in HIV-associated burkitt lymphoma patients in the USA: a nationwide readmission database (NRD) analysis

BackgroundPeople with human immunodeficiency virus have an increased risk of developing AIDS-defining malignancies including Burkitt lymphoma. Survival outcomes in HIV-associated Burkitt lymphoma remain worse than non-HIV-associated Burkitt lymphoma, despite widespread implementation of antiretroviral therapy. We aimed to determine the association between HIV status and risk for 30-day and 90-day readmission in the US after index hospitalization for Burkitt lymphoma.MethodsData were abstracted from the 2010–2020 Nationwide Readmissions Database; hospitalizations included patients with a primary BL diagnosis and were stratified by comorbid HIV. The primary outcome was all-cause readmission (30-day and 90-day). Secondary outcomes were in-hospital mortality, length of stay (LOS), and hospital cost. Between-HIV differences were evaluated via logistic and log-normal regression; multivariable models adjusted for comorbid kidney disease, hypertension, fluid and electrolyte disorders, and sepsis.ResultsOverall, there were 8,453 hospitalizations for BL and 6.0% carried an HIV diagnosis. Of BL hospitalizations, 68.4% were readmitted within 30-days post index BL hospitalization and 6.8% carried a HIV diagnosis. HIV-associated BL was associated with 43% higher adjusted odds of 30-day readmission (aOR 95% CI: 4% higher to 97% higher, p = 0.026). For 90-day readmission, 76.0% of BL patients were readmitted and 7.0% carried a HIV diagnosis. HIV-associated BL was not statistically associated with all-cause 90-day readmission (aOR 1.46, aOR 95% CI: 0% higher to 115% higher, p = 0.053).ConclusionsHIV-positive status is associated with an increased risk for 30-day readmission after index hospitalization for Burkitt lymphoma.

Outpatient Administration of High-Dose Methotrexate for Leukemia and Lymphoma in Adults without Drug Monitoring: Risk Factors for Acute Kidney Injury

Introduction: Methotrexate is an antifolate that has been an essential part of regimens for acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), when it is used in high-dose (HD, ≥ 1 g/m2) to overcome the blood-brain barrier. Nephrotoxicity is the major toxicity of HDMTX, inducing critical organ damage and death if not early detected and treated. Therefore, these regimens are usually administered in the hospital, with intravenous (IV) hydration, drug level, urine pH monitoring, and MTX-guided leucovorin rescue. Although some factors for drug-induced acute kidney injury (AKI) have been pointed and recommendations are published, the reality is that in resource-poor settings, HDMTX is usually administered in an outpatient clinic and without drug monitoring. The exact incidence of AKI after MTX in these conditions was not reported in adults yet. In this study, we intend to summarize our toxicity data after outpatient administration of HDMTX without drug monitoring. We aim to find risk factors and describe their outcomes. Methods This is a retrospective nested case-control study conducted at an academic medical center in Sao Paulo, Brazil. Patients from 16 years old and above with ALL and NHL who received at least one outpatient infusion of HDMTX without drug level monitoring between Jan/2010 and Jun/2020 were included. Most patients with ALL received a 6-hour infusion, while those with NHL received a 2-hour infusion in a day clinic, along with intravenous hydration, urine alkalinization, and leucovorin rescue. Patients were followed outpatient by a multidisciplinary team. Cases were those patients who developed AKI by KDIGO definition or with delayed MTX clearance (serum MTX level > 0.1 mM after 72h from drug infusion), when clinically suspected. A nested cohort of controls was composed of patients who did not develop the complication, sampling from a larger cohort of patients who received HDMTX. Cases and controls were randomly matched 1:2 for the employed protocol only. Hematologic and liver toxicity were graduated according to CTCAE v5.0. Conditional logistic regression was used to find baseline risk factors. Results A total of 404 patients received at least one HDMTX infusion, with 102 not fulfilling the inclusion criteria. Among 302 patients included, 840 infusions were performed (median 2 infusions/patient, range 1-10). Most patients had a diffuse large B-cell lymphoma (DLBCL) (37%), Burkitt lymphoma (BL) (19.5%), or ALL (18%) diagnosis, followed by other NHL subtypes (25.5%). Most subjects received HDMTX within a course of Hyper-CVAD (HCVAD) or monotherapy (61%). Hospitalization occurred in 8.6% of infusions during the MTX nadir, with 4.6% needing intensive care, being febrile neutropenia the most common complication (63%). Twenty-five patients presented AKI after HDMTX administration, corresponding to 3% (95% CI 2-4.4) of MTX infusions and 8.3% (95% CI 5.5-12.1) of patients. Characteristics of cases are summarized in Table 1. Univariate analysis for finding pre-treatment factors related to AKI after HDMTX were age>44 y (OR 3.2 [95% CI 1 - 9.7], p=0.045), body surface≥1.76 m2 (OR 3.4 [95% CI 1.2-9.9], p=0.039), BMI≥23.8 kg/m2 (OR 3.5 [95% CI 1.2-9.9], p=0.02), baseline creatinine clearance (OR 0.96 [95% CI 0.93-0.99], p=0.012), thrombocytopenia (<150x109/L) (OR 4.7 [95% CI 1.7-13.1], p=0.002). Multivariate analysis for adjusting such factors found that only BMI is independently related to AKI after HDMTX in our setting (OR 3.8 [95% CI 1.2-11.8], see figure 1). Among those patients with AKI, 9/25 had their MTX serum level measured at the AKI, with delayed MTX clearance in 7/9. HIV-associated BL was more frequent in cases (18 vs. 6.8%, p=0.03). Concerning remaining toxicities, grade 3 or more thrombocytopenia, neutropenia, and hyperbilirubinemia were found in 36%, 64%, and 36%, respectively. 22/25 needed hospitalization, with infection diagnosed in 23/25 e need for dialysis in 5/25 cases. Death after AKI occurred in 56% (14/25). Conclusions Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fare worse than expected, with more hospitalizations and death. Higher BMI was associated with MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RISK FACTORS FOR ACUTE KIDNEY INJURY IN OUTPATIENT ADMINISTRATION OF HIGH-DOSE METHOTREXATE IN ADULTS WITHOUT DRUG MONITORING

Methotrexate is an antifolate that has been an essential part of chemotherapy regimens for acute lymphoblastic leukemia (ALL) and specific subtypes of non-Hodgkin lymphoma (NHL), when it is used in high-dose (HD, ≥ 1 g/m2) to overcome the blood-brain barrier. Nephrotoxicity is the major toxicity of HDMTX, possibly inducing critical organ damage and death if not early treated. Although some factors for drug-induced acute kidney injury (AKI) have been pointed out, the reality is that in resource-poor settings, HDMTX is usually administered in an outpatient clinic and without drug monitoring. The exact incidence of AKI after MTX in these conditions was not reported in adults yet. In this study, we intend to summarize our toxicity data after outpatient administration of HDMTX without drug monitoring. We aim to find risk factors and describe their outcomes in a real-life setting. This is a retrospective nested case-control study conducted at a large academic medical center in Sao Paulo, Brazil. Patients from 16 years old and above with ALL and NHL who received at least one outpatient infusion of HDMTX without drug level monitoring between Jan/2010 and Jun/2020 were included. Cases were those patients who developed AKI by KDIGO definition or with delayed MTX clearance (serum MTX level > 0.1 mM after 72h from drug infusion), when clinically suspected. A nested cohort of controls was composed of patients who did not develop the complication, sampling from a larger cohort of patients who received HDMTX. Cases and controls were randomly matched 1:2 for the employed protocol only. Conditional logistic regression was used to find baseline risk factors. A total of 404 patients received at least one HDMTX, with 102 not fulfilling the inclusion criteria. Among 302 patients included, 840 infusions were performed (median 2 infusions/patient, range 1-10). Most patients had a diffuse large B-cell lymphoma (DLBCL) (37%), Burkitt lymphoma (BL) (19.5%), or ALL (18%) diagnosis. Most subjects received HDMTX within a course of Hyper-CVAD (HCVAD) or monotherapy (61%). Hospitalization occurred in 8.6% of infusions during the MTX nadir, with 4.6% needing intensive care, being febrile neutropenia the most common complication (63%). Twenty-five patients presented AKI after HDMTX administration, corresponding to 3% (95% CI 2-4.4) of MTX infusions and 8.3% (95% CI 5.5-12.1) of patients. Univariate analysis for finding pre-treatment factors related to AKI after HDMTX were age>44 y (OR 3.2 [95% CI 1 - 9.7], p = 0.045), body surface≥1.76 m2 (OR 3.4 [95% CI 1.2-9.9], p = 0.039), BMI≥23.8 kg/m2 (OR 3.5 [95% CI 1.2-9.9], p = 0.02), baseline creatinine clearance (OR 0.96 [95% CI 0.93-0.99], p = 0.012), thrombocytopenia (<150x109/L) (OR 4.7 [95% CI 1.7-13.1], p = 0.002). Multivariate analysis for adjusting such factors found that only BMI is independently related to AKI after HDMTX in our setting (OR 3.8 [95% CI 1.2-11.8], p = 0.06). Among these cases, 9/25 had their MTX serum level measured at the AKI, with delayed MTX clearance in 7/9. HIV-associated BL was more frequent in cases (18 vs. 6.8%, p = 0.03). 22/25 needed hospitalization, with infection diagnosed in 23/25 e need for dialysis in 5/25 cases. Death after AKI occurred in 56% (14/25). Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fare worse than expected, with more hospitalizations and death. Higher BMI was associated with MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients.

Burkitt lymphoma – no impact of HIV status on outcomes with rituximab-based chemoimmunotherapy

We analyzed the prognostic factors for treatment outcomes amongst 34 patients with adult Burkitt lymphoma (BL) who received rituximab with standard first-line chemotherapy. Seven patients had human immunodeficiency virus (HIV)-associated BL. Overall, we observed a complete remission (CR) rate of 91.2%, and 10-year progression-free survival (PFS) and overall survival (OS) was 84.8 and 88.2%, respectively. In patients with concomitant HIV, the prognosis was not different with 10-year PFS of 100% and OS of 88.2%. The majority (71.4%) of HIV-associated BL patients received dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) and had excellent outcomes with 100% CR and no relapses. Central nervous system (CNS) disease, bone marrow involvement and elevated serum lactate dehydrogenase (LDH) levels more than 3 times upper limit of normal (ULN) were associated with poorer survival outcomes. Patients with refractory disease, whilst uncommon (n = 4), had dismal outcomes. Patients with adult BL, including HIV-related cases, harbor generally good prognosis in the modern era.

S1512 HIV-Associated Burkitt Lymphoma Mimicking Stage IV Metastatic Pancreatic Cancer, Presenting as Jaundice and Pancreatitis With EUS-Guided FNA

S1512 HIV-Associated Burkitt Lymphoma Mimicking Stage IV Metastatic Pancreatic Cancer, Presenting as Jaundice and Pancreatitis With EUS-Guided FNA

Modulation of Cellular MicroRNA by HIV-1 in Burkitt Lymphoma Cells-A Pathway to Promoting Oncogenesis.

Viruses and viral components have been shown to manipulate the expression of host microRNAs (miRNAs) to their advantage, and in some cases to play essential roles in cancer pathogenesis. Burkitt lymphoma (BL), a highly aggressive B-cell derived cancer, is significantly over-represented among people infected with HIV. This study adds to accumulating evidence demonstrating that the virus plays a direct role in promoting oncogenesis. A custom miRNA PCR was used to identify 32 miRNAs that were differently expressed in Burkitt lymphoma cells exposed to HIV-1, with a majority of these being associated with oncogenic processes. Of those, hsa-miR-200c-3p, a miRNA that plays a crucial role in cancer cell migration, was found to be significantly downregulated in both the array and in single-tube validation assays. Using an in vitro transwell system we found that this downregulation correlated with significantly enhanced migration of BL cells exposed to HIV-1. Furthermore, the expression of the ZEB1 and ZEB2 transcription factors, which are promotors of tumour invasion and metastasis, and which are direct targets of hsa-miR-200c-3p, were found to be enhanced in these cells. This study therefore identifies novel miRNAs as role players in the development of HIV-associated BL, with one of these miRNAs, hsa-miR-200c-3p, being a candidate for further clinical studies as a potential biomarker for prognosis in patients with Burkitt lymphoma, who are HIV positive.

HIV-associated Burkitt lymphoma: outcomes from a US-UK collaborative analysis

AbstractData addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis

Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis

HIV Nef enhances the expression of oncogenic c-MYC and activation-induced cytidine deaminase in Burkitt lymphoma cells, promoting genomic instability

BackgroundNon-Hodgkin lymphoma is of high prevalence among HIV-infected people. In particular, the incidence of HIV-associated Burkitt lymphoma (BL) remains high despite the advent of Highly Active Anti-Retroviral Therapy. Recent evidence shows that serum-soluble HIV proteins can enhance oncogenesis, particularly in lymphoid tissues. This study sought to define the role of HIV protein Negative regulatory factor (Nef) in BL development by assessing its effect on key lymphoma driver genes.MethodsA recombinant Nef protein was used to assess changes in expressions of activation-induced cytidine deaminase (AICDA/AID) and c-MYC in B lymphocytes exposed extracellularly to the protein. Additionally, changes in the promoter activities of these genes were measured using a Nef-expressing cellular model and reporter assays. Confocal microscopy was used to observe c-MYC and AID expression and localization, and genomic integrity via the recruitment of phosphorylated γ-H2AX, in Nef-exposed cells.ResultsmRNA transcription of c-MYC and AICDA were significantly enhanced in lymphoma cells, up to 2-fold for c-MYC and up to 4-fold for AICDA, when exposed to varying concentrations of Nef (0–1000 ng/ml) and for different periods of time (3, 6 and 12 h). The protein expressions of AID and c-MYC followed a similar pattern and these effects were specific to BL but not lymphoblastoid cells. While the promoter activity of c-MYC was enhanced in the presence of Nef in a dose-dependent manner, the same was not observed for AICDA. Both AID and c-MYC accumulated within the cytoplasmic and nuclear spaces of Nef-exposed lymphoma cells, with a concomitant increase in DNA double strand breaks within the genome.ConclusionsExposure to HIV Nef leads to significant increases in AID and c-MYC, leading to genomic instability, potentially enhancing the oncogenic potential of Burkitt lymphoma. Our findings align with that of others to show that HIV proteins can directly contribute to the development and pathogenesis of HIV-associated lymphoma and accounts for the elevated incidence of BL observed in the HIV-infected population.

Correction to: In the South African setting, HIV-associated Burkitt lymphoma is associated with frequent leukaemic presentation, complex cytogenetic karyotypes, and adverse clinical outcomes.

The article "In the South African setting, HIV-associated Burkitt lymphoma is associated with frequent leukaemic presentation, complex cytogenetic karyotypes, and adverse clinical outcomes".

A case of HIV-associated Burkitt lymphoma diagnosed via cytology of cerebrospinal fluid collected at autopsy

A case of HIV-associated Burkitt lymphoma diagnosed via cytology of cerebrospinal fluid collected at autopsy

Outcomes of HIV-associated Burkitt Lymphoma in Brazil: High treatment toxicity and refractoriness rates – A multicenter cohort study

BackgroundAlthough the increased use of combined antiretroviral therapy (cART) has decreased the incidence of lymphomas HIV-associated, Burkitt lymphoma (BL) incidence remains stable. Reported outcomes on HIV-associated BL from developed countries seem to corroborate that the regimens do not need to be tailored to the HIV-positive population. Materials and methodsThis is a retrospective multicenter cohort study from Brazil, including HIV-positive patients aged 15 years and above diagnosed with BL. ResultsA total of 54 patients were included. Median age was 39 years (range, 15–64). At diagnosis, advanced disease was found in 86% and 52% had a CD4+ count lower than 200 cells/mm3. Five patients died before starting any regimen. Among the remaining 49 patients, most were treated with Hyper-CVAD (53%) and CODOX-M IVAC (18%). Rituximab was used in frontline in only 16% of the patients. Primary refractory disease was found in 14%. A treatment-related mortality of 38.7% and a complete response rate of 44.9% were found. At 4 years, estimated overall survival (OS) was 39.8%. All relapsed and primary refractory patients eventually died. Remaining patients died from infections (24/34), despite antimicrobial prophylaxis and associated cART. ConclusionEarly mortality and toxicity were higher in our cohort than in developed countries. A faster diagnosis, better understanding of the biology of the disease, establishment of low toxicity regimens, inclusion of rituximab and improvement of supportive care may decrease the mortality of HIV-associated BL in developing countries.

Outcomes of HIV-Associated Burkitt Lymphoma in Brazil: High Treatment Toxicity and Refractoriness Rates - a Multicenter Cohort Study

Introduction: Burkitt lymphoma (BL) has become an AIDS-defining disease by Centers for Disease Control (CDC) definition since 1993, emphasizing the strong relationship between this subtype of non-Hodgkin Lymphoma (NHL) and the Human Immunodeficiency Virus (HIV) infection. Although it is widely recognized that the HIV-associated BL represents a distinct entity and a more difficult-to-treat disease, reported results from developed countries seem to corroborate that these regimens do not need to be tailored to the HIV-positive population. There is no available data on outcomes of this population in developing countries. In this study, we report a real-world cohort of adult HIV-associated BL patients in Brazil. Methods: This is a retrospective multicenter cohort encompassing 4 academic hospitals in Brazil. Ethics approval for the study was obtained in all centers. Patients were treated according to their local protocol, which included Hyper-CVAD, CODOX-M IVAC or CHOP-like regimens, on a clinical judgement basis. Further reductions in the dose could be done at discretion of physician in case of excessive toxicity. For all patients who were not using cART, HIV-directed therapy was promptly started and administered along with chemotherapy. A cytoreductive regimen could be administered prior to the actual regimen to minimize the risk of tumor lysis. Survival analysis was performed using the Kaplan-Meier method and log-rank test for comparison. Cumulative incidence of relapse (CIR) was calculated using death as a competitor. Results: A total of 54 patients with HIV-associated BL were included in this analysis. Median age was 39 years (range, 15 - 64) and the vast majority were male (78%). 41% of patients were using cART prior to the BL diagnosis. Advanced disease was found in 86% of patients. CNS disease was observed in 31%. Regarding the immune status at the presentation, 52% had CD4+ T-cells count lower than 200 cells/mm3 and 19% had undetectable levels of HIV viral load. Other features are summarized in Table 1. Five patients died before starting any regimen due to sepsis. Among the 49 patients, most were treated with a modified Hyper-CVAD (26/49, 53%), CODOX-M IVAC (9/49, 18%) and a CHOP-like regimen (8/49). Only 8/49 (16%) patients received rituximab in upfront therapy. Radiotherapy was used in 4/49 patients (2 cranial irradiation, 1 in initial bulky site and 1 in testicles). A treatment-related mortality of 38.7% (95% confidence interval [CI] 25.5 - 53.7) was found and the complete response (CR) rate was 44.9% (95% CI 30.9 - 59.6). Primary refractory disease was found in 14%. Regarding the patients who achieved a CR at the end of treatment, 3-year CIR was 6.2% (95% CI 1.6 - 15.7%). There was no recommended regimen for salvage, and most patients received an alternate classic regimen for BL if feasible. Only one relapsed patient proceeded to autologous stem-cell transplantation, but eventually died after a second relapse. Median follow-up time was 4.4 years. A 4-year OS of 36.1% (95% CI 25.2 - 51.8) for total cohort and 39.8% (95% CI 28.1 - 56.5) for those patients who received any regimen was calculated (Figure 1). A univariate analysis for CR and OS did not show any statistically significant difference regarding sex, age, staging, CD4+, viral load, prior cART, extranodal infiltration, blood counts, lactate dehydrogenase (LDH), employed regimen or use of rituximab. All relapsed and primary refractory patients eventually died in our cohort. Aside from those patients who died from disease progression per se, remaining patients died from infections (24/34), despite intensive antimicrobial prophylaxis and associated cART. Conclusion: Outcomes of HIV-positive BL population are scarcely reported worldwide. While HIV patients seem to have a higher relapse rate in other studies, our early mortality and overall survival were far worse than those reported in developed countries and with more selected cohorts. In comparison with literature, our patients experienced higher toxicity with classic regimens and higher refractoriness rate. Therefore, these findings warrant further cooperative multicenter studies in developing countries, aiming at improving supportive care and optimizing regimens locally feasible. Disclosures Delamain: Novartis: Honoraria.

Response-Adapted Therapy with Infusional EPOCH Chemotherapy Plus Rituximab in HIV-Associated, B-Cell Non-Hodgkin's Lymphoma

Introduction: Six cycles of rituximab plus infusional EPOCH is considered a preferred regimen for first-line treatment of HIV-associated diffuse large B-cell lymphoma (DLBCL), HHV8-positive DLBCL, and primary effusion lymphoma, and is among the preferred regimens for HIV-associated Burkitt's lymphoma in the 2019 NCCN guidelines. A phase III trial demonstrated non-inferiority of 4 cycles of R-CHOP (followed by 2 additional doses of rituximab) compared with 6 cycles of R-CHOP in immunocompetent patients with low-risk DLBCL (stage I-II, age 18-60 years, and an age-adjusted International Prognostic Index score of 0), indicating that de-escalation of treatment duration may be safely achieved without compromising curability in an appropriately selected patient population. Here we report the outcomes for patients with HIV-associated DLBCL and high-grade non-Hodgkin lymphoma (NHL) treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy under a completed prospective clinical trial (AMC-034). Methods: One hundred-six patients with HIV-associated DLBCL or high-grade CD20-positive NHL enrolled at multiple centers across the U.S. were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of dose-adjusted EPOCH regimen tailored for HIV+ patients. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by IV bolus cyclophosphamide every 21 days for 4 to 6 cycles. Patients received 2 additional cycles of therapy after documentation of a complete response (CR) by computerized tomography after cycles 2 and 4. Results: Sixty-four of 106 patients (60%, 95% CI 50%, 70%) had a CR in both treatment arms; characteristics of entire population and CR proportions stratified by number of EPOCH treatment cycles were similar (Table 1).The 2-year event-free survival (EFS) rates were similar in the 24 patients with CR who received 4 or fewer EPOCH cycles (78%, 95% confidence intervals [55%, 90%]) due to achieving a CR after 2 cycles, compared with those who received 5-6 cycles of EPOCH (85%, 95% CI 70%, 93%) due to failure to achieve a CR after 2 cycles (Table 2 and Figure 1). Time to disease progression and overall survival wer also similar for those treated with 4 or fewer cycles compared with 5-6 cycles (91% vs. 87%, and 78% vs. 90%, respectively) (Table 2 and Figure 1). Conclusion: A response-adapted strategy may permit a shorter treatment duration without compromising therapeutic efficacy in an appropriately selected population of patients with HIV-associated NHL, which merits further evaluation in additional prospective trials. Disclosures Noy: Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding.

AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma

AbstractThe toxicity of dose-intensive regimens used for Burkitt lymphoma prompted modification of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for HIV-positive patients. We added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, capped vincristine, and used combination intrathecal chemotherapy. Antibiotic prophylaxis and growth factor support were required; highly active antiretroviral therapy (HAART) was discretionary. Thirteen AIDS Malignancy Consortium centers enrolled 34 patients from 2007 to 2010. Median age was 42 years (range, 19-55 years), 32 of 34 patients were high risk, 74% had stage III to IV BL and CD4 count of 195 cells per μL (range, 0-721 cells per μL), and 5 patients (15%) had CD4 <100 cells per μL. Twenty-six patients were receiving HAART; viral load was <100 copies per mL in 12 patients. Twenty-seven patients had at least one grade 3 to 5 toxicity, including 20 hematologic, 14 infectious, and 6 metabolic. None had grade 3 to 4 mucositis. Five patients did not complete treatments because of adverse events. Eleven patients died, including 1 treatment-related and 8 disease-related deaths. The 1-year progression-free survival was 69% (95% confidence interval [CI], 51%-82%) and overall survival was 72% (95% CI, 53%-84%); 2-year overall survival was 69% (95% CI, 50%-82%). Modifications of the CODOX-M/IVAC regimen resulted in a grade 3 to 4 toxicity rate of 79%, which was lower than that in the parent regimen (100%), without grade 3 to 4 mucositis. Despite a 68% protocol completion rate, the 1-year survival rate compares favorably with 2 studies that excluded HIV-positive patients. This trial was registered at http://clinicaltrials.gov as #NCT00392834.