Abstract
People living with HIV/AIDS (PLWHA) are at a higher risk of developing non-Hodgkin lymphoma (NHL). The influence of combined antiretrovirals (cART) on the presentation, treatment, and outcomes of HIV-associated NHL (HIV-NHL) warrants further investigation. We performed a retrospective analysis of PLWHA diagnosed with NHL who received care at the Infectious Diseases Ponce de Leon Center in Atlanta, Georgia, from January 1, 2004 to December 31, 2010. Thirty-five patients with HIV-NHL were identified. Among these patients, 7 had Burkitt lymphoma (BL), 20 had diffuse large B cell lymphoma (DLBCL), 7 had plasmablastic lymphoma (PL), and 1 had primary effusion lymphoma (PEL). The majority of patients (82.9%) presented with advanced disease, and 63% were not on ART at diagnosis. Despite having good performance status at presentation, the majority of patients presented with high International Prognostic Index (IPI) scores. There were differences between the histologic subtypes of NHL in regard to treatment, complications, and outcomes. The median CD4 lymphocyte count at diagnosis was 110 cells/mm3 for patients with DLBCL [interquartile range (IQR): 66, 203], 165 cells/mm3 for Burkitt lymphoma (IQR: 36, 199), and 98 cells/mm3 for plasmablastic lymphoma (IQR: 34, 214). Overall, patients completed 67% of planned chemotherapy cycles. Common causes for chemotherapy termination were persistent myelosuppression (18.2%), social factors (22.7%), and disease progression (36.4%). Social factors included lack of transportation, substance abuse, unstable housing, and poor adherence. Two-year overall survival was 40% for all HIV-NHL. Half of the patients with DLBCL (n=10), 42% of patients with PL (n=3), and only 14.3% of patients with BL (n=1) were alive at 2 years. Among the overall survivors at 2 years, 85.7% had CD4 >200 cells/mm3 and 78.6% had undetectable HIV viral loads (VL) at that time.
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The use of combination antiretroviral therapy (cART) has significantly improved clinical outcomes for patients with HIV-NHL to a level approaching that of HIV-uninfected patients. 1,11 –14 However, some data suggest that HIV is still an independent risk factor for mortality among patients with NHL, regardless of histologic subtype or stage. 15 Of note, this association was not observed in patients with HIV-NHL who had a CD4 lymphocyte count of 200/mm3 or higher and had no prior AIDS-defining illness. Treatment of NHL remains problematic in HIV-infected individuals. Chemotherapy may further depress the immune system resulting in an increased risk of opportunistic infection or it may interact with antiretroviral regimens resulting in treatment interruptions. However, in the established antiretroviral therapy (ART) era, with more tolerable and less toxic ART regimens, the survival of HIV-infected patients with NHL has improved consistently. Recent studies have shown that patients in the cART era who are successfully treated for HIV-NHL are at risk for non-AIDS-defining-cancers (NADC) as well as infections and other AIDS-defining cancers. 16 We present our experience with HIV-NHL in an urban clinic.
We performed a retrospective descriptive analysis of a cohort of PLWHA diagnosed with NHL who received care at the Infectious Diseases Ponce de Leon Center in Atlanta, Georgia from January 1, 2004 to December 31, 2010. The Ponce de Leon Center is an urban Ryan White-funded clinic in midtown Atlanta that that provides care annually to ∼5,000 individuals, a unique population consisting mostly of impoverished African American individuals with advanced AIDS and limited access to care. Patients with primary central nervous system (CNS) lymphoma were excluded from this study due to lack of histopathologic diagnostic confirmation. All diagnoses were assessed by the central pathology laboratory at Grady Memorial Hospital. Medical records and electronic charts were abstracted for demographic data, cancer stage, CD4+ cell count, HIV viral load, ART use, Eastern Cooperative Oncology Group (ECOG) performance status, histologic subtype, International Prognositic Index (IPI), site(s) of involvement, presence of B cell symptoms (fever, night sweats, and weight loss), chemotherapy, completed chemotherapy cycles, and death. Overall survival scores were calculated using an end date of December 31, 2012. In addition, immunohistochemical expression of B cell markers and other cytogenetic abnormalities were obtained from pathology records whenever possible. ECOG performance status grade is defined as (0) fully active, (1) restricted in physical strenuous activity, (2) ambulatory and capable of all self care, (3) capable of only limited self care, and (4) completely disabled. IPI is calculated by assigning 1 point to each of the following: age greater than 60 years, cancer stage III or IV disease, elevated serum LDH, ECOG performance status of 2, 3, or 4, and more than one extranodal site.
Complete response was defined using radiologic evidence based on a negative positron emission tomography (PET) scan upon completion of treatment. The treating oncologist assessed relapse. The IPI scores ranged from 0 to 5, with a higher score indicating a poorer prognosis. Cause of death for those patients who were lost to follow-up was verified by the clinical staff at the Ponce De Leon Center. Statistical analyses were conducted using SAS, version 9.2 (SAS Institute Inc). The study was approved by the Emory Institution Board Review and by the Grady Research Oversight Committee.
Thirty-five patients with HIV-NHL were identified from January 2004 to December 2010. Their baseline characteristics are displayed in Table 1. Of these patients, 7 had BL, 20 had DLBCL, 7 had PL, and 1 had primary effusion lymphoma (PEL).
DLBCL, diffuse large B cell lymphoma; PL, plasmablastic lymphoma; BL, Burkitt lymphoma; IQR, interquartile range; NHL, non-Hodgkin lymphoma; VL, viral load; ART, antiretroviral therapy.
The majority of patients (82.9%) presented with advanced disease and 63% were not on ART at diagnosis (Tables 1 and 2). Characteristics of lymphoma presentation are summarized in Tables 2 and 3. Despite having good performance status at presentation, the majority of patients presented with high IPI scores indicating prognosis. In addition, nearly half (44%) of the patients in this study had NHL as their AIDS-presenting diagnosis.
ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index.
ARV, antiretroviral.
The immunohistochemical staining patterns varied among the histologic subtypes. All DLBCL were CD20+, while only five out of seven BL were Cd20+ (71.4%). Among patients with plasmablastic lymphoma, six out of seven had plasma cell marker immunohistochemical profiles (85.7%). The proliferation fraction as determined by Ki67+ was present in two patients with DLBCL and one patient with PL. Among BL patients, 71% (n=5) had reciprocal translocation of the protooncogene c-myc.
All HIV-NHL in this cohort with the exception of one PL patient received chemotherapy. Overall, patients completed 67% of planned chemotherapy cycles. Common causes for chemotherapy termination were persistent myelosuppression (18.2%), social factors (22.7%), and death (36.4%). Social factors included lack of transportation, substance abuse, unstable housing, and poor adherence. All DLBCL patients received chemotherapy. The majority of DLBCL patients received CHOP (n=19) therapy. One patient was treated with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; n=1). Dose-adjusted therapy EPOCH therapy is an infusional regimen defined by a reduction in the cyclophosphamide dose according to the CD4 count and absolute neutrophil nadir in order to minimize hematopoietic toxicity while maintaining maximum dose intensity. 11 Half of these patients also received rituximab (n=10). Patients completed 68.9% of planned chemotherapy cycles. Of the chemotherapy cycles completed, 13 of 84 cycles (15.5%) were delayed from the scheduled administration date. The most common reasons for delay were social (23.1%) and infectious complications, febrile neutropenia, and myelosuppression (76.9%). The average length of delay was 23.5 days.
Six out of seven PL patients received chemotherapy. Chemotherapy regimens included CHOP (n=4) and EPOCH (n=2). A minority of patients received rituximab (n=2). The reason for withholding rituximab in those patients was low CD4 count or lack of CD20 expression. Patients completed 69% of planned chemotherapy cycles. Of these, 3 of 29 cycles (10.3%) were delayed from the scheduled administration date. Reasons for delay included rash (33.3%) and social (66.6%) concerns. The average length of delay was 40 days.
All BL patients in this study received treatment with chemotherapy. The majority of patients with BL received HCVAD (n=6) therapy. One patient received ICE (ifosfamide, carboplatin, etoposide; n=1). Four of seven patients (57%) also received rituximab. Rituximab was withheld in patients with a CD4 count less than 50/mm3 due to the increased risk of infection in these patients. 17 BL patients completed 59.3% of planned chemotherapy cycles. Of the chemotherapy cycles completed, 7 of 35 cycles (22.6%) were delayed with an average length of delay of 21.6 days from the scheduled administration date. The most common reasons for delay were social (28.6%) or cytotoxic effects of the chemotherapy (71.4%). Cytotoxic effects of the chemotherapy included infectious complications, febrile neutropenia, and myelosuppression. One patient had primary effusion lymphoma and was treated with CHOP and rituximab. This patient completed three of six (50%) planned chemotherapy cycles and also received rituximab. The patient did not experience any delays in treatment, but was discharged to hospice due to lymphoma progression.
Of the 35 patients, 18 (51.4%) were assessed for response to chemotherapy treatment after two to three cycles using PET. Of these patients, 72.2% (n=13) had achieved a complete response at this time. Two-year overall survival was 69.2% among patients who had an observed complete response after two to three cycles of chemotherapy (n=9). If patients with Burkitt lymphoma are excluded, then 2-year overall survival for patients with complete response after two to three cycles was 88.9% (n=8). The reasons for noncompletion of a PET scan after cycle two or three were patient preference, death, and social factors such as lack of transportation and substance abuse.
Two-year overall survival was 40% for all non-Hodgkin lymphoma. Half of patients with DLBCL (n=10), 42% of patients with PL (n=3), and only 14.3% of patients with BL (n=1) were alive at 2 years. Among the overall survivors at 2 years, 85.7% had CD4 >200 cells/mm3 and 78.6% had undetectable HIV viral loads (VL) at that time.
Two-year overall survival was 40% for all non-Hodgkin lymphoma. Half of patients with DLBCL (n=10), 42% of patients with PL (n=3), and only 14.3% of patients with BL (n=1) were alive at 2 years.
Despite national trends showing a decreased incidence of HIV-NHL in the late ART era, HIV-NHL remains a significant problem in urban settings primarily as a result of barriers to care. Barriers to care include socioeconomic hardships, poor adherence, and substance dependence. Management of patients in an urban setting with limited resources remains a challenge. Despite these difficulties, our results confirm that it is possible to deliver effective therapy in this population. The median survival for DLBCL and BL among PLWHA, however, was still poor when compared to the general population for these lymphoma types (21 months versus 52 months median survival for DLBCL and 8 months versus 71 months for BL). 18 This may be due to the fact that the majority of patients presented with advanced stage disease and adverse prognostic features. Unfortunately, 44% (15/34) of individuals were diagnosed with HIV only after they presented with NHL. Perhaps these HIV-NHL could have been prevented had their HIV been diagnosed earlier and cART initiated earlier.
Of note, 25% of patients with DLBCL also had hepatitis B. Systemic chemotherapy and rituximab treatment can influence immunity against HBV, resulting in HBV reactivation and/or increasing viral replication. The combination of rituximab and chemotherapy treatment for NHL has been associated with an increased risk of fulminant liver failure in patients with hepatitis. Patients should be tested for hepatitis prior to initiating treatment for NHL to assess the need for antiviral treatment prior to initiating chemotherapy. 19 The relatively large percentage of patients with coexisting hepatitis B in this study underlines the importance of this screening measure so that their hepatitis can be treated before starting chemotherapy.
Limitations of our study include the fact that it was a retrospective study, relying on data abstraction from medical records, and a small sample size, which did not allow the analysis of predictors of survival. All included patients, however, received care from a single center with access to electronic medical records. This facilitated accurate information gathering and access to detailed histopathologic data.
In summary, patients with HIV-NHL receiving care at an urban clinic are able to receive effective chemotherapy for their lymphoma with reasonable expectations of surviving at least 2 years after diagnosis. This is particularly the case for patients diagnosed with DLBCL. Continued efforts to provide prompt and continuous antiretroviral therapy, as well as standard chemotherapy to patients with HIV-NHL, should be a high priority in this challenging population. Greater effort should be devoted to diagnosing HIV early and to get PLWHA into care earlier to prevent the occurrence of AIDS-defining malignancies.
Footnotes
Author Disclosure Statement
No competing financial interests exist.