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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3182a03e9b
Clinical Science

Treatment Outcomes in AIDS-Related Diffuse Large B-cell Lymphoma in the Setting Roll Out of Combination Antiretroviral Therapy in South Africa

de Witt, Pieter MBChB, MMedSc, MMed*; Maartens, Deborah J. MBChB, MMed†,‡; Uldrick, Thomas S. MD, MS§; Sissolak, Gerhard MBChB, MMed, MD*

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Author Information

*Department of Internal Medicine, Stellenbosch University, Cape Town, South Africa;

Department of Anatomical Pathology and National Health Laboratory Services (NHLS), Stellenbosch University, Cape Town, South Africa;

Faculty of Health Sciences, Tygerberg Academic Hospital, Stellenbosch University, Cape Town, South Africa; and

§HIV& AIDS Malignancy Branch, National Cancer Institute (NCI), Bethesda, MD.

Correspondence to: Dr G. Sissolak, Consultant Physician and Clinical Hematologist, Department of Medicine, Division of Clinical Hematology, PO Box 19063, Tygerberg, 7505, Cape Town, South Africa (e-mail: sissolak1@telkomsa.net).

Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

The authors have no conflicts of interest to disclose.

Received April 05, 2013

Accepted June 10, 2013

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Abstract

Background: Long-term survival for patients with AIDS-related diffuse large B-cell lymphoma (DLBCL) is feasible in settings with available combination antiretroviral therapy (cART). However, given limited oncology resources, outcomes for AIDS-associated DLBCL in South Africa are unknown.

Methods: We performed a retrospective analysis of survival in patients with newly diagnosed AIDS-related DLBCL treated at a tertiary teaching hospital in Cape Town, South Africa, with cyclophosphamide, doxorubicin, vincristine, and oral prednisone (CHOP) or CHOP-like chemotherapy (January 2004 until December 2010). HIV-related and lymphoma-related prognostic factors were evaluated.

Results: Thirty-six patients evaluated; median age 37.3 years, 52.8% men, and 61.1% black South Africans. Median CD4 count 184 cells per microliter (in 27.8% this was <100 cells/μL), 80% high risk according to the age-adjusted International Prognostic Index. Concurrent Mycobacterium tuberculosis in 25%. Two-year overall survival (OS) was 40.5% (median OS 10.5 months, 95% confidence interval: 6.5 to 31.8). Eastern Cooperative Oncology Group performance status of 2 or more (25.4% vs 50.0%, P = 0.01) and poor response to cART (18.0% vs 53.9%, P = 0.03) predicted inferior 2-year OS. No difference in 2-year OS was demonstrated in patients coinfected with M. tuberculosis (P = 0.87).

Conclusions: Two-year OS for patients with AIDS-related DLBCL treated with CHOP like regimens and cART is comparable to that seen in the United States and Europe. Important factors effecting OS in AIDS-related DLBCL in South Africa include performance status at presentation and response to cART. Patients with comorbid M. tuberculosis or hepatitis B seropositivity seem to tolerate CHOP in our setting. Additional improvements in outcomes are likely possible.

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INTRODUCTION

HIV infection increases the risk of diffuse large B-cell lymphoma (DLBCL) and other aggressive B-cell lymphomas,1 and approximately 80% of AIDS-related lymphomas (ARL) are DLBCL.2 In South Africa, a large proportion of DLBCL are attributable to HIV. In Johannesburg, where HIV seroprevalence is >30%, 79.8% of DLBCL cases between Januay 2004 and December 2006 were HIV related.3 In the Western Cape, where HIV seroprevalence is approximately 15%, the Tygerberg Lymphoma Study Group noted a proportional increase in ARL from 6% to 37% between 2002 and 2009, despite large-scale roll out of combination antiretroviral treatment (cART) starting in 2004.4

The standard of care for DLBCL in patients not infected with HIV is intravenous cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP)5,6 combined with the monoclonal anti-CD20 antibody, rituximab,7 in settings where rituximab is available. For patients with AIDS, successful management of HIV with cART results in significant immune reconstitution, improves long-term outcomes, and has allowed for evaluation of chemotherapeutic regimens for ARL. Several prospective studies have demonstrated dramatic improvement in outcomes in AIDS-related DLBCL compared with outcomes observed before the availability of cART.8–10

Chemotherapy regimens that have been evaluated include CHOP, and the following continuous infusional regimens: 96 hours etoposide, doxorubicin, vincristine combined with prednisone and cyclophosphamide (EPOCH)11; and 96 hours cyclophosphamide, doxorubicin, and etoposide (CDE).12 Each of these regimens has also been evaluated in combination with rituximab in patients with HIV.13,14 Although the combination of rituximab and CHOP is well established as first-line treatment in HIV-negative DLBCL, there remains equipoise regarding safety of rituximab in AIDS patients with CD4 counts <50 cells per microliter.15,16

Implementation of regimens developed in the United States and Europe to address the increasing burden of HIV-associated DLBCL in South Africa's public sector hospitals has been limited by lack of infrastructure to provide infusional regimens, lack of access to rituximab, and limited growth factors and other supportive care measures. As such, initial attempts to manage HIV-associated DLBCL in the setting of cART roll out in South Africa has relied on CHOP as the most feasible treatment option. CHOP was the standard of care for nearly all patients with DLBCL treated at Tygerberg Hospital affiliated to Stellenbosch University in the Western Cape, South Africa. Outcomes in HIV-positive patients treated with CHOP and cART seem comparable to outcomes in HIV-negative patients receiving CHOP for DLBCL in some settings.9 However, given differences in infectious comorbidities, differences in supportive care, and differences in health care delivery, outcomes using CHOP for the treatment of HIV-associated DLBCL in South Africa remains unknown. Furthermore, HIV-specific risk factors may remain relevant for prognosis in AIDS-related DLBCL in South Africa. Given uncertainties regarding the optimal approach to treatment of HIV-related DLBCL in South Africa, we evaluated outcomes and prognostic factors17–19 in patients treated with the most commonly used regimen, CHOP or a CHOP-like regimen, during the period of early cART roll out.

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PATIENTS AND METHODS

Study Design

We retrospectively analyzed all newly diagnosed DLBCL patients with documented HIV infection treated with CHOP or CHOP-like chemotherapy at Tygerberg Hospital over 7 years (January 1, 2004, until December 31, 2010). Clinical and therapeutic data were obtained from patient folders and laboratory data from the National Health Laboratory Service database. Deaths were identified by patient records and hospital databases. This study was approved by the Health Research Ethics Committee of Stellenbosch University and the National Institutes of Health Clinical Center Office for Human Research Protections and complies with Principles of the Declaration of Helsinki.20

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Patient Selection, Inclusion, and Exclusion Criteria

Patients were identified by a Systemized Nomenclature of Medicine search of diagnostic codes for DLBCL on the electronic database containing histological, cytological, and hematological data. Patients identified were reviewed for enzyme-linked immunosorbent assay confirmation of HIV and histologically confirmed DLBCL. Only patients aged 15 years and older undergoing treatment with CHOP or CHOP-like chemotherapy were included.

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Diagnosis, Staging, and Risk Assessment

Diagnosis and staging were based on standard-of-care practice at our institution. Lymph node and bone marrow histopathology and immunohistochemistry was supplemented by data from fine needle aspirations including flow cytometry. Results were reviewed by experienced histopathologist and hematopathologist. Diagnosis was made according to 2001 World Health Organization (WHO) classification criteria.21 Where diagnostic uncertainty regarding possible Burkitt lymphoma existed, fluorescent in situ hybridization analysis were performed to exclude MYC rearrangements (8q24) or translocation (8;14) fusion genes.22 No cases were sent for external review nor reclassified upon internal review.

Staging studies included physical exam, bone marrow trephine biopsy, and computerized axial tomography, with stage determined using the Ann Arbor staging system modified at Cotswold.23 Patients with symptoms or signs suggesting central nervous system (CNS) involvement or involvement of high-risk anatomical sites (paranasal sinuses, testis, orbit, bone marrow, and bone)24 underwent lumbar puncture for cytopathologic evaluation of cerebrospinal fluid and computerized axial tomography or magnetic resonance imaging of the brain. Baseline evaluation of left ventricular ejection fraction was performed in all patients.

In patients with clinical and radiographic features suggestive of active Mycobacterium tuberculosis coinfection [tuberculosis (TB)], relevant samples were collected for microscopy and culture and when indicated started antituberculous therapy. Serological evaluation for hepatitis B virus (HBV) and hepatitis C virus (HCV) was performed on some patients before initiation of chemotherapy. Presence of the HBV surface antigen was regarded as HBV infected and was managed using nucleoside reverse transcriptase inhibitors, lamivudine and tenofovir, agents with demonstrated activity against HBV, as part of cART. Presence of HBV surface antibodies without HBV surface antigen was regarded as immunity to HBV due to past infection as the national immunization schedule included HBV vaccination only since 1995.

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Patient Management and Treatment

Patients were treated with CHOP consisting of cyclophosphamide (750 mg/m2 intravenously on day 1), doxorubicin (50 mg/m2 intravenously on day 1), vincristine (1.4 mg/m2, max. 2 mg intravenously on day 1), and prednisone (100 mg orally) on days 1–5. Patients with a left ventricular ejection fraction of less than 45% received the CHOP-like regimen CNOP, which is administered in an identical manner, except doxorubicin (H) is substituted by an alternate anthracycline, mitoxantrone (N, 8 mg/m2 intravenously on day 1) to limit cardiotoxicity. For stages I or II, 4 cycles of chemotherapy was administered and for stages III and IV, 6–8 cycles. Intrathecal chemoprophylaxis (methotrexate 12 mg, cytarabine 30 mg, and dexamethasone 1 mg) was given at every cycle of chemotherapy to all patients with either documented involvement or high risk of CNS involvement.

Precautions to minimize infective complications included antiseptic mouthwash and prophylactic antibiotics during the time of neutropenia. Growth factors (granulocyte colony stimulating factor, G-CSF) were not available for primary prophylaxis or to ensure that chemotherapy cycles could be given on time. Patients who progressed despite treatment or had a relapse after an initial response were subsequently treated with second-line chemotherapies.

Patients not receiving cART at the time of diagnosis of DLBCL were referred to the Division of Infectious Diseases at Tygerberg Hospital to initiate cART, comprising primarily of stavudine, lamivudine, and efavirenz, as soon as possible while receiving chemotherapy. Follow-up regarding cART was done at HIV clinics during and after completion of chemotherapy. Virologic suppression was evaluated according to the WHO treatment guidelines at 8–12 weeks after initiating therapy.25

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Statistical Analysis

Our primary objective was to document 2-year overall survival (OS) in South African patients with AIDS-related DLBCL treated with CHOP or CNOP at an academic institution using Kaplan–Meier methodology. Secondary objectives included evaluation of response rates, progression-free survival (PFS), and prognostic factors for death. Individual prognostic factors evaluated included Eastern Cooperative Oncology Group (ECOG) performance status, presence of extranodal disease, diagnosis of AIDS before diagnosis of DLBCL, CD4 count <100 cells per microliter, WHO-defined virologic response to cART (sustained HIV viral load of <200 RNA copies/mL), TB, sex, and ethnicity. Patients were stratified by the International Prognostic Index (IPI),26 the age-adjusted International Prognostic Index (aaIPI),27 and an AIDS-related lymphoma score, and these were evaluated in our setting.

Response to therapy was classified as complete response (CR), partial response (PR), stable disease, or progressive disease (PD) according to the International Workshop criteria28 at 3 months, 6 months, and 12 months after initiation of therapy. In patients achieving a CR, clinical follow-up was generally done 3 monthly for 2 years; then 6 monthly for 2 years; then annually thereafter for a total of 5 years. OS was calculated from the time of DLBCL diagnosis; PFS was calculated as the time from DLBCL diagnosis to progression, relapse, or death. Patients were censored at time of last clinical evaluation.

The log-rank test was used to compare survival distributions between the groups. Patient characteristics were compared between the groups with χ2 or Fisher exact test in small sample situations. Differences between groups were regarded as significant for P values less than 0.05. Statistical evaluation was done in collaboration with the Center for Statistical Consultation of Stellenbosch University.

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RESULTS

Patient Characteristics

At Tygerberg Hospital, 281 cases of newly diagnosed DLBCL were identified in 2004–2010. HIV serology was available in 60% of these cases diagnosed in 2004–2006 compared with 81.9% diagnosed in 2007–2010, when the availability of cART improved.29 Fifty (17.8%) patients were known to be HIV infected of which 14 (28%) were excluded from our analysis due to not receiving chemotherapy. Nine of these 14 died shortly after the initial diagnosis and 5 patients were lost to follow-up before starting treatment. Thirty-six patients were treated with curative intent and included in the study (Table 1). Nineteen (52.8%) patients were male, 17 (47.2%) were female. Median age was 37 years (range: 23–64), only 1 patient was older than 60. Twenty-two (61.1%) patients were of black African and 14 (38.9%) of mixed ancestry.

Table 1
Table 1
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Twenty-one (58.3%) had WHO stage IV disease (AIDS) before or at the time of diagnosis, not including AIDS-related DLBCL as the sole diagnostic criterion for AIDS. Median CD4 lymphocyte count at lymphoma diagnosis was 184 cells per microliter (range: 28–2978), 10 (27.8%) patients were severely immunocompromised defined as CD4 count <100 cells per microliter. Active TB was present in 9 (25.0%) of 36 patients; 7 had pulmonary; and 2 had extrapulmonary disease as defined by the WHO criteria.30 Of 15 patients screened for Hepatitis B, 10 (66.7%) had serological evidence of prior exposure to HBV (HBsAb positive), which is similar to other urban HIV clinics in South Africa.31 Only 1 patient was HBV surface Ag positive with a detectable HBV viral load and was started on cART including tenofovir and lamivudine that effectively suppressed the replication of both viruses. No patient was seropositive for HCV. Additional comorbidities and baseline complications of DLBCL were noted. Seven (19.4%) patients had renal dysfunction due to acute kidney injury from tumor lysis syndrome (3 patients) or chronic kidney disease due to polycystic kidney disease, congenital single kidney with focal segmental glomerulosclerosis, or focal proliferative glomerulonephritis (4 patients). Lymphoma compressing the major airways, large blood vessels, or spinal cord complicated the management of 4 (10.8%) patients.

Most patients (86.1%) had advanced DLBCL, 28 (77.8%) had stage IV, and 3 (8.3%) had stage III (Table 1). Twenty-eight (77.8%) had DLBCL involving extranodal sites of which 6 (16.7%) had CNS involvement. When classified according to the IPI,26 19 (52.8%) patients had high-intermediate or high-risk indices compared with 17 (47.2%) with low or low-intermediate risk indices. In the 35 of 36 patients <60 years, 28 (80.0%) patients were classified as high-intermediate or high risk compared with 7 (20.0%) low or low-intermediate risk as classified by the aaIPI.27 By the AIDS-related lymphoma risk score,19 12 (33.3%) patients were classified as high risk, 16 (44.4%) intermediate risk and 8 (22.2%) as low risk.

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TREATMENT

Thirty-four patients (94.4%) received standard CHOP and 2 (5.6%) CNOP. A median of 5 cycles (range: 1–10) of first-line chemotherapy were administered. Fourteen (38.9%) patients completed planned first-line therapy. Reasons for failure to complete first-line therapy included 13 deaths (36.1%) occurring early during treatment, 5 (13.9%) PD, and 4 (11.1%) lost to follow-up. Early deaths were attributed to treatment-related complications (neutropenic sepsis and renal failure secondary to tumor lysis) in 6 cases, a direct consequence of lymphoma in 6. One outpatient died without a documented cause of death. Six patients received second-line chemotherapy, of these 3 died due to progression of lymphoma despite chemotherapy, 2 had a CR, and 1 was lost to follow-up.

A total of 28 (77.8%) patients received cART during their treatment for DLBCL: 9 [median CD4 count 162 cells/μL (range: 28–624)] were on cART at the time of diagnosis, 19 [median CD4 count 194 cells/μL (range: 28–472)] were started during chemotherapy, and 8 [median CD4 count of 130 cells/μL (range 28–2978)] failed to start cART either due to early death or loss to follow-up. Virologic suppression was demonstrated in 6 (67%) patient on cART at baseline and 15 (79%) of patients initiated on cART during chemotherapy. In the 7 patients who did not achieve virologic suppression, 4 had documented poor adherence and 3 died within 8–12 weeks after initiation of cART before an assessment could be made.

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Best Response to Treatment and Survival Outcomes

Twenty-six (72.2%) patients had an objective response to chemotherapy. Fourteen (38.9%) achieved a CR with first-line chemotherapy with 2 patients relapsing 3 and 6 months after completion of therapy. Twelve (33.3%) achieved a PR, of these 1 achieved CR with salvage therapy, 6 died (4 due to lymphoma, 1 due to renal failure, and 1 due to sepsis), and 4 were lost to follow-up. One (2.8%) patient had primary PD and died despite salvage chemotherapy. Nine (25.0%) patients died early during treatment before response evaluation could be performed (4 due to lymphoma, 3 due to sepsis, 1 due to tumor lysis, and in 1 no documented cause could be identified). The patients' response to CNOP was comparable to those who received CHOP: 1 achieved CR and relapsed 6 months after completion of therapy and 1 died within 1 month of initiation of treatment due to neutropenic sepsis. The estimated 2-year OS was 40.5%; median OS was 10.5 months (95% confidence interval:6.5 to 31.8), 2-year PFS was 34.0%; median PFS was 6.1 months (95% CI: 3.8 to –30.3) (Fig. 1A).

Figure 1
Figure 1
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Prognostic Factors and Indices

The majority of our study population was <60 years (97.2%), presented with advanced stages of disease (86.1%), and had elevated lactate dehydrogenase levels (91.7%). These individual factors were not prognostic. However, compared with subjects with an ECOG performance status of 0–1, those with an ECOG performance status of 2 or more had significantly worse 2-year OS (25.4% vs 50.0%, P = 0.02, Fig. 1B) and PFS rate of 18.5% vs 43.7% (P = 0.01). When comparing the presence and absence of extranodal site involvement, a nonsignificant trend toward a worse 2-year OS (33.9% vs 58.3%, P = 0.16) and PFS (30.6% vs 41.7%, P = 0.37) were observed in the group with extranodal involvement. Six (16.7%) patients had documented CNS involvement by DLBCL: 5 (83.3%) died due to lymphoma within 8 months of diagnosis with a median OS of 5.6 months (3 had a PR and 2 had primary PD); 1 patient with PR on first-line chemotherapy achieved a CR after salvage therapy, and this patient was alive 15 months after completing therapy. Differences in survival between patients with and without CNS involvement were not statistically significant (P = 0.24, Table 2). An additional 7 patients deemed to be at high risk of CNS involvement received prophylactic IT chemotherapy with systemic chemotherapy. No documented cases of CNS relapse in these patients nor the low-risk patients that did not receive IT chemoprophylaxis were identified. No differences in 2-year OS were observed for sex (P = 0.72), ethnicity (P = 0.38), or TB coinfection (P = 0.87).

Table 2
Table 2
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A diagnosis of AIDS before the diagnosis of DLBCL did not have a significant impact on the OS or PFS (P = 0.31 and P = 0.54). Advanced stages of immunosuppression (CD4 count <100 cells/µL) showed a trend for a worse OS but not PFS (P = 0.10 and 0.27, respectively) when compared with those with a CD4 count of ≥100 cells per microliter. Patients achieving a favorable virological response to cART (as defined by WHO criteria) had statistically significant superior 2-year OS (53.9% vs 18.0%, P = 0.03) and PFS (45.4% vs 14.1%, P = 0.03 Fig. 1C) compared with patients who did not. Outcomes with first line chemotherapy of patients on cART at the time of diagnosis (4 CR, 2 PR, 1 PD, 4 deaths) and patients that started cART during chemotherapy (9 CR, 8 PR, 5 deaths, 2 lost to follow-up) were superior to those patients that failed to receive cART (1 CR, 5 deaths, 2 lost to follow-up). The median OS in the 3 groups were 6.93 months, 10.53 months, and 1.03 months, respectively.

Established indices for prognosticating survival in patients with DLBCL or AIDS-associated lymphoma could not be validated in this small cohort. Using the aaIPI, high/high-intermediate risk patients and a low/low-intermediate risk patients had a 2-year OS of 36.8% compared with 71.4% (P = 0.50) and PFS rates of 33.7% compared with 42.7% (P = 0.99). The large absolute differences in OS did not reach statistical significance most likely due to few low-risk patients. The AIDS-related lymphoma risk score divided our patients in high-, intermediate-, and low-risk groups with 2-year OS rates of 27.8%, 33.5%, and 72.9% (P = 0.18, Fig. 1D) and 2-year PFS rates of 27.8%, 24.6%, and 62.5% (P = 0.24), respectively.

Baseline factors that were significant (P < 0.05) or showed significant trends (P ≤ 0.1) in predicting 2-year OS in univariate analyses, ECOG performance score (<2 vs ≥ 2), CD4 count (<100 cells/μL vs ≥ 100 cells/μL) and virological response to cART (favorable vs unfavorable) were evaluated in an exploratory multivariate analysis; however, none remained statistically significant independent predictors of death in this study (data not shown).

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DISCUSSION

Policies regarding public sector availability of cART have a large effect on the approach to diagnosing and treating AIDS-related DLBCL and other malignancies in South Africa. This retrospective study of HIV-positive patients with DLBCL treated with standard chemotherapy (CHOP or CHOP-like regimens) at Tygerberg Hospital with curative intent from January 2004 until December 2010 is an early attempt to evaluate outcomes in this patient population when treated with CHOP. As noted in other studies of AIDS-related lymphomas, a majority of patients presented with stage III/IV disease.9,15,17–19,32 Additionally, 40% of patients in this study had an ECOG performance status of ≥2. Despite these high risk features and despite limited use of G-CSF, 2-year OS of 40% and 2-year PFS of 34% were comparable to other studies of CHOP from United States and European centers.15,33

Besides demonstrating the feasibility of treating AIDS-related DLBCL is South Africa, our study evaluated several individual prognostic factors and indices. Both lymphoma-related and HIV-specific factors seem important in our setting. Poor performance status, generally attributed to lymphoma, was a significant risk factor for death. Patients who were severely immunosuppressed (baseline CD4 lymphocyte count < 100 cells/μL) had a 2-year OS of 22.9% compared with 48.0% (P = 0.10) for those with more preserved immunity (baseline CD4 lymphocyte count ≥ 100 cells/μL). Although the differences in outcomes did not reach statistical significance in our study, a clear trend toward a worse outcome is consistent with that seen in most studies of AIDS-related malignancies.17,26,34–36 On the other hand, response to cART was associated with improved OS and PFS.10,17 Importantly, a prior AIDS diagnosis or TB did not play a major role in the outcome of our patients. This was encouraging as TB is particularly important comorbidity in our patient population. Importantly, 9 (25.0%) patients were diagnosed with and treated for active TB during the time they received treatment for lymphoma.

Although we used CHOP to treat AIDS-related DLBCL during this period, other therapeutic regimens have demonstrated the potential to further improve lymphoma-related outcomes in other settings. Treatment of HIV-negative DLBCL using rituximab (R), a monoclonal anti-CD20 antibody, in combination with CHOP (R-CHOP) resulted in improved survival outcomes compared with CHOP, but with a dramatic increase in costs.37,38 A randomized controlled trial of R-CHOP compared with CHOP in HIV-positive patients did not demonstrate improved OS with the addition of rituximab, despite improved response rates, due to increase in infectious deaths in patients with low CD4 counts.22 However, subsequent studies suggest R-CHOP is safe and effective in a selected HIV-positive population.7 Furthermore, OS of 60% and PFS of 73% at 53 months has been demonstrated with the 96-hour infusional regimen dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin).11 Subsequent published data on dose-adjusted EPOCH with the sequential or concurrent addition of rituximab reported a 2-year PFS of 63% or 66%, respectively, and a 2-year OS of 67% or 70%, respectively.13 However, significant cost related to infusion pumps, central lines and necessary G-CSF also make dose-adjusted EPOCH more difficult to implement in resource limited settings than CHOP.

Oral chemotherapy is desirable in resource-limited settings. Mwanda et al32 reported on their results of a prospective study evaluating dose-modified oral chemotherapy in patients with AIDS-related lymphomas in Kenya and Uganda. The overall response rate (ORR) (72.2%) and 2-year OS (40.5%) of CHOP for AIDS-related DLBCL in our study vs that of oral chemotherapy in patients with a range of AIDS-related lymphomas (documented ORR by intention-to-treat 64%, ORR in assessable patients 78%; estimated 2-year OS ∼40%) were similar. However, comparison of these results should be interpreted with caution. On one hand, only 37% of patients in the East African study vs 77.8% in this series received cART during or immediately after completion of chemotherapy. On the other hand high-risk patients such as those with ECOG performance score of >3, patients who were not expected to survive 6 weeks and unacceptable end-organ function, and those with CNS disease were excluded; patient selection led to treatment of 49 (32.9%) of a total of 149 patients with proven lymphoma and HIV infection in the study of Mwanda et al, compared with 36 (72%) of 50 of patients in our series. Furthermore, prospective clinical trials may benefit from close monitoring and follow-up that is not part of routine practice in resource-limited settings. Further research on alternatives to CHOP is needed.

Our study adds to a growing body of evidence that cART significantly improves OS in patients with AIDS-related lymphoma in resource-limited settings. cART improves outcomes in patients treated with either oral chemotherapy32 or those treated with CHOP.10 We further demonstrate that virologic suppression is associated with a significantly improved 2-year survival (53.9% vs 18.0%, P = 0.03).

Given the high burden of HIV infection and AIDS-related lymphoma in South Africa, curative intent approaches are urgently needed.39 Given current resource limitations, standard therapies for AIDS-related lymphoma that often include rituximab, G-CSF, and/or infusional chemotherapy regimens are currently not feasible at the scale needed to address the burden of disease, and further experience with oral regimens is required. Patients diagnosed with DLBCL in South Africa should be tested for HIV, and those with AIDS-related DLBCL should at least receive CHOP with appropriate supportive care. Improved therapy is needed for patients with CNS involvement, and clinical trials evaluating the safety and feasibility of implementation of other established therapies or novel approaches are urgently needed for the treatment of AIDS-related DLBCL in South Africa.

Despite our encouraging findings with CHOP and cART, it should be noted that a significant proportion of patients (28%) diagnosed with HIV-associated DLBCL at our institution never received treatment, mainly due to late presentation or loss to follow-up. Common reasons for delays in diagnosing lymphoproliferative disorders such as DLBCL include empiric use of antituberculous treatment for lymphadenopathy in immunocompromised patients and limited access to existing specialty health care due in part to language barriers and lack of transportation. By the exclusion of these patients, our study population probably included a slightly more favorable risk group compared with the general patient population that presents with AIDS-related DLBCL to our institution. This might have resulted in more favorable survival outcomes than would otherwise be expected. Furthermore, of the patients treated for DLBCL in this study, HIV viral suppression was not achieved within the first 3 month of starting cART in 33% due to limitations in availability (8 patients, between 2004 and 2006), and poor drug adherence (4 patients). Additional strategies to improve the outcomes in HIV-associated DLBCL in South Africa may be possible through (1) testing all patients with DLBCL for HIV; (2) further improving accessibility and adherence to cART for patients with AIDS-related malignancies; (3) earlier diagnosis and treatment through community health care worker education, increased diagnostic capacity, and improved accessibility to referral hospitals; and (4) identifying patients who would benefit most from more intensive supportive measures and closer follow-up using CD4 count, ECOG performance status, or established risk scores like the aaIPI and AIDS-related lymphoma risk score.

In conclusion, an estimated 34% of patients with AIDS-related DLBCL who initiated CHOP at Tygerberg Hospital were alive and lymphoma free at 2 years. Patients with AIDS-related DLBCL in South Africa generally present with poor risk features including: high-risk indices according to the aaIPI and advanced levels of immunosuppression (CD4 count < 100 cells/μL). Response to cART was an important factor influencing OS. Importantly, the high prevalence of coinfections in our population did not have a significant impact on outcome, demonstrating that lymphoma therapy can be integrated with antimicrobial therapy in this setting. Further improvements in the treatment of AIDS-related DLBCL in South Africa will likely require investment in infrastructure, access to affordable cancer drugs for treating AIDS-related malignancies in South Africa, and evaluation of novel regimens within the setting of clinical trials.

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ACKNOWLEDGMENTS

The authors would like to thank Mr Justin Harvey for the statistical analysis of the data and Prof Judith Jacobson from Columbia University, New York, NY.

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Keywords:

diffuse large B-cell lymphoma; AIDS-related lymphoma; South Africa; AIDS-related lymphoma risk score

© 2013 by Lippincott Williams & Wilkins

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