AIDS-Related Lymphomas

The pathogenesis of NHL development in the setting of HIV infection is not well elucidated. However, the following factors are thought to play an important role:

• Chronic B-cell stimulation ^[4]
• Cytokine dysregulation
• Co-infection with oncogenic viruses (Epstein-Barr virus [EBV], human herpesvirus 8 [HHV-8], hepatitis B and C viruses) in the setting of immune dysregulation, resulting in decreased surveillance for tumor antigens ^{[5, 6]}
• Genetic abnormalities (decreased BCL-2 activation and increased BCL-6 and MYC expression) ^{[7, 8]}

Different clinicopathologic categories of AIDS-related lymphomas arise from distinct B-cell subtypes, and the factors mentioned above interplay in varying proportions to give rise to different varieties of NHL.

It is estimated that 25% to 40% of patients with HIV infection will develop a malignancy and approximately 10% will develop NHL.[9]  AIDS-related lymphoma is more common in males than in females.[10] With the advent of anti-retroviral therapy (ART), the incidence rate of AIDS-defining lymphoma has substantially declined; however, it still remains substantially higher compared with the general population.[11]  A meta-analysis of over 400,000 patients showed the observed rate of lymphoma development in the HIV population to be 11.03 times that of the general population.[12]

Up to 85% of AIDS-related lymphomas are highly aggressive and include DLBCL, immunoblastic variant; and Burkitt lymphoma. Incidences and relative risks of AIDS-related lymphomas are shown in Table 1, below.[13, 14, 15, 16, 17]  

Table 1: Incidence and relative risk of AIDS-related lymphoma subtypes (Open Table in a new window)

Risk factors for developing AIDS-related lymphoma include the following:[18]

• Low CD4 count - A study of 52,278 patients from the French Hospital Database found CD4 cell count to be the most predictive risk factor of AIDS-related cancer incidence: Hodgkin lymphoma was 5.4 times more likely to develop in patients with CD4 cell count < 50/μL than in those with CD4 count > 500/μL. ^[19]
• High HIV viral load
• EBV co-infection
• Genetic factors -  CCR5-32 deletion is associated with favorable prognosis, whereas CXCR-4 is associated with increased risk for NHL development ^{[20, 21]}  
• Other undefined risk factors that increase the risk of NHL in the general population

ART can significantly affect the outcomes of AIDS-related lymphoma by reducing viral replication, and its use plays a pivotal role in improving prognosis. In addition, the prognosis of patients with AIDS-related lymphoma have been associated with the following factors:[3]

• Stage (extent of disease, extranodal or CNS involvement)
• Age
• Severity of the underlying immunodeficiency (measured by CD4 cell count)
• Performance status
• Prior AIDS diagnosis (ie, history of opportunistic infection or Kaposi sarcoma)

An AIDS-related lymphoma International Prognostic Index (IPI) has been developed and employs the age adjusted-IPI in addition to CD4 count, viral load, and prior history of AIDS.[22] This index performed better in predicting risk of death compared to the age-adjusted IPI.

Prognosis in patients with AIDS-related lymphoma varies depending on histologic subtype. A large body of evidence indicates that HIV-infected patients whose HIV disease is well controlled with ART and are treated with standard chemotherapies for DLBCL, Burkitt lymphoma, and Hodgkin lymphoma have outcomes similar to those of their uninfected counterparts.[23]  However, a diagnosis of primary effusion lymphoma or plasmablastic lymphoma generally confers a poor prognosis.[24]

Presenting symptoms and signs of AIDS-related lymphomas depend on the site of involvement, which can be variable. Common clinical manifestations include lymphadenopathy, organomegaly, and/or constitutional B symptoms. Patients can also present with unexplained cytopenias.

Of note, manifestations of primary central nervous system (CNS) lymphoma can include altered mental status, headache, blurred vision, and cranial neuropathies although these symptoms can also occur with CNS involvement from systemic lymphoma.[25]  Patients with primary effusion lymphoma can present with pleural or pericardial effusions.

Patients with AIDS-related lymphoma are more likely to present with the following, compared with HIV-negative lymphoma patients:[26]

• Advanced-stage disease
• Constitutional B symptoms (fever, night sweats, weight loss > 10% over 6 months)
• Extranodal involvement (GI tract, liver, lung, pleura, CNS, bone marrow)
• Disease involving uncommon locations (body cavity, soft tissue)

Oral lesions are second in frequency (11–33%) after gastrointestinal symptoms. These lesions are not similar to an ulcer or plaque, and most commonly appear as a rapidly growing mass on the palate or gingiva.[27]

Because AIDS-related lymphoma is generally associated with aggressive lymphoma histologies, advanced-stage disease, and extranodal involvement, patients may experience oncologic emergencies such as tumor lysis syndrome (hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia), and acute organ dysfunction (cardiac tamponade or GI, biliary, or ureteral obstruction).

Although lymphomas may appear at any time during the course of HIV infection, certain emergence patterns have been noted, depending on histologic subtype. Diffuse large B-cell lymphoma (DLBCL) and primary CNS lymphoma tend to occur during CD4 count nadir. In contrast, Burkitt lymphoma generally occurs when CD4 counts are better preserved. Hodgkin lymphoma occurrence has been seen during the first few months of antiretroviral therapy, when CD4 counts are improving.[28]

The workup of AIDS-related lymphoma includes laboratory studies, imaging studies, and biopsies. Specific choices in the workup should be guided by the patient's signs and symptoms (see Presentation/History and Physical). In addition, opportunistic infections should be evaluated.

Laboratory studies should include the following:

• Complete blood count (CBC) with differential
• Complete metabolic panel (CMP)
• Lactate dehydrogenase (LDH)
• Tumor lysis assays (potassium, phosphorus, calcium, uric acid)
• CD4 count
• HIV viral load
• Hepatitis B and C screening

Position emission tomography (PET) and/or computed tomography (CT) are generally used for staging purposes.[30]  Bone marrow biopsy is recommended for unexplained cytopenias.[31]  In addition, endoscopy or bronchoscopy may be considered if gastrointestinal (GI) tract or pulmonary involvement is suspected.[32, 33]

If central nervous system (CNS) involvement is suspected, neuroimaging with contrast-enhanced MRI or CT and lumbar puncture is recommended.[34]  All patients with HIV-related Burkitt lymphoma and selected patients with diffuse large B-cell lymphoma (DLBCL) who are at high risk for CNS involvement should undergo CNS evaluation.[35]

Cerebrospinal fluid (CSF) analysis should include the following studies:

• Cell count
• Protein and glucose level
• Cytology
• Flow cytometry
• Immunoglobulin heavy-chain (IgH) rearrangement studies
• Polymerase chain reaction (PCR) for Epstein-Barr virus and JC virus

Histological confirmation is usually obtained with biopsy of involved tissue. Excisional biopsy or multiple core biopsies are preferred, while fine needle aspirations (FNA) are suboptimal.

In primary CNS lymphoma, diagnosis can also be obtained by cerebrospinal fluid evaluation (see Imaging Studies and Procedures). In primary effusion lymphoma, diagnosis can also be obtained from malignant cells with human herpesvirus 8 (HHV-8) in effusion or ascites samples.

The optimal treatment for AIDS-lymphoma has yet to be defined. Treatment regimen is determined by disease histological subtype and stage, along with patient performance status and comorbidities, including CD4 cell count, HIV viral load, and prior history of AIDS-related complications. Generally, treatments for AIDS-related lymphoma are extrapolated from their non–AIDS-related lymphoma counterparts, with the addition of antiretroviral therapy (ART). However, several prospective studies have clarified the treatment of these lymphomas.

Although ART and chemotherapy may have overlapping side effects, which can make treatment more challenging, all patients should be initiated on both ART and chemotherapy, as concurrent therapy has been associated with improved outcomes.[36, 37]  ART should be continued throughout the duration of chemotherapy.

Due to HIV-associated immunosuppression, which can be worsened with chemotherapy, all patients—regardless of CD4 cell count—should be started on prophylaxis against Pneumocystis jiroveci pneumonia and toxoplasmosis.[1]

Of note, the role of rituximab in AIDS-related lymphoma is not as clearly defined as it is in the HIV-negative population, due to rituximab-induced cellular and humoral immunodeficiency, which is worsened with HIV infection. Therefore, the addition of rituximab is generally recommended for CD20+ disease in patients whose CD4 count is above 50/μL.[38]

Diffuse large B-cell lymphoma (DLBCL)

Common chemotherapeutic options used in the initial treatment of AIDS-related DLBCL include the following:

Table 2: Common chemotherapeutic options for initial treatment of AIDS-related DLBCL (Open Table in a new window)

Central nervous system (CNS) prophylaxis is indicated for patients with double-hit lymphoma or lymphomatous involvement of bone marrow, testes, sinuses, or epidural regions.[42]  Patients with high CNS–international prognostic index levels should be offered prophylaxis.[1]

Burkitt lymphoma

Prospective trials of treatment for Burkitt lymphoma in HIV-positive patients have used the following regimens:

• Modified CODOX-M/IVAC-rituximab - Cyclophosphamide, vincristine (Oncovin]) doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine, rituximab ^[43]
• SC-EPOCH-RR - Short-course rituximab, etoposide, prednisone, vincristine (Oncovin), cyclophosphamide, doxorubicin (hydroxydaunorubicin), with dose-dense rituximab ^[44]
• CARMEN program - Dose-dense short-term chemoimmunotherapy

Modified CODOX-M/IVAC and SC-EPOCH-RR are reduced-intensity regimens designed to lower the toxicity of treatment in this vulnerable population. In a study of modified CODOX-M/IVAC in 34 patients, 1-year progression-free survival (PFS) was 69% and 2-year overall survival (OS) was 72%; however, 32% of patients failed to complete the protocol because of adverse events.[43] A study of SC-EPOCH-RR in 11 patients reported PFS of 100% and OS of 90% at 73 months follow-up; principal toxic events occurred in 10%.[44]

The CARMEN program was also designed to improve the tolerability and reduce the duration of Burkitt lymphoma treatment. It comprises a 36-day induction phase of sequential doses of fractionated cyclophosphamide, vincristine, rituximab, high-dose methotrexate, etoposide, and doxorubicin, with intrathecal chemotherapy. After induction, patients in complete remission receive high-dose-cytarabine–based consolidation; pts in partial response receive consolidation plus autologous stem cell transplantation (ASCT) and patients with stable or progressive disease receive intensification, concluding with ASCT; and patients with residual disease receive radiation therapy. A phase II trial in 20 HIV-positive patients with high-risk Burkitt lymphoma found that the approach is safe and effective in this setting, with PFS in 14 patients on median follow-up of 34 months, two deaths from toxicity, one case of mucositis, and no fungal infections.[45]

CNS prophylaxis is recommended in all patients with Burkitt lymphoma.

Plasmablastic lymphoma

For plasmablastic lymphoma, a highly aggressive lymphoma that is predominantly observed in persons with HIV disease, National Comprehensive Cancer Network (NCCN) guidelines recommend initial therapy with a more intensive regimen such as the following[42] :

Autologous SCT should be considered in first complete remission in select high-risk patients.​[46]  

Hodgkin lymphoma

Treatment of Hodgkin lymphoma in HIV-positive patients should be stage-adapted, as follows[47] :

Primary CNS lymphoma

For patients with primary CNS lymphoma who have adequate renal function, high-dose methotrexate, 3 g/m2 every 2 weeks for 6-8 doses, in conjunction with ART has been shown to be effective.[48, 49]  A retrospective study of 51 patients with HIV-related primary CNS lymphoma treated with high-dose methotrexate in conjunction with ART showed median overall survival of 5.7 years.[50] The addition of rituximab to methotrexate has not been associated with a clear benefit and should not be used, especially in the HIV-positive population.[51]  

For patients who cannot tolerate high-dose methotrexate, there is a paucity of evidence for alternative agents. However, whole-brain radiation or temozolomide can be considered.

Primary effusion lymphoma

Standard treatment approaches, such as CHOP, have yielded disappointing results in patients with primary effusion lymphoma (PEL). Therefore, patients with PEL should be offered clinical trials if possible. Novel treatment approaches include bortezomib,[52]  lenalidomide,[53]  or daratumumab.[54]

• CODOX-M-IVAC
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone, administered on a hyperfractionated schedule)
• Dose-adjusted EPOCH 
• Early favorable disease - Two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with subsequent 20-Gy involved-field radiotherapy
• Early unfavorable disease -  Four cycles of ABVD followed by 30-Gy involved-field radiotherapy
• Advanced-stage disease -  Six cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) or ABVD 

Relapsed/refractory disease is treated similarly to its HIV-negative counterpart, with platinum-based salvage regimens such as ICE (ifosfamide, carboplatin, etoposide), DHAP (dexamethasone, high-dose cytarabine [ARA-C], cisplatin [Platinol]), or GDP (gemcitabine, dexamethasone, cisplatin) followed by autologous stem cell transplantation. Several clinical trials have shown that intensive salvage regimens followed by high-dose chemotherapy and autologous stem-cell transplantation are feasible and effective in chemotherapy-sensitive relapsed or refractory AIDS-related lymphoma.[55, 56, 57, 58]

Chimeric antigen receptor (CAR) T-cell therapy has proved effective in the relapsed/refractory setting for some NHL subtypes and is recommended in patients with stable or progressive disease despite salvage therapy.[59] However, no studies have been done to specifically evaluate CAR T-cell therapy in the HIV-positive population.

Allogeneic stem cell transplantation has been performed in selected cases of relapsed HIV-related lymphoma in patients receiving combined antiretroviral therapy. Both reduced-intensity conditioning and myeloablative conditioning proved feasible. However, given the limited amount of experience and the lack of long-term efficacy data, no firm conclusions can be drawn.[60]

The following is recommended for all patients with AIDS-related lymphoma[42] :

• Begin growth factor support 24-48 hours after chemotherapy and continue past nadir to recovery of blood counts of each cycle.
• Continue PJP prophylaxis until CD4 > 200/μL after completion of chemotherapy.
• Provide antimicrobial prophylaxis with a quinolone during the period of neutropenia.
• Hold azole antifungals from 24 hours prior through 24 hours post chemotherapy with agents that have CYP3A4 metabolism.
• Provide  Mycobacterium avium complex (MAC) prophylaxis for patients with CD4 < 100/μL.
• Strongly consider varicella-zoster virus/herpes simplex virus (VZV/HSV) prophylaxis
• Encourage consultation with an infectious disease specialist for febrile neutropenia in the context of extensive prophylaxis and for refractory diarrhea.
• COVID-19 vaccination

Follow-up visits are usually arranged every 3-4 months initially, depending on the individual patient, but these may be tailored as the condition mandates. These visits are utilized to follow response to treatment and to provide psychosocial support for the patient. During follow-up visits, it is important to ask patients about constitutional symptoms, new lymphadenopathy, or pain; patients should be educated about reporting any of these signs and symptoms to the physician.

The physical examination should focus on the presence of enlarged lymph glands and an enlarged liver or spleen. Laboratory workup should be repeated, including the minimum of a complete blood cell count with differential and a comprehensive metabolic panel. Imaging should be done only if there is suspicion of recurrence.