Approach Considerations
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]
Medical Care
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)
Chemotherapy |
Outcomes (complete remission rate %) |
Indication |
CHOP |
63 [39] |
Most patients with advanced-stage disease; addition of rituximab recommended for CD20+ disease when CD4 count over 50 /μL |
Dose-adjusted EPOCH |
74 [40] |
Patients with a high proliferation index or plasmabatic histology; addition of rituximab recommended for CD20+ disease when CD4 count > 50 /μL |
CDE |
45 [41] |
|
CDE = cyclophosphamide, doxorubicin, etoposide; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (hydroxydaunorubicin) |
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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
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Early unfavorable disease - Four cycles of ABVD followed by 30-Gy involved-field radiotherapy
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Advanced-stage disease - Six cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone) or ABVD
Treatment for Relapsed or Refractory Disease
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]
Supportive Care
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.
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COVID-19 vaccination
Long-Term Monitoring
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.
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Burkitt lymphoma under low magnification showing sheets of atypical mononuclear cells. Scattered macrophages can be seen (as demonstrated by the green arrows) giving rise to classical "starry-sky" pattern.
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Burkitt lymphoma under high magnification showing sheets of atypical mononuclear cells. The cells are intermediate to large in size with scant cytoplasm, round to irregular nuclear contour, smudged chromatin and some with nucleoli. Mitosis and apoptosis are frequent with scattered macrophages giving focal "starry-sky" pattern. Green arrows = macrophages; yellow arrows = mitosis.
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Diffuse large B cell lymphoma under low magnification showing diffuse proliferation of large atypical lymphoid cells in this lymph node specimen.
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Diffuse large B cell lymphoma under high power showing cells that have moderate to abundant cytoplasm, round to irregular nuclear contour, vesicular nuclear chromatin and one to multiple nucleoli. Scattered small mature lymphocytes are seen. Green arrows = atypical lymphocytes; yellow arrows = small lymphocytes.
Tables
Lymphoma subtype |
Incidence (% of HIV-related lymphomas) |
Relative risk (compared with the general population) |
DLBCL, immunoblastic variant |
64 |
652 |
Burkitt lymphoma |
21 |
260 |
Indolent B-cell lymphoma |
< 10 |
15 |
T-cell lymphoma |
3 |
15 |
Hodgkin lymphoma |
< 10 |
15-30 |
Primary CNS lymphoma |
2-6 |
1000 |
Plasmablastic lymphoma |
3 |
>1000 |
Primary effusion lymphoma |
< 1 |
>1000 |
Chemotherapy |
Outcomes (complete remission rate %) |
Indication |
CHOP |
63 [39] |
Most patients with advanced-stage disease; addition of rituximab recommended for CD20+ disease when CD4 count over 50 /μL |
Dose-adjusted EPOCH |
74 [40] |
Patients with a high proliferation index or plasmabatic histology; addition of rituximab recommended for CD20+ disease when CD4 count > 50 /μL |
CDE |
45 [41] |
|
CDE = cyclophosphamide, doxorubicin, etoposide; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; EPOCH = etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (hydroxydaunorubicin) |
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