HIV-Related Lymphomas

Most lymphomas seen in patients who have HIV infection are of an aggressive histology and advanced stage at presentation. Extranodal disease is common, with unusual sites of presentation, including the GI tract, CNS, and multiple soft tissue masses. Some patients present with primary CNS lymphoma. Poor-risk factors include a high LDH level, large tumor bulk, extranodal disease, and low CD4 cell counts (< 100/µL). Because of their increased risk of opportunistic infections and impaired hematologic reserve, many patients with HIV-related lymphomas historically have been unable to tolerate aggressive chemotherapy regimens. Current antiviral medications have allowed for the use of more traditional regimens, including R-CHOP and EPOCH-R, with results comparable to those of other NHL patients with similar histologies and presentations. CNS prophylaxis with intrathecal chemotherapy is necessary to prevent meningeal dissemination. (For a more detailed discussion of HIV-related NHL, see the “AIDS-Related Malignancies” chapter.)

Posttransplant Lymphoma

Posttransplant lymphoproliferative disorders (PTLDs) remain a morbid complication associated with SOT. The incidence varies from 1% to 2% in renal transplant recipients and up to 12% to 14% in heart or multi-organ transplant recipients; the latter patient groups require more potent immunosuppressive therapy.

The pathologic spectrum of PTLD is heterogeneous, comprising a spectrum ranging from hyperplastic-appearing lesions to frank aggressive lymphoma. The most frequent subtype seen is monomorphic, of which the most common histology is akin to DLBCL. PTLDs are fully depicted in the updated WHO classification (see Table 4). Historically, PTLDs were reported to occur at a median of 6 months from SOT, although recent data suggest this interval is likely longer (ie, median 40 to 50 months). Early PTLD cases (ie, < 12 months after SOT) more often express EBV, whereas late-onset cases are typically EBV-negative.

Recent evidence suggests improved outcomes for PTLD in the modern era. Treatment initially involves the reduction of immunosuppression (usually by at least 50%), especially for early EBV-positive cases. EBV-negative PTLD will respond to immunosuppression reduction, but less frequently than EBV-positive cases. In addition, the status of the transplanted organ will in part dictate the amount of immunosuppression safely allowable to avoid organ rejection. The exact role of rituximab in B-cell PTLD continues to be defined. Single-agent rituximab was evaluated in two phase II studies of patients in whom reduction of immunosuppression failed, with reported overall response rates of 42% and 73% and modest survival rates. A retrospective series using frontline rituximab-based therapy, in conjunction with reduced immunosuppression, was associated with significantly improved survival compared with prior reports. In addition, a recent prospective PTLD clinical trial using sequential rituximab followed by CHOP therapy showed good outcomes. Final results of the latter trial, which studied a response-adapted therapeutic strategy with frontline single-agent rituximab, are eagerly awaited.

The decision of initially treating with rituximab alone vs concurrent or sequential rituximab with chemotherapy (eg, R-CHOP) is often determined on a patient-by-patient basis. Factors in small studies associated with lower response to rituximab in PTLD include EBV-negative disease and elevated LDH levels. In addition, chemotherapy may be needed as initial therapy for patients who have a large tumor burden warranting rapid response of disease. Of note, during chemotherapy, immunosuppressant medication doses should be either significantly reduced or carefully stopped completely, in part to avoid infectious complications. Carefully selected patients with relapsed/refractory monomorphic PTLD are able to receive high-dose chemotherapy followed by autologous SCT, with long-term survival noted in some reports.

Anecdotal reports have described the activity of thymidine kinase inhibitor antiviral therapies such as ganciclovir and acyclovir to prevent and/or treat PTLD, although the data are not convincing. This finding is not surprising, because EBV survives as an episome outside the lymphocyte genome, and these drugs do not eradicate latently infected B cells. However, one group has shown that arginine butyrate was able to induce EBV tyrosine kinase activity in EBV-immortalized B cells and convert patient-derived latently infected B-cell lymphoma tumor cells that were resistant to ganciclovir to a sensitive phenotype. A phase I/II study with encouraging clinical results was reported. In hematopoietic SCT-related PTLD, EBV-specific cytotoxic T lymphocytes (CTLs) have been used with encouraging results. In addition, the use of adoptive immunotherapy with EBV-specific CTLs continues to be explored in PTLD (Sidebar).

Sidebar: Recent studies from the Baylor group have shown the utility of T cells primed against EBV and other viruses in patients with EBV-related immune deficiency associated lymphomas. In novel studies, the Baylor group has used genetically modified expanded CTLs that were enriched for specificity against type II latency latent membrane protein (LMP) antigens. When these were infused into 50 patients with EBV-associated lymphoma, there were no infusion-related toxicities. Furthermore, 28 of 29 high-risk or multiply-relapsed patients receiving LMP-CTLs as adjuvant therapy remained in remission a median of 3.1 years after infusion. Of 21 patients who had active disease at the time of infusion, 13 had responses, including 11 complete responses. Duration of the responses in patients with active disease were not described. It is clear from these and similar studies that this approach to EBV-mediated and other virus-mediated lymphomas may be addressed by T-cell–mediated, immunotherapy-based approaches (Bollard CM et al: J Clin Oncol 32:798-808, 2014; Papadopoulou A et al: Science Transl Med 6:242ra83, 2014; Leen AM et al: Immunol Rev 258:12-29, 2014).

Primary CNS Lymphoma

Primary CNS lymphoma is a rare form of NHL, arising within and confined to the CNS. Histologically, primary CNS lymphomas are indistinguishable from systemic NHLs. A stereotactic needle biopsy is the procedure of choice for diagnosis. Resection does not appear to improve survival. More than 40% of patients have evidence of leptomeningeal dissemination, and 15% have ocular disease at presentation. Thus, examination of the eyes for lymphoma (slit lamp) at diagnosis is important, as is MRI of the entire neurospinal axis, to rule out multifocal disease.

The two most important prognostic factors in primary CNS lymphoma are age (> 50 years) and poor performance status (Karnofsky performance score < 70). Retrospective studies have documented that treatment of primary CNS lymphoma with whole-brain radiotherapy (WBRT) alone (with or without corticosteroids) results in a median survival of 10 to 15 months, with a 5-year survival of 3% to 4%. Current standard therapy for newly diagnosed primary CNS lymphoma is systemic chemotherapy, including high-dose intravenous methotrexate-based therapy (at least 2,500 to 3,500 mg/m² per cycle) commonly combined with agents that penetrate the CNS (vincristine, procarbazine, and high-dose cytarabine). This regimen results in median survival rates of 50 to 60 months. The most important component in the treatment of primary CNS lymphoma is the use of high-dose methotrexate therapy (at least 2,000 mg/m² and up to doses of 8,000 mg/m²). WBRT had been considered a standard component following chemotherapy; however, long-term neurotoxicity remains a major concern, especially for patients older than 60 years.

A study by Morris and colleagues reported encouraging results for primary CNS lymphoma patients who achieved complete remission following five to seven cycles of high-dose methotrexate-based chemoimmunotherapy and subsequently received reduced-dose WBRT (23.4 Gy) compared with the standard WBRT of 45 Gy. A German study randomized 551 patients, of whom 318 were treated per protocol, to high-dose methotrexate and ifosfamide with or without WBRT. The non-inferiority hypothesis was not proved statistically; however, the median overall survival in the WBRT population was 32.4 months vs 37.1 months without WBRT. In addition, the Alliance US Cooperative Group recently reported outcomes using a non–radiation-based therapeutic regimen.

Long-term survival data are also available using autologous or allogeneic SCT for relapsed/refractory primary CNS lymphoma, although an important prognostic factor is control of CNS disease immediately before transplant. Further, most transplant conditioning regimens for CNS lymphoma have incorporated thiotepa-based therapy (eg, busulfan, cyclophosphamide, and thiotepa).

Sidebar: Rubenstein and colleagues used a treatment regimen consisting of methotrexate, temozolomide, and rituximab induction followed by high-dose consolidation with etoposide plus cytarabine for patients with untreated primary CNS lymphoma. With median follow-up of nearly 5 years, the 2-year progression-free survival was 57%, which appears comparable with radiation-related regimens. In addition, older patients appeared to fare as well as younger patients, while high tumor BCL6 expression correlated with inferior survival (Rubenstein JL et al: J Clin Oncol 31:3061-3068, 2013).