Long-term survival in AIDS-related primary central nervous system lymphoma

Abstract

Background: The optimal therapeutic approach for patients with AIDS-related primary central nervous system lymphoma (AR-PCNSL) remains undefined. While its incidence declined substantially with combination antiretroviral therapy (cART), AR-PCNSL remains a highly aggressive neoplasm for which whole brain radiotherapy (WBRT) is considered a standard first-line intervention.

Methods: To identify therapy-related factors associated with favorable survival, we first retrospectively analyzed outcomes of AR-PCNSL patients treated at San Francisco General Hospital, a public hospital with a long history of dedicated care for patients with HIV and AIDS-related malignancies. Results were validated in a retrospective, multicenter analysis that evaluated all newly diagnosed patients with AR-PCNSL treated with cART plus high-dose methotrexate (HD-MTX).

Results: We provide evidence that CD4+ reconstitution with cART administered during HD-MTX correlates with long-term survival among patients with CD4 <100. This was confirmed in a multicenter analysis which demonstrated that integration of cART regimens with HD-MTX was generally well tolerated and resulted in longer progression-free survival than other treatments. No profound differences in immunophenotype were identified in an analysis of AR-PCNSL tumors that arose in the pre- versus post-cART eras. However, we detected evidence for a demographic shift, as the proportion of minority patients with AR-PCNSL increased since advent of cART.

Conclusion: Long-term disease-free survival can be achieved in AR-PCNSL, even among those with histories of opportunistic infections, limited access to health care, and medical non-adherence. Given this, as well as the long-term toxicities of WBRT, we recommend that integration of cART plus first-line HD-MTX be considered for all patients with AR-PCNSL.

Keywords: AIDS; HAART; brain tumor; lymphoma; methotrexate.

Fig. 1.

Long-term survival of AR-PCNSL patients treated with cART plus HD-MTX–based therapy and comparison to WBRT. 1A. Median survival for all 75 AR-PCNSL patients in the pre-cART era was 2 months and only slightly longer for the cohort of 57 patients who received WBRT, 2.5 months; P<.0001. During the pre-cART era at SFGH, there was only one AR-PCNSL patient who survived beyond 30 months (>191 mo, WBRT cohort). 1B. Median survival for the 20 patients who received cART plus HD-MTX–based therapy has not been reached, with median follow-up of 27 months (range 1–156.3 mo).

Fig. 2.

Control of HIV viral load and CD4+ cell reconstitution with cART instituted with HD-MTX during initial treatment of AR-PCNSL in 4 responding patients. Orange line: viral load (copies/mL); blue line: CD4 count (cells/mL). Grey line: duration of HD-MTX–based therapy. 2A. Patient 7 received high-dose methotrexate monotherapy (8 cycles) plus a combination of nonnucleoside and nucleoside analogue reverse transcriptase inhibitors: efavirenz, lamivudine plus zidovudine. 2B. Patient 2 received HD-MTX (8 cycles) plus temozolomide followed by consolidative chemotherapy with infusional etoposide plus high-dose cytarabine. During chemotherapy, this patient received an antiretroviral regimen containing a nucleoside reverse transcriptase inhibitor, abacavir, plus ritonavir-boosted darunavir. 2C. Patient 4 received high-dose methotrexate monotherapy (6 cycles) plus a regimen of nucleoside reverse transcriptase inhibitors abacavir, lamivudine, zidovudine, and tenofovir plus ritonavir-boosted loprinavir. 2D. Patient 8 received HD-MTX (9 cycles) plus rituximab in combination with a regimen consisting of 2 nucleoside analogue reverse transcriptase inhibitors, lamivudine plus stavudine, as well as nelfinavir, a protease inhibitor. Each of these AR-PCNSL patients achieved complete responses to induction HD-MTX plus cART regimens and none has progressed after a median follow-up of greater than 95 months.