Trial Information

AIDS-Related Primary Central Nervous System Lymphoma: A Phase II Pilot Study of High-Dose Intravenous Methotrexate With Rituximab Leucovorin Rescue and Highly Active Antiretroviral Therapy

Background: AIDS-related primary central nervous system lymphoma (AR-PCNSL) is an
Epstein-Barr virus (EBV)-driven lymphoproliferative process that typically results in death
within a few months. Essentially all of the cases are immunoblastic CD20+ tumors, and occur
once the CD4+ cells have fallen to below 50 cells/mm3 . Highly active antiretroviral therapy
(HAART) can result in immune reconstitution that decreases the risk of AR-PCNSL. However, a
subset of HIV-infected patients still develop ARPCNSL, often because they are unaware that
they are HIV infected, or they do not take HAART. Treatment options for such patients are
limited. In the non-AIDS setting, chemotherapy has become the standard of care for primary
central nervous system lymphoma (PCNSL) and late neurocognitive decline consequent to
radiotherapy can be avoided by such approaches. In the pre-HAART era, AR-PCNSL was generally
treated with whole brain radiotherapy, however death due to recurrent lymphoma or to other
AIDS complications occurred prior to the potential manifestations of late occurring
radiation-related neurotoxicity. Radiation-sparing approaches have not been studied in
AR-PCNSL in the HAART era, where advances in antiretroviral therapy have made curative
intent chemotherapy feasible for most patients with HIV infection.

Objectives: The primary objective of this study is to estimate the fraction of patients with
AR-PCNSL receiving experimental treatment consisting of HAART, combined with rituximab,
high-dose methotrexate and leucovorin (R-HD-MTX) who are alive and without recurrent
lymphoma or severe cognitive problems at two years. Secondary objectives include evaluation
of safety and toxicities associated with R-HD-MTX plus HAART in patients with AR-PCNSL as
well as estimating the complete response rate, progression-free, disease-free, overall
survivals and long-term neurocognitive outcomes. Additionally, this study will assess
overall survival, progression-free survival, and longterm neurocognitive outcomes in
patients with AR-PCNSL in who HD-MTX is contraindicated and are therefore treated with
radiation-sparing therapy consisting of dose-modified, dose-dense rituximab combined with
HAART but no HD-MTX.

Eligibility: HIV-infected, age 18 years or older, AR-PCSNL that has not previously been
treated, and be able to give informed consent or have a durable power of attorney who can
provide informed consent, HIV profile that makes them likely to respond to HAART. There are
a number of other specific inclusion and exclusion criteria, in part to exclude patients who
would be unlikely to tolerate the therapy.

Design: Phase II pilot study investigating R-HD-MTX given with leucovorin rescue and HAART
as a treatment for AR-PCNSL. Evaluation will include quantitative measurement of lymphocyte
subsets, quantitative polymerase chain reaction (PCR) of HIV and EBV viral loads (including
both blood and cerebrospinal fluid in the case of EBV) to assess immune response and
anti-viral effects. Tumor evaluation with brain magnetic resonance imaging (MRI) and brain
fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET scans) will be used for
staging and response assessment. Longitudinal neuropsychologic testing after complete
responses are documented will serve to evaluate neurocognitive parameters post therapy.

a separate cohort for additional secondary endpoints.