ZIA BC 011654 (ZIA) | |||
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Title | TEDDI-R in PCNSL | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Wilson, Wyndham | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $146,012 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2017 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (80.0%) |
Brain (95.0%) Nervous System (95.0%) Non Hodgkins Lymphoma (5.0%) |
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Research Type | |||
Systemic Therapies - Discovery and Development | |||
Abstract | |||
Primary CNS lymphoma (PCNSL) is a rare disease representing less than 3% of all non-Hodgkin lymphoma. It refers to lymphomas that arise in the brain parenchyma, spinal cord, eyes, cranial nerves and meninges. Most of these (>90%) are diffuse large B-cell lymphomas (DLBCL) but other B-cell and T-cell lymphomas are rarely encountered in the CNS. Interestingly, many epidemiological studies show an increased incidence of PCNSL over recent years. PCNSL can occur in both HIV negative and positive patients. HIV-associated PCNSL is virtually always associated with EBV and biologically is a different disease from PCNSL (B-cell type) in immunocompetent patients (HIV negative), which is virtually never EBV positive. PCNSL is typically confined to the CNS and disease spreads outside the CNS in less than 5% of cases. The following study is for PCNSL (aggressive B cell type) in HIV negative and immunocompetent patients. Treatment of PCNSL Compared to patients with systemic DLBCL, the outcome for patients with PCNSL is a great deal worse. Treatment of PCNSL differs significantly from systemic DLBCL because many chemotherapy agents do not adequately penetrate the blood-brain barrier. Historically, radiotherapy has been a mainstay of treatment because it is effective and side stepped the limitations of chemotherapy in penetrating the CNS. However, when used alone, responses are typically short-lived and virtually all patients relapse. Due to the poor outcome of radiotherapy and significant cognitive side effects, investigators have been developing chemotherapy regimens to be given with radiotherapy and more recently without radiotherapy, respectively. The development of the chemotherapy-based treatments relied heavily on strategies used for solid brain tumors and were not optimized for the treatment of DLBCL. High dose methotrexate (HD-MTX), an agent with good CNS penetration, has been the centerpiece of PCNSL treatment for years; however, when used alone it produces a progression-free survival of only 7 months. When HD-MTX was followed by whole brain radiotherapy, it produced an impressive 82-88% complete remission rate and median progression free-survivals of 32-40 months, but no evidence of cure. Unfortunately, such combined modality treatment is associated with severe long-term neurotoxicity. For this reason, there has been much interest in developing regimens that obviate or defer the need for radiation until relapse. Most promising in this regard are combinations of high dose methotrexate with systemic agents that cross the blood brain barrier, such as cytarabine and ifosfamide, particularly in patients under 60 years of age. The Bonn group and others have adopted such an approach and have reported promising results with chemotherapy and deferred radiation in younger patients. In their trial, 9% died of treatment related toxicity. Overall, the median time to treatment failure was 21 months with a median follow-up of 26 months; for those over 60 years of age, the TTF was 15 months and for those under 60 years old, 60% were progression-free at 4 years. While these are promising results for PCNSL, they nonetheless show that current strategies have a poor outcome with an unacceptably high treatment related mortality, and low rates of cure. Thus, there is an important need to develop more effective and less toxic strategies for PCNSL. While one approach is the addition of rituximab, there is a need to develop chemotherapy platforms that are based on the most effective strategies in systemic DLBCL and to incorporate new ideas based on the molecular biology of PCNSL. Studies that have incorporated rituximab, such as the CALGB 50202 study, are still based on HD methotrexate and cytarabine. In a preliminary report, the CALGB reported median PFS of 2.3 years, indicating that few patients are cured even with the addition of rituximab to these agents (Rubenstein et al ASH Abstract 763; 2010). Genetics and Molecular Biology of PCNSL PCNSL has a high |