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Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma

Matthias Holdhoff, Maciej M. Mrugala, Christian Grommes, Thomas J. Kaley, Lode J. Swinnen, Carlos Perez-Heydrich, and Lakshmi Nayak

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3–8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX–based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX–based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

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Non-Hodgkin’s Lymphomas

Andrew D. Zelenetz, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, John C. Byrd, Myron S. Czuczman, Luis Fayad, Andres Forero, Martha J. Glenn, Jon P. Gockerman, Leo I. Gordon, Nancy Lee Harris, Richard T. Hoppe, Steven M. Horwitz, Mark S. Kaminski, Youn H. Kim, Ann S. LaCasce, Tariq I. Mughal, Auyporn Nademanee, Pierluigi Porcu, Oliver Press, Leonard Prosnitz, Nashitha Reddy, Mitchell R. Smith, Lubomir Sokol, Lode Swinnen, Julie M. Vose, William G. Wierda, Joachim Yahalom, and Furhan Yunus

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Non-Hodgkin's Lymphomas

Andrew D. Zelenetz, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, Naresh Bellam, John C. Byrd, Myron S. Czuczman, Luis E. Fayad, Martha J. Glenn, Jon P. Gockerman, Leo I. Gordon, Nancy Lee Harris, Richard T. Hoppe, Steven M. Horwitz, Christopher R. Kelsey, Youn H. Kim, Ann S. LaCasce, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Barbara Pro, Nashitha Reddy, Lubomir Sokol, Lode J. Swinnen, Christina Tsien, Julie M. Vose, William G. Wierda, Joachim Yahalom, and Nadeem Zafar

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Central Nervous System Cancers, Version 1.2015

Louis Burt Nabors, Jana Portnow, Mario Ammirati, Joachim Baehring, Henry Brem, Paul Brown, Nicholas Butowski, Marc C. Chamberlain, Robert A. Fenstermaker, Allan Friedman, Mark R. Gilbert, Jona Hattangadi-Gluth, Matthias Holdhoff, Larry Junck, Thomas Kaley, Ronald Lawson, Jay S. Loeffler, Mary P. Lovely, Paul L. Moots, Maciej M. Mrugala, Herbert B. Newton, Ian Parney, Jeffrey J. Raizer, Lawrence Recht, Nicole Shonka, Dennis C. Shrieve, Allen K. Sills Jr, Lode J. Swinnen, David Tran, Nam Tran, Frank D. Vrionis, Stephanie Weiss, Patrick Yung Wen, Nicole McMillian, and Anita M. Engh

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.

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Non-Hodgkin’s Lymphomas, Version 4.2014

Andrew D. Zelenetz, Leo I. Gordon, William G. Wierda, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, John C. Byrd, Myron S. Czuczman, Luis E. Fayad, Richard I. Fisher, Martha J. Glenn, Nancy Lee Harris, Richard T. Hoppe, Steven M. Horwitz, Christopher R. Kelsey, Youn H. Kim, Susan Krivacic, Ann S. LaCasce, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Rachel Rabinovitch, Nishitha Reddy, Erin Reid, Ayman A. Saad, Lubomir Sokol, Lode J. Swinnen, Christina Tsien, Julie M. Vose, Joachim Yahalom, Nadeem Zafar, Mary Dwyer, and Hema Sundar

Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

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Non-Hodgkin’s Lymphomas, Version 3.2012

Andrew D. Zelenetz, William G. Wierda, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, Naresh Bellam, John C. Byrd, Myron S. Czuczman, Luis Fayad, Martha J. Glenn, Jon P. Gockerman, Leo I. Gordon, Nancy Lee Harris, Richard T. Hoppe, Steven M. Horwitz, Christopher R. Kelsey, Youn H. Kim, Susan Krivacic, Ann S. LaCasce, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Barbara Pro, Nishitha Reddy, Lubomir Sokol, Lode Swinnen, Christina Tsien, Julie M. Vose, Joachim Yahalom, Nadeem Zafar, Maoko Naganuma, and Mary A. Dwyer

These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin’s Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

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Central Nervous System Cancers, Version 2.2014

Louis Burt Nabors, Jana Portnow, Mario Ammirati, Henry Brem, Paul Brown, Nicholas Butowski, Marc C. Chamberlain, Lisa M. DeAngelis, Robert A. Fenstermaker, Allan Friedman, Mark R. Gilbert, Jona Hattangadi-Gluth, Deneen Hesser, Matthias Holdhoff, Larry Junck, Ronald Lawson, Jay S. Loeffler, Paul L. Moots, Maciej M. Mrugala, Herbert B. Newton, Jeffrey J. Raizer, Lawrence Recht, Nicole Shonka, Dennis C. Shrieve, Allen K. Sills Jr, Lode J. Swinnen, David Tran, Nam Tran, Frank D. Vrionis, Patrick Yung Wen, Nicole R. McMillian, and Maria Ho

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.

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NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016

Steven M. Horwitz, Andrew D. Zelenetz, Leo I. Gordon, William G. Wierda, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, John C. Byrd, Luis E. Fayad, Richard I. Fisher, Martha J. Glenn, Thomas M. Habermann, Nancy Lee Harris, Francisco Hernandez-Ilizaliturri, Richard T. Hoppe, Mark S. Kaminski, Christopher R. Kelsey, Youn H. Kim, Susan Krivacic, Ann S. LaCasce, Matthew Lunning, Auayporn Nademanee, Oliver Press, Rachel Rabinovitch, Nishitha Reddy, Erin Reid, Kenneth Roberts, Ayman A. Saad, Lubomir Sokol, Lode J. Swinnen, Julie M. Vose, Joachim Yahalom, Nadeem Zafar, Mary Dwyer, Hema Sundar, and Pierluigi Porcu

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

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Diffuse Large B-Cell Lymphoma Version 1.2016

Andrew D. Zelenetz, Leo I. Gordon, William G. Wierda, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, Nancy Bartlett, John C. Byrd, Luis E. Fayad, Richard I. Fisher, Martha J. Glenn, Thomas M. Habermann, Nancy Lee Harris, Francisco Hernandez-Ilizaliturri, Richard T. Hoppe, Steven M. Horwitz, Mark S. Kaminski, Christopher R. Kelsey, Youn H. Kim, Susan Krivacic, Ann S. LaCasce, Matthew Lunning, Auayporn Nademanee, Pierluigi Porcu, Oliver Press, Rachel Rabinovitch, Nishitha Reddy, Erin Reid, Kenneth Roberts, Ayman A. Saad, Lubomir Sokol, Lode J. Swinnen, Julie M. Vose, Joachim Yahalom, Nadeem Zafar, Mary Dwyer, and Hema Sundar

Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

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NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017

Louis Burt Nabors, Jana Portnow, Mario Ammirati, Joachim Baehring, Henry Brem, Nicholas Butowski, Robert A. Fenstermaker, Peter Forsyth, Jona Hattangadi-Gluth, Matthias Holdhoff, Steven Howard, Larry Junck, Thomas Kaley, Priya Kumthekar, Jay S. Loeffler, Paul L. Moots, Maciej M. Mrugala, Seema Nagpal, Manjari Pandey, Ian Parney, Katherine Peters, Vinay K. Puduvalli, John Ragsdale III, Jason Rockhill, Lisa Rogers, Chad Rusthoven, Nicole Shonka, Dennis C. Shrieve, Allen K. Sills Jr, Lode J. Swinnen, Christina Tsien, Stephanie Weiss, Patrick Yung Wen, Nicole Willmarth, Mary Anne Bergman, and Anita Engh

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.