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Optimizing Patient Care in Chronic Phase Chronic Myelogenous Leukemia: A Multidisciplinary Approach

Hema Sundar and Jerald Radich

Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome arising from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This translocation results in the formation of the BCR-ABL fusion gene. The product of this fusion gene, p210, a protein with deregulated tyrosine kinase activity, plays a central role in the pathogenesis of CML. Tyrosine kinase inhibitor (TKI) therapy with small molecule inhibitors of BCR-ABL tyrosine kinase has significantly reduced the annual mortality rate among patients with CML. Although most of these patients respond to first-line TKI therapy, the use of TKIs is complicated by the development of resistance or intolerance in some patients, resulting in a loss of response or discontinuation of treatment. Inadequate response to TKI therapy is associated with poor long-term outcome, and the cases of patients with resistance or intolerance should be carefully evaluated for alternative treatment options. This report discusses the challenges associated with the management of newly diagnosed chronic phase CML in a patient with intolerance to multiple TKI therapies.

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NCCN Task Force Report: Tyrosine Kinase Inhibitor Therapy Selection in the Management of Patients With Chronic Myelogenous Leukemia

Susan O'Brien, Ellin Berman, Joseph O. Moore, Javier Pinilla-Ibarz, Jerald P. Radich, Paul J. Shami, B. Douglas Smith, David S. Snyder, Hema M. Sundar, Moshe Talpaz, and Meir Wetzler

The advent of imatinib has dramatically improved outcomes in patients with chronic myelogenous leukemia (CML). It has become the standard of care for all patients with newly diagnosed chronic-phase CML based on its successful induction of durable responses in most patients. However, its use is complicated by the development of resistance in some patients. Dose escalation might overcome this resistance if detected early. The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib provide effective therapeutic options for managing patients resistant or intolerant to imatinib. Recent studies have shown that dasatinib and nilotinib provide quicker and potentially better responses than standard-dose imatinib when used as a first-line treatment. The goal of therapy for patients with CML is the achievement of a complete cytogenetic response, and eventually a major molecular response, to prevent disease progression to accelerated or blast phase. Selecting the appropriate TKI depends on many factors, including disease phase, primary or secondary resistance to TKI, the agent's side effect profile and its relative effectiveness against BCR-ABL mutations, and the patient's tolerance to therapy. In October 2010, NCCN organized a task force consisting of a panel of experts from NCCN Member Institutions with expertise in the management of patients with CML to discuss these issues. This report provides recommendations regarding the selection of TKI therapy for the management of patients with CML based on the evaluation of available published clinical data and expert opinion among the task force members.

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NCCN Task Force Report: Molecular Markers in Leukemias and Lymphomas

Jerald P. Radich, Andrew D. Zelenetz, Wing C. Chan, Carlo M. Croce, Myron S. Czuczman, Harry P. Erba, Sandra J. Horning, Jane Houldsworth, B. Douglas Smith, David S. Snyder, Hema M. Sundar, Meir Wetzler, and Jane N. Winter

The introduction of targeted therapies has revolutionized treatment and improved outcomes in patients with leukemias and lymphomas. However, many patients experience relapse caused by the persistence of residual malignant cells. Cytogenetic and molecular techniques are increasingly being used to assess and quantify minimal residual disease (MRD). The emergence of advanced technologies has led to the discovery of multiple novel molecular markers that can be used to detect MRD and predict outcome in patients with leukemias and lymphomas. Gene expression signatures that predict clinical outcomes in patients with non-Hodgkin's lymphoma have been identified. In chronic myelogenous leukemia, molecular monitoring has become more important in assessing response and detecting resistance to therapy. In acute leukemias, several new markers have shown potential in prognostication and monitoring treatment. In leukemias and lymphomas, microRNAs have been identified that may be useful in diagnostics and prognostication. To address these issues, the National Comprehensive Cancer Network (NCCN) organized a task force consisting of a panel of experts in leukemia and lymphoma to discuss recent advances in the field of molecular markers and monitoring MRD.

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NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors

George D. Demetri, Margaret von Mehren, Cristina R. Antonescu, Ronald P. DeMatteo, Kristen N. Ganjoo, Robert G. Maki, Peter W.T. Pisters, Chandrajit P. Raut, Richard F. Riedel, Scott Schuetze, Hema M. Sundar, Jonathan C. Trent, and Jeffrey D. Wayne

The standard of care for managing patients with gastrointestinal stromal tumors (GISTs) rapidly changed after the introduction of effective molecularly targeted therapies involving tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. A better understanding of the molecular characteristics of GISTs have improved the diagnostic accuracy and led to the discovery of novel immunomarkers and new mechanisms of resistance to TKI therapy, which in turn have resulted in the development of novel treatment strategies. To address these issues, the NCCN organized a task force consisting of a multidisciplinary panel of experts in the fields of medical oncology, surgical oncology, molecular diagnostics, and pathology to discuss the recent advances, identify areas of future research, and recommend an optimal approach to care for patients with GIST at all stages of disease. The task force met for the first time in October 2003 and again in December 2006 and October 2009. This supplement describes the recent developments in the field of GIST as discussed at the October 2009 meeting.

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Chronic Myelogenous Leukemia, Version 1.2014

Susan O’Brien, Jerald P. Radich, Camille N. Abboud, Mojtaba Akhtari, Jessica K. Altman, Ellin Berman, Daniel J. DeAngelo, Michael Deininger, Steven Devine, Amir T. Fathi, Jason Gotlib, Madan Jagasia, Patricia Kropf, Joseph O. Moore, Arnel Pallera, Javier Pinilla-Ibarz, Vishnu VB. Reddy, Neil P. Shah, B. Douglas Smith, David S. Snyder, Meir Wetzler, Kristina Gregory, and Hema Sundar

The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ≤10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).

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Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology

Ruben Mesa, Catriona Jamieson, Ravi Bhatia, Michael W. Deininger, Aaron T. Gerds, Ivana Gojo, Jason Gotlib, Krishna Gundabolu, Gabriela Hobbs, Rebecca B. Klisovic, Patricia Kropf, Sanjay R. Mohan, Stephen Oh, Eric Padron, Nikolai Podoltsev, Daniel A. Pollyea, Raajit Rampal, Lindsay A. M. Rein, Bart Scott, David S. Snyder, Brady L. Stein, Srdan Verstovsek, Martha Wadleigh, Eunice S. Wang, Mary Anne Bergman, Kristina M. Gregory, and Hema Sundar

Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.

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Hepatobiliary Cancers, Version 2.2014

Al B. Benson III, Michael I. D’Angelica, Thomas A. Abrams, Chandrakanth Are, P. Mark Bloomston, Daniel T. Chang, Bryan M. Clary, Anne M. Covey, William D. Ensminger, Renuka Iyer, R. Kate Kelley, David Linehan, Mokenge P. Malafa, Steven G. Meranze, James O. Park, Timothy Pawlik, James A. Posey, Courtney Scaife, Tracey Schefter, Elin R. Sigurdson, G. Gary Tian, Jean-Nicolas Vauthey, Alan P. Venook, Yun Yen, Andrew X. Zhu, Karin G. Hoffmann, Nicole R. McMillian, and Hema Sundar

Hepatobiliary cancers include a spectrum of invasive carcinomas arising in the liver (hepatocellular carcinoma), gall bladder, and bile ducts (cholangiocarcinomas). Gallbladder cancer and cholangiocarcinomas are collectively known as biliary tract cancers. Gallbladder cancer is the most common and aggressive type of all the biliary tract cancers. Cholangiocarcinomas are diagnosed throughout the biliary tree and are typically classified as either intrahepatic or extrahepatic cholangiocarcinoma. Extrahepatic cholangiocarcinomas are more common than intrahepatic cholangiocarcinomas. This manuscript focuses on the clinical management of patients with gallbladder cancer and cholangiocarcinomas (intrahepatic and extrahepatic).

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Bone Cancer

J. Sybil Biermann, Douglas R. Adkins, Mark Agulnik, Robert S. Benjamin, Brian Brigman, James E. Butrynski, David Cheong, Warren Chow, William T. Curry, Deborah A. Frassica, Frank J. Frassica, Kenneth R. Hande, Francis J. Hornicek, Robin L. Jones, Joel Mayerson, Sean V. McGarry, Brian McGrath, Carol D. Morris, Richard J. O'Donnell, R. Lor Randall, Victor M. Santana, Robert L. Satcher, Herrick J. Siegel, Margaret von Mehren, Mary Anne Bergman, and Hema Sundar

Primary bone cancers are extremely rare neoplasms, accounting for fewer than 0.2% of all cancers. The evaluation and treatment of patients with bone cancers requires a multidisciplinary team of physicians, including musculoskeletal, medical, and radiation oncologists, and surgeons and radiologists with demonstrated expertise in the management of these tumors. Long-term surveillance and follow-up are necessary for the management of treatment late effects related to surgery, radiation therapy, and chemotherapy. These guidelines discuss the management of chordoma, giant cell tumor of the bone, and osteosarcoma.

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Chronic Myelogenous Leukemia, Version 1.2015

Susan O’Brien, Jerald P. Radich, Camille N. Abboud, Mojtaba Akhtari, Jessica K. Altman, Ellin Berman, Peter Curtin, Daniel J. DeAngelo, Michael Deininger, Steven Devine, Amir T. Fathi, Jason Gotlib, Madan Jagasia, Patricia Kropf, Joseph O. Moore, Arnel Pallera, Vishnu VB. Reddy, Neil P. Shah, B. Douglas Smith, David S. Snyder, Meir Wetzler, Kristina Gregory, and Hema Sundar

Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML.

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NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019

William G. Wierda, John C. Byrd, Jeremy S. Abramson, Syed F. Bilgrami, Greg Bociek, Danielle Brander, Jennifer Brown, Asher A. Chanan-Khan, Julio C. Chavez, Steve E. Coutre, Randall S. Davis, Christopher D. Fletcher, Brian Hill, Brad S. Kahl, Manali Kamdar, Lawrence D. Kaplan, Nadia Khan, Thomas J. Kipps, Shuo Ma, Sami Malek, Anthony Mato, Claudio Mosse, Vishala T. Neppalli, Mazyar Shadman, Tanya Siddiqi, Deborah Stephens, Nina Wagner, Mary A. Dwyer, and Hema Sundar

Chronic lymphocytic leukemia (CLL) is generally characterized by an indolent disease course. Histologic transformation (also known as Richter's transformation) to more aggressive lymphomas, such as diffuse large B-cell lymphoma or Hodgkin lymphoma, occurs in approximately 2% to 10% of patients and is associated with a poor prognosis. These NCCN Guidelines Insights discuss the recommendations for the diagnosis and management of patients with histologic transformation.