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Jason Gotlib and Peter L. Greenberg

Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term “biospecific” has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS.

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Susan O'Brien, Camille N. Abboud, Mojtaba Akhtari, Jessica Altman, Ellin Berman, Daniel J. DeAngelo, Steven Devine, Amir T. Fathi, Jason Gotlib, Madan Jagasia, Joseph O. Moore, Javier Pinilla-Ibarz, Jerald P. Radich, Vishnu V.B. Reddy, Neil P. Shah, Paul J. Shami, B. Douglas Smith, David S. Snyder, Meir Wetzler and Furhan Yunus

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Susan O'Brien, Ellin Berman, Hossein Borghaei, Daniel J. DeAngelo, Marcel P. Devetten, Steven Devine, Harry P. Erba, Jason Gotlib, Madan Jagasia, Joseph O. Moore, Tariq Mughal, Javier Pinilla-Ibarz, Jerald P. Radich, Neil P. Shah, Paul J. Shami, B. Douglas Smith, David S. Snyder, Martin S. Tallman, Moshe Talpaz and Meir Wetzler

Chronic Myelogenous Leukemia Clinical Practice Guidelines in Oncology NCCN Categories of Evidence and Consensus Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus. Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus. Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement). Category 3: The recommendation is based on any level of evidence but reflects major disagreement. All recommendations are category 2A unless otherwise noted. Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Overview Chronic myelogenous leukemia (CML) accounts for 15% of adult leukemias. Although the median age of disease onset is 67 years, CML occurs in all age groups (Surveillance, Epidemiology, and End Results [SEER] statistics). In 2009, an estimated 5050 cases will be diagnosed and 470 patients will die from the disease in the United States.1 CML is a hematopoietic stem cell disease, which is characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome (Ph chromosome). This translocation t(9;22) results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22 at band q11 and the Abelson murine leukemia (ABL) gene located on chromosome 9 at band q34.2 The product of the fusion gene (BCR-ABL) is believed to play a central role in the...
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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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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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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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Jason Gotlib, Aaron T. Gerds, Prithviraj Bose, Mariana C. Castells, Michael W. Deininger, Ivana Gojo, Krishna Gundabolu, Gabriela Hobbs, Catriona Jamieson, Brandon McMahon, Sanjay R. Mohan, Vivian Oehler, Stephen Oh, Eric Padron, Philip Pancari, Nikolaos Papadantonakis, Animesh Pardanani, Nikolai Podoltsev, Raajit Rampal, Erik Ranheim, Lindsay Rein, David S. Snyder, Brady L. Stein, Moshe Talpaz, Swapna Thota, Martha Wadleigh, Katherine Walsh, Mary Anne Bergman and Hema Sundar

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

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Jerald P. Radich, Michael Deininger, Camille N. Abboud, Jessica K. Altman, Ellin Berman, Ravi Bhatia, Bhavana Bhatnagar, Peter Curtin, Daniel J. DeAngelo, Jason Gotlib, Gabriela Hobbs, Madan Jagasia, Hagop M. Kantarjian, Lori Maness, Leland Metheny, Joseph O. Moore, Arnel Pallera, Philip Pancari, Mrinal Patnaik, Enkhtsetseg Purev, Michal G. Rose, Neil P. Shah, B. Douglas Smith, David S. Snyder, Kendra L. Sweet, Moshe Talpaz, James Thompson, David T. Yang, Kristina M. Gregory and Hema Sundar

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.

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Ruben A. Mesa, Catriona Jamieson, Ravi Bhatia, Michael W. Deininger, Christopher D. Fletcher, Aaron T. Gerds, Ivana Gojo, Jason Gotlib, Krishna Gundabolu, Gabriela Hobbs, Brandon McMahon, Sanjay R. Mohan, Stephen Oh, Eric Padron, Nikolaos Papadantonakis, Philip Pancari, Nikolai Podoltsev, Raajit Rampal, Erik Ranheim, Vishnu Reddy, Lindsay A.M. Rein, Bart Scott, David S. Snyder, Brady L. Stein, Moshe Talpaz, Srdan Verstovsek, Martha Wadleigh, Eunice S. Wang, Mary Anne Bergman, Kristina M. Gregory and Hema Sundar

Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.

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Brady L. Stein, Jason Gotlib, Murat Arcasoy, Marie Huong Nguyen, Neil Shah, Alison Moliterno, Catriona Jamieson, Daniel A. Pollyea, Bart Scott, Martha Wadleigh, Ross Levine, Rami Komrokji, Rebecca Klisovic, Krishna Gundabolu, Patricia Kropf, Meir Wetzler, Stephen T. Oh, Raul Ribeiro, Rita Paschal, Sanjay Mohan, Nikolai Podoltsev, Josef Prchal, Moshe Talpaz, David Snyder, Srdan Verstovsek and Ruben A. Mesa

The classical Philadelphia chromosome–negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2 V617F and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.