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Paul J. Shami

With the development of tyrosine kinase inhibitors (TKIs), the management and outlook for patients with chronic myelogenous leukemia (CML) have completely changed over the past 10 years. Imatinib was the first TKI approved to treat CML in the chronic phase. After their initial approval as second-line agents, dasatinib and nilotinib were compared with imatinib in the first-line setting in 2 randomized trials. Both trials showed that therapeutic milestones (complete cytogenetic remission and major molecular remission) occurred earlier with these newer agents, leading to their approval for the treatment of newly diagnosed CML. Therefore, 3 different TKIs are now available for treating CML. Long-term follow-up of patients treated with imatinib shows that the attainment of therapeutic milestones by 12 months of therapy leads to better long-term outcomes. Most patients who experience disease progression on imatinib do so within the first 3 years of therapy. Therefore, one can argue that dasatinib or nilotinib should be chosen to treat patients with newly diagnosed CML. However, these agents do not have the long-term track record of imatinib. This article summarizes the published data and reviews the rationale in choosing the appropriate TKI for first-line treatment of CML in the chronic phase.

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Samuel J. Slomowitz and Paul J. Shami

Extramedullary involvement is considered to be an uncommon presentation of acute myeloid leukemia (AML), although some data suggest it may be present in up to 30% of patients. Extra-medullary involvement by AML can present in a variety of clinical manifestations, most notably in the form of myeloid sarcoma, leukemia cutis, and central nervous system involvement. Each presents a unique clinical scenario in terms of symptoms and management. Extramedullary disease in any form presenting without evidence of bone marrow disease is still considered evidence of systemic disease and is usually treated as such. Most commonly, extramedullary disease presents concurrently with bone marrow disease, and although it may require additional local therapy in the form of intrathecal chemotherapy or radiation, the principles of systemic treatment remain unchanged. The prognostic impact of extramedullary disease is unclear. Specifically, whether hematopoietic stem cell transplantation should be considered in first remission irrespective of other prognostic factors has not been established. Patients who undergo transplantation have similar outcomes as patients without extramedullary disease, although they do have a higher rate of extramedullary relapse. More research is needed to define the molecular basis for extramedullary disease, its prognostic impact, and optimal management.

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Peter L. Greenberg, Cynthia K. Rigsby, Richard M. Stone, H. Joachim Deeg, Steven D. Gore, Michael M. Millenson, Stephen D. Nimer, Margaret R. O'Donnell, Paul J. Shami and Rashmi Kumar

The National Comprehensive Cancer Network (NCCN) convened a multidisciplinary task force to critically review the evidence for iron chelation and the rationale for treatment of transfusional iron overload in patients with myelodysplastic syndromes (MDS). The task force was charged with addressing issues related to tissue iron toxicity; the role of MRI in assessing iron overload; the rationale and role of treating transfusional iron overload in patients with MDS; and the impact of iron overload on bone marrow transplantation. This report summarizes the background data and ensuing discussion from the NCCN Task Force meeting on transfusional iron overload in MDS.

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David D. Stenehjem, Frederick Albright, Kuan-Ling Kuo, Karina Raimundo, Hillevi Bauer, Paul J. Shami, Michael W. Deininger, Lei Chen and Diana I. Brixner

Retrospective review of imatinib monitoring through electronic health records (EHR) can provide valuable insight into the current management of chronic myelogenous leukemia (CML). This study retrospectively reviewed EHRs from 2001 to 2010 of patients with chronic phase CML (CP-CML) treated with first-line imatinib. Chart evaluations included a review of cytogenetic and molecular testing, overall survival, adverse drug events (ADEs), and therapy modifications. A total of 54 patients with CP-CML were treated with first-line imatinib and had either cytogenetic or molecular testing within 18 months of imatinib initiation. Within the first 18 months of treatment, 33 of 45 patients (73%) undergoing cytogenetic testing experienced a complete cytogenetic response (median, 241 days; range, 110-542 days) and 24 of 48 patients (50%) receiving molecular testing achieved at least a major molecular response (median, 253 days; range, 99-546 days). The average number of cytogenetic and molecular tests conducted within the first 18 months was 2.5 and 3.8, respectively. Nineteen of 54 (35%) had a dose increase of imatinib (>400 mg; median, 329 days; range, 21-1968 days). The 5-year estimated overall survival rate was 88.5%. Between 2006 and 2010 (n=30; 56%), 7 patients (23%) transitioned to dasatinib or nilotinib (median, 399 days from diagnosis; range, 180-1046 days) because of suboptimal response or treatment failure (n=5) and imatinib ADEs (n=2). Forty-six imatinib-associated ADEs occurred in 31 patients (57%), of which 10 (32%) received dose reductions (median, 52 days) and 6 (19%) had discontinuations (median, 139 days). Closely monitored patients with CML treated with imatinib at an NCCN Member Institution experienced outcomes comparable to those reported in key clinical trials.

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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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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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Peter L. Greenberg, Eyal Attar, John M. Bennett, Clara D. Bloomfield, Carlos M. De Castro, H. Joachim Deeg, James M. Foran, Karin Gaensler, Guillermo Garcia-Manero, Steven D. Gore, David Head, Rami Komrokji, Lori J. Maness, Michael Millenson, Stephen D. Nimer, Margaret R. O'Donnell, Mark A. Schroeder, Paul J. Shami, Richard M. Stone, James E. Thompson and Peter Westervelt

Overview The myelodysplastic syndromes (MDS) represent myeloid clonal hemopathies with relatively heterogeneous spectrums of presentation. The major clinical problems in these disorders are morbidities caused by cytopenias and the potential for MDS to evolve into acute myeloid leukemia (AML). In the general population, MDS occur in 5 per 100,000 people. However, among individuals older than 70 years, the incidence increases to between 22 and 45 per 100,000 and increases further with age. Managing MDS is complicated by the generally advanced age of the patients (median ages, 65–70 years), attendant nonhematologic comorbidities, and relative inability to tolerate certain intensive forms of therapy among older patients. In addition, when the illness progresses to AML, these patients experience lower response rates to standard therapy than those with de novo AML.1 Diagnostic Classification Initial evaluation of patients with suspected MDS requires careful assessment of their peripheral blood smear and blood counts, marrow morphology, duration of their abnormal blood counts, other potential causes for their cytopenias, and concomitant illnesses. The French-American-British (FAB) classification initially categorized patients for the diagnostic evaluation of MDS.2 Dysplastic changes in at least 2 of the 3 hematopoietic cell lines have been used by most histopathologists to diagnose MDS. These changes include megaloblastoid erythropoiesis, nucleocytoplasmic asynchrony in the early myeloid and erythroid precursors, and dysmorphic megakaryocytes.3 Patients with MDS are classified as having 1 of 5 subtypes of disease: refractory anemia (RA); RA with ringed sideroblasts (RARS); RA with excess of blasts (RAEB); RAEB in transformation (RAEB-T); or chronic myelomonocytic leukemia...
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Margaret R. O'Donnell, Camille N. Abboud, Jessica Altman, Frederick R. Appelbaum, Steven E. Coutre, Lloyd E. Damon, James M. Foran, Salil Goorha, Lori J. Maness, Guido Marcucci, Peter Maslak, Michael M. Millenson, Joseph O. Moore, Farhad Ravandi, Paul J. Shami, B. Douglas Smith, Richard M. Stone, Stephen A. Strickland, Martin S. Tallman and Eunice S. Wang

Overview In 2010, approximately 12,330 people were diagnosed with and 8950 died of acute myeloid leukemia (AML).1 As the population ages, the incidence of AML, along with myelodysplasia, seems to be rising. Equally disturbing is the increasing incidence of treatment-related myelodysplasia and leukemia in survivors of childhood tumors and young adulthood, such as Hodgkin disease, sarcomas, breast and testicular cancers, and lymphomas. Ionizing radiation and occupational exposure to benzene and petrochemicals are also associated with AML.2 The NCCN AML Panel convenes annually to update guidelines for the diagnosis and treatment of AML in adults. Clinical trials have led to significant improvements in treatment in some areas, primarily in acute promyelocytic leukemia (APL). However, recent large clinical trials have highlighted the need for new, innovative strategies because outcomes for patients, particularly older patients, have not substantially changed in the past 3 decades. The panel has focused on outlining reasonable treatment options based on recent clinical trials and data from basic science, which may identify new risk factors and treatment approaches. In some areas, panel members have divergent opinions about the relative risks and benefits of various treatment options. Therefore, these guidelines attempt to provide a rationale for the inclusion of several treatment options in some categories. Initial Evaluation Initial evaluation has 2 objectives. The first is to characterize the disease process, including factors such as 1) prior toxic exposure, 2) myelodysplasia, and 3) karyotypic or molecular abnormalities, which may provide prognostic information that could influence responsiveness to chemotherapy and risk of...
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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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Peter L. Greenberg, Eyal Attar, John M. Bennett, Clara D. Bloomfield, Uma Borate, Carlos M. De Castro, H. Joachim Deeg, Olga Frankfurt, Karin Gaensler, Guillermo Garcia-Manero, Steven D. Gore, David Head, Rami Komrokji, Lori J. Maness, Michael Millenson, Margaret R. O’Donnell, Paul J. Shami, Brady L. Stein, Richard M. Stone, James E. Thompson, Peter Westervelt, Benton Wheeler, Dorothy A. Shead and Maoko Naganuma

The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.