OPTIMIZING TREATMENT OF CHRONIC LEUKEMIA: CHRONIC LYMPHOCYTIC LEUKEMIA AND CHRONIC MYELOID LEUKEMIA

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1 Volume 9 Number 12S December 2012 OPTIMIZING TREATMENT OF CHRONIC LEUKEMIA: CHRONIC LYMPHOCYTIC LEUKEMIA AND CHRONIC MYELOID LEUKEMIA S77 Managing the patient with chronic lymphocytic leukemia: initial evaluation and first-line treatment decisions Stephanie A. Gregory, MD, FACP S85 Management of relapsed chronic lymphocytic leukemia: applying guidelines to practice Loretta J. Nastoupil, MD; and Christopher R. Flowers, MD S93 Optimizing treatment of chronic myeloid leukemia Alfonso Quintás-Cardama, MD This supplement was supported by Teva Pharmaceuticals, Frazer, PA.

2 December 2012 VOLUME 9, NUMBER 12S Editor-in-Chief Editors David H. Henry, MD, FACP Pennsylvania Hospital Philadelphia, PA Jame Abraham, MD West Virginia University Morgantown, WV Linda D. Bosserman, MD, FACP Wilshire Oncology Medical Group La Verne, CA Debra A. Patt, MD, MPH Texas Oncology Cancer Center, Austin, TX Alan Imhoff, President and Publisher Mary Jo Dales, Editorial Director Reneé Matthews, Managing Editor Matt Stenger, Contributing Writer Rebecca Slebodnik, Production Specialist Peter Murphy, Stuart Williams, National Accounts Managers Devin Gregorie, National Accounts Manager Oncology Projects a publication by IMNG Medical Media, a division of Frontline Medical Communications Inc. COMMUNITY ONCOLOGY (ISSN ) is published monthly by Frontline Medical Communications Inc, 7 Century Drive, Suite 302, Parsippany, NJ Periodicals postage paid at Parsippany, NJ, and additional mailing offices. Change of Address Postmaster: send changes of address to COMMUNITY ONCOLOGY, Subscription Service, 151 Fairchild Ave., Suite 2, Plainview, NY Recipient: to change your address, contact Subscription Services Editorial Board Johanna Bendell, MD Sarah Cannon Research Institute, Nashville, TN Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia, SC Roy A. Beveridge, MD US Oncology, Houston, TX Ralph V. Boccia, MD Georgetown University, Washington, DC Matt Brow US Oncology, Washington, DC Michael J. Fisch, MD, MPH The University of Texas MD Anderson Cancer Center, Houston, TX John A. Fracchia, MD Lenox Hill Hospital, New York, NY James N. George, MD University of Oklahoma Health Sciences Center Oklahoma City, OK James Gilmore, PharmD Georgia Cancer Specialists, Atlanta, GA Patrick Grusenmeyer, ScD Helen F. Graham Cancer Center, Newark, DE David M.J. Hoffman, MD Tower Hematology Oncology Medical Group Beverly Hills, CA Jimmie Holland, MD Memorial Sloan-Kettering Cancer Center New York, NY Leslie Rodgers Laufman, MD Blood and Cancer Care of Ohio, Columbus, OH Stuart M. Lichtman, MD Memorial Sloan-Kettering Cancer Center, Commack, NY Charles Loprinzi, MD Mayo Medical School, Rochester, MN John L. Marshall, MD Lombardi Comprehensive Cancer Center Washington, DC Cathy Maxwell, RN, OCN, CCRC Advanced Medical Specialties, LLC, Miami, FL Bradley J. Monk, MD, FACOG Creighton University School of Medicine at St. Joseph s Hospital and Medical Center, Phoenix, AZ Anne Moore, MD Weill Medical College of Cornell University New York, NY Deborah A. Nagle, MD Beth Israel Deaconess Medical Center, Boston, MA Geoffrey R. Norman, PhD McMaster University, Hamilton, Ontario, Canada Steven O Day, MD The Angeles Clinic & Research Institute Los Angeles, CA Theodore A. Okon, MBA Supportive Oncology Services, Memphis, TN Philip A. Philip, MD, PhD Barbara Ann Karmanos Cancer Institute, Detroit, MI Jondavid Pollock, MD, PhD Schiffler Cancer Center, Wheeling, WV Nicholas J. Robert, MD US Oncology, Fairfax, VA Peter J. Rosen, MD Roy & Patricia Disney Family Cancer Research Center, Burbank, CA Myrna R. Rosenfeld, MD, PhD University of Pennsylvania School of Medicine, Philadelphia, PA Philip Schulman, MD Memorial Sloan-Kettering Cancer Center Commack, NY Lee S. Schwartzberg, MD, FACP The West Clinic, Memphis, TN David Streiner, PhD, CPsych University of Toronto, Toronto, Ontario, Canada Debu Tripathy, MD University of Southern California/ Norris Comprehensive Cancer Center, Los Angeles, CA Steven Tucker, MD Pacific Cancer Centre, Singapore, Malaysia

3 Managing the patient with chronic lymphocytic leukemia: initial evaluation and first-line treatment decisions Stephanie A. Gregory, MD, FACP Rush University Medical Center, Chicago, IL Chronic lymphocytic leukemia (CLL) is the most common adult hematologic malignancy in Western countries. 1-4 In the United States, the National Cancer Institute estimated that adults will be diagnosed with CLL in CLL is typically diagnosed in the seventh decade of life, although the disease can emerge in patients of any age. CLL is a B-cell malignancy that presents as a clonal accumulation of abnormal CD5-positive B cells in the bone marrow and blood. The abnormal B cells may carry a variety of genetic mutations including chromosomal deletions [del(13q), del(17p), and del(11q)] and trisomy 12. 2,6-9 The genetic and cellular heterogeneity of CLL is reflected in the clinical heterogeneity of the disease course. A proportion of patients will have a slowly progressing, indolent form of the disease that requires only watchful waiting. Others will experience a more aggressive disease course requiring prompt and aggressive therapy and perhaps referral from community to tertiary care. In most patients, the disease will manifest between these two extremes, and hence most will likely receive the majority of their care in the community setting. As such, community oncologists play a critical role in the diagnosis, evaluation, and ongoing care of patients with CLL. Current first-line treatment options for patients presenting with CLL include chemotherapy alone, immunotherapy alone, or chemoimmunotherapy, depending on their age, mutation status, Correspondence: Stephanie A. Gregory, MD, FACP, Professor of Medicine, The Elodia Kehm Chair of Hematology, Rush University Medical Center/Rush University, 1725 West Harrison Street, Suite 834, Chicago, IL Phone: ( [email protected]). Disclosure: Dr Gregory is a member of advisory boards for Amgen, Genentech, Novartis, and Spectrum; a member of a Global Safety Committee for Cephalon; and a past member of speakers bureaus for Cephalon and Genentech. and health status. 2 This paper provides guidance on best practice for community-based oncologists with regard to the initial evaluation of patients following a diagnosis of CLL, and the key factors influencing treatment decisions. CLL: a heterogeneous patient population CLL is primarily, but not exclusively, a disease of the elderly. Most patients ( 75%) are first diagnosed after the age of 50 years and the median age of onset is 72 years. The disease is often found incidentally when a patient visits his/her physician for a routine examination and is found to have an abnormal blood count. As a result, most patients are asymptomatic at initial diagnosis. However, as the disease advances, signs and symptoms may emerge such as lymphadenopathy, hepatosplenomegaly, fevers, night sweats, weight loss, and secondary infections. The genetic heterogeneity of the disease is important in terms of disease course and prognosis and can influence treatment decisions. The most common genetic mutation is deletion of the long arm of chromosome 13 [del(13q)]. This abnormality is seen in approximately 50% of patients with CLL and is associated with a favorable prognosis. In these patients the disease is usually slowly progressive and patients may not require treatment for many years, if at all. The next most frequent genetic abnormality is trisomy 12, occurring in 20% to 25% of patients. This abnormality is associated with an intermediate prognosis. Deletions in chromosomes 17 and 11 [del(17p) and del(11q), respectively] each occur in 5% to 10% of patients and both are associated with an unfavorable prognosis. These patients are likely to require treatment relatively soon after their initial diagno- Commun Oncol 2012;9:S77-S Frontline Medical Communications Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S77

4 TABLE 1 Key information required for the development of an individual care plan for patients with chronic lymphocytic leukemia Area Information/tests Implications Demographics and Age Appropriateness of aggressive intervention disease burden Impact of disease on daily and work life Disease status Cytogenetics Prognostic value Genetic status [del(17p), del(11q), trisomy 12] IgVH status (unmutated vs mutated) CD38 and ZAP-70 expression Blood biomarkers LDH level 2 -microglobulin expression NOTCH1 gene mutation status Comorbidities CIRS score Presence and severity of comorbid conditions will guide the appropriateness of interventions and may inform the selection of individual therapies Immune status Presence/absence of autoimmune phenomena Need for immune supportive therapies Abbreviations: CIRS, Cumulative Illness Rating Scale; IgVH, immunoglobulin variable-region heavy chain; LDH, lactate dehydrogenase; ZAP-70, zeta-chain-associated protein kinase 70. sis as their disease often progresses more rapidly and they are more resistant to the usual therapies. Evaluation of patients with CLL: what information do we need to build a care plan? The initial work-up of patients presenting with CLL requires the collation of a range of information that will help the physician develop an individual care plan (Table 1). 10,11 The age of the patient, their overall health status, as well as an evaluation of the impact of the disease on their daily or work life will provide valuable information on the need for, and appropriateness of, aggressive intervention. The patient s disease should be staged at the time of diagnosis. There are 2 main staging systems: the Rai staging system, used mainly in the United States, and the Binet classification, used primarily in Europe. After staging, patients can be classed as low, intermediate, or high risk (Table 2) Routine blood work should be undertaken, including: a complete blood count; a differential blood count; lactic dehydrogenase (LDH) level; flow cytometry of peripheral blood including CD38; and fluorescence in situ hybridization (FISH) for cytogenetic determination. Another prognostic marker is the mutation status of the gene coding for the immunoglobulin variable-region heavy chain (IgVH), but this is not routinely assessed because of cost and time implications. In most patients with CLL, the IgVH gene is mutated in B cells; patients with unmutated IgVH genes normally have advanced disease and a poor prognosis. A surrogate marker for the IgVH mutation status is the zeta-chainassociated protein kinase 70 (ZAP-70), a tyrosine kinase normally expressed on T cells and natural killer cells, which can be evaluated by flow cytometry or immunohistochemical staining of bone marrow. Bone marrow aspirate and biopsy is not necessary for diagnosis but the pattern of infiltration can provide prognostic information. A number of other biomarkers that may also provide valuable prognostic information have recently emerged, including 2 -microglobulin expression (thought to correlate with tumor mass) and the mutation status of the NOTCH1 gene. 8,16 18 In 2011, Wierda and colleagues 19 reported on the development of a model to identify patients at high risk for disease progression who require prompt intervention. This model builds on previous riskassessment models by incorporating the newer prognostic factors described above; high-risk patients are thus defined as those with del(17p), del(11q), unmutated IgVH status, CD38- or ZAP-70-positive cells, a lymphocyte doubling time 6 months, and a 2 -microglobulin level 3.5 mg/l. The presence of comorbidities, especially in older patients, may also determine the appropriateness of intervention versus watchful waiting. The Cumulative Illness Rating Scale (CIRS) provides a useful scoring system in this context, and patients with a score of 6 or more warrant more conservative treatment than those with lower scores (fewer comorbidities). 20 The CIRS requires an evaluation of each body system (eg, cardiac, vascular, respiratory) on a scale of 1 (no impairment) to 5 (extremely severe, life-threatening impairment). A total of 14 body systems are considered, thus the score can theoretically range from 14 to 70. S78 COMMUNITY ONCOLOGY December

5 Gregory TABLE 2 Chronic lymphocytic leukemia disease staging Rai staging system Stage 0 Absolute lymphocytosis ( /mm 3 ) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia Stage I Absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia Stage II Absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy Stage III Absolute lymphocytosis and anemia (hemoglobin 11 g/dl) with or without lymphadenopathy, hepatomegaly, or splenomegaly Stage IV Absolute lymphocytosis and thrombocytopenia ( /mm 3 ) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia Modified Rai risk for disease progression Low Intermediate High Binet classification Clinical stage A No anemia or thrombocytopenia and 3 areas of lymphoid involvement Clinical stage B No anemia or thrombocytopenia with 3 areas of lymphoid involvement Clinical stage C Anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement TABLE 3 Critical factors in deciding if and when to treat patients presenting with chronic lymphocytic leukemia Approach Patient type Treatment modality Watch and wait Younger patient No systemic therapy Low risk for disease progression Largely asymptomatic older patients Good functional status Go go High risk for disease progression Intensive systemic therapy (goal: long-lasting remission) Good functional status (good performance status and low comorbidity burden) Slow go High risk for disease progression Poor functional status Mild systemic therapy (goal: symptomatic control) such as monotherapy with chlorambucil or bendamustine, or reduced-dose combination regimens No go Severely functionally impaired Palliative care High levels of comorbidity Reduced life expectancy Adapted from Halleck. 21 Patients with CLL often present with autoimmune phenomena, such as autoimmune hemolytic anemia or thrombocytopenia. However, this does not necessarily mean that the CLL itself is more advanced or less amenable to treatment. Rather, the presence of such phenomena indicates a need to incorporate immune support into the care plan. When to treat and when to wait Having gathered all the information and test results described in the previous section, the next most important decision is when, and indeed whether, to initiate systemic treatment. There are essentially 3 choices: watch and wait, initiate systemic therapy (either at a full or reduced dose), or provide supportive or palliative care only (Table 3). 21 Watch and wait For some patients, CLL is a relatively indolent disease with a low symptom burden and slow rate of progression. Given that there is no cure for the disease, there is a strong argument for withholding aggressive systemic therapy with its associated side effects in patients whose disease is not currently progressive or life threatening. For elderly patients with established disease, adverse changes in blood counts are not necessarily indicative of a need for intervention, especially if they remain physically fit and largely asymptomatic. 22 In both cases, patients should be Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S79

6 monitored regularly for signs of disease progression and managed with appropriate immune support. Systemic treatment A variety of clinical features indicate a need for intervention including markers of active disease such as so-called B symptoms (weight loss, fever, and night sweats) and marked fatigue; progressive bone marrow failure (evidenced by worsening anemia or thrombocytopenia); the emergence of autoimmune phenomena that do not respond well to steroids; splenomegaly 6 cm below the costal margin; nodal masses 10 cm; and progressive lymphocytosis of 50% over 2 months or a doubling time of 6 months. 23 For these patients, a decision must be made with regard to the intensity of systemic therapy. Intensive therapies may be most appropriate for younger patients with good functional status and no comorbidities with a treatment goal of long-lasting remission. For older patients with poorer functional status, milder systemic therapy may be more appropriate. In this case, the goal of treatment may be to control symptoms and maximize functioning and quality of life (QOL). Palliative care At the far end of the disease spectrum, withholding active treatment may be the most appropriate course of action for patients with aggressive, active disease, a high level of comorbidity, and reduced life expectancy. 22 These patients should be referred for palliative care. Patient priorities are of particular relevance here in terms of the balance between prolonging life versus maintaining QOL. Selecting treatment Once a decision to treat has been made, the next stage is to select an appropriate systemic therapy. Current guidelines recommend that therapy be selected firstly on the basis of the presence or absence of the del(17p) and del(11q) mutations, and secondly based on patient age and physical status (see Figure 1 for an overview of the clinical guidelines and details of the approved indications for the recommended drugs). 2 Chemotherapy with alkylating agents has formed the backbone of first-line systemic therapy for CLL since the 1960s. 24 These early agents (chlorambucil and cyclophosphamide) were associated with complete response rates (CRRs) of around 5%. 25 In the 1980s, the introduction of the purine nucleosides fludarabine, pentostatin, and cladribine pushed up the CRR to between 20% and 30%. 26 Combining agents from the 2 classes offered a moderate improvement in CRR to around 35%. 24 The last decade has seen the advent of immunotherapy for CLL with the development of monoclonal antibody-based therapies including rituximab and alemtuzumab, as well as the novel alkylating chemotherapeutic agent bendamustine. Combining chemotherapy and immunotherapy (chemoimmunotherapy) has increased CRRs further still to between 50% and 70%. 24 Today, physicians have a choice of first-line treatment regimens that can be tailored to suit the needs of individual patients. 2,27 Chemotherapy The alkylating agent chlorambucil was the first systemic chemotherapeutic agent to improve outcomes for patients with CLL. The purine analog fludarabine and the novel bifunctional alkylating agent bendamustine have both demonstrated improved response rates compared with chlorambucil monotherapy. Despite this, chlorambucil still has a role in CLL treatment, especially in frail elderly patients, owing to its oral bioavailability and low incidence of adverse side effects. Both fludarabine (indicated only for refractory/relapsed CLL) and bendamustine have demonstrated considerable clinical efficacy in the treatment of CLL when given as single agents and both are now key components of recommended first-line combination regimens. 2,27,28 Immunotherapy The most recent additions to the battery of first-line treatments for CLL are the monoclonal antibodies rituximab and alemtuzumab. 29,30 Rituximab is currently only approved for use in combination with fludarabine and cyclophosphamide; alemtuzumab, although included in the first-line recommendations for CLL, is currently only approved for use in the second-line setting. Alemtuzumab in combination with methylprednisone may be particularly effective in patients with del(17p) mutations. 31 Lenalidomide is an immunomodulatory drug that has established efficacy and is indicated in the treatment of multiple myeloma and myelodysplastic syndromes. A recent study in 65 patients aged 65 years with treatmentnaive CLL treated with oral lenalidomide 5 mg/d titrated up to 25 mg/d as tolerated, had a 2-year progression-free survival rate of 60% and an overall response rate of 65%, including complete response in 10% of patients. 29 A study is also underway to evaluate the efficacy and tolerability of lenalidomide in combination with rituximab as a first-line regimen. 32 Studies are ongoing with the humanized anti- CD20 antibody obinutuzumab (GA101), which has demonstrated superior activity to rituximab in preclinical studies and is under investigation in heavily pretreated patients and those with relapsed disease. 33 Another monoclonal antibody, ofatumumab, has recently been S80 COMMUNITY ONCOLOGY December

7 Gregory FIGURE 1 First-line treatment recommendations for patients requiring systemic treatment for chronic lymphocytic leukemia. Adapted from National Comprehensive Cancer Network. 2 Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S81

8 approved for the treatment of CLL refractory to alemtuzumab and fludarabine; additional data will be required to determine the place of this agent in first-line treatment strategies. 34,35 Chemoimmunotherapy The last decade has seen the advent of chemoimmunotherapy for CLL A number of such regimens are now well established for the treatment of CLL including fludarabine, cyclophosphamide, and rituximab (FCR) and bendamustine and rituximab (BR; although recommended, this combination is not currently approved for use in the United States). 2 The standard FCR regimen induces responses in 95% of patients but is associated with a high rate of grade 3/4 neutropenia and hence it is not widely used for the treatment of older patients. A recent study suggests that lowering the fludarabine and cyclophosphamide doses the so-called FCR-lite regimen retains the efficacy of FCR in untreated patients while reducing the rate of grade 3/4 neutropenia. 39 A recent phase II study of the BR regimen for the first-line treatment of CLL in a cohort of 117 adults yielded a response rate of 88%, with 23% of patients achieving a complete response. 40 Overall tolerability was good, with around half of patients experiencing hematologic toxicity of grade 3 or 4. In this study 26% of patients were aged 70 years and among these patients the overall response rate was 85%. Adjusting treatment for slow go patients Appropriate treatments for patients requiring a more conservative approach ( slow go patients) are poorly defined. These patients are underrepresented in clinical trials and evidence-based strategies remain undefined. 41 Monotherapy with systemic agents, such as chlorambucil or bendamustine, is a viable first-line option given their relatively benign side-effect profiles. 28,42,43 In slow go patients, the benefit of adding immunotherapies, such as rituximab or the newer anti-cd20 antibodies, remains in question given the potential for additional side effects. Comorbidities and their impact on treatment selection Patients presenting with CLL often also have a range of comorbid conditions. In 2008, Thurmes and colleagues 44 found that among 1195 patients newly diagnosed with CLL, 89% had at least 1 comorbidity at diagnosis and in 46% this was a major comorbidity. Although comorbidities appear to be of less significance in determining patient prognosis, they are of considerable relevance when selecting treatment type and intensity. For example, patients with a high level of comorbidities may not tolerate intensive systemic therapy and so may be suitable for a slow go approach with chlorambucil or bendamustine monotherapy or reduced-dose combination regimens such as FCR-lite. Immunosupportive care is essential and immune status (immunoglobulin G levels) should be routinely monitored. 2,45 Of considerable importance is the management of underlying hypogammaglobulinemia and recurrent infections. These individuals should receive monthly intravenous infusions of immunoglobulins to prevent life-threatening bacterial infections. 46 Neurological complications of the disease are emerging as a relevant comorbidity for patients with CLL. 47 Such conditions arise as a consequence of central nervous system infiltration and while appropriate systemic treatments are currently lacking for such sequelae it is important for clinicians to be vigilant for their emergence. Case study The case of Mrs A, a 70-year-old woman who was referred to my clinic by her hematologist, illustrates a number of the challenges we face in managing elderly patients with CLL. Initial evaluations showed that Mrs A had a white blood cell (WBC) count of cells/ L with 70% lymphocytes. Flow cytometric evaluation was ordered and the results were consistent with a diagnosis of CLL (dim CD20, CD19, CD5, and CD23, along with a low level of CD38 expression accompanied by immunoglobulin M and kappa light chain restriction). Examination revealed no lymphadenopathy or hepatosplenomegaly, and laboratory evaluation revealed that Mrs A had normal immunoglobulins, was ZAP-70 negative, and had a del(13q) mutation (FISH). Mrs A was reluctant to initiate treatment and had no indications for intervention. Of note, the patient s husband had progressive CLL and had died 6 years previously. He had been cared for by the same hematologist and had only agreed to oral chlorambucil during the last 6 months of his life. His disease was moderately controlled and he eventually succumbed to pneumonia. A watch and wait approach was agreed upon for Mrs A. Over the subsequent 3 years, Mrs A s WBC count increased to cells/ L and she slowly developed progressive adenopathy with anemia and thrombocytopenia. Despite now being symptomatic, Mrs A was still reluctant to initiate any systemic therapy and she was monitored without intervention for another 3 months. At this point, Mrs A had generalized lymphadenopathy and a palpable spleen 6 cm below the left costal margin, a hemoglobin level of 8 g/dl and a platelet count of cells/ L. Physically she was fatigued and had lost 10 lb due to her decreased appetite. S82 COMMUNITY ONCOLOGY December

9 Gregory Mrs A now agreed to treatment and oral chlorambucil was initiated. After 8 weeks of treatment her WBC count had increased to L and her hemoglobin level had dropped further, while her platelet count remained at cells/ L. Mrs A required a blood transfusion and she agreed to try a cycle of reduced-dose bendamustine (50 mg/m 2 ) in combination with rituximab. Unfortunately, Mrs A reacted to the rituximab and the entire infusion was stopped. She had received bendamustine for 2 days. Despite the low dose and premature discontinuation of systemic therapy, Mrs A experienced a marked decrease in her WBC count (to cells/ L); she also had an absolute neutrophil count of 600 cells/ L, a platelet count of cells/ L, and a hemoglobin level of 8 g/dl. Mrs A refused further therapy and remained relatively stable for 3 months. She finally succumbed to bacterial pneumonia. Mrs A s case highlights the urgent need for evidencebased data on appropriate treatment strategies for elderly patients who are reluctant to undergo, or are physically too frail for, intensive systemic therapy. Such evidence may have helped Mrs A to overcome her reluctance to receive any therapy for her CLL and allowed earlier intervention. Future directions and emerging treatments With a number of new agents under active investigation for the treatment of CLL, the future seems promising for patients newly diagnosed with this common hematologic malignancy. Future efforts may also focus on strategies to manage this disease with a view to extending life expectancy to near normal levels through novel strategies such as treatment sequencing or by reserving alkylating agents for patients with more advanced disease. Clinical trial data are urgently needed to define optimal first-line treatment strategies for patients requiring a slow go strategy including elderly patients and those with multiple comorbidities and poor performance status. A number of novel treatments are in the early stages of development and are likely to join the treatment armamentarium for CLL over the next decade. These include targeted therapies that may have an improved tolerability profile compared with systemic chemotherapy, such as the kinase inhibitor CAL-101 and the small modular immunopharmaceutical TRU-016, a humanized anti-cd37 immunoglobulin G fusion protein. 48,49 Conclusions CLL affects a range of patients, many of whom have traditionally been ineligible for clinical trials of chemotherapeutic agents. 50 Patients outside the traditional clinical trial demographic (eg, the elderly, those with poor cytogenetics, or comorbidities) are often regarded as having a poor prognosis with limited treatment options. However, with the development of newer drugs and regimens, chemotherapeutic and biological treatment options are available that can significantly extend the life and QOL of these more difficult to manage patients. Acknowledgment Medical writing support was provided by Tracey Lonergan of Anthemis Consulting Ltd, funded by Teva Pharmaceuticals, Frazer, PA. Teva provided a single medical accuracy review of the final draft. The author was not compensated and retained full editorial control over the content of the paper. References 1. Hsi ED. Pathologic and molecular genetic features of chronic lymphocytic leukemia. Semin Oncol. 2012;39(1): National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. Version (NCCN Guidelines ) physician_gls/pdf/cml.pdf. Published September Accessed August 17, Schnaiter A, Mertens D, Stilgenbauer S. Genetics of chronic lymphocytic leukemia. Clin Lab Med. 2011;31(4): Siegel R, Naishadham D, Jemal A. 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Blood. 2012;119(22): Hoyle M, Crathorne L, Garside R, et al. Ofatumumab for the treatment of chronic lymphocytic leukemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK. Health Technol Assess. 2011;15(suppl 1): Veliz M, Pinilla-Ibarz J. Role of ofatumumab in treatment of chronic lymphocytic leukemia. J Blood Med. 2011;2: Molica S. Progress in the treatment of chronic lymphocytic leukemia: results of the German CLL8 trial. Expert Rev Anticancer Ther. 2011;11(9): Parikh SA, Keating MJ, O Brien S, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011; 118(8): Woyach JA, Ruppert AS, Heerema NA, et al. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study J Clin Oncol. 2011;29(10): Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(4): Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the Germany Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012; 30(26): Del Giudice I, Mauro FR, Foà R. Chronic lymphocytic leukemia in less fit patients: slow-go. Leuk Lymphoma. 2011;52(12): Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(26): Eichhorst BF, Busch R, Stilgenbauer S, et al; German CLL Study Group (GCLLSG). First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114(6): Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2008;49(1): Riches JC, Ramsay AG, Gribben JG. Immune reconstitution in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2012; 7(1): Young JA. Epidemiology and management of infectious complications of contemporary management of chronic leukemias. Infect Disord Drug Targets. 2011;11(1): Lopes da Silva R. Spectrum of neurologic complications in chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk. 2012; 12(3): Castillo JJ, Furman M, Winer ES. CAL-101: a phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies. Expert Opin Investig Drugs. 2012;21(1): Robak T, Robak P, Smolewski P. TRU-016, a humanized anti- CD37 IgG fusion protein for the potential treatment of B-cell malignancies. Curr Opin Investig Drugs. 2009;10(12): Lamanna N. Treatment of older patients with chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2012;7(1): S84 COMMUNITY ONCOLOGY December

11 Management of relapsed chronic lymphocytic leukemia: applying guidelines to practice Loretta J. Nastoupil, MD; and Christopher R. Flowers, MD Winship Cancer Institute, Emory University, Atlanta, GA Correspondence: Christopher R. Flowers, MD, Bone Marrow and Stem Cell Transplantation, Winship Cancer Institute, 1365 Clifton Road, N.E. Building B, Suite 4302, Emory University, Atlanta, GA Phone: ( Disclosures: Dr Nastoupil has received an honorarium from Hoffman-La Roche and is a consultant to Genentech/Roche. Dr Flowers is a consultant to Celgene, Clinical Care Options, Genentech/Roche (unpaid), Millennium/Takeda (unpaid), Prescription Solutions, Seattle Genetics, and Spectrum, and has received research funding from Abbott, Calistoga Pharmaceuticals, Celgene, Eastern Cooperative Oncology Group, Janssen Pharmaceutical, Memorial Sloan-Kettering Cancer Center, Millennium/Takeda, National Cancer Institute, National Institute of Health, Northwestern University, Southwest Oncology Group, and Spectrum. Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world. 1 Despite improvements in care, CLL is incurable and patients usually relapse after initial treatment. Although mortality in the US has declined since 1993, 4580 individuals are expected to die of this disease in ,3 The most frequently used first-line chemoimmunotherapy regimen is the combination of fludarabine, cyclophosphamide, and rituximab (FCR). However, after treatment with FCR, approximately 6% of patients relapse within 6 to 12 months, a further 14% do so within 2 years, and all surviving patients are expected to eventually relapse. 4,5 Treatment of relapsed CLL often hinges on providing therapy that maximizes survival and disease control while minimizing toxicity with the overall goal of improving quality of life (QOL). Current data from the Connect CLL Disease Registry (n 899) show that health-related QOL (assessed using the Functional Assessment of Cancer Therapy-Leukemia, EuroQol 5-Dimensions, and Brief Fatigue Inventory questionnaires) in newly diagnosed and relapsed patients in routine clinical care decreased with worsening Eastern Cooperative Oncology Group (ECOG) performance status, and was lower in patients with fatigue. 6 Performance status and the presence of comorbidities are therefore important factors in deciding the best treatment options for the patient. Because treatments can be associated with severe adverse events (AEs), the choice of appropriate therapy for patients with relapsed disease should account for performance status when defining the goal and role of treatment. Other key factors to be considered when deciding treatment are the chronic nature of the disease, and the number and types of prior therapy. CLL has a variable course, but patients may remain stable and asymptomatic for years before progressing. An interesting fact to consider in treatment decision making is that the median age at death for patients with leukemia is 79 years, and that the average life expectancy in the United States is approximately the same age. 7 As CLL is characterized by relapses, even after prolonged responses to therapy, many patients receive multiple lines of treatment. In this article we discuss treatment options for patients with CLL who have relapsed after at least 1 prior treatment. How should a patient with relapsed CLL be evaluated? A relapsed patient is defined as one who has previously achieved complete remission or partial remission, but who exhibits evidence of disease progression after a period of 6 months or more (Table 1). 8 Relapse may occur after a prolonged complete remission following initial treatment, or within months following a later line of treatment. In general, relapsed patients should be evaluated in the same way as newly diagnosed patients. Evidence of CLL at relapse should be confirmed by Commun Oncol 2012;9:S85-S Frontline Medical Communications Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S85

12 TABLE 1 Response definitions for chronic lymphocytic leukemia 1 NCCN guidelines Response IWCLL guidelines 8 Group A a Complete remission Partial remission Progressive disease Blood lymphocytes c /L; no significant lymphadenopathy (lymph node diameter 1.5 cm) d ; no hepato/splenomegaly d ;no constitutional symptoms; neutrophils e /L; platelets e /L; Hb 110 g/l without transfusions/erythropoietin Blood lymphocyte decrease of 50% from baseline; reduction in lymphadenopathy f ; neutrophils e /L; platelets e /L or 50% increase from baseline; Hb 110 g/l or 50% increase from baseline without transfusions/ erythropoietin Any new lesion: enlarged lymph nodes ( 1.5 cm), increase in enlarged liver/spleen by 50% or de novo spleno/hepatomegaly (or other organ infiltrates); blood lymphocyte increase of 50% (with 5000 B lymphocytes/ L); transformation to more aggressive histology; cytopenia attributable to CLL Peripheral blood lymphocytes /L; no lymph nodes 1.5 cm; no spleno/ hepatomegaly; bone marrow normocellular and no B-lymphoid nodules; 30% lymphocytes in bone marrow Blood lymphocyte decrease of 50% from baseline; decrease in summed products of lymph nodes by 50%; decrease in spleno/hepatomegaly by 50%; 50% reduction in marrow infiltrate or B-lymphoid nodules Blood lymphocyte increase of 50% from baseline; increase in summed products of lymph nodes by 50%; increase in spleno/hepatomegaly by 50% Group B b Platelets e /L; Hb 110 g/l without transfusions/growth factors; neutrophils e /L Neutrophils e /L or 50% increase from baseline; platelets e /L or 50% increase from baseline; Hb 110 g/l or 50% increase from baseline without transfusions/ growth factors Platelets decreased by 50% from baseline secondary to CLL; Hb decreased by 20 g/l from baseline secondary to CLL Abbreviations: CLL, chronic lymphocytic leukemia; Hb, hemoglobin; IWCLL, International Workshop on Chronic Lymphocytic Leukemia; NCCN, National Comprehensive Cancer Network. a Group A criteria define the tumor load. b Group B criteria define hematopoietic system (or marrow) function. c By blood and differential count. d By physical examination. e Without growth factor support. f Decreased lymph node size by 50% in sum products of 6 nodes (or largest diameter of enlarged nodes) relative to baseline, and no increase in any node, and no new enlarged nodes (except increases of 25% in nodes 2 cm wide). flow cytometry and a complete blood count demonstrating B lymphocytes/l in the peripheral blood. Differential diagnoses to consider include prolymphocytic leukemia and transformation to an aggressive lymphoma. 1,8 As described in the previous article, there are 2 widely accepted staging systems for CLL: the Rai system and the Binet system. 9 Currently, both systems use physical examination and standard laboratory tests to stratify patients into 3 risk groups, which correlate with clinical outcome. 10,11 A history of previous treatment should always be taken. In this era of fludarabine-based therapy, it is important to note that patients refractory to fludarabine respond relatively poorly to subsequent fludarabine-based therapy. 12 Cytogenetic tests should also be performed following each relapse, as genetic defects may develop over the course of the disease, and may be more common in patients with early relapse. 4 Interphase fluorescence in situ hybridization (FISH) should be used to detect cytogenetic abnormalities, including specific deletions, trisomy, and translocations of chromosomal bands, which are key predictive markers for response to therapy and patient outcome. 13 The presence of a deletion in the short arm of chromosome 17, del(17p), which frequently results in abnormalities in the key tumor suppressor gene TP53, is a marker of inferior prognosis. Patients bearing this mutation are poor responders to common treatments for CLL, including purine analogs, which are common and preferred treatments for relapsed disease in suitable, fit patients. 12,14,15 The presence of del(11p) has been associated with extensive lymphadenopathy, progression, and shorter survival time. 13,16 However, untreated patients bearing this abnormality do respond to treatments containing fludarabine and cyclophosphamide. 17,18 The presence of del(13p) as the sole cytogenetic abnormality is favorable. 13 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines recommend the evaluation of cytogenetic markers to aid in providing patients with prognostic information, but cytogenetic markers are S86 COMMUNITY ONCOLOGY December

13 Nastoupil & Flowers not recommended to guide treatment. 8 However, the more recent National Comprehensive Cancer Network (NCCN) guidelines state that cytogenetic information may be used to guide treatment choice, as discussed below. 1 The role of cytogenetic testing at relapse should be discussed with each patient to determine the optimal use of this test in clinical decision-making for each individual. Other prognostic markers include the presence of an unmutated immunoglobulin heavy chain variable region (IgVH), as detected by DNA sequencing. This has been associated with significantly shorter survival when compared with the presence of mutated IgVH. 19 Increased expression of CD38 or zeta-chain-associated protein kinase 70 (ZAP-70) is also associated with poor outcome IWCLL guidelines do not recommend testing for either of these markers in routine clinical practice. 8 The NCCN guidelines, on the other hand, do recommend testing for these markers to provide prognostic information. 1 Minimal residual disease has recently received interest as a prognostic marker for progression-free survival (PFS), although this is not currently recognized by either the IWCLL or NCCN guidelines. 1,8,27 Bone marrow aspiration and biopsy may be useful to assess the cause of anemia or thrombocytopenia (eg, leukocyte infiltration of the bone marrow). A biopsy is recommended before restarting treatment to determine susceptibility to drug-induced cytopenias. 1,8 When should a patient with relapsed CLL be treated? Although NCCN and IWCLL guidelines and Rai and Binet criteria offer guidance on when it is appropriate to initiate therapy in relapsed patients, no study has identified the optimal timing of therapy in the setting of relapse. Since many CLL patients are elderly and frail and may present with comorbidities, it is important to counterbalance the risks and benefits of therapy for a particular individual. On the one hand, chemotherapy with an inherent risk of severe AEs should not be introduced to a patient in whom disease is minimal and not progressing. On the other hand, treatment should not be deferred until the patient has a high disease burden and has become too weak to tolerate a preferred regimen. Progressive disease (PD; Table 1) or symptomatic disease should be evident before treatment is initiated in the relapsed setting. Although patients with CLL may present with an elevated leukocyte count, this alone should not trigger the start of re-treatment; the symptoms caused by leukocyte aggregates in acute leukemias are rarely observed in CLL. 8 Likewise, hypogammaglobulinemia or paraproteinemia (monoclonal or oligoclonal) are not criteria for restarting treatment, although these laboratory abnormalities should be monitored once the patient is treated. 8 What is the optimal treatment for relapsed CLL? In general, the NCCN guidelines recommend re-treatment with the regimen used as first-line therapy if the first-line response was of long duration. 1 If the response to initial treatment was of short duration, other therapy options should be considered. In the Connect CLL Disease Registry, the most commonly recorded first-line regimens among patients treated predominantly in community-based practices in the United States were FCR (33%), bendamustine rituximab (19%), fludarabine rituximab (15%), or investigational therapies (15%). For patients who received second-line or later regimens, the most frequently recorded regimens were bendamustine rituximab (30%), FCR (23%), other fludarabine-based regimens (13%), or investigational therapies (8%). Although commonly employed in the past, the use of chlorambucil was infrequent. As noted above, ECOG performance status influenced treatment selection, but predominantly in older patients. 5 The German CLL Study defined patient groups suitable for initial treatment: go go for patients in good physical condition; slow go for those with relevant comorbidities; and a poor-risk group comprising those with symptomatic refractory disease and del(17p)/p53 deletions. 28 These concepts can be extended to relapsed patients. The treatment options discussed below for these 3 patient groups are summarized in Figure 1. Go go patients In go go patients, preferred choices of treatment for the patient with relapsed CLL should include FCR. This combination therapy has been shown to be highly effective in untreated patients, and is frequently used in this setting. 5,29 If the response duration with first-line FCR was 3 years, then FCR can also be considered as secondline treatment. In an initial phase II trial in relapsed and refractory patients (n 177), FCR was associated with an overall response rate (ORR) of 73%, including complete remissions in 25% of patients. 30 A follow-up study in relapsed patients alone (n 284), reported similar ORR and complete remission rates (74% and 30%, respectively). FCR remained effective in patients who received this combination therapy as initial treatment. 12 However, patients who were refractory to fludarabine (ORR 56%; P.001) or with chromosome 17 abnormalities (ORR 35%; P.001) responded relatively poorly. Follow-up data from a phase III trial showed that FCR was a common treatment following relapse 24 months after initial treat- Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S87

14 Go-go patients (Good physical condition) Patients with chromosomal abnormalities and/or symptomatic aggressive-behaving refractory disease Fludarabine sensitive FCR Fludarabine insensitive Alemtuzumab alone, ofatumumab alone, BR, a fludarabine + alemtuzumab, a R-HDMP, a PCR, a OFAR, a rituximab + alemtuzumab, a R-CHOP, a R-hyperCVAD, a dose-adjusted EPOCH, a HSCT b Slow-go patients (aged 70 years or comorbidities) Reduced-dose FCR, bendamustine alone, alemtuzumab alone, ofatumumab alone, reduced-dose PCR, a BR, a R-HDMP, a rituximab + alemtuzumab, a dose-dense rituximab a Clinical trial, if possible. If not, the following treatments are suitable for patients with chromosomal abnormalities Del(17p) FCR, alemtuzumab alone, ofatumumab alone, HDMP, rituximab + alemtuzumab, a R-CHOP, a CFAR, a R-HDMP, a OFAR, a R-hyperCVAD a Del(11p) Aged <70 years or no comorbidities FCR, alemtuzumab alone, ofatumumab alone, PCR, a BR, a FR, a R-CHOP, a R-hyperCVAD, a rituximab + dose-adjusted EPOCH, a OFAR, a rituximab + alemtuzumab, a R-HDMP a Aged 70 years Reduced-dose FCR, bendamustine alone, reduced-dose PCR, a BR, a R-HDMP, a rituximab + alemtuzumab, a dose-dense rituximab a FIGURE 1 Treatment options for patients with relapsed chronic lymphocytic leukemia. 1 Abbreviations: BR, bendamustine and rituximab; CFAR, cyclophosphamide, fludarabine, alemtuzumab, and rituximab; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; FCR, fludarabine, cyclophosphamide, and rituximab; FR, fludarabine and rituximab; HDMP, highdose methylprednisolone; HSCT, hematopoietic stem cell transplantation; OFAR, oxaliplatin, fludarabine, cytarabine, and rituximab; PCR, pentostatin, cyclophosphamide, and rituximab; R-CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab; R-HDMP, high-dose methylprednisolone plus rituximab; R-hyperCVAD, rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine. a Off label. b In patients with short response to prior treatment, without comorbidities, and following re-establishment of remission. ment with fludarabine and cyclophosphamide (FC) rituximab, and that it was the most effective second-line treatment studied in patients initially treated with FC. 31 The benefit of FCR over FC in patients with relapsed CLL was shown in the international, randomized phase III Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia (REACH) trial. 32 In this study, patients were randomized to receive fludarabine (25 mg/m 2 /d IV) and cyclophosphamide (250 mg/m 2 /d), each for 3 days, repeated every 28 days, for 6 cycles, or FC with rituximab on Day 1 of each cycle (375 mg/m 2 in Cycle 1, and 500 mg/m 2 in subsequent cycles). Patients had Binet stage A (10%), B (59%), or C (31%) disease. After a median follow-up of 25 months, PFS (the primary endpoint) was significantly longer in the FCR group than in the FC group (30.6 months vs 20.6 months; hazard ratio, 0.65; P.001). FCR was generally well tolerated and did not substantially alter QOL. The benefit of FCR was maintained in patient subgroups with high-risk features, including those with unmutated IgVH, the chromosomal abnormality del(11q), and increased ZAP-70 expression. However, in this study, no PFS benefit for FCR over FC was observed in patients previously treated with FC rituximab, alkylatorrefractory patients, those diagnosed 10 years beforehand, female or nonwhite patients, patients aged 65 years, those with ECOG performance status 1, patients with B symptoms, patients with a diffuse/nodular pattern of bone marrow involvement, and those with the chromosomal abnormalities trisomy 12 or del(17p). 32 Although the benefits of the addition of rituximab can be debated for these subgroups of relapsed patients, it is commonly incorporated into therapy for most patients as the above data were derived from unconfirmed exploratory analyses, and the immunotherapy adds minimal toxicity to the regimen. Resistance to fludarabine is an important consideration when choosing treatment. As stated above, patients with fludarabine-resistant disease commonly respond poorly to FCR. Moreover, many of these patients will have previously been exposed to and have become resistant to alkyl- S88 COMMUNITY ONCOLOGY December

15 Nastoupil & Flowers ating agents. On-label options suggested by the NCCN for patients with fludarabine-resistant disease who would be regarded as being in the go go category include monotherapy with alemtuzumab or ofatumumab. 1 Alemtuzumab is a humanized anti-cd52 monoclonal antibody shown in a series of studies to be active as monotherapy in relapsed/refractory patients (including those who had previously received fludarabine, or who had p53 or del(17p) abnormalities). The ORRs were 13% to 54% in patients with fludarabine-refractory disease Ofatumumab is a human anti-cd20 monoclonal antibody. Its activity in patients with relapsed/refractory CLL was reported in a phase I/II study in It has since been approved for use in patients with CLL refractory to fludarabine and alemtuzumab on the basis of data from a phase II study. 41 In this study (n 138), ORRs were 58% and 47% in patients refractory to alemtuzumab or fludarabine, respectively. A post-hoc analysis showed that ofatumumab was effective irrespective of prior rituximab treatment. 42 Off-label treatments recommended by the NCCN include bendamustine plus rituximab (BR; rituximab is currently indicated for use only in combination with FC in patients with previously treated CLL), fludarabine plus alemtuzumab, and several rituximab-containing combination therapies: rituximab plus high-dose methylprednisolone (R-HDMP); pentostatin, cyclophosphamide, and rituximab (PCR); oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR), and alemtuzumab plus rituximab. Lymphoma regimens such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R- CHOP), rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (R-hyperCVAD), and doseadjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) plus rituximab can also be used in certain instances. 1 Bendamustine is approved in the United States for the treatment of CLL. Although bendamustine is an alkylating agent, it has incomplete cross-resistance with other such agents. 43 Bendamustine monotherapy was initially shown to have activity in relapsed/refractory patients and an acceptable safety profile in a number of small trials Interim data from a larger, randomized study comparing fludarabine and bendamustine (n 96) revealed ORRs of 65% and 78%, respectively, including complete remissions in 10% and 29% of patients, respectively. 47 Clinical data support the use of bendamustine following relapse with FCR and the use of BR following relapse with other therapies. 32,48 Allogeneic hematopoietic stem cell transplantation is a viable option for some patients without significant comorbidities with short responses to chemoimmunotherapy, but is more generally suitable following reestablishment of remission. 1 Slow go patients Reduced-dose FCR should be considered in patients aged 70 years or in younger patients with comorbidities (ie, slow go patients). 1 Data in predominantly younger patients suggest that this can be effective in the first-line setting, but limited data exist on the use of dose-reduced FCR in the relapsed setting. 49 Other on-label treatment options recommended by the NCCN for this patient population include monotherapy with bendamustine, ofatumumab, or alemtuzumab. Off-label treatments recommended by the NCCN include rituximab-based treatments, such as reduced-dose PCR, BR, R-HDMP, alemtuzumab plus rituximab, and dose-dense rituximab. 1 Patients with chromosomal abnormalities The NCCN guidelines provide further guidance for patients with chromosomal abnormalities. For patients with del(17p), enrollment in a clinical trial is highly recommended. If this is not possible, FCR, ofatumumab or alemtuzumab monotherapy, and high-dose methylprednisolone are other on-label options. Off-label options include: alemtuzumab plus rituximab; R-CHOP; cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR); R-HDMP; R-hyperCVAD; and OFAR. 1 For those with del(11p), enrollment in a clinical trial is again a preferred option. If the patient progressed following a complete remission, first-line therapy may be repeated depending on the duration of the response. FCR can be used in patients aged 70 years or in older patients without comorbidities. Other on-label options for all patients with this abnormality include ofatumumab or alemtuzumab monotherapy. Off-label options include PCR, BR, FR, R-CHOP, R-hyperCVAD, dose-adjusted EPOCH plus rituximab, OFAR, alemtuzumab plus rituximab, and R-HDMP. Reduced-dose FCR and bendamustine monotherapy are approved in those aged 70 years. Off-label treatments include reduced-dose PCR, BR, R-HDMP, alemtuzumab plus rituximab, and dosedense rituximab. 1 Clinical trials It is important that treatment is not withheld from older and less fit patients with PD if it would increase their QOL. New treatments are constantly being developed. If it is unlikely that a patient will respond to standard treatment, then the option of a clinical trial should be explored. While detailed discussion of compounds in development is beyond the scope of this article, there are several Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S89

16 promising agents being assessed in clinical trials as single agents and in combination with other agents. One such agent is ibrutinib (PCI-32765), an oral Bruton tyrosine kinase inhibitor. 50 Interim data from a phase I/IIb study suggest it may be highly active (ORR, 73%) in elderly patients with untreated CLL. 51 Another promising agent is CAL-101, a phosphatidylinositol 3-kinase-delta inhibitor. 52 Early data from phase I studies showed this agent to have promising activity and acceptable safety profiles in patients previously treated for CLL, either as monotherapy or combined with anti-cd20 monoclonal antibody therapy and/or bendamustine. 53,54 Recent data from a phase I/II study show that, in combination with ofatumumab, CAL-101 was associated with marked and rapid reductions in lymphadenopathy. 55 However, the effect that these agents will ultimately have on the management of patients with relapsed CLL remains to be seen. A case history A 67-year-old man was diagnosed 5 years ago with CLL. His leukemia cells expressed unmutated IgVH and increased expression of ZAP-70 (both poor prognostic features). FISH studies revealed no abnormalities. He was initially observed without treatment (ie, watch and wait ) as he was asymptomatic with a low disease burden. Eighteen months later he developed progressive and symptomatic CLL and began treatment with FCR; after 6 cycles he attained a partial remission. In the last month of treatment he began experiencing progressive fatigue and increasing lymphadenopathy. At the last assessment, the patient had multiple cervical, supraclavicular, and axillary lymph nodes 4 to 5 cm in size, and his spleen was palpable 10 cm below the left costal margin. Laboratory assessments demonstrated a white blood cell count of 33,900/ L (14% neutrophils, 84% lymphocytes), a platelet count of 129,000/ L, and a hemoglobin level of 12.4 g/dl. His serum beta-2 microglobulin level was 4 mg/l, and his lactate dehydrogenase level was 240 U/L. Bone marrow biopsy revealed a hypercellular marrow mostly comprising well-differentiated lymphocytes, with tri-lineage hematopoiesis, a reduced level of megakaryocytes, and no dysplasia. Flow cytometry testing confirmed that the lymphocytes had the phenotype of CLL cells. Abnormal karyotype and FISH data demonstrated the presence of del(11q) (a poor prognostic factor). The patient had few, well-compensated comorbidities, and his ECOG performance status was 1. After discussion of available clinical trials and the standard therapies, the patient has initiated treatment with BR. Although not interested in a clinical trial at this juncture, the patient did express interest in pursuing treatment in a clinical trial at his next relapse. Conclusions Assessment of the patient with relapsed/refractory CLL requires as much attention as evaluation of patients at initial presentation. Treatment of relapsed CLL is highly personalized due to the typical age of the patient population, the risk of severe AEs, and the chronic nature of this disease. Patients with asymptomatic, stable disease should be monitored without treatment. Patients with documented PD should be treated when it is most likely to benefit the patient. Numerous treatment options exist for less fit patients with relevant comorbidities, fludarabine resistance, or chromosomal abnormalities. Treatment should be tailored based on patient characteristics and should aim to maximize survival, minimize toxicity, and improve overall QOL. Acknowledgments Medical writing support was provided by Neil Fisher on behalf of Anthemis Consulting Ltd, funded by Teva Pharmaceuticals, Frazer, PA. The authors were not compensated and retained full editorial control over the content of the paper. This work was supported in part by Dr. Flowers Georgia Cancer Coalition Distinguished Scientist Award and Cancer Research Award, American Society of Hematology Amos Medical Faculty Development Award, National Cancer Institute R21 CA A1, and a Leukemia and Lymphoma Society Translational Research Award. References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology TM : Non-Hodgkin s Lymphomas. Version Published July Accessed July American Cancer Society. Cancer Facts & Figures Atlanta, GA: American Cancer Society; groups/content/@epidemiologysurveilance/documents/document/acspc pdf. Accessed July National Cancer Institute. Surveillance Epidemiology and End Results. SEER Stat Fact Sheets: Chronic lymphocytic leukemia. seer.cancer.gov/statfacts/html/clyl.html. Accessed July Zenz T, Busch R, Fink A, et al. Genetics of patients with F- refractory CLL or early relapse after FC or FCR: Results from the CLL8 trial of the GCLLSG. Blood (ASH Annual Meeting Abstracts). 2010; 116(21): Sharman J, Flowers CR, Weiss M, et al. Patterns of care for patients with chronic lymphocytic leukemia (CLL): The Connect CLL Disease Registry. Blood (ASH Annual Meeting Abstracts). 2011; 118(21): Flowers C, Pashos CL, Weiss MA, et al. Variation in healthrelated quality of life (HRQOL) by ECOG performance status (PS) and fatigue among patients with chronic lymphocytic leukemia (CLL). J Clin Oncol. 2012;30(15 suppl): Central Intelligence Agency. The World Factbook. Country Comparison: Life expectancy at birth. publications/the-world-factbook/rankorder/2102rank.html. Accessed July Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. 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17 Nastoupil & Flowers 9. Gregory SA. Managing the patient with chronic lymphocytic leukemia: initial evaluation and first-line treatment decisions. Comm Oncol. 2012;9(12 Suppl):S77-S Rai KR, Sawitsky A, Cronkite EP, et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2): Binet JL, Auquier A, Dighiero G, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48(1): Badoux XC, Keating MJ, Wang X, et al. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011;117(11): Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343(26): Döhner H, Fischer K, Bentz M, et al. p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias. Blood. 1995;85(6): Grever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007;25(7): Neilson JR, Auer R, White D, et al. Deletions at 11q identify a subset of patients with typical CLL who show consistent disease progression and reduced survival. Leukemia. 1997;11(11): Tsimberidou AM, Tam C, Abruzzo LV, et al. Chemoimmunotherapy may overcome the adverse prognostic significance of 11q deletion in previously untreated patients with chronic lymphocytic leukemia. Cancer. 2009;115(2): Oscier D, Wade R, Davis Z, et al; Chronic Lymphocytic Leukaemia Working Group; UK National Cancer Research Institute. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica. 2010;95(10): Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V H genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6): Del Poeta G, Maurillo L, Venditti A, et al. Clinical significance of CD38 expression in chronic lymphocytic leukemia. Blood. 2001; 98(9): Ibrahim S, Keating M, Do KA, et al. CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood. 2001;98(1): Kröber A, Seiler T, Benner A, et al. V H mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100(4): Crespo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348(18): Orchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet. 2004; 363(9403): Gentile M, Mauro FR, Calabrese E, et al. The prognostic value of CD38 expression in chronic lymphocytic leukaemia patients studied prospectively at diagnosis: a single institute experience. Br J Haematol. 2005;130(4): Del Principe MI, Del Poeta G, Buccisano F, et al. Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia. Blood. 2006;108(3): Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9): Hallek M, Pflug N. Chronic lymphocytic leukemia. Ann Oncol. 2010;21(suppl 7):vii154-vii Hallek M, Fischer K, Fingerle-Rowson G, et al; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747): Wierda W, O Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18): Cramer P, Fink A-M, Busch R, et al. Second-line therapies after treatment with fludarabine, cyclophosphamide, and rituximab (FCR) or fludarabine and cyclophosphamide alone (FC) for chronic lymphocytic leukemia (CLL) within the CLL8-protocol of the German CLL Study Group (GCLLSG). Blood (ASH Annual Meeting Abstracts). 2011; 118(21): Robak T, Dmoszynska A, Solal-Céligny P, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010;28(10): Keating MJ, Flinn I, Jain V, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99(10): McCune SL, Gockerman JP, Moore JO, et al. Alemtuzumab in relapsed or refractory chronic lymphocytic leukemia and prolymphocytic leukemia. Leuk Lymphoma. 2002;43(5): Rai KR, Freter CE, Mercier RJ, et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002;20(18): Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004;103(9): Osuji NC, Del Giudice I, Matutes E, et al. The efficacy of alemtuzumab for refractory chronic lymphocytic leukemia in relation to cytogenetic abnormalities of p53. Haematologica. 2005;90(10): Fiegl M, Falkner A, Hopfinger G, et al; Austrian Collaborative Study Group on Alemtuzumab in Chronic Lymphocytic Leukemia. Routine clinical use of alemtuzumab in patients with heavily pretreated B-cell chronic lymphocytic leukemia: a nation-wide retrospective study in Austria. Cancer. 2006;107(10): Ferrajoli A, Wierda WG, LaPushin R, et al. Pilot experience with continuous infusion alemtuzumab in patients with fludarabinerefractory chronic lymphocytic leukemia. Eur J Haematol. 2008;80(4): Coiffier B, Lepretre S, Pedersen LM, et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-cd20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008;111(3): Wierda WG, Kipps TJ, Mayer J, et al; Hx-CD Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia [published correction appears in J Clin Oncol. 2010;28(22):3670]. J Clin Oncol. 2010; 28(10): Wierda WG, Padmanabhan S, Chan GW, et al. Hx-CD Study Investigators. Ofatumumab is active in patients with fludarabinerefractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011;118(19): Strumberg D, Harstrick A, Doll K, et al. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs. 1996;7(4): Kath R, Blumenstengel K, Fricke HJ, et al. Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol. 2001;127(1): Bergmann MA, Goebeler ME, Herold M, et al; German CLL Study Group. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica. 2005;90(10): Lissitchkov T, Arnaudov G, Peytchev D, et al. Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S91

18 lymphocytic leukaemia (Binet stages B and C) requiring therapy. J Cancer Res Clin Oncol. 2006;132(2): Niederle N, Balleisen L, Heit W, et al. Bendamustine vs fludarabine as second-line treatment for patients with chronic lymphocytic leukemia first interim results of a randomized study. Ann Oncol. 2008; 19(suppl 4):iv194. Abstract Fischer K, Cramer P, Busch R, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011; 29(26): Foon KA, Boyiadzis M, Land SR, et al. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(4): Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI Blood. 2011;117(23): Byrd JC, Furman RR, Coutre SE, et al. The Bruton s tyrosine kinase (BTK) inhibitor PCI (P) in treatment-naive (TN) chronic lymphocytic leukemia (CLL) patients (pts): Interim results of a phase Ib/II study. J Clin Oncol. 2012;30(15 suppl): Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2): Coutre SE, Byrd JC, Furman RR, et al. Phase I study of CAL- 101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110d, in patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2011;29(15 suppl): Flinn IW, Schreeder MT, Coutre SE, et al. A phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3-kinase P110, in combination with anti-cd20 monoclonal antibody therapy and/or bendamustine in patients with previously treated B-cell malignancies. J Clin Oncol. 2011;29(15 suppl): Furman RR, Barrientos JC, Sharman JP, et al. A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3K ) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL). J Clin Oncol. 2012; 30(15S):6518. S92 COMMUNITY ONCOLOGY December

19 Optimizing treatment of chronic myeloid leukemia Alfonso Quintás-Cardama, MD Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX Chronic myeloid leukemia (CML; also known as chronic myelogenous leukemia) accounts for approximately 15% of all adult cases of leukemia in the United States. 1 In 90% of cases it is caused by the activity of the oncogenic fusion gene BCR-ABL1, which is formed when an acquired reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)] creates the so-called Philadelphia chromosome. The BCR-ABL1 gene is constitutively activated and encodes a protein (BCR-ABL1) with tyrosine kinase activity that activates several intracellular signaling pathways, leading to deregulated cellular proliferation. The development of imatinib a tyrosine kinase inhibitor (TKI) has vastly improved outcomes for patients with CML; however there is still a great need for improvements in disease management. This paper focuses on 3 commonly encountered issues in the treatment of patients with CML: how to optimize initial treatment; when and why to perform mutation testing; and how to treat a patient with the T315I mutation. Correspondence: Alfonso Quintás-Cardama, MD, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX Phone: ( [email protected]). Disclosures: Dr Quintás-Cardama has received honoraria from Bristol-Myers Squibb and Novartis. Optimizing initial treatment Achieving an early response in patients with CML is desirable because it is associated with improved patient outcomes. For example, a study in patients receiving first-line imatinib therapy showed that patients with a BCR-ABL1:ABL1 transcript ratio of 1% at 3 months had a 4% chance of progression; by contrast, patients with a transcript ratio of 1% 10% at 3 months had an 11% risk of progression. 2 The risk of progression increased and the probability of achieving complete cytogenetic response (CCyR) or major molecular response (MMR) significantly decreased with each successive time point (from the start of treatment) at which the patient had not yet achieved a CCyR. 2 In other words, the achievement of an early response in patients with CML averts adverse events, including disease progression and death. Similar observations have been made by other independent groups both in patients treated with imatinib or with newer TKIs such as nilotinib or dasatinib. While imatinib is established as a first-line treatment, there is now evidence that newer TKIs may be more effective in this setting, as they produce early responses in a much higher proportion of patients. The National Comprehensive Cancer Network (NCCN) guidelines recommend the use of standard dose imatinib, nilotinib, or dasatinib as initial therapy; high-dose imatinib is not recommended as initial therapy. 1 Nilotinib is approved in the United States for the treatment of patients with newly diagnosed chronic-phase CML (CP-CML). It has higher binding affinity for ABL compared with imatinib and is at least 10- to 30-fold more potent than imatinib in inhibiting proliferation of BCR-ABLexpressing cells. 3 An ongoing phase III head-tohead study has demonstrated the superior efficacy of nilotinib compared with imatinib as first-line treatment in patients with CP-CML. 4 The Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients (ENESTnd) study compared nilotinib 300 mg twice daily (bid) with nilotinib 400 mg bid and imatinib 400 mg once daily (qd; increased to bid in the event of a suboptimal response). The MMR and CCyR rates were consistently significantly higher in patients treated with nilotinib compared with those receiving imatinib (Table 1). 4-6 The complete molecular response rates were also higher with nilotinib than with imatinib. Analysis of the molecular response at 36 months showed that molecular response 4.5 (ie, a 4.5-log reduction in BCR-ABL transcript from the Commun Oncol 2012;9:S93-S Frontline Medical Communications Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S93

20 TABLE 1 Key results of studies investigating the use of nilotinib or dasatinib vs imatinib as first-line therapy in patients with chronic myeloid leukemia 4-8 Dasatinib vs imatinib Nilotinib vs imatinib (ENESTnd), % of patients (DASISION), % of patients Outcome a Nilotinib 300 mg bid Nilotinib 400 mg bid Imatinib 400 mg qd Dasatinib 100 mg qd Imatinib 400 mg qd Major molecular response 12 months 44 b 43 b b months 71 b 67 b b months 73 b 70 b 53 Molecular response months 25 b 19 b 9 17 c 8 36 months 32 b 28 b 15 Complete cytogenetic response 12 months 80 b 78 b b months 87 c 85 d Estimated overall survival (CML-related deaths only) 24 months 97.4 (98.9) 97.8 (98.9 d ) 96.3 (96.7) months 95.1 (98.1 d ) 97.0 (98.5 d ) 94.0 (95.2) Abbreviations: bid, twice daily; CML, chronic myeloid leukemia; DASISION, Dasatinib Versus Imatinib Study in Treatment-Naive CML patients; ENESTnd, Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients study; qd, once daily. a For major molecular response (MMR), molecular response 4.5, and complete cytogenetic response, results are presented as being achieved by the time point, with the exception of 12-month MMR data for ENESTnd, which are presented at the time point. b P.001 vs imatinib. c P.01 vs imatinib. d P.05 vs imatinib. standardized baseline; % BCR-ABL IS ) was achieved in significantly more patients treated with nilotinib compared with those treated with imatinib. 4 Progression to accelerated phase/blast crisis occurred at a significantly lower rate in patients receiving nilotinib compared with those receiving imatinib: 2, 3, and 12 patients progressed by 24 months in the groups receiving nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib 400 mg qd, respectively; there were no further cases of progression at the 36-month analysis. 4,6 Taking only CML-related deaths into account, the estimated overall survival rates at 36 months were significantly higher in the nilotinib-treated groups compared with the imatinib-treated group. 4 With the limitations of a short median follow-up, data from the 36-month analysis suggested that nilotinib may also protect against the development of emerging mutations. 9 The safety analysis conducted at 12 months showed that compared with imatinib, nilotinib treatment was associated with higher rates of rash, headache, pruritus, and alopecia, but lower rates of nausea, diarrhea, vomiting, muscle spasm, and edema. 5 Grade 3/4 neutropenia and anemia were more frequent with imatinib treatment than with nilotinib treatment, while thrombocytopenia was more common in patients receiving nilotinib. 5 Good tolerability of nilotinib has been reported in elderly patients (aged 65 years) who participated in the ENESTnd study. 10 An analysis of nilotinib dosing noted that reductions can be applied in order to manage adverse events without significant loss of efficacy. 11 Physicians should, however, be aware of the black-box warnings that accompany nilotinib regarding QT interval prolongation and sudden death. 12 Another TKI approved in the United States for the treatment of newly diagnosed adults with CP-CML is dasatinib. Dasatinib has greatly increased potency against unmutated BCR-ABL compared with imatinib. 13 The phase III Dasatinib Versus Imatinib Study in Treatment- Naive CML patients (DASISION) compared dasatinib 100 mg qd with imatinib 400 mg qd. The 24-month follow-up data showed significantly improved molecular response rates compared with imatinib and fewer patients with transformation to accelerated- or blast-phase CML, however, there was no significant difference between dasatinib and imatinib with regard to overall survival (Table 1). 8 Dasatinib resulted in faster and deeper molecular responses compared with imatinib. 8 Analysis of the safety data reported during the first year of the DASISION trial showed similar adverse-event profiles for dasatinib and S94 COMMUNITY ONCOLOGY December

21 Quintás-Cardama imatinib. 7 Dose reduction to manage adverse events did not cause significant loss of efficacy. 11,14 Other TKIs in development may also prove effective for first-line treatment. For example, bosutinib a dual SRC/ABL kinase inhibitor approved for use in patients with CML with resistance or intolerance to prior therapy has been compared with imatinib in a phase III study in patients with newly diagnosed CP-CML. By 24 months of follow-up, bosutinib was as effective as imatinib in achieving a CCyR, but achieved a significantly higher MMR rate (P.019), accompanied by lower rates of disease progression and on-treatment transformation to accelerated- or blast-phase disease. 15 Bosutinib was associated with higher rates of gastrointestinal adverse events compared with imatinib, but lower rates of grade 3/4 neutropenia. Also being investigated in clinical trials is ponatinib, a TKI developed specifically to work against BCR-ABL mutations, including the T315I mutation against which neither imatinib nor the newer TKIs nilotinib and dasatinib are efficacious. Reports from the ongoing phase II Ponatinib Ph ALL and CML Evaluation (PACE) study suggest that ponatinib is effective in patients with CML resistant to or intolerant of dasatinib or nilotinib, or with the T315I mutation. 16 A phase II study of its effectiveness as a first-line treatment has recently been initiated in patients with CP- CML (ClinicalTrials.gov ID No. NCT ). The value of mutational testing A considerable proportion of patients do not achieve an optimal response with imatinib. For example, over 30% of newly diagnosed patients did not achieve an optimal response or were judged to have an unsatisfactory therapeutic response to imatinib in the 8-year follow-up to the International Randomized Study of Interferon vs ST1571 (IRIS). 17 In clinical practice, the rate of suboptimal response or treatment failure may be higher: a study in the United Kingdom reported that at 24 months of follow-up, 45% of newly diagnosed patients treated with imatinib had failed to respond adequately. 18 There are a range of possible reasons for a poor response that should be considered, including lack of patient adherence to the prescribed therapy and low serum drug levels. Another important cause is drug resistance. Approximately 50% to 90% of cases of imatinib resistance are due to mutations in the kinase domain of BCR-ABL. 19 Over 100 mutations have been detected in this protein domain in patients with CML but not all result in drug resistance. 20 Mutation testing can reveal which mutations are present and aid the physician to determine the choice of TKI or other treatment when drug resistance is suspected. When should mutation testing be performed? Both the European LeukemiaNet (ELN) and NCCN have issued guidance on mutation testing (Figure 1). 1,21 As a general rule, testing is not necessary at the time of diagnosis in patients with CP-CML; however it should be performed when there is evidence of failure to respond, suboptimal response, loss of response (as per established criteria 22 ), or progression to accelerated phase or blast crisis in patients with CP-CML treated with TKIs. Analysis should be conducted as close to the intended start of treatment as possible. A study in patients with imatinib-resistant disease who entered a trial of second-line nilotinib showed that approximately 2% of patients without known T315 mutation before study enrollment subsequently had the T315I mutation at study baseline. 23 There is some debate over the best method of mutation analysis to use in clinical practice. Although guidelines recommend direct sequencing, 21 there is evidence that more sensitive methods can detect low-level mutations that predict poor outcomes. 24 How do the mutation analysis results aid treatment choice? The impact of mutations on response to treatment varies. Depending on where the mutation occurs and what amino acid substitution it leads to, some mutations have little effect on drug sensitivity while others render the CML cells insensitive to the different TKIs to varying degrees. For example, if the T315I mutation is present, none of the currently approved TKIs will provide an adequate response and an alternative treatment approach will be required. For many mutations in particular the rarer ones the impact on response to therapy is currently unknown. In vitro studies have determined the half maximal inhibitory concentration (IC 50 ) values for TKIs with regard to some of the BCR-ABL mutations. 21,25 A study in patients with imatinib-resistant CP-CML showed that those with mutations with a low IC 50 for the second-line TKI they received had higher eventfree and overall survival rates compared with patients possessing mutations with intermediate or high IC 50 values. 26 Very frequently there is a good correlation between the in vitro data on individual mutations and the clinical response observed in patients. For example, based on IC 50 data, if the Y253H mutation is present in a sample of a patient s cells, it can be expected that their disease will be resistant to imatinib and nilotinib but may respond to dasatinib. 21 This is supported by clinical data: 61% of patients carrying the Y253H mu- Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S95

22 FIGURE 1 Summary of mutation analysis recommendations in patients with chronic myeloid leukemia. Abbreviations: CCA/Ph, appearance of clonal chromosomal abnormalities in the Philadelphia chromosome-positive clone as detected by chromosome banding analysis; CCyR, complete cytogenetic response; CHR, complete hematologic response; CP, chronic phase; CyR, cytogenetic response; MCyR, major cytogenetic response; MMR, major molecular response; PCyR partial cytogenetic response. a Hematologic or cytogenetic relapse or 1 log increase in BCR-ABL transcript levels and loss of MMR; disease progression. tation achieved a CCyR as best response to dasatinib treatment in a 2-year period, but in a separate study none of the patients with this mutation who were treated with nilotinib for 12 months achieved a CCyR. 23,27 Conversely, IC 50 data predict that the presence of F317L or V299L will markedly impair the activity of dasatinib, and indeed a low response rate has been observed in clinical studies of dasatinib in patients carrying F317L or V299L mutations. 27 In vitro IC 50 data do not tell the whole story and there are other factors that need to be taken into consideration when choosing a TKI, notably those affecting the pharmacokinetic profile of the drugs, such as differences in how the drugs interact with food and with other drugs, as well as patient comorbidities. 19,25 Based on clinical evidence, current guidelines recommend certain treatment options depending on the presence of some of the better defined mutations (Figure 2). 21 It should be remembered, however, that patients can have more than one mutation in the same clone or in different clones. Patients with more than one mutation tend to have poorer responses to second-line TKI therapy and shorter survival times. 28 FIGURE 2 Flow chart showing treatment options depending on mutations present, based on European LeukemiaNet recommendations. 21 Abbreviation: HSCT, hematopoietic stem cell transplantation. What are the pharmacological options for patients with the T315I mutation? Patients with the T315I mutation are not suitable for a second-line TKI treatment. In clinical practice it has been reported that T315I was detected in 14% of imatinibtreated patients who had mutations (7.5% of those with CP-CML), and it was the most commonly detected mu- S96 COMMUNITY ONCOLOGY December

23 Quintás-Cardama tation, accounting for almost 11% of all mutations detected. 29 For patients known to have T315I-positive CML, current guidelines recommend allogeneic stem cell transplantation or drugs in development. Indeed, a major avenue of research in the area of CML treatment is to identify drugs that are active even in the presence of the T315I mutation. Ponatinib has been developed with the aim of retaining activity in the presence of a range of BCR-ABL mutations, including the T315I mutation. Data from phase I and II trials have shown good responses to ponatinib in heavily pretreated patients. 16,30 In the phase II PACE trial, after a median follow-up of 6.6 months, a major cytogenetic response (MCyR) was achieved in 62% of patients with CP-CML who had the T315I mutation, a CCyR was seen in 57%, and an MMR in 47%. 16 Responses were also encouraging in patients with T315I-positive acceleratedphase or blast-crisis CML. In those with acceleratedphase CML, major hematologic response (MHR), MCyR, and CCyR was achieved in 50%, 53%, and 24%, respectively; in patients with blast-crisis CML, the MHR, MCyR, and CCyR rates were 37%, 39%, and 29%, respectively. 16 Initial reports (median follow-up 57 days) from the PACE trial identified the most common drug-related serious adverse events associated with ponatinib as pancreatitis (3.7%), diarrhea, anemia, febrile neutropenia, and pyrexia (each 1.2%). 31 At a median follow-up of 6.6 months, thrombocytopenia and rash were the most commonly reported drug-related adverse events (each reported in 33% of patients). 16 An alternative approach to treating CML via inhibition of tyrosine kinase activity is to target aurora kinases. A number of aurora kinase inhibitors are being evaluated, with the expectation that their activity will not be affected by the presence of BCR-ABL mutations. One such agent is danusertib, an aurora kinase inhibitor that also binds with high affinity to BCR-ABL, including BCR-ABL with the T315I mutation. Preliminary results of a phase I study in patients with advanced CML or Philadelphiapositive acute lymphoblastic leukemia who were resistant to imatinib and/or newer TKIs (including patients with the T315I mutation) demonstrated clinical responses in 6 of 14 patients; further results are awaited. 32 Other aurora kinases, AT9283 and KW-2449, have also shown some activity in phase I studies in patients with the T315I mutation. 33,34 In addition to the development of new agents, attention has returned to older drugs that were used before the advent of TKIs. One such is interferon- (IFN- ). In the 1980s and early 1990s, before the development of TKIs, IFN- was considered the standard first-line therapy for CML, with the potential to provide long-term event-free survival in a small proportion of patients. 35 More recently there have been reports that IFN- or pegylated IFN- combined with TKIs may be effective in combating T315I-positive CML. 36,37 A phase I/II study investigating the use of pegylated IFN- 2a combined with imatinib in imatinib-resistant patients has demonstrated promising results, with 93% patient survival after a median follow-up of 43 months. 38 Another older drug receiving renewed interest is omacetaxine mepesuccinate ( omacetaxine ) a semisynthetic formulation of homoharringtonine. Omacetaxine is a subcutaneously administered, first-in-class cephalotaxine alkaloid. It acts independently of BCR-ABL, and its activity is therefore not compromised by mutations in BCR-ABL. Preliminary data from a phase II/III study have demonstrated the effectiveness of omacetaxine in patients with imatinib-resistant T315I-positive CML. 39 In patients with CP-CML a reduction in baseline T315Imutated BCR-ABL occurred in 56.7% of patients; the overall cytogenetic response rate was 27.5% and the MCyR rate was 15.0%. Another study in TKI-resistant patients with the T315I mutation has reported a complete hematologic response rate of 76%, an MCyR rate of 24%, and a 24-month survival rate of 65.2%. 40 Case histories and smaller studies have also noted the disappearance of BCR-ABL carrying the T315I mutation following omacetaxine treatment. 41,42 There is some evidence to support its use in combination with TKIs and it has been suggested that treatment with omacetaxine following resistance to a TKI may allow rechallenge with a TKI. 41,43,44 An analysis of pooled data from 3 studies of omacetaxine demonstrated an acceptable safety profile, with thrombocytopenia being the most commonly reported adverse event: 52% of patients experienced treatment-related grade 3/4 thrombocytopenia. 45 In the United States, ponatinib, danusertib, AT9283, and KW-2449 are not currently approved for use, although ponatinib is currently under review by the Food and Drug Administration; IFN- 2a is indicated for treatment of Philadelphia-positive CP-CML in patients who have been minimally pretreated; pegylated IFN- is not indicated for use in CML; omacetaxine is approved for the treatment of adult patients with chronic- or acceleratedphase CML with resistance and/or intolerance to two or more TKIs. Conclusions Recent advances in drug development and our understanding of the impact of BCR-ABL mutations have greatly increased the potential for long-term remission in patients with CML. Such advances should be implemented in clinical practice, in accordance with evidence- Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S97

24 based guidelines such as those issued by the ELN or the NCCN. Acknowledgment Medical writing support was provided by Julie Ponting of Anthemis Consulting Ltd, funded by Teva Pharmaceuticals, Frazer, PA. Teva provided a single medical accuracy review of the final draft. The author was not compensated and retained full editorial control over the content of the paper. References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. Version (NCCN Guidelines ). physician_gls/pdf/cml.pdf. Published July Accessed August 17, Quintás-Cardama A, Kantarjian H, Jones D, et al. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood. 2009;113(25): Jabbour E, Cortes J, Kantarjian H. Nilotinib for the treatment of chronic myeloid leukemia: an evidence-based review. Core Evid. 2010; 4: Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year followup. Leukemia. 2012;26(10): Saglio G, Kim DW, Issaragrisil S, et al; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24): Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial [published correction appears in Lancet Oncol. 2011;12(11):989]. Lancet Oncol. 2011;12(9): Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. 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25 Quintás-Cardama 31. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al; the PACE Study Group. Initial findings from the PACE trial: A pivotal Phase 2 study of ponatinib in patients with CML and Ph ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Blood (ASH Annual Meeting Abstracts). 2011;118(21): Cortes-Franco J, Dombret H, Schafhausen P, et al. Danusertib hydrochloride (PHA ), a multi-kinase aurora inhibitor, elicits clinical benefit in advanced chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. Blood (ASH Annual Meeting Abstracts). 2009;114(22): Cortes J, Roboz GJ, Kantarjian HM, et al. A phase I dose escalation study of KW-2449, an oral multi-kinase inhibitor against FLT3, Abl, FGFR1 and aurora in patients with relapsed/refractory AML, ALL and MDS or resistant/intolerant CML. Blood (ASH Annual Meeting Abstracts). 2008;112(11): Foran JM, Ravandi F, O Brien SM, et al. Phase I and pharmacodynamic trial of AT9283, an aurora kinase inhibitor, in patients with refractory leukemia. J Clin Oncol. 2008;26(15 Suppl): Kantarjian HM, O Brien S, Cortes JE, et al. Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis. Cancer. 2003;97(4): Cornelison AM, Welch MA, Koller C, et al. Dasatinib combined with interferon-alfa induces a complete cytogenetic response and major molecular response in a patient with chronic myelogenous leukemia harboring the T315I BCR-ABL1 mutation. Clin Lymphoma Myeloma Leuk. 2011;11(suppl 1):S111-S Itonaga H, Tsushima H, Hata T, et al. Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa. Int J Hematol. 2012;95(2): Nicolini FE, Hayette S, Legros L, et al. Pegylated IFN-alpha2a combined to imatinib mesylate 600mg daily can induce complete cytogenetic and molecular responses in a subset of chronic phase CML patients refractory to IFN alone or to imatinib 600mg daily alone. Leuk Res. 2011;35(1): Cortes-Franco J, Khoury HJ, Nicolini FE, et al. Safety and efficacy of subcutaneous-administered omacetaxine mepesuccinate in imatinibresistant chronic myeloid leukemia (CML) patients who harbor the Bcr- Abl T315I mutation results of an ongoing multicenter phase 2/3 study. Blood (ASH Annual Meeting Abstracts). 2009;114(22): Nanda N, Cortes C, Lipton J, et al. Treatment of chronic phase (CP) chronic myeloid leukemia (CML) patients who harbour the BCR- ABL T315I mutation with subcutaneous omacetaxine results in improved survival compared to historical data. Haematologica. 2011; 96(suppl 2):422. Abstract Coude MM, Luycx O, Cariou ME, et al. Undetectable molecular residual disease after omacetaxine and nilotinib combination therapy in an imatinib-resistant chronic myeloid leukaemia patient harbouring the BCR-ABL1 T315I gatekeeper mutation. Br J Haematol. 2012; 157(3): Nicolini F, Legros L, Roy L, et al. Homo-harringtonine (omacetaxine mepesuccinate) induces a dramatic and sustained reduction of BCR-ABL T315I mutated transcripts in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors. Blood (ASH Annual Meeting Abstracts). 2008;112(11): Marin D, Kaeda JS, Andreasson C, et al. Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib. Cancer. 2005;103(9): Nicolini FE, Chomel JC, Roy L, et al. The durable clearance of the T315I BCR-ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallenge. Clin Lymphoma Myeloma Leuk. 2010; 10(5): Wetzler M, Kantarjian H, Nicolini FE, et al. Pooled safety analysis of omacetaxine mepesuccinate in patients with chronic myeloid leukemia (CML) resistant to tyrosine-kinase inhibitors (TKIs). J Clin Oncol. 2012;30(15 suppl):6604. Volume 9/Number 12S December 2012 COMMUNITY ONCOLOGY S99

26 December 2012 VOLUME 9, NUMBER 12S Information for Authors and Advertisers Aims and Scope COMMUNITY ONCOLOGY is an independent journal that publishes peerreviewed research, review articles and commentary on all aspects of clinical oncology practice. Article types include original clinical studies in practice-based settings, state-of-the-art review papers, peer viewpoints, commentaries, and letters to the editor. For a full and complete guide for authors, go to ees.elsevier.com/co/ For further information, contact the Managing Editor, Renée Matthews, at or , [email protected]. Correspondence For general, noneditorial enquiries, write to COMMUNITY ONCOLOGY, 7 Century Drive, Suite 302, Parsippany, NJ Letters to the Editor should be addressed to the Editor-in-Chief, David H. Henry, MD, FACP, [email protected]. Advertising For information regarding advertising rates, contact Peter Murphy (tel: ; [email protected]) or Stuart Williams (tel: ; [email protected]); for information regarding supplements and projects, contact Devin Gregorie (tel: ; [email protected]). CME Supplements For information on CME supplements to COMMUNITY ONCOLOGY, contact Sylvia Reitman of Global Academy for Medical Education, LLC, at [email protected]. Annual Subscription Rates For 12 issues (in US$): Individual $380, Canada $413, International $413; Institutional $380, Canada $413, International, $413; Single copy $45. For further information regarding subscriptions, contact Subscription Inquiry Line COMMUNITY ONCOLOGY (ISSN ) is published monthly by Frontline Medical Communications Inc, 7 Century Drive, Suite 302, Parsippany, NJ Copyright Copyright 2012 by Frontline Medical Communications Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission from the Publisher. Disclaimer Discussions, views, opinions, and recommendations as to medical procedures, products, choice of drugs, and drug dosages are the responsibility of the authors or advertisers. No responsibility is assumed by the Publisher, Editor, or Editorial Board for any injury and/or damage to persons or property as a matter of product liability, negligence, or otherwise or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of rapid advances in the medical sciences, independent verification of diagnoses and drug dosages should be made. Advertiser and advertising agency recognize, accept, and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed and also assume responsibility for any claims made against the Publisher arising from or related to such advertisements. In the event that legal action or a claim is made against the Publisher arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the Publisher and to pay any judgment, expenses, and legal fees incurred by the Publisher as a result of said legal action or claim. The Publisher reserves the right to reject any advertising that he feels is not in keeping with the publication s standards. The Publisher is not liable for delays in delivery and/or nondelivery in the event of Act of God, action by any government or quasigovernmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slowdown, or any condition beyond the control of the Publisher that affects production or delivery in any manner. This journal is printed on paper meeting the requirements of ANSI/ NISO Z (Permanence of Paper) effective with Volume 1, Issue 1, Community Oncology is indexed by EMBASE and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) S100 COMMUNITY ONCOLOGY December