Decision Making in CML 2010

Transcription

1 Decision Making in CML 2010 Imatinib is the standard treatment for chronic myeloid leukaemia (CML), but approximately 25% of patients are resistant or non-responsive to imatinib. 1 While physicians have previously escalated the imatinib dose in suboptimal responders, there is an emerging consensus that switching to a second-generation tyrosine kinase inhibitor (TKI) at the first sign of suboptimal response may be a better strategy. In the Asian setting, escalating the dose is often problematic because of toxicities, so alternative strategies could be particularly relevant for Asian patients. The CML landscape is changing rapidly and recent trials demonstrating superiority of second-generation agents over imatinib in first-line use 2,3 are set to further revolutionize treatment of this disease. The Decision Making in CML 2010 meeting brought together experts from Hong Kong, Canada, Australia and Italy to update oncologists on these exciting developments. SESSION 1: TKIs IN CML THERAPY Newly diagnosed CML patients: Are we ready to move beyond imatinib? Michael Copeman Visiting Oncologist, Northern Beaches Cancer Service, Sydney, Australia The International Randomized Study of Interferon and STI571 (IRIS) trial is the cornerstone study for imatinib, and has now reached over 8 years of follow-up. 4 More than half of the patients remain on imatinib, and after 8 years, the event-free survival (EFS) rate is 81% and overall survival is 85%. The major molecular response (; <0.1% BCR-ABL/control gene ratio on international scale [IS]) rate is 86%. Factors predicting success on imatinib Dr Copeman noted three factors that predict a patient s success on imatinib: Trough imatinib level over 1,000 ng/ml. Low trough levels make molecular response less likely; however, more adverse events occur if the trough is above 2,000 ng/ml. 5 Patient adherence to therapy. Non-adherence after complete cytogenetic response to imatinib is common and has a critical effect on a patient s chance of achieving (28% in non-adherent patients vs 95% in adherent patients; p<0.0001)(figure 1). 6 This should be stressed to patients and families. Adherence is lower in younger patients, those taking concomitant medications, and those with a higher co-payment. 7 No patient who achieved by 12 months and remained on imatinib subsequently progressed... in the next 7 years achieved by 1 year. No patient who achieved by 12 months and remained on imatinib subsequently progressed to advanced phase/blast crisis (AP/BC) CML in the next 7 years. 4 Conversely, predictors of treatment failure include a high Sokal score, frequent dose interruptions (particularly >2 weeks), and inability to maintain a trough level associated with a 400-mg dose. 5 Evolving strategies in first-line CML Several strategies have been investigated to improve upon results with imatinib in first-line treatment of CML, including imatinib dose escalation, combination therapy with interferon (IFN) and use of second-generation TKIs. Dose escalation A trial starting patients on 600 mg/day and escalating to 800 mg/day in cases of suboptimal response found superior 5-year EFS in patients maintaining doses 600 mg compared with those who had been dose-reduced to <600 mg (89% vs 56%; p<0.001). 8 However, only 55% of patients were able to maintain a dose >600 mg throughout the first year. Another trial explored an imatinib starting dose of 800 mg compared with the usual 400 mg. 9 The 800-mg dose did not Figure 1. Non-adherence has a critical effect on a patient s chance of achieving 6 Chance of achieving (%) , major molecular response Non-adherent Adherent

2 result in better outcomes up to 24 months, and was associated with more dose interruptions and more discontinuations due to toxicities. Clearly, alternative strategies with fewer side effects are needed for first-line CML patients. Figure 2. Hong Kong imatinib outcomes after a median follow-up of 61 months Hong Kong patients on imatinib Combination therapy with IFN Three studies have investigated imatinib high- or standard-dose with standard-dose plus IFN While the SPIRIT trial showed some advantage with added pegylated IFN, the associated toxicities are very limiting. 12 Less than half of the patients taking combination therapy remained on IFN at 12 months, 11,12 and Dr Copeman commented that adding IFN back into the equation may not be the best answer to improving response rates to imatinib. 72% 17% 8% 3% Still on imatinib Switched to nilotinib Bone marrow transplant Died (unrelated causes) Use of second-generation TKIs Recent studies of second-generation TKIs in first-line therapy have demonstrated superiority over imatinib. 2,3 The results for nilotinib were discussed by Professor Saglio in the final presentation of the day. Genetic factors influencing imatinib response Several genes are linked to a lower imatinib response, including those encoding the transporter hoct1 and its regulator, HNF4A; drug pumps BCRP (ABCG2) and MDR (ABCB1); and markers involved in DNA repair, ERCC5 and XRCC Unlike imatinib, nilotinib is not affected by hoct1 or ABCB1, and is less affected by ABCG2. 16 These characteristics may prove to be an advantage. Dr Copeman concluded that, currently, imatinib retains its position as a valuable first-line CML therapy because of its unsurpassed long-term efficacy and safety. Once mature data from phase III trials of second-generation TKIs are available, decisions about a new first-line drug can be made. Outcomes of CML patients on TKIs: The Hong Kong experience Yok-Lam Kwong Professor, Division of Haematology/Oncology and Bone Marrow Transplantation, Department of Medicine, The University of Hong Kong, Hong Kong Professor Kwong presented data on all CML patients in Hong Kong treated with imatinib since it became available in He noted that imatinib dose escalation could be difficult in Hong Kong because a subsidized patient who started on 400 mg could not be changed to 600 mg without government approval. As of May 2010, 157 CML patients have been treated with imatinib in Hong Kong. Of the 103 chronic-phase CML patients, 91 have remained in chronic phase, 10 relapsed as chronic phase after bone marrow transplantation (BMT) and two cases were re-induced to chronic phase after blast crisis. Treatment outcomes after a median follow-up of 61 months are given in Figure 2. Of those switching to nilotinib, half later switched again to dasatinib. Hong Kong results with imatinib are congruent with results reported in the international literature, and the use of second- generation TKIs in the first-line setting is now being explored in clinical trials. Haematopoietic stem cell transplantation still has a minor role to play in the management of advanced CML. SESSION 2: MANAGEMENT AND MONITORING OF CML CML patients resistant/intolerant to imatinib: The recommended approach to management Pierre Laneuville Associate Professor, Department of Medicine and Oncology, McGill University, Montreal, Canada Switching to a second-generation TKI is appropriate when patients experience intolerance to imatinib, suboptimal response to imatinib or imatinib failure. 17 Dr Laneuville stated that while dose escalation was a useful option in the past, better alternatives are now available. While dose escalation was a useful option in the past, better alternatives are now available Choices of second-generation TKI Second-generation TKIs are much more potent than imatinib. Dasatinib is a dual ABL and Src inhibitor (with Src as its first target), whereas nilotinib s first target is BCR-ABL. Bosutinib is distinguished by its lack of Kit inhibition. Efficacy There are no randomized head-to-head comparisons of nilotinib and dasatinib. Their pivotal studies had different eligibility criteria, and these differences make direct comparisons of response rates problematic. However, Dr Laneuville commented that overall efficacy appeared similar for the two drugs. They do have different toxicities and these, along with any clinically meaningful mutations an individual patient may have, should drive therapy selection for patients (Table 1).

3 Table 1. Comparison of relative toxicities of TKIs Imatinib (STI571) Gleevec Nilotinib (AMN 107) Tasigna Dasatinib (BMS ) Sprycel Bosutinib (SK606) Haematologic Pleural effusion Hepatic Pancreatitis Hyperglycaemia GI Bleeding Platelet function ? Immune ? Diarrhoea QTc prolongation ? GI, gastrointestinal; TKI, tyrosine kinase inhibitor Toxicities The most common Grade 3 or 4 adverse events (AEs) are haematologic for both dasatinib and nilotinib, but the incidence is approximately two-fold higher for dasatinib than nilotinib. 18 Rates of Grade 3 or 4 non-haematologic AEs, such as pleural effusion, gastrointestinal bleeding, arrhythmia and pneumonia/infection, were >2 7 times higher for dasatinib than nilotinib, although they occurred in <5% of the population. 18 While pancreatitis and hyperglycaemia occur more often with nilotinib, the reported incidence is very small and leads to discontinuation in only 0.2% and 0.1% of patients, respectively. 19 While there is a perception that nilotinib is more cardiotoxic than dasatinib, the only cardiac event associated with nilotinib is QTc prolongation. 20 In a cohort of 1,793 patients, only 0.3% experienced QTc prolongation. 19 Dr Laneuville highlighted that while care should be taken in patients with cardiac risk factors, doctors do not need to be more cautious with nilotinib than dasatinib with regard to cardiac safety. Cross intolerance When patients are intolerant to imatinib, they usually do better if switched to nilotinib rather than trying to continue with imatinib and manage the side effects. Only 1% of patients with nonhaematologic imatinib intolerance experienced a recurrence of similar grade 3 or 4 AEs during nilotinib therapy. 21 As imatinib is a long-term therapy, intolerance may continue for years and it is better for the patient to switch to a drug that does not cause them problematic side effects. Mutations There are a number of clinically significant mutations that are relevant when choosing a TKI for patients (Table 2). However, most resistant chronic-phase patients do not have mutations, 22 and compliance (presenting as apparent resistance) is a more frequent issue in clinical practice. Dr Laneuville argued that the importance of mutations has been over-emphasized. He stressed that in vitro data on sensitivities of mutations to various drugs are not as relevant for clinicians as in vivo data on actual patient response. There is a poor correlation between clinical responses to both nilotinib and dasatinib and several of the mutations in vivo. 23 Dr Laneuville urged physicians to base their treatment decisions on clinical data when deciding whether or not to switch a patient with mutations. Table 2. Clinically relevant mutations in TKI therapy (courtesy of Dr Pierre Laneuville) Imatinib Nilotinib Dasatinib Bosutinib T315I T315I T315I T315I >100 other E255K/V F317L/I/S/V E255K mutations Y253H V299L V299L F359C/V TKI, tyrosine kinase inhibitor Monitoring of CML patients on TKIs: Current recommendations of the ELN Gianantonio Rosti Institute of Hematology and Clinical Oncology Seràgnoli University of Bologna, Bologna, Italy Dr Rosti discussed changes in the most recent update of the European LeukemiaNet (ELN) CML recommendations, including changes in response definitions (Table 3). 17 Following these recommendations ensures close monitoring of patient response and allows for timely decision making in the course of this potentially fatal disease. The most important difference is the emphasis on an earlier response to imatinib. Now that second-generation TKIs are available, suboptimal responses should be handled with closer monitoring given the availability of new treatment strategies. Table 3. Current ELN response definitions 17 (changes from the previous version are highlighted in red text) ELN Recommendations-Response Definition 2009 Optimal response Suboptimal response Failure Warnings Baseline NA NA NA - High risk - CCA/Ph Any time - CHR, and - At least minor CyR (Ph+ 65%) - At least PCyR (Ph+<35%) - No CyR (Ph+>95%) PCyR (Ph+>35%) - CCyR - PCyR (Ph+ 35%) - - Stable or improving - Loss of - Mutations* CHR - No CyR (Ph+>95%) PCyR (Ph+>35%) CCyR - Loss of CHR - Loss of CCyR - Mutations ** - CCA/Ph+ NA NA NA - Any rise in transcripts level - CCA/Ph- * Low level of insensitivity of imatinib / ** highly insensitive to imatinib ELN, European LeukemiaNet; CCA/Ph-, clonal chromosome abnormalities in Ph-negative cells; CCA/ Ph+, clonal chromosome abnormalities in Ph-positive cells; CCyR, complete cytogenetic response; CyR, cytogenetic response; CHR, complete haematologic response;, major molecular response; NA, not applicable; PCyR, partial cytogenetic response; Ph+, Philadelphia chromosome-positive.

4 Second-generation TKIs are a recommended second-line therapy for patients who are imatinib-intolerant or who have a suboptimal or failed response. 17 Monitoring response Cytogenetic testing is recommended at 3 and 6 months, and then at least every 6 months until a complete cytogenetic response (CCyR) has been achieved. Testing should then be repeated at least every 12 months. Molecular testing is recommended every 3 months until has been confirmed, and then repeated at least every 6 months. If test results are borderline between one category and another, or not congruent, they should be checked again before treatment plans are altered. Patients who achieve early molecular responses are more likely to achieve durable cytogenetic responses and are less likely to experience disease progression. 24 In addition, monitoring BCR- ABL transcript levels may also provide an early indication of loss of response. 24 Patients who achieve early molecular responses are more likely to achieve durable cytogenetic responses and are less likely to experience disease progression Addressing suboptimal response Fortunately, relatively few patients have suboptimal responses. 25 However, as these patients have significantly worse outcomes than optimally responding patients, 25 early identification and a change in treatment is vital. Dr Rosti advised that, in general, switching to a second-generation TKI is a better strategy for suboptimal responders than imatinib dose escalation. Molecular monitoring of CML in Hong Kong Edmond Ma Director, Clinical Pathology and Molecular Pathology, Specialist in Haematology, Hong Kong Sanatorium & Hospital (HKS&H), Hong Kong Hong Kong has four molecular testing laboratories, and all are standardized and participate in quality control programmes. Quality control is important because reverse transcription polymerase chain reaction (RT-PCR) is not as precise an assay as clinicians may think, and a significant degree of measurement uncertainty exists in each result. Therefore, clinicians using molecular monitoring should not place too much emphasis on a change in level that is less than their laboratory s level of significant increase ; instead, the test should be repeated to document result consistency or otherwise. Local mutation results Of 60 requests for kinase domain mutation testing for patients with poor response or advanced disease, 23 (38.3%) were found to have mutations (Table 4). The most common mutations were F317L and T315I. Table 4. Mutations identified at the HKS&H laboratory Spectrum of ABL kinase domain mutation seen at HKS&H Found in 23 out of 60 (38.3%) P-loop mutations = 14 up to early April M244V = 4 Double mutation = 5; triple = 1 - L248V = 2 (i.e. total 30 mutations) - G250E = 1 - Y253F/H = 2 - E255K = 4 - E255V = 1 E279K = 1 T315I = 5 F317L = 6 M351T = 1 F359V/C = 3 HKS&H, Hong Kong Sanatorium & Hospital Mutations and response to second-generation TKIs A local study has investigated BCR-ABL kinase domain mutational status in 25 patients who failed imatinib, and its effect on response to second-generation TKIs. 26 Forty-eight percent of these patients had kinase domain point mutations, the most frequent being E255K. They also noted that discordance between projected response based on in vitro drug sensitivity and actual in vivo response was not uncommon. Standardization collaborations The International Scale (IS) for reporting BCR-ABL transcript levels has been introduced to standardize practice and facilitate communication between different laboratories. On the IS, 100% represents the baseline level as established in the IRIS trial, and 0.1% represents a 3-log reduction from baseline (ie, ). 27 Dr Ma noted that the conversion factor of a laboratory may change over time as a result of personnel changes, instrumentation changes or reagent changes. To help overcome these and other problems, and to propagate assay standardization, the HKS&H has participated in a project to develop reference materials with assigned IS values corresponding approximately to 10%, 1%, 0.1% and 0.01% IS, respectively. These materials are now approved by the World Health Organization and available for the calibration of secondary reference agents. 28 CML therapy with TKIs: What is the endpoint? Gianantonio Rosti Institute of Hematology and Clinical Oncology Seràgnoli University of Bologna, Bologna, Italy A consensus is emerging that, in the future, (<0.1% IS) will replace CCyR as the primary therapeutic endpoint for patients with newly diagnosed CML. At present, issues with standardization and assay costs mean that this has not yet occurred. Currently, molecular response levels are not incorporated into ELN definitions of response in the first 12 months of treatment. Although this may change in the future, CCyR remains the most important measure of response in the first 12 months.

5 will replace CCyR as the primary therapeutic endpoint in CML Current issues with molecular monitoring While enormous efforts are being made to standardize across laboratories, not all laboratories have gone through the process of determining their conversion factors for the IS. Dr Rosti questioned if setting the level for an at <0.1% was too strict, as patients with levels of <1% also have good clinical outcomes. Given that the level of residual disease fluctuates, a range for may be more clinically relevant than a single cutoff. Fluctuations that do not involve loss of are not clinically relevant. The definition of a complete molecular response (CMR) is undetectable BCR-ABL transcripts. However, the limit of detection is highly variable and can range from 0 to 10 7 leukaemic cells depending on the quality of the RNA and the efficiency of the reverse transcription reaction. 29 Dr Rosti suggested that was a more important measure than CMR, as it is currently unknown if CMR has prognostic significance. Can TKI treatment be stopped? The question of whether treatment can be stopped has been investigated in 50 patients with a 2-year CMR (STIM study). 30 Relapses occurred in 38% (mostly within 6 months of stopping treatment), but 62% maintained their CMR after ceasing imatinib. 30 The role of IFN pre-treatment in maintaining CMR after imatinib cessation is not yet clear. SESSION 3: THE FUTURE OF CML THERAPY Practical approaches to selecting second-generation TKIs Michael Copeman Visiting Oncologist, Northern Beaches Cancer Service, Sydney, Australia Dr Copeman outlined some factors assisting in TKI choice in clinical practice (Table 5). Drug selection is based primarily on the suitability of the side-effect profile for the individual patient, as discussed by Dr Laneuville. For example, if a patient has cytopenia, bosutinib is the best choice; if a patient has pancreatitis, dasatinib or bosutinib could be used; whereas if a patient has irritable bowel syndrome, nilotinib would be the drug of choice. Drug selection is based primarily on the suitability of the side-effect profile for the individual patient Table 5. Factors influencing the choice of secondgeneration TKI In favour of dasatinib Evidence of early disease transformation to accelerated phase/blast crisis Unstable diabetes mellitus Metabolic syndrome requiring to avoid fasting History of pancreatitis or biliary tract disorder History of poor compliance Nilotinib-resistant mutation TKI, tyrosine kinase inhibitor In favour of nilotinib Persistent haematologic toxicity while on imatinib Pulmonary disease Cardiac disease Peptic ulceration Bleeding disorder Immune deficiency History of autoimmunity Dasatinib-resistant mutation Food-related factors can have a significant effect on TKI levels. While imatinib should be taken with meals, nilotinib should be taken on an empty stomach, as its concentrations (and associated toxicities) increase significantly with food. Dasatinib requires an acidic environment for optimal absorption and, thus, long-acting antacids decrease systemic exposure to this drug. 31 One strategy to improve dasatinib intolerance has been to move to intermittent dosing. Dr Copeman questioned if intermittent BCR-ABL kinase inhibition was as effective as continuous inhibition, as once-daily dasatinib dosing results in a pronounced peak that allows for complete recovery of BCR-ABL kinase activity within 8 to 12 hours after a daily dose. 32 Dr Copeman speculated that this may promote genomic damage and transformation, and may lead to fewer CMRs over time with an intermittent schedule. For nilotinib, most Grade 3 or 4 AEs occur in the first 50 days and last between 1 and 3 weeks; they can usually be managed by temporary treatment interruption or dose adjustment, and infrequently lead to permanent discontinuation of nilotinib. 33 Practice points Dr Copeman offered some useful practice points on the use of TKIs: CYP3A4 inducers (eg, rifampicin, carbamazepine) may reduce TKI levels by 80%, abolishing their efficacy Strong CYP3A4 inhibitors (eg, ketoconazole, diltiazem) increase TKI levels five-fold, inducing toxicity In a CML-AP/BC patient on a second-generation TKI, failure to achieve complete haematologic response (CHR) with a major cytogenetic response is associated with poor prognosis. 34 In the absence of a quick response to a secondgeneration TKI, always consider other therapies such as BMT Dose optimization of second-generation TKIs: Nilotinib 400 mg twice daily is effective and well tolerated. The dose should not be increased, but can be reduced to 400 mg once daily in cases of persistent toxicity. Dasatinib 100 mg/day for CP-CML and dasatinib 140 mg/day for CML-AP/BC are both effective, but toxicity often requires a dose reduction to 70 or 50 mg/day. Twice-daily dosing results in much higher levels of second-generation TKIs than the equivalent dose given once daily, because TKIs limit their own absorption and hepatic metabolism. The choice of second-line therapy for CML depends on individual patient characteristics. Nilotinib is emerging as the best tolerated second-generation TKI for chronic-phase CML, and may soon move to first-line therapy.

6 Figure 3. rates over time (ITT) in the ENESTnd trial 2 Major molecular response () ((%) ITT, intention-to-treat population Nilotinib 300 mg Nilotinib 400 mg Imatinib Month p<0.001 p< Figure 4. Patients on first-line nilotinib were significantly less likely to experience disease progression 2 Number of patients with event a 1 b a p= b p= Accelerated phase/ Blast crisis Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Navigating the future of CML Giuseppe Saglio Director, Division of Internal Medicine and Haematology, San Luigi Hospital, University of Turin, Orbassano-Torino, Italy Professor Saglio presented exciting results from the ongoing Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients (ENESTnd) trial. 2 This is an international, randomized, phase III trial of nilotinib versus imatinib used first-line in patients with newly diagnosed, chronic phase CML. A unique feature of the ENESTnd trial is that a lower dose of nilotinib (300 mg twice daily) is also being trialled along with 400 mg twice daily (versus imatinib 400 mg once daily) to explore the relative efficacy and tolerability of this dose. Patient characteristics in all three arms were well balanced at baseline, and Professor Saglio noted the high percentage of high Sokal risk patients in each arm (28%). Efficacy results At 12 months, both nilotinib arms demonstrated double the rate seen with imatinib (p<0.001)(figure 3). Both nilotinib groups achieved and CCyR milestones faster than the imatinib group, and by 12 months both nilotinib groups had superior CCyR results (80% for 300 mg twice daily and 78% for 400 mg twice daily, vs 65% for imatinib-treated patients; p<0.001 At 12 months, both nilotinib arms demonstrated double the rate seen with imatinib for both comparisons). 2,35 Higher rates were seen with nilotinib across all Sokal risk groups. Nilotinib also improved disease control compared with imatinib (Figure 4). Time to progression to either accelerated phase or blast crisis was significantly slower in the nilotinib groups (p=0.01 for 300 mg twice daily; p=0.004 for 400 mg twice daily). At a median of 14 months follow-up, less than 1% of nilotinibtreated patients had progressive disease, compared with 4% of imatinib-treated patients. 2 Tolerability results The 300-mg twice-daily regimen of nilotinib had the lowest rates of discontinuation due to adverse events. Gastrointestinal and fluidretention events were more common in imatinib-treated patients, whereas dermatological events and headache were more frequent in nilotinib-treated patients. 2 Patients were closely monitored for QTc prolongation and changes in left ventricular ejection fraction. No patient in any group had a QT interval corrected for heart rate (QTcF) of more than 500 ms. 2 This trial has clearly established that nilotinib is more effective than imatinib in terms of, CCyR and disease-progression endpoints. Based on these results, nilotinib may become the new standard of care in newly diagnosed CML. If second-generation TKIs are registered for first-line use, doctors will have a different set of decisions to make. Should second-generation TKIs be used for all patients immediately, or only for subgroups of higher-risk patients (high Sokal scores, or mutations associated with suboptimal response)? Should imatinib 400 mg continue to be the first-line therapy, but with switching occurring as soon as a suboptimal response is seen (3 or 6 months)? Definitive answers to these questions will only come in time as the data mature. References 1. Apperley JF. Lancet Oncol 2007;8: Saglio G, et al. N Engl J Med 2010;362: Kantarjian H, et al. 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Blood (ASH Annual Meeting Abstracts) 2009;114:Abstract Fava C, et al. Blood 2009;113: Saglio G, et al. N Engl J Med 2010 Jun 5; Supplementary appendix [Epub ahead of print]. Sponsored as a service to the medical profession by Novartis. Editorial development by CMPMedica. The opinions expressed in this publication are not necessarily those of the editor, publisher or sponsor. Any liability or obligation for loss or damage howsoever arising is hereby disclaimed CMPMedica. All rights reserved. No part of this publication may be reproduced by any process in any language without the written permission of the publisher. CMPMedica Pacific Ltd 27th Floor, OTB Building, 160 Gloucester Road, Wan Chai, Hong Kong T F enquiry.hk@asia.cmpmedica.com HK-NOV-096