Volume 10, Issue 10, Supplement 19 October 2012
Clinical Roundtable Monograph: Emerging Treatment Options for TKI-Resistant Chronic Myelogenous Leukemia
Jorge Cortes, MD
Deputy Department Chair
Department of Leukemia
Division of Cancer Medicine
The University of Texas
MD Anderson Cancer Center
Jerald Radich, MD
Director, Molecular Oncology Lab
Clinical Research Division
Fred Hutchinson Cancer Research Center
Professor of Medicine and Adjunct Professor of Pathology
University of Washington
Michael J. Mauro, MD
Knight Cancer Institute
Center for Hematologic Malignancies
Oregon Health & Science University
A CME Activity
Approved for1.0 AMA PRA Category 1 Credit(s)TM
Release Date: October 2012
Expiration Date: October 31, 2013
Estimated time to complete activity: 1 hour
Project ID: 8940
Abstract: The development of tyrosine kinase inhibitors (TKIs) that inhibit signaling of the constitutive BCR-ABL protein revolutionized the treatment of chronic myelogenous leukemia (CML). These agents have dramatically changed the treatment landscape for CML, shifting the use of allogeneic stem cell transplantation to selected patients in the salvage setting. Four BCR-ABL TKIs are now commercially available for the treatment of CML: the first-generation TKI imatinib, and the second-generation TKIs dasatinib, nilotinib, and bosutinib. Continuous treatment with these agents induces durable responses in a high proportion of patients with chronic-phase CML. Research is focused on identifying which patients can discontinue therapy without a recurrence of disease. For the group of patients with resistance to TKIs, multiple alternative therapies are being evaluated. The third-generation TKI ponatinib is a BCR-ABL inhibitor that has demonstrated significant activity, including in patients with the TKI resistance mutation T315I. The homoharringtonine derivative omacetaxine mepesuccinate, which inhibits protein synthesis, has also demonstrated clinical activity in CML, including in patients with TKI resistance due to T315I and in patients who have TKI resistance despite no evidence of ABL mutations. It is essential that clinicians implement these new agents with care and change therapies only when appropriate in order to preserve as many options as possible for future use if needed.
Sponsored by the Postgraduate Institute for Medicine
Supported through an educational grant from Teva Pharmaceutical Industries Ltd.
This activity has been designed for hematologists/oncologists, oncologists, oncology nurses, and hematology/oncology pharmacy specialists who treat patients with chronic myelogenous leukemia.
Statement of Need/Program Overview
The tyrosine kinase inhibitor (TKI) imatinib and the second-generation TKIs nilotinib and dasatinib have revolutionized the treatment of chronic myelogenous leukemia (CML) by effectively targeting the BCR-ABL oncogenic kinase. However, many patients do not respond well to treatment and/or lose their response over time. This unmet need has led to the investigation of novel agents that specifically target TKI resistance in CML. Physicians require education regarding the development of TKI resistance, as well as on the efficacy and safety of emerging treatment options in CML. The US Food and Drug Administration recently approved the use of bosutinib for the treatment of patients with Philadelphia chromosome–positive CML who are intolerant to or have become resistant to prior therapy. Other novel agents with positive results in phase II trials include ponatinib and omacetaxine mepesuccinate. Physicians must be aware of the data supporting the use of these newer agents and become familiar with their optimal implementation.
After completing this activity, the participant should be better able to:
• Define tyrosine kinase inhibitor (TKI) resistance in patients with chronic myelogenous leukemia (CML)
• Identify CML patients who should undergo BCR-ABL mutational testing
• Incorporate newly approved agents into the treatment of CML patients with TKI resistance
• Recognize when to discontinue an agent and resume treatment with another one
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and Millennium Medical Publishing, Inc. PIM is accredited by the ACCME to provide continuing medical education for physicians.
The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Disclosure of Conflicts of Interest
PIM assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of continuing medical education (CME) activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest or a commercial interest.
The contributing speakers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:
Jorge Cortes, MD—Advisor or consultant: Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc; Speaker or member of a speakers bureau: Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc.; Clinical research grants: Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc.
Jerald Radich, MD—Consultant: Novartis, BMS, ARIAD, and Pfizer; Laboratory research support: Novartis.
Michael J. Mauro, MD—Research support: ARIAD Pharmaceuticals, Inc., Bristol-Myers Squibb, and Novartis.
The following PIM planners and managers, Laura Excell, ND, NP, MS, MA, LPC,NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; Jan Schultz, RN, MSN, CCMEP; and Patricia Staples, MSN, NP-C, CCRN hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.Jacquelyn Matos: No real or apparent conflicts of interest to report. Melinda Tanzola, PhD: No real or apparent conflicts of interest to report.
Method of Participation
There are no fees for participating in and receiving CME credit for this activity. During the period October 2012 through October 31, 2013, participants must 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test by recording the best answer to each question in the answer key on the evaluation form; 4) complete the evaluation form; and 5) mail or fax the evaluation form with answer key to Postgraduate Institute for Medicine. You may also complete the post-test online at www.cmeuniversity com. On the navigation menu, click on “Find Post-tests by Course” and search by project ID 8940. Upon successfully completing the post-test and evaluation, your certificate will be made available immediately.
A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed post-test with a score of 70% or better. Your statement of credit will be mailed to you within three weeks.
Disclosure of Unlabeled Use
This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. PIM, Millennium Medical Publishing, Inc., and Teva Pharmaceutical Industries Ltd., do not recommend the use of any agent outside of the labeled indications.
The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, Millennium Medical Publishing, Inc., and Teva Pharmaceutical Industries Ltd. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.
Funding for this clinical roundtable monograph has been provided through an educational grant from Teva Pharmaceutical Industries Ltd. Support of this monograph does not imply the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc., the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.
©2012 Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.
Current Management for Chronic Phase Chronic Myelogenous Leukemia
Jerald Radich, MD
Chronic myelogenous leukemia (CML) is characterized by the proliferation of a clone of hematopoietic cells driven by the Philadelphia chromosome [t(9;22)(q34;q11)]. This translocation leads to formation of the fusion BCR-ABL gene, which encodes a constitutively active BCR-ABL tyrosine kinase. CML is most often diagnosed in the chronic phase (CP-CML), which is characterized by a proliferation of the myeloid spectrum of cells. In the absence of curative therapy, the disease would progress after a period of approximately 4 years to an accelerated phase (AP-CML) heralded by an increase in the number of immature blasts and the presence of new cytogenetic abnormalities aside from the Philadelphia chromosome. From there, patients would progress to blast crisis (BC), which would typically cause death due to bleeding or infectious causes.
The first therapeutic intervention to offer the potential of cure in CML was allogeneic stem cell transplantation (SCT), which is associated with overall survival rates of greater than 5 years in more than 85% of patients in CP-CML, 40% of patients in AP-CML, and 20% of patients in BC-CML (Figure 1).1-3 The next major advance in CML, the development of the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib, revolutionized the therapy of CML. Whereas transplantation was previously undertaken as soon as possible after diagnosis, it is now used only as a salvage regimen in selected patients, since the success of TKIs in chronic phase disease is so profound.
This evolution in the treatment paradigm for CML is a testament to the highly effective nature of the TKIs. Among patients with CP-CML who start therapy with the first-generation TKI imatinib, approximately 70% attain the treatment goals set forth by the National Comprehensive Cancer Network (NCCN)4 and the European LeukemiaNet (ELN),5 which include a major cytogenetic response (MCyR) by 12 months and a complete cytogenetic response (CCyR) by 18 months.6 Long-term data support this short-term efficacy and reflect the remarkable change TKIs have made in the natural history of the disease. Overall, approximately 85% of patients who initiate imatinib therapy are alive after 8 years (Figure 2).7
Three second-generation TKIs are also available: nilotinib, dasatinib, and, most recently, bosutinib. These agents have demonstrated more potent activity than imatinib in laboratory studies and enhanced efficacy in randomized clinical trials. Compared with imatinib, nilotinib and dasatinib have demonstrated higher CCyR rates, lower rates of progression to AP and BC, and a higher likelihood of major molecular response (MMR; Table 1).8,9 Bosutinib has not demonstrated a significant improvement in 12-month CCyR rates over imatinib, but it is associated with other efficacy improvements, including a higher 12-month MMR rate, faster time to response, less disease progression, and fewer CML-related deaths.10
One notable endpoint that has not been observed with second-generation TKIs is an improvement in overall survival over imatinib. It is unclear whether there truly is no difference in survival between first- and second-generation TKIs, or whether there has just not been sufficient follow-up to detect any differences. Second-generation TKIs promote deeper molecular responses, which may eventually translate into an overall survival benefit.
The optimal implementation of TKIs is an important issue. Clinicians and their newly diagnosed patients are presented with the option of starting with the standard first-line therapy, imatinib, or a second-generation TKI. In my clinic, we weigh the pros and cons of each agent. Some patients may prefer imatinib due to its longer track record of impressive safety, thus, reserving dasatinib and nilotinib if the initial therapy fails. However, other patients may prefer to start with a more active second-generation TKI, which is also a reasonable option. Other factors to consider include the patient’s risk profile as assessed by the Sokal, Hasford, or European Treatment and Outcome Study [EUTOS] scores. Many clinicians feel comfortable using imatinib in patients with low-risk disease but may opt for a more potent second-generation agent in patients with intermediate- or high-risk disease who may be further along in the natural history of the disease.11,12
Resistance to TKIs can occur in several settings. “Primary” resistance occurs when the treatment does not induce the response criteria as defined by the ELN and NCCN guidelines. “Acquired” resistance occurs when patients experience a relapse following an initial response. Approximately half of relapses are characterized by point mutations in the ABL kinase domain that cause a change in the conformational structure of ABL, inhibiting TKI binding and thus allowing the reactivation of the BCR-ABL kinase activity.
Resistance to TKI therapy can be detected early based on BCR-ABL RNA levels as assayed by polymerase chain reaction (PCR) and cytogenetic studies. A BCR-ABL transcript level of greater than 10% after 3 months of therapy is associated with a relatively poor response.13 Thus, there is an impetus for these patients to switch therapy (eg, to a second-generation TKI if the patient has started on imatinib) if this milestone is not achieved. It should be emphasized, however, that there is no strong data suggesting that treatment changes for any of the milestones alters the natural history of the disease. Indeed, patients who fail to reach milestones should enroll in a clinical trial, if possible.
In the case of patients who initially respond to imatinib and then develop resistance, the choice of next therapy can be influenced by the patient’s ABL mutation status. For patients with no detectable ABL mutation, any second-generation TKI would be acceptable, weighing in contraindications based on patient history and known drug side effects. For patients with an ABL mutation that is characterized by greater sensitivity to one second-generation TKI over another, the choice could be more straightforward. For patients with the T315I mutation, which confers resistance to imatinib, dasatinib, and nilotinib, options include transplantation or a clinical trial with an agent that is active against T315I, such as the third-generation TKI ponatinib.
One important issue in the care of patients with acquired resistance is how long to continue the new agent before proceeding to salvage therapy that may include transplantation. Two major studies have prospectively evaluated this issue. Investigators at the MD Anderson Cancer Center found that a 12-month trial with a different TKI is acceptable, at which point the depth of response should be assessed and the decision to transplant should be made. However, Milojkovic and colleagues determined that BCR-ABL transcript levels should be assessed at 3 months.14 Patients without a cytogenetic response at that time would then proceed to transplant. Fortunately, previous therapy with a TKI does not negatively affect the transplant, unlike other drugs for CML, such as busulfan and interferon.15
Finally, for the group of patients with AP- or BC- CML, a TKI alone is unlikely to be curative; transplantation would be required. However, most investigators would opt for some therapy before transplantation to try to attain the best response possible before proceeding to transplant. Therefore, most patients with AP or BC would be treated immediately with a second-generation drug, followed by transplantation upon attaining a maximal response.
Dr. Radich is a consultant for Novartis, BMS, ARIAD, and Pfizer, and receives laboratory research support from Novartis.
1. Radich JP, Gooley T, Bensinger W, et al. HLA-matched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood. 2003;102:31-35.
2. Saussele S, Lauseker M, Gratwohl A, et al. Allogeneic hematopoietic stem cell transplantation (allo SCT) for chronic myeloid leukemia in the imatinib era: evaluation of its impact within a subgroup of the randomized German CML Study IV. Blood. 2010;115:1880-1885.
3. Gratwohl A, Brand R, Apperley J, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2006;91:513-521.
4. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. Version 1.2013. Updated July 5, 2012.
5. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041-6051.
6. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
7. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood (ASH Annual Meeting Abstracts). 2009;114: Abstract 1126.
8. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259.
9. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123-1129.
10. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012 Sep 4. [Epub ahead of print]
11. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303-2309.
12. le Coutre P, Ottmann OG, Giles F, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111:1834-1839.
13. Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol. 2012;30:232-238.
14. Milojkovic D, Nicholson E, Apperley JF, et al. Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica. 2010;95:224-231.
15. Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood. 2008;112:3500-3507.
16. Hughes TP, Hochhaus A, Saglio G, et al. ENESTnd update: continued superiority of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Blood (ASH Annual Meeting Abstracts). 2010;116: Abstract 206.
17. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270.
Emerging Therapies for Patients With TKI-Resistant Chronic Myelogenous Leukemia: Clinical Trial Data
Jorge Cortes, MD
BCR-ABL TKIs are a highly effective initial therapy in CP-CML, inducing durable responses in the majority of patients. However, alternative approaches are needed for the 20–30% of patients who fail an initial TKI due to disease progression, relapse, or intolerance.1 To meet the needs of these patients, a variety of new agents have since been developed, including second-generation and third-generation TKIs and agents with novel mechanisms of action.
Second-Generation BCR-ABL TKIs
After it was recognized that some patients develop resistance or intolerance to imatinib, several newer-generation TKIs were developed. The first of these was dasatinib, a TKI that can bind both the active and inactive forms of ABL, thus retaining activity against imatinib-resistant BCR-ABL mutations.2 In the phase II START-C (SRC/ABL Tyrosine Kinase Inhibition Activity: Research Trials of Dasatinib) trial, dasatinib dosed at 70 mg twice daily demonstrated significant activity in patients with imatinib-resistant or intolerant CP-CML, with 52% of patients attaining a major cytogenetic response (MCyR).3 Responses were durable, with 2-year MCyR and complete cytogenetic response (CCyR) rates of 62% and 53%, respectively. Approximately 75–80% of patients who achieved an MCyR maintained the response for about 2 years.4 In 2010, Shah and colleagues reported results from a randomized dose-optimization study showing that administration of dasatinib at 100 mg once daily in patients with CP-CML is as effective as administration at 70 mg twice daily and is better tolerated.5
Around the same time, a third BCR-ABL TKI, nilotinib, was developed. Like dasatinib, nilotinib was designed for use in patients with resistance or intolerance to imatinib. In a phase II trial in patients with CP-CML, nilotinib demonstrated significant clinical activity, with overall MCyR and CCyR rates of 59% and 44%, respectively, at 2 years.6 Responses tended to be durable, with 84% of patients maintaining a CCyR and 77% of patients maintaining an MCyR at 2 years.
Based on these clinical trials, dasatinib and nilotinib have become a standard approach for patients with imatinib resistance. Experience in treating these patients has revealed the importance of early recognition of TKI resistance. It is now understood that the longer the delay between the development of resistance and the switch to an alternative TKI, the lower the likelihood that the patient will respond to the second agent. Data suggest that the response rate to the second agent is at least 50–60% lower in patients who switch only upon loss of a complete hematologic response (CHR) than in patients who switch immediately upon loss of an MCyR. It is therefore important to monitor patients closely in order to recognize treatment failure early and act immediately once resistance is definitively identified.
Although dasatinib and nilotinib induce durable responses in many patients with imatinib-resistant CP-CML, approximately half of patients do not achieve a CCyR with a second-line TKI, and another subset of patients initially respond but eventually develop resistance to these agents.3,6 Alternative approaches are needed for this small, but significant, patient population. There is also a need for alternative treatment strategies for the small subset of patients with a detectable T315I mutation in the ABL kinase domain, which is associated with significant resistance to imatinib, dasatinib, and nilotinib.7 Although a third TKI could be considered in patients who had failed 2 prior lines of TKI therapy, responses to a third TKI tend to be minimal and not very durable.8
Research efforts have led to the development of a variety of agents for the treatment of TKI-resistant CML. Although some of these agents have not yielded the anticipated efficacy, others have demonstrated significant clinical activity. One such active agent is bosutinib, a BCR-ABL TKI with similarities to dasatinib and nilotinib but with a unique kinase inhibition profile. For example, bosutinib targets SRC, ABL, and TEC, but it does not inhibit KIT or platelet-derived growth factor receptor (PDGFR).9
In a phase I/II study, bosutinib demonstrated activity in patients with failure of at least 2 prior TKIs (imatinib and dasatinib and/or nilotinib), with MCyR and CCyR rates of 32% and 24%, respectively.10 Response rates vary somewhat according to the sequence of therapies. In the second-line setting, in patients with resistance or intolerance to only imatinib, the efficacy of bosutinib is similar to that of dasatinib or nilotinib, with CCyR and MCyR rates of 41% and 53%, respectively.11 Bosutinib was recently approved for use in patients with CML in any stage of disease with resistance or intolerance to prior therapy.12
Emerging Therapies for TKI-Resistant CML
Several other novel agents are currently in the investigational stages of development. One agent that has demonstrated significant clinical activity is the third-generation TKI ponatinib, which was structurally designed to bind and inhibit ABL even in the setting of T315I and other BCR-ABL mutants.13 The phase II PACE (Ponatinib Ph+ALL and CML Evaluation) trial is evaluating the efficacy and safety of ponatinib in 449 patients with resistance or intolerance to dasatinib or nilotinib or with the T315I mutation. Among patients with CP-CML, ponatinib has demonstrated significant activity, with a CCyR observed in 66% of patients with T315I and in 37% of patients with resistance or intolerance to dasatinib or nilotinib.14 Ponatinib is active in patients with other ABL mutations and in patients with wild-type BCR-ABL, although it appears to be most effective in patients with ABL mutations. In regard to previous lines of therapy, ponatinib has demonstrated activity in patients exposed to either 2 or 3 prior TKIs. In patients who have failed imatinib, dasatinib, and nilotinib, ponatinib induced CCyR in 34% of patients without T315I and 48% of patients with T315I.
The PACE trial also enrolled patients with advanced disease, including 85 patients with accelerated-phase (AP) CML and 94 patients with blast-phase (BP) CML or Ph+ ALL. Ponatinib was active in these patients, inducing major hematologic responses in 58% of patients with AP-CML and 34% of patients with BP-CML or Ph+ ALL.14 MCyR responses were observed in 39% and 30% of patients, respectively. However, as has been observed for other TKIs, responses to therapy are less durable in AP-CML than in CP-CML, and are even less durable in patients with BP-CML. An ongoing phase II study is evaluating combination therapy with ponatinib and hyper-CVAD to attempt to induce a more durable response.15 Overall, ponatinib appears to be a very active drug in the setting of resistance to multiple therapies, including in patients with T315I. In vitro data suggest that resistance to ponatinib will not readily develop. Ponatinib is currently under FDA review for accelerated approval.
Another interesting agent in development is omacetaxine mepesuccinate. Omacetaxine is a semi-synthetic derivative of homoharringtonine, an investigational agent that initially demonstrated clinical activity during the interferon era and is now gaining renewed interest.16 Omacetaxine acts not through kinase inhibition but by inhibiting synthesis of proteins with a rapid turnover. Thus, it has no effect on structural proteins but it does inhibit synthesis of proteins implicated in cell-cycle progression. Unlike the TKIs, omacetaxine is administered via subcutaneous injection. In a phase II study in patients with T315I who had failed a TKI, omacetaxine was associated with an MCyR rate of 23%.17
Omacetaxine may also be an alternative for patients without relevant ABL mutations, in whom the mechanism of TKI resistance may be unrelated to persistence of kinase activity. Among patients with CP-CML (regardless of mutation status) who had received at least 2 prior TKIs, omacetaxine was associated with an MCyR rate of 27% in patients who had received 2 prior TKIs and in 11% of patients who had received 3 TKIs.18 Responses appeared durable, with a median MCyR duration of 18 months. Survival was also longer than expected for this patient population, with a median OS of 30 months in patients who had failed 2 TKIs and not reached in patients with 3 prior TKIs. Omacetaxine is also active in AP- and BP-CML, although responses are less durable in these settings. Omacetaxine is also currently under review by regulatory authorities. Both ponatinib and omacetaxine appear to be active and may be useful for at least a subset of patients with CML.
Applying New and Emerging Therapies in CML
The expanding treatment options for CML raise the issue of how best to use these agents at different stages of disease. Many clinicians continue to use imatinib as initial therapy. For patients requiring a change of therapy after imatinib, a second-generation TKI (dasatinib, nilotinib, or bosutinib) would be a logical choice. The 2 agents currently under FDA review—ponatinib and omacetaxine—have not been well studied in the imatinib-refractory setting, aside from in patients with T315I.
With the FDA approval of dasatinib and nilotinib for the first-line treatment of CML, a growing number of patients are receiving these agents as initial therapy. For patients who discontinue dasatinib or nilotinib, the selection of second-line therapy may vary based on the reason for discontinuation. Patients who discontinue initial dasatinib or nilotinib due to tolerability issues may be candidates for imatinib, which may be better tolerated. Patients who discontinue dasatinib or nilotinib due to resistance would most likely not be candidates for imatinib, given the low probability of response; however, data on this sequence are limited. Bosutinib is an interesting option for these patients, as it has demonstrated activity after failure of 2 or more TKIs. Additional data on the efficacy of bosutinib in different settings are awaited. Ponatinib would also be a very attractive option, considering its mechanism of action and demonstrated clinical efficacy. Omacetaxine is another intriguing option for TKI-refractory disease, particularly for patients who have developed resistance to TKIs through a mechanism other than an ABL mutation.
The treatment armamentarium for CML is continuing to evolve with the introduction of several new therapeutics and additional agents under review. Ongoing studies will provide information that should help guide the optimal use of these agents. A greater understanding of the activity of these agents in various clinical settings and their relevant mechanisms of resistance should help guide treatment selection and sequencing of therapies based on patient, disease, and therapeutic factors, in order to improve outcomes for individuals living with CML.
Dr. Cortes has served as an advisor or consultant for Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc. He has served as a speaker or a member of a speakers bureau for Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc. He has received grants for clinical research from Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc.
1. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.
2. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399-401.
3. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303-2309.
4. Jabbour E, Cortes J, Kantarjian H. Long-term outcomes in the second-line treatment of chronic myeloid leukemia: a review of tyrosine kinase inhibitors. Cancer. 2011;117:897-906.
5. Shah NP, Kim DW, Kantarjian H, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010;95:232-240.
6. Kantarjian HM, Giles FJ, Bhalla KN, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011;117:1141-1145.
7. Jabbour E, Kantarjian H, Jones D, et al. Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy. Blood. 2008;112:53-55.
8. Garg RJ, Kantarjian H, O’Brien S, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114:4361-4368.
9. Remsing Rix LL, Rix U, Colinge J, et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009;23:477-485.
10. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119:3403-3412.
11. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567-4576.
12. www.FDA.gov. Approved drugs: bosutinib tablets. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm318203.htm. Updated September 5, 2012.
13. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401-412.
14. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. PACE: a pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerance to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl): Abstract 6503.
15. www.ClinicalTrials.gov. Hyper-CVAD and ponatinib in Ph-positive and/or BCR-ABL positive acute lymphoblastic leukemia (ALL). http://clinicaltrials.gov/ct2/show/NCT01424982. Identifier: NCT01424982.
16. O’Brien S, Talpaz M, Cortes J, et al. Simultaneous homoharringtonine and interferon-alpha in the treatment of patients with chronic-phase chronic myelogenous leukemia. Cancer. 2002;94:2024-2032.
17. Cortes J, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012 Aug 15. [Epub ahead of print]
18. Nicolini FE, Lipton JH, Kantarjian HM, et al. Subcutaneous omacetaxine mepesuccinate in patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) resistant/intolerant to two or three approved tyrosine kinase inhibitors (TKIs). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl). Abstract 6513.
Role of Stem Cell Transplantation in Chronic Myelogenous Leukemia
Michael J. Mauro, MD
Historically, allogeneic stem cell transplantation (SCT) has played an important role in the treatment of CML, as it induces long-term remission in a high proportion of patients. However, allogeneic SCT is associated with a significant risk of morbidity and mortality, and many patients are not candidates for transplantation due to comorbidities, advanced age, or lack of a suitable human leukocyte antigen (HLA)-matched donor. For the group of patients with early CP-CML who have an available donor, a favorable risk profile, and a low risk of transplant-related morbidity or mortality, outcomes with transplantation have been favorable. However, allogeneic SCT is associated with significant morbidity and mortality even for this lower-risk group, highlighting the need for an effective alternative.
The introduction of highly effective therapy has led to a paradigm shift in CML, changing the role of transplant dramatically. TKIs have eliminated the upfront morbidity and mortality associated with transplantation. Longer-term follow-up is confirming the favorable short-term efficacy of TKIs, demonstrating that TKIs can also induce long-term, stable remission, perhaps leading to a functional cure.
Although therapeutic advances have significantly diminished the role of transplantation in CML, allogeneic SCT may still have a role in selected patients with resistance or intolerance to TKIs.
Opinions differ regarding the optimal time to introduce or reintroduce transplantation in these patients. My opinion is that for a patient of an appropriate age and with a favorable transplant risk profile, it is wise to delineate the option early, as it may frame a patient’s tolerability for differing degrees of nonresponse or intolerance to TKI therapy.
If a younger patient is responding poorly to multiple TKI therapies and has a small projected likelihood of long-term stable remission, a stem cell transplant might be pursued directly. Conversely, for an older patient in whom transplant morbidity represents a risk, and who may not have an identified donor, there will be a greater need to remain within the realm of TKI therapy and to establish a stable remission using available non-transplant options.
Another important question regarding transplantation today is whether it is harmful for patients to have been exposed to TKIs prior to transplant. Data from a large prospective registry study suggest that in the case of CP-CML that is not highly proliferative, outcomes after transplant are similar regardless of prior TKI exposure. The effect of therapeutic resistance conferred by a TKI mutation or another mechanism is currently unknown. In general, however, the introduction of TKIs has not affected outcomes after allogeneic SCT.
An important consideration in allogeneic transplantation is the type of conditioning regimen used. Reduced-intensity conditioning regimens decrease the risks associated with transplantation; however, CML is a tenacious disease that may not be amenable to a reduced-intensity conditioning regimen due to the risk of relapse. It may be possible to use a combination of reduced-intensity conditioning transplantation and TKI therapy to enhance therapeutic efficacy while lowering the risks of transplantation.
In addition to their role prior to transplantation, TKIs may also have a role after transplant to protect against relapse. Several studies have reported a benefit with the use of TKI therapy post-transplant to protect against relapse. Thus, TKIs and transplantation may not be mutually exclusive. Overall, the selection of appropriate patients, the use of lower-dose conditioning therapy, and the application of advances in protection against graft-versus-host disease and infection all lower the risks associated with allogeneic transplantation. The use of allogeneic SCT in CML has declined dramatically, but it still remains a viable treatment option for selected patients.
Feasibility of Stem Cell Eradication of CML
TKI therapy provides exquisite control of leukemia down to a level detectable only by DNA or RNA sequencing analysis. An increasing proportion of patients are able to maintain a state of remission that is either consistent or fairly consistent with no detectable evidence of CML by any means. Although this state may represent a functional cure, the leukemic potential still appears to exist, at least for many patients. An actual cure, defined as a lack of disease regrowth in the absence of therapy, remains an important goal.
The effect of CML therapy, including TKIs, at the stem-cell level is a topic of research. The STIM (Stop Imatinib) study prospectively evaluated whether imatinib could be discontinued without relapse in patients with a complete molecular remission (CMR) of at least 2 years’ duration.1 In an interim analysis, approximately 40% of patients remained in molecular remission for at least 12 months. For the remaining 60% of patients who relapsed off therapy, reintroduction of imatinib led to a response in all cases. Thus, while imatinib may allow some patients to stop therapy, it does not necessarily eradicate a punitive stem cell that may harbor BCR-ABL.
Even among patients who respond rapidly to imatinib and attain long-term molecular remission that permits discontinuation of therapy without relapse, there may still be a population of cells that harbor the BCR-ABL translocation but have been rendered nonproliferative. Perhaps we should reconsider the definition of an actual cure and not require that the marker be absent, but rather accept the presence of residual nonproliferative CML cells. Other hematologic malignancies use similar approaches, such as the detection of core binding factor in leukemia or inversion 16 or t(8;21) in AML.
In vitro studies have shown that quiescent stem cells are resistant not only to imatinib, but also to more potent second-generation TKIs, such as dasatinib,2 suggesting that ongoing therapy would be necessary to suppress the CML clone. However, as noted by Melo and Ross, this pessimistic prediction does not align with the outcomes observed when therapy was stopped in the STIM trial.3 The absence of early relapse does not indicate that a patient is cured. It may, however, indicate that proliferation of CML is just below the limit of detection by standard assays.
Moving forward, our ongoing quest remains to define the residual CML population that must be managed, assess its potential for proliferation in the setting of more potent TKI therapy, and determine whether it is necessary to eradicate residual CML cells, or whether “cure” in CML can be redefined as a prolonged period without proliferation.
Dr. Mauro has received research support from ARIAD Pharmaceuticals, Inc., Bristol-Myers Squibb, and Novartis.
1. Mahon FX, Réa D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029-1035.
2. Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532-4539.
3. Melo JV, Ross DM. Minimal residual disease and discontinuation of therapy in chronic myeloid leukemia: can we aim at a cure? Hematology Am Soc Hematol Educ Program. 2011;2011:136-142.
Discussion: Role of Novel Agents in Chronic Myelogenous Leukemia
H&O What is your overall assessment of the current state of chronic myelogenous leukemia (CML) treatment?
Jorge Cortes, MD: In many cases, patients will respond to initial treatment and, with careful managing and monitoring, will have good long-term outcomes. The treatment is more complicated for patients with more refractory disease. Previously, we had few options for these patients, but now our treatment options are expanding.
Michael J. Mauro, MD: Yes; we now have multiple active agents with different properties and mechanisms of action, including novel tyrosine kinase inhibitors (TKIs) and new drugs with alternative mechanisms of action. The development of these agents gives us more options for patients with refractory disease.
Jerald Radich, MD: There is almost an embarrassment of riches for treating chronic phase CML, with several highly effective TKIs available. Alas, we have made far less impressive progress on advanced phase disease. Thus, a main goal in therapy is to keep patients out of advanced phase disease. Monitoring and compliance are big considerations.
Jorge Cortes, MD: One caveat as we discuss these new therapies is the importance of careful implementation of each therapy. In our referral patients, we are seeing a growing number of patients who have jumped quickly from one drug to another for reasons of minor adverse effects rather than true TKI intolerance. This observation is supported by the discontinuation rates being reported in the frontline studies, which are higher than expected based on the established efficacy and safety profiles of these agents. In these patients, rapidly switching between TKIs could be a dangerous practice, as it may eliminate the availability of these valuable options down the road, before they are properly evaluated.
Therefore, clinicians must be careful that the increased availability of drugs does not lead them to switch prematurely to alternative agents. Patients should be educated about the side effects associated with these drugs, and they should be supported in the management of those effects. In some cases, however, switching to another drug is clearly the correct decision. The challenge will be finding the right balance between switching prematurely and continuing too long on an ineffective drug.
Michael J. Mauro, MD: I agree; we must be careful not to drive patients into states of resistance through the inappropriate use of multiple drugs. The good news is that even our prototype drug is highly effective in a large number of patients, and the higher doses are even more effective. Hopefully, a conservative approach and very careful use of newer drugs will reign supreme. On the other hand, we must counter the notion that CML is like a cold that we can treat with a simple antibiotic first and then with a more potent antibiotic second. We do have data showing that careful consideration of our best treatment options first really can give us the best outcome.
Jerald Radich, MD: For chronic phase disease, the adage “just don’t do something, stand there” is often appropriate—give the TKI time to work, and follow guidelines from the National Comprehensive Cancer Network and the European LeukemiaNet in regards to treatment milestones. Don’t jump ship by expecting miraculous results quickly.
Dr. Cortes has served as an advisor or consultant for Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc. He has served as a speaker or a member of a speakers bureau for Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc. He has received grants for clinical research from Bristol-Myers Squibb Company and ARIAD Pharmaceuticals, Inc. Dr. Mauro has received research support from ARIAD Pharmaceuticals, Inc., Bristol-Myers Squibb, and Novartis. Dr. Radich is a consultant for Novartis, BMS, ARIAD, and Pfizer, and receives laboratory research support from Novartis.