tap vol 3 issue 17 supplement - monitoring, treatmentresistance, and treatment failure in cml

Supplement • Volume 3, Issue 17 • November 15, 2012

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

Monitoring, Treatment Resistance, and Treatment Failure in Chronic Myeloid Leukemia

Breaking Barriers to Improved Outcomes and Looking Forward to a CureReported by Marie Sabo Recine, MS; Gail V. Flores, PhD; and Eugene R. Tombler, PhD

Timothy Hughes, MD, MBBS John Goldman, DM, FRCP, FRCPath, FMedSci

Jorge Cortes, MD

This activity is sponsored by Medical College of Wisconsin and MediCom Worldwide, Inc.

This activity was supported by an unrestricted educational grant from ARIAD Pharmaceuticals.

Advances in Patient Survival in the Era of Tyrosine Kinase Inhibitor Therapy and Identification of Addressable Barriers to Improved Outcomes

Treatment Goals, Molecular Monitoring, and the Role and Use of Guideline Recommendations

Beyond Molecular Monitoring: Cytogenetic Testing and Mutational Analysis in Chronic Myeloid Leukemia

Defining and Recognizing the Causes of Imatinib Resistance and the Importance of Adherence

Managing Treatment Failure in Chronic Myeloid Leukemia

Defining a Cure for Chronic Myeloid Leukemia and Strategies to Achieve this Goal

INSIDE THIS SUPPLEMENTFACULTY

A Harborside Press® Publication

HIGHLIGHTS OF AN ESH–iCMLf SATELLITE SYMPOSIUM

Editorial CorrespondenceJames O. Armitage, MDEditor-in-Chief e-mail: [email protected]

Cara H. Glynn Director of Editorial e-mail: [email protected]: 631.935.7654

Andrew Nash Assoc. Director of Editorial e-mail: [email protected]: 631.935.7657

Rights & Permissionse-mail: [email protected]

Advertising Rates, reprints, or supplements

Leslie Dubine-mail: [email protected] Phone: 631.935.7660

Editorial OfficeHarborside Press 37 Main Street Cold Spring Harbor, NY 11724Phone: 631.692.0800 Fax: 631.692.0805

ASCOPost.com HarborsidePress.com

Contact The ASCO Post

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices.

Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at [email protected]. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email [email protected] or fax (631) 692-0805.

Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact [email protected].

Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact [email protected].

Correspondence: Address general inquiries to Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: [email protected].

Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: [email protected].

Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.”

Advertiser and advertising agency 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 or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards.

The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

The ASCO Post • Volume 3, Issue 17 • Supplement

Breaking Barriers to Improved Outcomes and Looking Forward to a Cure

1

This supplement to The ASCO Post highlights the proceedings of a satellite symposium that was presented as a case-based roundtable discussion titled, Monitoring, Treatment

Resistance, and Treatment Failure in Chronic Myeloid Leukemia: Breaking Barriers to Improved Outcomes and Looking Forward to a Cure, and moderated by Timothy Hughes, MD, MBBS, of the Centre for Cancer Biology, Adelaide, South Australia. Dr. Hughes was joined by two distinguished faculty members, John Goldman, DM, FRCP, FRCPath, FMedSci, of Imperial College London, and Jorge Cortes, MD, of The University of Texas MD Anderson Cancer Center, Houston. The event was held in conjunction with the European School of Haematology (ESH)–International Chronic Myeloid Leukemia Foundation (iCMLf) 14th International Conference on Chronic Myeloid Leukemia: Biology and Therapy, on the morning of September 21, 2012, in Baltimore.

The goal of the satellite symposium was to assess current clinical trial findings and translate these into implications for practice. Issues discussed included the role of cytogenetic and molecular monitoring, defining responses, recognition of resistance, and treatment failure and its underlying mechanisms. Also discussed were treatment interventions with available and emerging therapies and strategies, including the recently FDA-approved tyrosine kinase inhibitor bosutinib (Bosulif ) and protein translation inhibitor omacetaxine (Synribo), as well as the third-generation tyrosine kinase inhibitor ponatinib, which has been submitted for FDA review. Finally, the issue of defining a “functional” or “operational” cure for chronic myeloid leukemia was discussed along with approaches to potentially realize this goal in practice. ■Corresponding author: MediCom Worldwide, Inc, 101 Washington Street, Morrisville, PA 19067, e-mail: [email protected]

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact [email protected].

INTRODUCTION



2

Monitoring, Treatment Resistance, and Treatment Failure in Chronic Myeloid Leukemia Breaking Barriers to Improved Outcomes and Looking Forward to a Cure

Reported by Marie Sabo Recine, MS; Gail V. Flores, PhD; and Eugene R. Tombler, PhD*

*Corresponding author, MediCom Worldwide, Inc, 101 Washington Street, Morrisville, PA 19067, e-mail: [email protected]

Activity Release Date: November 15, 2012 Period of Validity: November 15, 2013

Program Overview This activity presents highlights from a satellite

symposium held in conjunction with the European School of Haematology (ESH)–International Chronic Myeloid Leukemia Foundation (iCMLf) 14th Inter-national Conference on Chronic Myeloid Leukemia: Biology and Therapy, held September 20–23, 2012, in Baltimore. Using clinical evidence as a guide, three world-renowned experts discuss overcoming barriers to improved chronic myeloid leukemia (CML) patient outcomes using a case-based format. Topics included addressing controversial issues regarding how to best assess response to tyrosine kinase inhibitor therapy, and how monitoring should be conducted. Strategies for overcoming imatinib (Gleevec) resistance and pre-venting it are currently available, including the recently approved tyrosine kinase inhibitor bosutinib (Bosulif) and omacetaxine (Synribo), which has a mechanism of action different from tyrosine kinase inhibitors, but ad-ditional options are still needed. Included in the discus-sions is the investigational third-generation tyrosine ki-nase inhibitor ponatinib. New next-generation tyrosine kinase inhibitors and alternative therapies, once made available, will open new questions regarding optimal se-lection and sequencing. Finally, the question of how a functional cure may be defined and whether tyrosine ki-nase inhibitor therapy can be discontinued has become an area of significant clinical interest.

Target Audience This activity is designed for physicians, physi-

cian assistants, nurses, nurse practitioners, and other health-care professionals who have an interest in en-hancing their knowledge and understanding of the management of CML.

Learning Objectives Upon completion of this activity, participants should be able to:

■ Recall evidence-based approaches for treatment re-sponse monitoring, assessing adherence, and tailor-ing of therapy based on responses

■ Relate causes of primary and secondary resistance, appropriate testing and monitoring, as well as strate-gies for overcoming resistance

■ Convey clinical findings relating to efficacy and safe-ty, as well as trial limitations for agents undergoing investigation for overcoming tyrosine kinase inhibi-tor refractory disease

■ Recognize how a cure for CML might be defined and whether discontinuation of treatment is cur-rently an appropriate option for CML patients

Activity Instructions This activity is eligible for credit through November

15, 2013. After this date, this activity will expire and no further credit will be awarded.

Expected time to complete this activity as designed: 60 minutes

The content of this supplement, Highlights of an ESH–iCMLf Satellite Symposium – Monitoring, Treatment Resis-tance, and Treatment Failure in Chronic Myeloid Leukemia: Breaking Barriers to Improved Outcomes and Looking For-ward to a Cure, is a component of an online CME activity accessible at this link: http://www.hbrsd.com/9Fc.

CE Accreditation CME Credit Accreditation Statement: The Medical College of Wis-

consin is accredited by the Accreditation Council for

HIGHLIGHTS OF AN ESH–iCMLf SATELLITE SYMPOSIUM



3

Continuing Medical Education to provide continuing medical education for physicians.

Designation of Credit: The Medical College of Wis-consin designates this enduring material a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their par-ticipation in the activity.

Nursing CreditAccreditation Statement: MediCom

Worldwide, Inc, 101 Washington Street, Morrisville, PA 19067 is approved by the California Board of Registered Nursing, Provider Number CEP11380. MediCom designates this CNE activity for 1.0 con-

tact hour. Program Number: 12-330-295

DisclaimerThis material has been prepared based on a review of

multiple sources of information, but it is not exhaustive of the subject matter. Participants are advised to critically appraise the information presented and encouraged to consult the above-mentioned resources as well as avail-able literature on any product or device mentioned in this program.

Disclosure of Unlabeled Uses This educational activity may contain discussion of

published and/or investigational uses of agents that are not approved by the U.S. Food and Drug Administra-tion. For additional information about approved uses, including approved indications, contraindications, and warnings, please refer to the prescribing information for each product, or consult the Physicians’ Desk Reference.

Disclosure As an organization accredited by the Accredita-

tion Council for Continuing Medical Education (ACCME), Accreditation Council for Pharmacy Ed-ucation (ACPE), and California State Board of Reg-istered Nursing, MediCom Worldwide, Inc, requires everyone who is in a position to control the content of an educational activity to disclose all relevant finan-cial relationships with any commercial interest. The ACCME defines “relevant financial relationships” as financial relationships in any amount, occurring with-in the past 12 months, including financial relation-

ships of a spouse or life partner, that could create a conflict of interest.

Faculty DisclosuresConsistent with the current Accreditation Council

for Continuing Medical Education policy, the CME Provider must be able to show that everyone who is in a position to control the content of an individual educational activity has disclosed all relevant financial relationships.

The CME Provider has a mechanism in place to iden-tify and resolve any conflicts of interest discovered in the disclosure process. The presenting faculty members have all made the proper disclosures, and the following rela-tionships are relevant:

Jorge Cortes, MD, has received consultant fees as well as grant support related to research activities from ARIAD Pharmaceuticals, Inc; Bristol-Myers Squibb; ChemGenex Pharmaceuticals Ltd; Novartis AG; and Pfizer, Inc.

John Goldman, DM, FRCP, FRCPath, FMedSci, has received honoraria related to speakers’ bureau ac-tivities from Amgen, Inc; ARIAD Pharmaceuticals, Inc; Bristol-Myers Squibb; and Novartis AG.

Timothy Hughes, MD, MBBS, has received hono-raria related to formal advisory activities and speakers’ bureau activities from ARIAD Pharmaceuticals, Inc; Bristol-Myers Squibb; and Novartis AG.

Planning Committee DisclosuresThe individuals listed below from the Medical Col-

lege of Wisconsin reported the following for this activ-ity: Linda D. Caples, MBA, has no relevant financial relationships.

The individuals listed below from MediCom Worldwide, Inc, reported the following for this activ-ity: Joan Meyer, RN, MHA, Executive Director, and Eugene R . Tombler, PhD, Medical Director, have no relevant financial relationships. Gail V. Flores, PhD, and Marie Sabo Recine, MS, medical writers, have no relevant financial relationships.

This activity is sponsored by Medical College of Wis-consin and MediCom Worldwide, Inc.

This activity was supported by an unrestricted educa-tional grant from ARIAD Pharmaceuticals, Inc.



4

Advances in Patient Survival in the Era of Tyrosine Kinase Inhibitor Therapy and Identification of Addressable Barriers to Improved Outcomes

John Goldman, DM, FRCP, FRCPath, FMedSci, opened

the satellite symposium with a brief discussion of historic landmarks in the understand-ing of chronic myeloid leu-kemia (CML). Dr. Goldman is Senior Research Investiga-tor, Division of Investigative Science, at Imperial College London.

Key ChallengesDr. Goldman then outlined some of the clinical

challenges for the current decade. In his opinion, one of the most important issues to be addressed is the abil-ity to predict failure, or in other words, resistance to currently available tyrosine kinase inhibitors. Another key challenge is the need to refine the methodology

for monitoring responding patients. Improving the definition of low-level residual disease is also of prac-tical clinical interest, but this is a controversial area because clinicians are currently working at the limits

of quantitative reverse-transcription polymerase chain reaction technology. Whether the use of a DNA-based genomic polymerase chain reaction would be more sensitive is also controversial. Dr. Goldman pointed out that, with the efficacy of current therapies, there is a need to someday define a patient for whom treat-ment can be stopped. Although one might assume this would need to be a patient who has been in complete molecular response for some time, this may or may not be an essential criterion for stopping therapy if there was another approach that could produce an extremely good response. Developing strategies for overcoming primary and secondary resistance is also an important goal, according to Dr. Goldman.

Managing Side EffectsAs we now have longer experience in treating CML

with tyrosine kinase inhibitors, it is becoming apparent that refining the management of side effects is a key clini-cal goal as well, since this may impact quality of life and adherence to therapy.

“If patients are going to live for decades, then the management of side effects that may only occur 5 or 10 years after starting a particular drug obviously assumes considerable importance in our attempt to ensure that patients have as normal a lifespan into decades of therapy as possible,” noted Dr. Goldman.

Finally, it is also becoming increasingly clear that ad-herence is an important challenge.

“People who have to be taking a drug for 5 years and feel very well but have symptoms possibly attributable to the therapy are not as reliable in taking the drug as one might wish,” he commented. As such, poor adherence may be an adverse feature in disease management. ■

If patients are going to live for decades, then the management of side

effects that may only occur 5 or 10 years after starting a particular drug obviously assumes considerable importance…

—John Goldman, DM, FRCP, FRCPath, FMedSci

John Goldman, DM, FRCP, FRCPath, FMedSci

The content of this supplement, Highlights of an ESH-iCMLf Satellite Symposium – Monitoring, Treatment Resistance, and Treatment Failure in Chronic Myeloid Leukemia: Breaking Barriers to Improved Outcomes and Looking Forward to a Cure, is a component of an online CE activity accessible at this link: http://www.hbrsd.com/9Fc.

Continuing Education

http://www.hbrsd.com/9Fc



5

Treatment Goals, Molecular Monitoring, and the Role and Use of Guideline Recommendations

The importance of achieving a certain level of re-sponse with imatinib (Gleevec) by 3 months in

patients with chronic myeloid leukemia (CML) had pre-viously been established in the IRIS (International Ran-domized Study of Interferon and STI571) trial.1 Analysis of data from this trial showed that patients who had BCR-ABL transcript levels of 10% or greater at 3 months had a low chance of achieving a major molecular response. It has since been demonstrated that early BCR-ABL tran-script levels are also predictive of future molecular re-sponse and long-term outcomes in patients treated with nilotinib (Tasigna) and dasatinib (Sprycel).2,3 For ex-ample, a landmark analysis of the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials—Newly Diagnosed Patients) trial demonstrated extremely good 3-year progression-free survival in patients receiving nilotinib who had BCR-ABL levels of 1% or lower at 3 months compared with those having levels greater than 10% (95.6% vs 82.9%, P = .14).2

Importance of Molecular MonitoringTimothy Hughes, MD, MBBS, Clinical Profes-

sor, Department of Medicine, Centre for Cancer Biol-ogy, in Adelaide, South Australia, introduced a case of a young man with high-risk chronic-phase CML to il-

lustrate the importance of molecular monitoring. The patient initially received ima-tinib, but was switched to ni-lotinib after 1 month due to intolerance and subsequently achieved a rapid reduction in BCR-ABL level (according to the standardized Internation-al Scale) to less than 1% with-in 3 months of starting nilo-tinib. One would thus expect

this patient to have a good response; this was supported by a very steep ongoing decline in BCR-ABL transcripts at 6 months and continuing at 9 months, at which point BCR-ABL was undetectable. In fact, according to Eu-ropean LeukemiaNet criteria for optimal response to imatinib (ie, achievement of major molecular response by 18 months),4 the patient was ahead of schedule hav-ing achieved this milestone within 6 months of starting therapy.

Continued molecular monitoring demonstrated a 2-log increase in transcript levels to 0.1% by 15 months, and when asked how to proceed, the majority of audi-ence respondents indicated that they would repeat quantitative reverse-transcription polymerase chain reaction on a monthly basis and perform a mutation

screen. According to European LeukemiaNet recom-mendations4 and National Comprehensive Cancer Network Clinical Practice Guidelines,5 both strategies are recommended in cases of such increased transcript levels. After a decline to 0.01% by 18 months, a rapid rise to above 1% was seen by 21 months, triggering a mutation screen and cytogenetic analysis. No muta-tions were detected. The patient had experienced a cytogenetic relapse (8/20 Philadelphia chromosome–positive cells) but was still in chronic phase.

Based on these findings, the majority of respondents would switch to another second-generation tyrosine ki-nase inhibitor with or without an allograft within 3 to 6 months due to the loss of complete cytogenetic response. However, further questioning of the family identified

Monitoring BCR-ABL Levels: Nonadherence or Resistance?

■ BCR-ABL doubling time can help distinguish nonadherence from resistance and is actually more reliable than fold-rise in BCR-ABL transcripts.

■ Rapid kinetics, or short BCR-ABL doubling times, can indicate blast crisis or relapse after imatinib discontinuation.

■ Slow kinetics, or long BCR-ABL doubling times, are typical with the emergence of BCR-ABL mutations in patients who maintain chronic phase.

Rapid rise and fall [of BCR-ABL1 levels] is very characteristic of a patient

with poor compliance.

—Timothy Hughes, MD, MBBS

Timothy Hughes, MD, MBBS



6

nonadherence as the cause of the fluctuating BCR-ABL levels.

Nonadherence vs Resistance

“The hint in this patient was this fluctuating level up and down, be-cause you virtually never see that sort of pattern in a patient,” noted Dr. Hughes. “You do not have a log rise and log fall in a patient who has acquired resistance.” With medica-tion monitoring by the patient’s mother, the patient again achieved a deep molecular response.

So how can one distinguish between nonadherence and resis-tance as a cause for a lost response? A recent study of BCR-ABL kinet-ics demonstrated that BCR-ABL doubling time could help distin-guish nonadherence from resis-tance and was actually more reliable than fold-rise in BCR-ABL transcripts.6 Rapid kinetics (ie, short doubling times) can indicate blast crisis or, interestingly, relapse after ima-tinib discontinuation, either after complete molecular re-sponse or while BCR-ABL is still detectable. Both suggest complete loss of kinase inhibition (Fig. 1). In contrast, slow kinetics (ie, long doubling times) are typical with the emergence of BCR-ABL mutations in patients who main-tain chronic phase, suggesting partial loss of kinase inhibi-tion.

Considering the case just presented, Dr. Hughes not-ed, “Rapid rise and fall is very characteristic of a patient with poor compliance.” ■References

1. Branford S, Rudzki Z, Harper A, et al: Imatinib produ-ces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diag-nosed chronic myeloid leukemia in chronic phase. Leukemia 17:2401-2409, 2003.

2. Hochhaus A, Guilhot F, Al-Ali KH, et al: Early BCR-ABL transcript levels predict future molecular response and long-term outcomes in newly-diagnosed patients with chronic myeloid leukemia in chronic phase: Analysis of ENESTnd 3-year data. Haematologica 97(suppl 1):Abstract 0584, 2012.

3. Hochhaus A, Saglio G, Chuah C, et al: Dasatinib- and imatinib-induced reductions in BCR-ABL transcript levels be-low 10% at 3 months are associated with improved responses in patients with newly diagnosed chronic myeloid leukemia in chronic phase: Analysis of molecular response kinetics in the DASISION trial. Blood 118(suppl 21):Abstract 2767, 2011.

4. Baccarani M, Cortes J, Pane F, et al: Chronic myelogenous leukemia: An update of concepts and management recommenda-tions of European LeukemiaNet. J Clin Oncol 27:6041-6051, 2009.

5. O’Brien S, Abboud CN, Akhtari M, et al: NCCN Clinical Practice Guidelines in Oncology: Chronic myelogenous leukemia. Version 2, 2013. Available at http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed September 25, 2012.

6. Branford S, Yeung DT, Prime JA, et al: BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: Implications for monitoring and management. Blood 119:4264-4271, 2012.

0

20

40

60

80

100

Dou

blin

g tim

e (d

ays)

resistance

Blastcrisis

(n = 12)

Mutation,maintained CP

(n = 29)

After stableCMR

(n = 17)

BCR-ABL1positive(n = 12)

9.0 daysMedian doubling

times48.0 days 9.0 days 9.4 days

discontinuation

Fig. 1: BCR-ABL1 doubling times according to clinical context. The kinetics of the rise can be measured as the number of days over which BCR-ABL1 doubles. *Significant differences between the doubling times (P < .0001), compared with the blast crisis, discontinued in CMR and complete interruption groups. CMR = complete molecular response; CP = chronic phase. Reprinted with permission from Branford S et al.6

visitASCOPost.com



7

Beyond Molecular Monitoring: Cytogenetic Testing and Mutational Analysis in Chronic Myeloid Leukemia

Cytogenetic analysis re-mains an important com-

ponent of patient monitoring until a complete cytogenetic re-sponse is achieved. In addition, the ability of conventional cy-togenetics to identify addition-al chromosomal abnormalities not detected by fluorescence in situ hybridization is note-worthy. Jorge Cortes, MD, Professor of Medicine in the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, introduced the case of a 74-year-old male patient with chronic myeloid leukemia (CML) who presented with a loss of chromosome Y and translocation t(9;9;22) to illustrate these points.

Differing Criteria for Chronic- vs Accelerated-phase CML

There was some disagreement among audience mem-bers regarding classification of the patient as being in chronic- (54%; 66/122) vs accelerated-phase CML (44%; 54/122), mainly due to the various criteria that are used to define accelerated-phase CML (eg, the Inter-national Bone Marrow Transplant Registry, the World Health Organization [WHO], and MD Anderson Can-cer Center).1 One of the distinct features of the WHO classification is that the presence of additional cytoge-netic abnormalities in Philadelphia chromosome–posi-tive cells (clonal evolution) at the time of diagnosis is not considered to be a feature of accelerated-phase CML. Dr. Cortes pointed out that in the European LeukemiaNet recommendations, which the majority of respondents indicated that they most frequently use in their practice, clonal evolution at the time of diagnosis is considered to be just a warning sign. Nevertheless, half of respondents (80/159) said they would treat the patient with stan-dard-dose imatinib (Gleevec), with the remainder using second-generation tyrosine kinase inhibitors.

Variant Philadelphia Chromosome Translocations

An important question is: Does the presence of chro-mosomal abnormalities at diagnosis affect prognosis? Ac-cording to an analysis of data on 809 patients treated with

imatinib at MD Anderson, the complete cytogenetic re-sponse rate was similar in patients with clonal evolution at diagnosis and those with chronic-phase CML (86% and 76%, respectively), and both groups had similar 3-year progression-free survival rates (92% and 89%, respec-tively).2 Likewise, a multivariate analysis of earlier data on patients receiving imatinib at MD Anderson (n = 721) showed that variant Philadelphia chromosome transloca-tions involving chromosomes other than 9 and 22 (variant Philadelphia chromosome) had no impact on response rate, duration of response, or overall survival compared with patients with classic Philadelphia chromosome trans-locations.3 Similar findings were reported last year by the GIMEMA CML Working Party, who showed there was no impact of variant Philadelphia chromosome transloca-tions on cytogenetic and molecular response and survival outcomes in 559 patients with early chronic-phase CML receiving imatinib therapy.4 Together, these data suggest that patients with variant translocations do not constitute a “warning” category in the imatinib era.

Impact of Y-chromosome LossMales have a tendency to lose the Y chromosome

with aging, and the frequency of loss is slightly increased in individuals with hematologic malignancies. The next

question is: Does loss of the Y chromosome constitute clonal evolution, and how does it affect outcome? In a series of 724 patients with chronic-phase CML treated with imatinib at MD Anderson, Y-chromosome loss was infrequent, being seen in only 2% of patients (10 at diagnosis, 5 during treatment).5 Although the major cytogenetic response rate was equivalent in patients with chronic-phase CML both with and without the Y chromosome (80%), the complete cytogenetic response rate was substantially lower in patients who lacked the Y chromosome (20% vs 74%). In addition, event-free survival was lower in patients with chronic-phase CML

The question is: What impact do these [chromosomal] abnormalities have on the long-term outcome of patients?

— Jorge Cortes, MD

Jorge Cortes, MD



8

with loss of the Y chromosome compared with patients with chronic-phase CML who have a Y chromosome, and with patients with accelerated-phase CML (ie, clon-al evolution). Thus, although uncommon, loss of the Y chromosome did appear to have an impact on outcome in this study.

In contrast, long-term observation of a large series of patients from CML Study IV (n = 1,151) showed no im-pact of loss of the Y chromosome on 5-year overall sur-vival.6 In addition, a trend toward shorter survival was observed in patients with variant Philadelphia chromo-some, which is also contrary to the earlier data presented. Thus, the impact of these chromosomal abnormalities is not totally clear.

In general, Dr. Cortes feels that most physicians would not treat patients with loss of the Y chromo-some any differently than they would normally treat chronic-phase CML. In the case presented, the patient did indeed receive imatinib (800 mg/d) and achieved a complete cytogenetic response by 3 months and sus-tained 4-log molecular response (MR4; BCR-ABL/ABL 0.01% International Scale) by 12 months. At that time, cytogenetic analysis still showed the loss of the Y chro-mosome, but now also showed loss of chromosome 8 in 80% of metaphases, with no Philadelphia chromosome present. Other than moderate fluid retention requiring diuretics, the patient is doing well. When asked if ther-apy should be changed based on these findings, almost half of respondents (45%; 71/158) said they would continue the current treatment, 30% (47/158) would reduce the dose of imatinib to address the edema, and 25% (39/158) would switch to nilotinib (Tasigna) or dasatinib (Sprycel). Only 1% (1/158) indicated they would proceed to stem cell transplant.

Long-term EffectsAccording to Dr. Cortes, chromosomal abnormali-

ties appear in Philadelphia chromosome–negative metaphases in approximately 10% to 15% of patients with CML treated with imatinib. Such chromosomal abnormalities are not unique to imatinib but are seen with all tyrosine kinase inhibitors, including newer and investigational agents. However, patients are less likely to lose their response with second-generation tyrosine kinase inhibitors.

“Curiously, these abnormalities tend to be more fre-quently the kind of abnormalities we see in myelodysplas-tic syndromes [MDS]: trisomy 8, –5, 20q–, etc,” noted Dr. Cortes. “The question is: What impact do these abnor-malities have on the long-term outcome of patients?” One of the fears is that these changes may lead to the develop-

ment of MDS or acute leukemia. In the few reported cases of MDS/acute leukemia

developing in Philadelphia chromosome–negative CML treated with imatinib, –7 is often seen, but a variety of other chromosomal abnormalities are also noted. As such, Dr. Cortes feels that there is always a need to fol-low up on such abnormalities, but they are not neces-sarily an indication to treat. An analysis of patients who developed chromosomal abnormalities in Philadelphia chromosome–negative metaphases with imatinib af-ter interferon failure showed a low (0.4%) incidence of MDS.7 In addition, the presence of chromosomal abnor-malities did not significantly impact overall survival or progression-free survival in patients achieving a major cytogenetic response in this study. An analysis of chro-mosomal abnormalities in Philadelphia chromosome–

negative metaphases after front-line imatinib undertaken at MD Anderson showed only one case of acute myeloid leukemia (0.4%), but revealed slightly lower overall sur-vival and progression-free survival in patients develop-ing chromosomal abnormalities.8 When progression did occur, Dr. Cortes noted that it mainly consisted of loss of response rather than transformation or non–CML-related death. However, there is not enough evidence at this time to indicate that a change in therapy would be warranted.

Increasing Transcript LevelsDr. Cortes concluded his session with a brief discus-

sion on the clinical significance of increasing transcript levels in CML, citing the landmark 2004 paper by Bran-ford et al, showing that a greater than twofold rise can indicate the presence of BCR-ABL kinase domain muta-

Chromosomal Abnormalities

■ Variant Philadelphia chromosome translocations involving chromosomes other than 9 and 22 generally had no impact on response rate, duration of response, or overall survival, compared with patients with classic Philadelphia chromosome translocations.

■ In one study, the complete cytogenetic response rate was substantially lower in patients who lacked the Y chromosome (20% without vs 74% with), but long-term observation patients in another study showed no impact on 5-year overall survival.

■ Abnormalities such as trisomy 8, –5, and 20q– appear in Philadelphia chromosome–negative metaphases in 10%–15% of patients with CML treated with imatinib.



9

Defining and Recognizing the Causes of Imatinib Resistance and the Importance of Adherence

Imatinib (Gleevec) is a highly effective therapy for the majority of patients with chronic myeloid leu-

kemia (CML). In the IRIS study, only 30% of patients could be considered to have failed imatinib treatment after 6 years.1 However, these 30% of patients are a substantial minority. John Goldman, DM, FRCP, FRCPath, FMedSci, of Imperial College London, provided an example of a case of a 50-year-old female patient with chronic-phase CML who received initial therapy with standard-dose imatinib. Due to her lack of a complete hematologic response and BCR-ABL transcript level above 10% at 3 months, she would be considered to have failed imatinib based on both Euro-pean LeukemiaNet and National Comprehensive Can-cer Network (NCCN) criteria, respectively.

Two Scoring SystemsThe basis for heterogeneity in response to imatinib

is not known, and efforts have been made to classify

patients at the time of diagnosis in order to determine prognosis. Until recently, assessment of the prognosis of patients treated with tyrosine kinase inhibitors has relied on risk stratification based on prognostic clas-sifications developed for patients treated with conven-tional chemotherapy2 or interferon alfa.3 A slight dis-cordance was demonstrated between these two scoring systems when used in the IRIS study. More recently, the EUTOS (European Treatment and Outcome Study

tions.9 A recent mutational data analysis performed by the GIMEMA CML Working Party to validate updated European LeukemiaNet recommendations for mutation-al analysis indicated a 27% incidence of mutations in pa-tients for whom imatinib fails (European LeukemiaNet response criteria), confirming the importance of mu-tational analysis in these cases.10 A low 4% incidence of mutations was seen in patients with suboptimal response losing a major molecular response, so mutational analysis may not be needed in this instance. ■References

1. Quintas-Cardama A, Cortes JE: Chronic myeloid leu-Chronic myeloid leu-kemia: Diagnosis and treatment. Mayo Clin Proc 81:973-988, 2006.

2. Cortes JE, Talpaz, M, O’Brien S, et al: Staging of chronic myeloid leukemia in the imatinib era: An evaluation of the World Health Organization proposal. Cancer 106:1306-1315, 2006.

3. El-Zimaity MM, Kantarjian H, Talpaz M, et al: Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol 125:187-195, 2004.

4. Marzocchi G, Castagenetti F, Luatti S, et al: Variant Phila-Variant Phila-delphia translocations: Molecular-cytogenetic characteriza-tion and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis. Blood 117:6793-6800, 2011.

5. Jabbour E, Kantarjian H, Ravandi-Kashani F, et al: Clini-cal significance of loss of chromosome Y (–Y) in patients with chronic myeloid leukemia (CML): Is it clonal evolution? Blood 108(suppl 11):Abstract 2117, 2006.

6. Fabarius A, Leitner A, Hochhaus A, et al: Impact of ad-ditional cytogenetic aberrations at diagnosis on prognosis of CML: Long-term observation of 1151 patients from the ran-domized CML Study IV. Blood 118:6760-6768, 2011.

7. Deininger MWN, Cortes J, Paquete R, et al: The prognosis for patients with chronic myeloid leukemia who have clonal cy-togenetic abnormalities in Philadelphia chromosome–negative cells. Cancer 110:1509-1519, 2007.

8. Jabbour E, Kantarjian HM, Abruzzo LV, et al: Chromo-somal abnormalities in Philadelphia chromosome–negative metaphases appearing during imatinib mesylate therapy in pa-tients with newly diagnosed chronic myeloid leukemia in chron-ic phase. Blood 110:2991-2995, 2007.

9. Branford S, Rudzki Z, Parkinson I, et al: Real-time quan-Real-time quan-titative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood 104:2926-2932, 2004.

10. Soverini S, Gnani A, De Benedittis C, et al: Validation of the new European LeukemiaNet (ELN) recommendations for Bcr-Abl kinase domain mutation analysis in chronic myeloid leukemia: An analysis of the GIMEMA CML Working Party studies. Blood 118(suppl 21):Abstract 112, 2011.

The 3-month point can be a very valuable time point at which to

classify a patient as resistant in terms of primary response to a [tyrosine kinase

inhibitor], such as in this case of imatinib unresponsiveness.

— John Goldman, DM, FRCP, FRCPath, FMedSci



10

for CML) score has been developed based on data from a registry of 2,060 patients enrolled in studies of first-line imatinib-based regimens.4 This scoring system is based on spleen size and percentage of basophils, and can discriminate between high- and low-risk patients with regard to probability of complete cytogenetic response and progression-free survival. However, the EUTOS scoring system remains to be independently confirmed and does not appear to correlate very well with data from Hammersmith Hospital in London, ac-cording to Dr. Goldman.

Benefit of 3-month CutoffSo, is there a better way to determine prognosis?

Assessment of BCR-ABL transcript level at 3 months appears to be the best way to identify patients destined to fare poorly. A recent analysis of 283 patients with chronic-phase CML at Hammersmith Hospital receiv-ing imatinib (or a second-generation tyrosine kinase-inhibitor in case of failure) who were followed for up to 8 years was reported by Marin et al.5 Receiver op-erating characteristic analysis was conducted to deter-mine the BCR-ABL transcript level cutoffs that would best predict patient outcome. Patients with transcript

levels of more than 9.84% at 3 months had significantly lower 8-year probabilities of overall survival (56.9% vs 93.3%; P < .001) and progression-free survival, as well as complete cytogenetic response and complete mo-lecular response, than those with higher transcript lev-els. Dr. Goldman pointed out the fact that a transcript level cutoff of 0.61 or lower at 3 months was able to de-fine the probability that a patient would subsequently achieve a complete molecular response.

Based on this analysis and other published pa-

pers corroborating these results, particularly that of Hanfstein et al6 published this year, Dr. Goldman con-cluded that “the 3-month point can be a very valuable time point at which to classify a patient as resistant in terms of primary response to a [tyrosine kinase in-hibitor], such as in this case of imatinib unresponsive-ness.” However, there was some disagreement among panel members about changing therapy if a patient has a transcript level above this cutoff at 3 months. Jorge Cortes, MD, suggested waiting until 6 months to con-sider a change, whereas Dr. Goldman pointed out the lack of prognostic value of the 6-month time point. Interestingly, the NCCN Clinical Practice Guidelines do not provide a recommendation for assessing a re-sponse to therapy at 6 months, while the European LeukemiaNet recommendations do provide for such an assessment.

Three Patterns of Molecular ResponseIn continuation of his presentation, Dr. Goldman

noted that three patterns of molecular response can be described in patients achieving complete cytoge-netic response following imatinib therapy.7 In the first, transcript levels continue to decline, reaching a level below 0.01%, and the patient does well. In the sec-ond, transcripts decline up to a point, reaching a level between a major molecular response and a complete cytogenetic response, and then level off (plateau). In the third, transcript levels initially decline, but then in-crease and the initial complete cytogenetic response is lost (cytogenetic relapse). It is important to note that patients with each pattern can have different levels of responsiveness or sensitivity to a particular tyrosine kinase inhibitor.

Mechanisms of ResistanceWhat are the mechanisms that underlie resistance?

Resistance can be primary or secondary (acquired), each of which may have a different molecular basis. Dr. Goldman has created a classification scheme for resis-tance that categorizes resistance as being pharmacologic, leukemia cell–related, or patient-related. Acquisition of ABL kinase domain mutations is an important acquired mechanism of resistance that can be categorized as be-ing leukemia cell–related. For example, the mutation caused by replacement of threonine by isoleucine at 315 (T315I) interferes with the binding of imatinib and the second-generation tyrosine kinase inhibitors; this resis-tance may be overcome with third-generation investiga-tional agents such as ponatinib.

Patient-related resistance is particularly related to

Mechanisms of Resistance in Chronic Myeloid Leukemia

■ In the IRIS study, imatinib treatment was considered to have failed in 30% of patients after 6 years.

■ The T314I mutation interferes with the binding of imatinib and second-generation tyrosine kinase inhibitors. This resistance may be overcome with third-generation tyrosine kinase inhibitors such as ponatinib.

■ Patient-related resistance is particularly related to poor adherence and refers primarily to patients who do not respond very well or lose their response rapidly. Microelectronic monitoring systems are standard methods of assessing adherence.



11

poor adherence and refers primarily to patients who do not respond very well or lose their response fairly rapidly. There are a number of indirect methods of as-sessing adherence, but microelectronic monitoring systems are considered to be the “gold standard.”

Marin and colleagues at Hammersmith Hospital used microelectronic monitoring systems to determine whether variability in adherence could account for the variability in level of molecular responses achieved with imatinib.8 In patients who achieved complete cytogenet-ic response, achievement of a major molecular response was strongly associated with adherence. The 6-year prob-ability of achieving a major molecular response was sig-nificantly higher in patients having an adherence rate of higher than 90% compared to those with rates of 90% or lower (94.5% vs 28.4%, P < .001). ■References

1. Hochhaus A, Druker BJ, Larson RA, et al: IRIS 6-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood 110(suppl 11):Abstract 25, 2007.

2. Sokol, JE, Cox EB, Baccarani M, et al: Prognostic dis-crimination in “good-risk” chronic granulocytic leukemia. Blood 63:789-799, 1984.

3. Hasford J, Pfirrmann M, Hehlmann R, et al: A new prognostic score for survival of patients with chronic my-eloid leukemia treated with interferon alfa. Writing Com-mittee for the Collaborative CML Prognostic Factors Proj-ect Group. J Natl Cancer Inst 90:850-858, 1998.

4. Hasford J, Baccarani M, Hoffmann V, et al: Predict-Predict-ing complete cytogenetic response and subsequent progres-sion-free survival in 2060 patients with CML on imatinib treatment: The EUTOS score. Blood 118:686-692, 2011.

5. Marin D, Ibrahim AM, Lucas C, et al: Assessment of BCR-ABL1 transcript levels at 3 months is the only require-ment for predicting outcome for patients with chronic my-eloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 20:232-238, 2012.

6. Hanfstein B, Muller MC, Hehlmann R, et al: Early mo-lecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leu-kemia (CML). Leukemia 26:22096-22102, 2012.

7. Marin D, Kaeda J, Szydlo R, et al: Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: Patterns of residual leukae-mia and prognostic factors for cytogenetic relapse. Leuke-mia 19:507-512, 2005.

8. Marin D, Bazeos A, Mahon F-X, et al: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytoge-netic responses on imatinib. J Clin Oncol 28:2381-2388, 2010.

Managing Treatment Failure in Chronic Myeloid Leukemia

As John Goldman, DM, FRCP, FRCPath, FMedSci, discussed earlier, a substantial mi-

nority of patients with chronic myeloid leukemia (CML) experience treatment failure. Jorge Cortes, MD, of The University of Texas MD Anderson Can-cer Center, introduced this session with two patient cases to illustrate how subsequent therapy must be tailored to the individual experiencing treatment failure. The first patient had been treated with ima-tinib (Gleevec) after having becoming intolerant of interferon. Her best response was a major cyto-genetic response, and after 26 months, she lost her complete hematologic response. At that time her only option was an increased dose of imatinib, which seems primarily to help those who have developed cytogenetic resistance, but is less likely to be effec-tive in patients losing a hematologic response, which was exactly what happened in this case. No muta-tions were detected, and the patient was started on dasatinib (Sprycel).

The patient rapidly achieved a complete cytogenetic response and a 2-log reduction in transcript levels, but

she lost her complete cytogenetic response (20% Phila-delphia chromosome–positive metaphases) 19 months later. Despite dose escalation of dasatinib, Philadelphia chromosome–positive metaphases increased to 100% with loss of complete hematologic response. Direct se-quencing revealed the presence of F486S and V299L mutations. Subsequent failure of bosutinib (Bosulif ) (mutation sensitivity data for this agent were not avail-able at the time), followed by a rapid response with nilotinib (Tasigna), which is effective against this mu-tation, highlights the need to tailor therapy based on mutations present and their tyrosine kinase inhibitor

One of the important things that we need to recognize about T315I is

that it is not necessarily the most aggressive mutation.

— Jorge Cortes, MD



12

sensitivity pattern. “In chronic-phase CML,

patients with mutations with a low half maximal inhibi-tory concentration [IC50] for a specific drug have a very good outcome, whereas those with mutations with an intermedi-ate IC50 do worse, and those with mutations with a high IC50, particularly T315I, do not do well at all,” noted Dr. Cortes. In accelerated-phase CML, it is not as clear; the cor-relation with response is there, but there is no correlation with event-free survival, likely due to additional molecular events characteristic of transforma-tion.

Dr. Cortes pointed out that the investigational agent ponatinib has been shown to be effective against all of the mutations commonly seen in the clinic in which it has been tested including the T315I mutation.1 More importantly, mutagenesis assays have demonstrated that this agent suppresses mutant outgrowth (resistant clones) at pharmacologic doses.

Early Intervention StressedThe patient introduced in the second case expe-

rienced treatment failure with front-line imatinib despite a dose increase. Although still in complete hematologic response, the G250E and F317L mu-tations were detected. At this point, the audience respondents were about equally divided between choosing dasatinib or nilotinib as second-line ther-apy. Dr. Cortes stressed the need to intervene early once it is clear that a patient has lost a response, and certainly for loss of a cytogenetic response. Some physicians will wait until a patient has lost a complete hematologic response before referring, but the prob-ability of achieving a good response with a second-line agent drops significantly at that point. Likewise, if a patient has not achieved a complete hematologic response by 3 months, a change in therapy should be considered.

The patient received nilotinib and achieved a com-plete cytogenetic response after 6 months. Follow-up sequencing analysis showed persistence of the two preexisting mutations, with the appearance of T315I. The patient had no sibling donors, so a registry search was undertaken while nilotinib was continued, since no other options were available at the time. The pa-tient remained in complete cytogenetic response, but after 15 months of therapy, the two original muta-tions were no longer detectable, T315I remained, and Y253H appeared. Despite the presence of T315I, the patient continued to be stable for over 1 year before receiving a transplant.

“One of the important things that we need to recog-nize about T315I is that it is not necessarily the most

Ponatinib and Omacetaxine

■ In the phase II PACE study of ponatinib, major cytogenetic response was achieved by 54% of chronic-phase patients, including 49% of patients who were refractory or intolerant to dasatinib or nilotinib and 70% with the T315I mutation.

■ In a phase II/III study of imatinib-resistant disease with T315I mutations, patients with chronic-phase CML had a major cytogenetic response rate of 27% when treated with omacetaxine mepesuccinate, with two-thirds of those being complete cytogenetic responses.

■ In a separate study of omacetaxine in patients not harboring T315I mutations who were resistant to two or more tyrosine kinase inhibitors, 10% of chronic-phase patients achieved complete cytogenetic response and 24% of accelerated-phase patients achieved complete hematologic response.

Ponatinib is not approved by the FDA for the treatment of CML.aComplete hematologic response maintained or achieved during study; 103 patients had complete hematologic response at baseline.bMajor cytogenetic response = primary endpoint.cPatients without a valid baseline major molecular response, or who meet the criteria for major molecular response at baseline, counted as nonresponders.dExcludes 3 patients who were unassigned (post-imatinib, non-T315I) but treated. R/I = refractory/intolerant.Reprinted with permission from Cortes JE et al.3

TABLE 1: PACE: Response to Ponatinib in Chronic-phase CML

Response

Number of Responses (%)

Overalld (n = 267)

R/I Cohort (n = 203)

T315I Cohort (n = 64)

Complete hematologic responsea 249 (93) 191 (94) 58 (91)

Major cytogenetic responseb 144 (54) 99 (49) 45 (70)

Complete cytogenetic response 118 (44) 76 (37) 42 (66)

Major molecular responsec 79 (30) 47 (23) 32 (50)



13

aggressive mutation,” noted Dr. Cortes. For example, Y253F is a much more efficient mutation in terms of transformation capacity.2 Although relapses may not necessarily happen immediately, they will occur, so new agents are needed to address them.

Agents Targeting T315I MutationThe third-generation tyrosine kinase inhibitor

ponatinib has been shown to be effective in patients harboring the T315I mutation as well as patients who are resistant or intolerant to previous tyrosine kinase inhibitor therapy. In the phase II PACE (Ponatinib Ph+ ALL and CML Evaluation) study, major cyto-genetic response (the primary endpoint for chronic-phase patients) was achieved by 54% of chronic-phase patients, including 49% of patients who were refrac-tory or intolerant to dasatinib or nilotinib and 70% of patients with the T315I mutation (Table 1, page 12).3 The rates of major hematologic response (the primary endpoint in accelerated- or blast-phase patients) in patients with advanced disease who were refractory or intolerant to previous tyrosine kinase inhibitor thera-py or who had the T315I mutation were also substan-tial (60% and 50%, respectively, in accelerated-phase CML and 35% and 33%, respectively, in blast-phase CML).

A phase II trial designed to evaluate ponatinib as front-line therapy in patients with early chronic-phase Philadelphia chromosome–positive CML is cur-rently enrolling patients (ClinicalTrials.gov identifier NCT01570868), as is a randomized, open-label, phase III trial comparing ponatinib and imatinib in adult pa-tients with newly diagnosed chronic-phase CML (Clini-calTrials.gov identifier NCT01650805). A New Drug Application for use of ponatinib in patients with resis-tant or intolerant CML and Philadelphia chromosome–positive acute lymphoblastic leukemia was submitted to the FDA in July 2012.

Omacetaxine mepesuccinate (Synribo) is a recent-ly approved agent that has demonstrated efficacy in patients with T315I mutation. In a phase II/III study in imatinib-resistant disease, a major cytogenetic re-sponse rate of 27% was seen in patients with chronic-phase CML, and two-thirds of these were complete cytogenetic responses.4 In a separate study of patients not harboring T315I who were resistant to two or more tyrosine kinase inhibitors, including imatinib, 10% of patients with chronic-phase CML achieved a complete cytogenetic response, and 24% of patients with accelerated-phase CML achieved complete he-matologic response.5

New Agent Approved for Ph+ CMLPatients without the T315I mutation have a new

option available to them, the tyrosine kinase inhibitor bosutinib, which was recently approved for use in the United States in adult patients with all phases of Phila-delphia chromosome–positive CML with resistance or intolerance to prior therapy. Among patients experi-encing failure of imatinib and a second-generation ty-rosine kinase inhibitor, between 30% and 35% achieved a major cytogenetic response with bosutinib, with many being complete cytogenetic responses.6 Patients who were resistant to imatinib and dasatinib were less likely to achieve complete cytogenetic response (14%) than patients who were resistant to imatinib and nilo-tinib (27%) and those who were imatinib-resistant/dasatinib-intolerant (28%). Responses also varied ac-cording to baseline mutation, with lower levels of re-sponses in patients who harbored F317L, which also confers resistance to dasatinib.7 Thus, it is essential to obtain mutational status. ■References

1. O’Hare T, Shakespeare WC, Zhu X, et al: AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, po-tently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:410-412, 2009.

2. Griswold IJ, MacPartlin M, Bumm T, et al: Kinase do-Kinase do-main mutants of Bcr-Abl exhibit altered transformation po-tency, kinase activity, and substrate utilization, irrespective of sensitivity of imatinib. Mol Cell Biol 26:6082-6093, 2006.

3. Cortes JE, Kim D, Pinilla-Ibarz J, et al: PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol 30(suppl 15):Abstract 6503, 2012.

4. Cortes-Franco J, Khoury HJ, Nicolini FE, et al: Safety and efficacy of subcutaneous-administered omacetaxine me-pesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients who harbour the Bcr-Abl T315I mutation-results of an ongoing multicenter phase 2/3 study. Blood 114(suppl 22):Abstract 644, 2009.

5. Cortes JE, Nicolini FE, Wetzler M, et al: Subcutaneous omacetaxine in chronic or accelerated chronic myeloid leu-kemia resistant to two or more tyrosine-kinase inhibitors in-cluding imatinib. Blood 118(suppl 21):Abstract 3761, 2011.

6. Khoury HJ, Cortes JE, Kantarjian HM, et al: Bosuti-nib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119:3403-3412, 2012.

7. Khoury HJ, Cortes JE, Gambacorti-Passerini C, et al: Activity of bosutinib by baseline and emergent mutation sta-tus in Philadelphia chromosome-positive leukemia patients with resistance or intolerance to other tyrosine kinase inhibi-tors. Blood 118(suppl 21):Abstract 110, 2011.



14

Defining a Cure for Chronic Myeloid Leukemia and Strategies to Achieve this Goal

In chronic myeloid leukemia (CML), continued long-term therapy that prevents both progression to ac-

celerated-phase disease and the emergence of resistance may be thought of as an “operational” or “functional” cure. However, long-term disease control without the requirement for continuous treatment is currently being sought, and there is much ongoing investigation in de-veloping strategies to eradicate leukemic stem cells.

Case StudyTimothy Hughes, MD, MBBS, of the Centre for

Cancer Biology, Adelaide, South Australia, introduced this discussion with a case of a 30-year-old female patient with CML. She is currently receiving imatinib (Gleevec) at 600 mg/d and had achieved a complete cytogenetic re-sponse by 18 months. However, she has not yet achieved a major molecular response. The patient hopes to start a family soon, and was looking to her clinician for guid-ance as to when it would be safe to proceed. She ques-tioned if switching to nilotinib (Tasigna) or dasatinib (Sprycel) would provide a greater chance of achieving a stable response, offering an opportunity for her to stop therapy while attempting a pregnancy.

It is desirable to achieve a deep molecular response in this situation based on observations from the French STIM (Stop Imatinib) study (Fig. 1)1 and the Austral-

asian Leukaemia & Lymphoma Group CML8 trial of imatinib withdrawal.2 Both studies have shown that about 40% of patients who achieved a stable complete molecular response of at least 2 years duration could

maintain that response after discontinuation of imatinib. Thus, these data may provide both hope and guidance for the patient.

Greater Stability with Early Major Molecular Response

However, the patient has not achieved a major mo-lecular response. What are her chances of being free of disease progression? If one looks at event-free survival data from the 18-month landmark analysis of the IRIS study, her probability of being progression-free with a complete cytogenetic response is 86%; this increases to 95% if she achieves a major molecular re-sponse.3 More importantly, what are her chances of losing her com-plete cytogenetic response? In the same 18-month landmark analy-sis, 29% of patients who achieved transcript levels between 0.1% and 1%, which is consistent with complete cytogenetic response without a major molecular re-sponse, lost their complete cyto-genetic response over the subse-

In the confines of a closely monitored clinical trial, where you have documented stable complete molecular

response for 24 months, [and] follow them with monthly polymerase chain

reaction with a sensitive test, it seems to be appropriate and safe to stop therapy

and watch those patients.

— Timothy Hughes, MD, MBBS

0.00.10.20.30.40.50.60.70.80.91.0

Surv

ival

with

out m

olec

ular

rela

pse

Months since discontinuation of imatinib

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60

39% (95% CI 29-48)at 24 and 36 months

Fig. 1: Overall probability of complete molecular response maintenance after discontinuation of imatinib in STIM trial. Molecular relapse occurred in 61 patients, with 58 relapses occurring during the first 7 months and 3 late relapses at month 19, 20, and 22, respectively. Reprinted with permis-sion from Mahon F-X et al.1



15

quent 5.5-year period. In contrast, only 4% of patients who had achieved a major molecular response lost their complete cytogenetic response during that time frame. Data from Hammersmith Hospital were similar.4 These data provide good reasons for why one would want this patient to achieve a major molecular response prior to considering treatment cessation.

Achievement of a major molecular response by 12 or 18 months is associated with a low risk of progres-sion. Long-term follow-up of 181 patients with chron-ic-phase CML in Adelaide who were treated with first-line imatinib suggests that earlier achievement of a major molecular response also leads to greater stability of response.5 In this study, the probability of achieving a confirmed complete molecular response

(defined as a complete molecular response on two consecutive tests) by 60 months was determined for patients who achieved a major molecular response. Patients who achieved a major molecular response by 6 months had a high probability (93%) of achieving complete molecular response by 5 years. As the time to achieve major molecular response became longer, the chances of achieving complete molecular response was considerably reduced (ie, 69% if major molecular response was achieved between 6 and 12 months and 37% if major molecular response was achieved be-tween 12 and 18 months). None of the patients who achieved a major molecular response after 18 months went on to achieve a complete molecular response.

“So, this woman is facing the reality that if she con-tinues her current therapy, her chances of achieving complete molecular response are close to zero,” noted Dr. Hughes. “Therefore, she would not even get to the

point where you would be even going to consider stop-ping, if your focus was to maintain durable complete molecular response.”

ENESTcmr TrialThis brought up the discussion of the ENESTcmr

study. This randomized trial focused on the idea that, in patients who are still BCR-ABL–positive after at least 2 years of imatinib therapy, it might be beneficial to switch to nilotinib due to its greater potency. By switching, one might be able to induce more patients to achieve deep molecular responses, including complete molecular re-sponse. Indeed, of patients on study at 12 months, twice as many who crossed over to nilotinib achieved a con-firmed complete molecular response compared to those remaining on imatinib (14.9% vs 6.1%, respectively; P = .04).6 Of particular relevance to the patient case, in patients who had not achieved a major molecular re-sponse at baseline, 75% of those switching to nilotinib achieved a major molecular response within 12 months compared to 36% of those remaining on imatinib. Even more convincingly, of patients not in major molecular response or better at baseline who were switched to ni-lotinib, 25.0% had achieved a deep molecular response (4.5-log reduction in BCR/ABL, or MR4.5) within 12 months compared to 3.6% of those remaining on ima-tinib (P = .040). Thus, it is possible in some cases to take a patient who is hovering at a transcript level greater than 0.1% and get him to a deep molecular response within a year.

CML8 StudyDr. Hughes commented that in the CML8 study, pa-

tients who had a molecular relapse after imatinib cessa-tion were started back on their previous therapy at their last effective dose, which rapidly restored complete mo-lecular response; there was no need to switch to a more potent drug.2 Importantly, there have been no cases of progression, mutation, or resistance in these patients. All patients remained in major molecular response at last follow-up; 64% never lost their major molecular re-sponse, and 86% were in complete molecular response at their latest visit.

“I think that in the confines of a closely monitored clinical trial, where you have documented stable com-plete molecular response for 24 months, where you fol-low them with monthly polymerase chain reaction with a sensitive test, it seems to be appropriate and safe to stop therapy and watch those patients,” Hughes noted. “But that should not be translated into stopping in a situation where you have suboptimal molecular moni-

Major Molecular Response in Chronic Myeloid Leukemia

■ About 40% of patients who achieve a stable complete molecular response of at least 2 years can maintain that response after discontinuation of imatinib.

■ As the time to achieve major molecular response becomes longer, the chances of achieving complete molecular response is considerably reduced (69% if major molecular response is achieved between 6 and 12 months vs 37% if between 12 and 18 months).

■ According to the ENESTcmr trial, switching patients who are still BCR-ABL–positive to nilotinib after 2 years of imatinib therapy improves their chances of achieving complete molecular response.



16

toring or it is not possible or realistic to monitor those patients very, very closely.”

Dr. Hughes concluded that the evidence suggests that switching would improve the patient’s chances of achiev-ing a complete molecular response or deep molecular re-sponse, which would be a good platform for stopping for an attempted pregnancy. Although it is unknown wheth-er the chances of sustained complete molecular response off-therapy would be improved, her chances are very low if she remains on imatinib.

Jorge Cortes, MD, asked whether one could just in-crease the dose of imatinib in this case. Dr. Hughes agreed that, based on data from the ENESTnd study, it could in-crease the probability of achieving a major molecular re-sponse. There was some discussion, however, regarding the need to consider the speed of obtaining the response, with imatinib acting more slowly. Use of interferon al-ways remains an option during pregnancy. ■References

1. Mahon F-X, Réa D, Guilhot J, et al: Discontinuation of imatinib in patients with chronic myeloid leukemia who have maintained complete molecular response: Update results of the STIM study. Blood 118(suppl 21):Abstract 603, 2011.

2. Ross M, Branford S, Seymour J, et al: Frequent and sus-tained drug-free remission in the Australasian CML8 trial of imatinib withdrawal. Haematologica 97(suppl 1):Abstract 0189, 2012.

3. Hughes TP, Hochhaus A, Branford S, et al: Long-term prognostic significance of early molecular response to ima-tinib in newly diagnosed chronic myeloid leukemia: An analy-sis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 116:3758-3765, 2010.

4. Marin D, Milojkovic D, Olavarria E, et al: European Leu-kemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood 12:4437–4444, 2008.

5. Branford S, Lawrence R, Grigg A, et al: Long term follow up of patients with CML in chronic phase treated with first-line imatinib suggests that earlier achievement of a major mo-lecular response leads to greater stability of response. Blood 112(suppl 11):Abstract 2113, 2008.

6. Hughes TP, Lipton JH, Leber B, et al: Complete mo-lecular response (CMR) rate with nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) without CMR after 2 years on imatinib: Preliminary results from the randomized ENESTcmr trial of nilotinib 400 mg twice daily (BID) vs imatinib. Blood 118(suppl 21):Abstract 606, 2011.

The content of this supplement, Highlights of an ESH-iCMLf Satellite Symposium – Monitoring, Treatment Resistance, and Treatment Failure in Chronic Myeloid Leukemia: Breaking Barriers to Improved Outcomes and Looking Forward to a Cure, is a component of an online CE activity accessible at this link: http://www.hbrsd.com/9Fc.

Continuing Education

http://www.hbrsd.com/9Fc

©2012 by Harborside Press

This activity is sponsored by Medical College of Wisconsin and MediCom Worldwide, Inc.

This activity was supported by an unrestricted educational grant from ARIAD Pharmaceuticals.

tap vol 3 issue 17 supplement - monitoring, treatmentresistance, and treatment failure in cml

Documents

asco members

asco postthe asco post

asco member services

main street cold spring

mailing address

treatment failure

treatment resistance

chief email