Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Annals of Hematology
Published in: Annals of Hematology 2/2015

01-04-2015 | Review Article

Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenous leukemia patients

Authors: Andreas Hochhaus, Thomas Ernst, Ekkehard Eigendorff, Paul La Rosée

Published in: Annals of Hematology | Special Issue 2/2015

Login to get access

Abstract

For patients with chronic myelogenous leukemia who fail first-line therapy, several factors should be considered for the decision of the next treatment option. Second-generation tyrosine kinase inhibitors (TKIs) dasatinib, nilotinib, and bosutinib offer improved potency and a high likelihood of success for these patients. Overall, efficacy data are comparable for these agents, and so physicians should consider the BCR-ABL1 mutation profile and the patient’s history to make a decision on the best choice. Only a few BCR-ABL1 mutations seem to be less responsive to any of the three drugs, and it is recommended to choose the second-line TKI that has shown clinical activity against the specific mutation in these cases. For patients with all other mutations and for patients with no mutations, it is recommended to choose the second-generation TKI based on the patient’s disease history. The third-generation TKI ponatinib is available after dasatinib or nilotinib failure or for patients with T315I mutations. However, optimal dose of ponatinib is still under investigation. Overall, it is recommended to select a drug that minimizes the likelihood of worsening the patient’s past side effects or comorbid conditions. In any case, chance and risk of allogeneic stem cell transplantation should be compared with the long-term outcome of TKI therapy in patients eligible for this procedure.
Literature
1.
Hochhaus A, La Rosée P (2004) Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 18:1321–1331CrossRefPubMed
2.
Ernst T, Hochhaus A (2012) Chronic myeloid leukemia: clinical impact of BCR-ABL1 mutations and other lesions associated with disease progression. Semin Oncol 39:58–66CrossRefPubMed
3.
Hanfstein B, Müller MC, Hehlmann R, Erben P, Lauseker M, Fabarius A et al (2012) Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 26:2096–2102CrossRefPubMed
4.
Jabbour E, Deininger M, Hochhaus A (2011) Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia 25:201–210CrossRefPubMed
5.
Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD (2007) Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7:345–356CrossRefPubMed
6.
Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A et al (2006) In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res 66:11314–11322CrossRefPubMed
7.
O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F et al (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401–412CrossRefPubMedCentralPubMed
8.
9.
Sprycel® (dasatinib) capsules [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2014
10.
Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M, Kiefer SE et al (2006) The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 66:5790–5797CrossRefPubMed
11.
O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J et al (2005) In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 65:4500–4505CrossRefPubMed
12.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R et al (2006) Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354:2531–2541CrossRefPubMed
13.
Hochhaus A, Kantarjian H (2013) The development of dasatinib as a treatment for chronic myeloid leukemia (CML): from initial studies to application in newly diagnosed patients. J Cancer Res Clin Oncol 139:1971–1984CrossRefPubMedCentralPubMed
14.
Shah NP, Kantarjian HM, Kim DW, Réa D, Dorlhiac-Llacer PE, Milone JH (2008) Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 26:3204–3212
15.
Shah NP, Kim DW, Kantarjian H, Rousselot P, Llacer PE, Enrico A (2010) 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 95:232–240CrossRefPubMedCentralPubMed
16.
Hochhaus A, Baccarani M, Deininger M, Apperley JF, Lipton JH, Goldberg SL (2008) Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 22:1200–1206CrossRefPubMed
17.
Quintás-Cardama A, Kantarjian H, Ravandi F, O’Brien S, Thomas D, Vidal-Senmache G et al (2009) Bleeding diathesis in patients with chronic myelogenous leukemia receiving dasatinib therapy. Cancer 115:2482–2490CrossRefPubMedCentralPubMed
18.
Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N et al (2011) Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood 117:1141–1145CrossRefPubMed
19.
Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S et al (2014) Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol 89:732–742CrossRefPubMedCentralPubMed
20.
Kantarjian H, Pasquini R, Lévy V, Jootar S, Holowiecki J, Hamerschlak N et al (2009) Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R). Cancer 115:4136–4147CrossRefPubMed
21.
Apperley JF, Cortes JE, Kim DW, Roy L, Roboz GJ, Rosti G et al (2009) Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START A trial. J Clin Oncol 27:3472–3479CrossRefPubMed
22.
Cortes J, Kim DW, Raffoux E, Martinelli G, Ritchie E, Roy L et al (2008) Efficacy and safety of dasatinib in imatinib-resistant or intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 22:2176–2183
23.
Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G et al (2011) BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118:1208–1215CrossRefPubMed
24.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884CrossRefPubMed
25.
Mustjoki S, Auvinen K, Kreutzman A, Rousselot P, Hernesniemi S, Melo T et al (2013) Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy. Leukemia 27:914–924CrossRefPubMed
26.
Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A et al (2005) Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7:129–141CrossRefPubMed
27.
Hochhaus A, La Rosée P, Müller MC, Ernst T, Cross NC (2011) Impact of BCR-ABL mutations on patients with chronic myeloid leukemia. Cell Cycle 10:250–260CrossRefPubMed
28.
Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B et al (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–2551CrossRefPubMed
29.
Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG et al (2013) Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia 27:107–112CrossRefPubMed
30.
le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N et al (2008) 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 111:1834–1839
31.
Giles FJ, Kantarjian HM, le Coutre PD, Baccarani M, Mahon FX, Blakesley RE et al (2012) Nilotinib is effective in imatinib-resistant or intolerant patients with chronic myeloid leukemia in blastic phase. Leukemia 26:959–962
32.
Cortes JE, Hochhaus A, le Coutre PD, Rosti G, Pinilla-Ibarz J, Jabbour E et al (2011) Minimal cross-intolerance with nilotinib in patients with chronic myeloid leukemia in chronic or accelerated phase who are intolerant to imatinib. Blood 117:5600–5606CrossRefPubMedCentralPubMed
33.
Kim TD, Rea D, Schwarz M, Grille P, Nicolini FE, Rosti G et al (2013) Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 27:1316–1321CrossRefPubMed
34.
Giles FJ, Mauro MJ, Hong F, Ortmann CE, McNeill C, Woodman RC et al (2013) Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 27:1310–1315CrossRefPubMed
35.
Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M et al (2009) Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 27:469–471CrossRefPubMed
36.
Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX et al (2011) Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118:4567–4576CrossRefPubMed
37.
Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW et al (2012) Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 119:3403–3412CrossRefPubMed
38.
Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K et al (2014) Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood 123:1309–1318CrossRefPubMed
39.
Hanaizi Z, Unkrig C, Enzmann H, Camarero J, Sancho-Lopez A, Salmonson T et al (2014) The European medicines agency review of bosutinib for the treatment of adult patients with chronic myelogenous leukemia: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist 19:421–425CrossRefPubMedCentralPubMed
40.
Zhou T, Commodore L, Huang WS, Wang Y, Thomas M, Keats J et al (2011) Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des 77:1–11CrossRefPubMed
41.
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C et al (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369:1783–1796CrossRefPubMed
42.
Ernst T, La Rosée P, Müller MC, Hochhaus A (2011) BCR-ABL mutations in chronic myeloid leukemia. Hematol Oncol Clin N Am 25:997–1008CrossRef
43.
Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Müller MC et al (2009) Impact of baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in chronic phase. J Clin Oncol 27:4204–4210CrossRefPubMed
44.
Müller MC, Cortes JE, Kim DW, Druker BJ, Erben P, Pasquini R et al (2009) Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 114:4944–4953CrossRefPubMed
45.
Hochhaus A (2011) Educational session: managing chronic myeloid leukemia as a chronic disease. Hematology Am Soc Hematol Educ Program 2011:128–135CrossRefPubMed
46.
Kantarjian HM, Cortes J, La Rosée P, Hochhaus A (2010) Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase. Cancer 116:1419–1430CrossRefPubMed
47.
Jabbour E, Hochhaus A, Cortes J, La Rosée P, Kantarjian HM (2010) Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib: weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history. Leukemia 24:6–12CrossRefPubMed
48.
Quintás-Cardama A, Kantarjian H, O’Brien S, Borthakur G, Bruzzi J, Munden R, Cortes J (2007) Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 25:3908–3914CrossRefPubMed
49.
Montani D, Bergot E, Günther S, Savale L, Bergeron A, Bourdin A et al (2012) Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125:2128–2137CrossRefPubMed
50.
Sano M, Saotome M, Urushida T, Katoh H, Satoh H, Ohnishi K, Hayashi H (2012) Pulmonary arterial hypertension caused by treatment with dasatinib for chronic myeloid leukemia -critical alert-. Intern Med 51:2337–2340CrossRefPubMed
51.
Dumitrescu D, Seck C, ten Freyhaus H, Gerhardt F, Erdmann E, Rosenkranz S (2011) Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J 38:218–220CrossRefPubMed
52.
Tasigna (nilotinib) capsules [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014
53.
Porkka K, Khoury HJ, Paquette RL, Matloub Y, Sinha R, Cortes JE (2010) Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy in unaffected in patients who develop pleural effusion. Cancer 116:377–386CrossRefPubMedCentralPubMed
54.
Wang X, Roy A, Hochhaus A, Kantarjian HM, Chen TT, Shah NP (2013) Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study. Clin Pharmacol 5:85–97PubMedCentralPubMed
55.
Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N et al (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634–1642CrossRefPubMed
56.
Deininger MW, Kopecky KJ, Radich JP, Kamel-Reid S, Stock W, Paietta E et al (2014) Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 164:223–232CrossRefPubMedCentralPubMed
57.
58.
La Rosée P, Martiat P, Leitner A, Klag T, Müller MC, Erben P et al (2013) Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib. Ann Hematol 92:1345–1350CrossRefPubMed
59.
Rousselot P, Mollica L, Etienne G, Bouchet S, Guerci A, Nicolini FE et al (2012) Pharmacologic monitoring of dasatinib as first line therapy in newly diagnosed chronic phase chronic myelogenous leukemia (CP-CML) identifies patients at higher risk of pleural effusion: a sub-analysis of the OPTIM-dasatinib trial. [abstract]. Blood 120:abstract 3770
60.
Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE et al (2014) BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 26:428–442CrossRefPubMed
61.
Milojkovic D, Nicholson E, Apperley JF, Holyoake TL, Shepherd P, Drummond MW et al (2010) Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia. Haematologica 95:224–231CrossRefPubMedCentralPubMed
62.
Stein AM, Martinelli G, Hughes TP, Müller MC, Beppu L, Gottardi E et al (2013) Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia. BMC Cancer 13:173CrossRefPubMedCentralPubMed
63.
Branford S, Kim DW, Soverini S, Haque A, Shou Y, Woodman RC et al (2012) Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. J Clin Oncol 30:4323–4329
64.
Jabbour E, le Coutre PD, Cortes J, Giles F, Bhalla KN, Pinilla-Ibarz J et al (2013) Prediction of outcomes in patients with Ph+ chronic myeloid leukemia in chronic phase treated with nilotinib after imatinib resistance/intolerance. Leukemia 27:907–913CrossRefPubMedCentralPubMed
Metadata
Title
Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenous leukemia patients
Authors
Andreas Hochhaus
Thomas Ernst
Ekkehard Eigendorff
Paul La Rosée
Publication date
01-04-2015
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue Special Issue 2/2015
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-015-2323-1

Other articles of this Special Issue 2/2015

Annals of Hematology 2/2015 Go to the issue

Review Article

A review of the European LeukemiaNet recommendations for the management of CML

Review Article

The interferon-alpha revival in CML

Review Article

Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia

Review Article

Changing the cost of care for chronic myeloid leukemia: the availability of generic imatinib in the USA and the EU

Review Article

The role of hematopoietic stem cell transplantation in chronic myeloid leukemia

Review Article

The choice of first-line Chronic Myelogenous Leukemia treatment
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits