Baccarani

A Critical History of Chronic Myeloid Leukemia

Michele Baccarani1 and Fabrizio Pane2

1 University of Bologna and GIMEMA, Italy
2 University of Naples “Federico II” and CEINGE Biotecnologie Avanzate, Naples, Italy 

Corresponding author: Michele Baccarani, MD. Via Albertazzi 16/2, 40137 Bologna, E-mail: michele.baccarani@unibo.it

Published: January 2, 2014
Received: November 22, 2013
Accepted: November 23, 2013
Meditter J Hematol Infect Dis 2014, 6(1): e2014010, DOI 10.4084/MJHID.2014.010
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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Editorials and Comments

The history of chronic myeloid leukemia has marked one of the most remarkable and exciting success of modern medicine, transforming an almost always fatal cancer in a chronic conditions that can be medically controlled, and opening space and hope for a cure in an increasing number of patients.[1-6] The discovery of the molecular bases of CML and of a class of agents, the tyrosine kinase inhibitors (TKIs), targeting the molecule that causes the leukemic transformation of hemopoietic stem cells, has provided a strongly positive support to the concept that cancer treatment must be based on the knowledge of cancer biologic characteristics and on the development of agents targeting specifically these characteristics. Until this concept remained a chimera, for many years, the treatment of cancer was necessarily based on cancer destruction exploiting the subtle differences in sensitivity among normal and cancer cells. This policy, a policy of “last cell kill”, gave positive results in many cancers. Examples, in hematology, are lymphomas, particularly Hodgkin’s lymphoma, and acute leukemia, particularly acute lymphoblastic leukemia in children. TKIs in CML as well as transretinoic acid in acute promyelocytic leukemia have at last shown that the concept of cancer-specific treatment is no longer a chimera and can be applied to clinical practice, in an increasing number of hematologic and non-hematologic malignancies.
The way was neither easy nor rapid. CML was described in the 19th century and was managed with radiation and chemotherapy until the end of the 20th century, until the introduction and the wide application of allogeneic stem cell transplantation (SCT) and of recombinant Interferon-alfa (rIFNɑ).[1-6] SCT was in a sense the sublimation of the last cell kill theory, based on stem cell kill by radiation and alkylating agents and on residual stem cell control by the transplanted immune system. SCT is still the most important curative treatment of CML, but in spite of  progress, the mortality and the morbidity are still important and limiting the application.[6-8] As a matter of fact, SCT does not fit the concept of cancer specific treatment. rIFNɑ was a great success, and an unexpected one, but also the benefit of rIFNɑ was limited, because less than 50% of patients had a significant response, and side-effects were remarkable.[1,5,6,9] Again, rIFNɑ was not specifically directed against Ph+ cells, and it is intriguing to admit that after many years its mechanism of action is poorly known. After radiation and conventional chemotherapy, after allogeneic SCT, after rIFNɑ, the true breakthrough was made by imatinib, the first of a class of small molecules inhibiting the TK.[10] Soon after imatinib, other TKIs were rapidly developed and tested, and other four TKIs are now available, though not yet in all countries, and with different indications, dasatinib, nilotinib, bosutinib, and ponatinib.[11-15] These compounds are similar and inhibit very effectively the kinase activity of BCR-ABL1, with a good therapeutic response, but are not identical. There are differences, in metabolism, pharmacokinetics and pharmacodynamics, there are differences in the ability of inhibiting BCR-ABL1 and particularly the mutated forms of BCR-ABL1, and there are differences in the inhibition of other different TK, leading to some differences in efficacy and to some differences in safety and side-effects. The major effect of the availability of more TKIs has been the relief of patients from dependence on only one drug, a condition that left too many patients at risk of dying of leukemia, and that was a cause of fear also in the responding patients. No more than 10 years ago, the big question was how long will the response last, how long will survival be.[1] The early recognition of the development of TKIs-resistant mutations was a cause of fear and anxiety.[1,16] We now know that with imatinib the responses are durable, that the risk of developing mutations decreases with time, that the majority of the patients who fail imatinib or are intolerant of imatinib can be rescue with other TKIs, and that a stable and deep response to imatinib may herald a treatment-free remission, a kind of clinical cure.[4,6,17,18] However, the area of TKI and CML is still marked by a strong competition among drugs and companies, a competition that has comprehensible commercial bases, but has sound medical, ethical, and social consequences.[19] Overall, the availability of more TKIs provides an unprecedented opportunity of designing the treatment according to disease and patient, that is to say of optimizing treatment, a goal that has not yet been reached because we must still learn how to do the best and proper use of these drugs. Many current treatment recommendations are based on efficacy, and the evaluation of efficacy is based sometimes too much on the so-called early surrogate markers of the outcome and sometimes too few on the outcomes, that are progression-free survival, overall survival, and treatment-free survival.[6] Since the efficacy is high, it is necessary to take into consideration more and more also the safety and the tolerability, that affects so much the quality of life, and also the compliance, that in turn is important for the efficacy.[20-22] It is true that the TKIs are targeted against BCR-ABL1 and are much less toxic and much better tolerated than most antileukemic and anticancer agents. But even TKIs are not completely specific, can cause important, and even life-threatening, clinical complications, as well as minor chronic side-effects that in the long term can become hard to tolerate.[20-26] A careful monitoring of efficacy is necessary, based primarily on quantitative molecular testing and in case of failure also on mutational analysis, but also on cytogenetics, whenever molecular monitoring is not available or is not standardized according to the international scale.[6,27,28] Monitoring is expensive, but the cost of careful monitoring is only a small fraction of the cost of treatment, and allows to make a proper use of any drug, from the clinical and also the financial point of view. However, monitoring the efficacy is not sufficient. Monitoring must be coupled with a careful attention to the patient, the comorbidities, the age, the complaints, the style of life, and ultimately the will of the patient.[20,26-29] There is still a long and dedicated way to success. This issue of the Mediterranean Journal of Hematology and Infectious Disease covers some of the most important topics on the treatment of CML, to help health care professionals to walk along this way and to improve the management of CML patients.  ]

References

  1. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108:1809-1820. http://dx.doi.org/10.1182/blood-2006-02-005686 PMid:16709930     
  2. Hehlmann R, Hochhaus A, Baccarani M, on behalf of the European LeukemiaNet. Chronic myeloid leukemia. Lancet 2007; 370:342-50. http://dx.doi.org/10.1016/S0140-6736(07)61165-9   
  3. Bjorkholm M, Ohm L, Eloranta S et al. Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol 2011;29:2514-2520. http://dx.doi.org/10.1200/JCO.2011.34.7146 PMid:21576640  PMCid:PMC3138632  
  4. Kantarjian H, O'Brien S, Jabbour E et al. Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience. Blood 2012;119(9):1981-1987 http://dx.doi.org/10.1182/blood-2011-08-358135 PMid:22228624  PMCid:PMC3311242  
  5. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;27:6041-6051 http://dx.doi.org/10.1200/JCO.2009.25.0779 PMid:19884523      
  6. Baccarani M, Deininger M, Rosti A. et al. European LeukemiaNet 2013 recommendations for the management of chronic myeloid leukemia. Blood 2013;122:885-892. http://dx.doi.org/10.1182/blood-2013-05-501569 PMid:23803709      
  7. Pavlu J, Szydlo RM, Goldman JM, and Apperley JF. Three decades of transplantation for chronic myeloid leukemia: what have we learned? Blood 2011;117(3):755-763. http://dx.doi.org/10.1182/blood-2010-08-301341 PMid:20966165      
  8. Goldman M. How I treat chronic myeloid leukemia in the imatinib era. Blood 2007; 110:2828-2837 http://dx.doi.org/10.1182/blood-2007-04-038943 PMid:17626839      
  9. Talpaz M, Hehlmann R, Quintas-Cardama A, et al. Re-emergence of interferon-? in the treatment of chronic myeloid leukemia. Leukemia 14 december 2012;doi:10.1038/leu.2012.313 http://dx.doi.org/10.1038/leu.2012.313   
  10. O'Brien SG, Guilhot F, Larson R, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348:994-1004 http://dx.doi.org/10.1056/NEJMoa022457 PMid:12637609      
  11. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260-70. http://dx.doi.org/10.1056/NEJMoa1002315 PMid:20525995      
  12. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362(24):2251-9. http://dx.doi.org/10.1056/NEJMoa0912614  PMid:20525993      
  13. Cortes JE, Kim DW, Kantarjian HM, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 2012;30(28):3486-3492 http://dx.doi.org/10.1200/JCO.2011.38.7522 PMid:22949154      
  14. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory chromosome-positive leukemias. N Engl J Med 2012;367:2075-2088. http://dx.doi.org/10.1056/NEJMoa1205127 PMid:23190221 PMCid:PMC3777383  
  15. Cortes J, Kim DW, Pinilla-Ibarz J, et al. A pivotal phase 2 trial of ponatinib in patients with chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-month follow-up of the PACE trial. Blood 2012 (ASH Annual Meeting);120:abstract 163  
  16. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutations analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Recommendations from an expert panel on behalf of European LeukemiaNet. Blood 2011;118(5):1208-1215. http://dx.doi.org/10.1182/blood-2010-12-326405 PMid:21562040      
  17. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11: 1029-1035 http://dx.doi.org/10.1016/S1470-2045(10)70233-3   
  18. Shami PJ, Deininger M. Evolving treatment strategies for patients newly diagnosed with chronic myeloid leukemia: the role of second-generation BCR-ABL inhibitors as first-line therapy. Leukemia 2012;26:214-224. http://dx.doi.org/10.1038/leu.2011.217 PMid:21844872      
  19. Experts in Chronic Myeloid Leukemia (Kantarjian H. et al). The price of drugs for chronic myeloid leukemia: a reflection on the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 2013; April 25 2013; http://dx.doi.org/10.1182/blood-2013-03-490003     
  20. Efficace F, Baccarani M, Breccia M, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared to the general population. Blood 2011;118(17):4554-4560 http://dx.doi.org/10.1182/blood-2011-04-347575 PMid:21750313      
  21. Valent P. Severe adverse events associated with the use of second-line BCR/ABL tyrosine kinase inhibitors: preferential occurrence in patients with comorbidities. Haematologica 2011;96(10):1395-1397. PMid:21972208      
  22. Steegmann JL, Cervantes F, le Coutre P, et al. Off-target effects of BCR-ABL1 inhibitors and their potential long term implications in patients with chronic myeloid leukemia. Leuk Lymphoma 2012;53(12):2351-2362 http://dx.doi.org/10.3109/10428194.2012.695779 PMid:22616642      
  23. Rosti G, Castagnetti F, Gugliotta G, et al. Physician's guide to the clinical management of adverse events on nilotinib therapy for the treatment of CML. Cancer Treat Rev 2012;38:241-248. http://dx.doi.org/10.1016/j.ctrv.2011.07.004 PMid:21840128      
  24. Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood 2009;113:5401-5411. http://dx.doi.org/10.1182/blood-2008-12-196543 PMid:19349618
  25. Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic response on imatinib. J Clin Oncol 2010;28:2381-2388. http://dx.doi.org/10.1200/JCO.2009.26.3087 PMid:20385986      
  26. Efficace F, Baccarani M, Breccia M, et al. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia 2013;27(7):1511-1519. http://dx.doi.org/10.1038/leu.2013.51 PMid:23417029      
  27. Efficace F, Baccarani M, Breccia M, Saussele S, Abel G, Caocci G et al. International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24. Qual Life Res 2013, in press
  28. Baccarani M, Efficace F, Rosti G. Moving towards patient-centered decision-making in chronic myeloid leukemia: assessment of quality of life and symptom burden. Haematologica, 2013, in press.
  29. Williams LA, Garcia Gonzales AC, Ault P, Mendoza TR, Sailors ML et al. Measuring the symptom burden associated with the treatment of chronic myeloid leukemia. Blood 2013;122(5):641-647 http://dx.doi.org/10.1182/blood-2013-01-477687 PMid:23777764    

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