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      Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV

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          Abstract

          Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI ( n=61) and interferon-α only ( n=3). The most common malignancies ( n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63–1.20)) for men and 1.06 (95% CI 0.69–1.55) for women. SIRs were between 0.49 (95% CI 0.13–1.34) for colorectal cancer in men and 4.29 (95% CI 1.09–11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.

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          Most cited references35

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          European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013.

          Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors, mandate regular updating of concepts and management. A European LeukemiaNet expert panel reviewed prior and new studies to update recommendations made in 2009. We recommend as initial treatment imatinib, nilotinib, or dasatinib. Response is assessed with standardized real quantitative polymerase chain reaction and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, 10% at 6 months and >1% from 12 months onward define failure, mandating a change in treatment. Similarly, partial cytogenetic response (PCyR) at 3 months and complete cytogenetic response (CCyR) from 6 months onward define optimal response, whereas no CyR (Philadelphia chromosome-positive [Ph+] >95%) at 3 months, less than PCyR at 6 months, and less than CCyR from 12 months onward define failure. Between optimal and failure, there is an intermediate warning zone requiring more frequent monitoring. Similar definitions are provided for response to second-line therapy. Specific recommendations are made for patients in the accelerated and blastic phases, and for allogeneic stem cell transplantation. Optimal responders should continue therapy indefinitely, with careful surveillance, or they can be enrolled in controlled studies of treatment discontinuation once a deeper molecular response is achieved.
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            Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.

            A topic that has received attention in both the statistical and medical literature is the estimation of the probability of failure for endpoints that are subject to competing risks. Despite this, it is not uncommon to see the complement of the Kaplan-Meier estimate used in this setting and interpreted as the probability of failure. If one desires an estimate that can be interpreted in this way, however, the cumulative incidence estimate is the appropriate tool to use in such situations. We believe the more commonly seen representations of the Kaplan-Meier estimate and the cumulative incidence estimate do not lend themselves to easy explanation and understanding of this interpretation. We present, therefore, a representation of each estimate in a manner not ordinarily seen, each representation utilizing the concept of censored observations being 'redistributed to the right.' We feel these allow a more intuitive understanding of each estimate and therefore an appreciation of why the Kaplan-Meier method is inappropriate for estimation purposes in the presence of competing risks, while the cumulative incidence estimate is appropriate.
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              Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score.

              The outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.
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                Author and article information

                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group
                0887-6924
                1476-5551
                June 2016
                09 February 2016
                26 February 2016
                : 30
                : 6
                : 1255-1262
                Affiliations
                [1 ]III. Medizinische Klinik, Universitätsmedizin, Medizinische Fakultät Mannheim der Universität Heidelberg , Mannheim, Germany
                [2 ]Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität , München, Germany
                [3 ]Universitätsklinik für Hämatologie und Hämatologisches Zentrallabor, Inselspital , Bern, Switzerland
                [4 ]Klinik für Hämatologie, Universitätsspital , Basel, Switzerland
                [5 ]II. Medizinische Klinik, Universitätsklinikum Eppendorf , Hamburg, Germany
                [6 ]Medizinische Klinik und Poliklinik III, Klinikum der Ludwig-Maximilians-Universität , München, Germany
                [7 ]Medizinische Klinik 5, Universitätsklinikum , Erlangen, Germany
                [8 ]Klinik für Hämatologie, Onkologie, Immunologie, Palliativmedizin, Infektiologie und Tropenmedizin, Klinikum Schwabing , München, Germany
                [9 ]Medizinische Klinik IV, Uniklinik RWTH , Aachen Germany
                [10 ]Zentrum für ambulante Hämatologie und Onkologie , Bonn, Germany
                [11 ]Klinik für Knochenmarktransplantation und Hämatologie/Onkologie, Klinikum , Idar-Oberstein, Germany
                [12 ]Klinik für Hämatologie, Onkologie und Palliativmedizin, Klinikum , Kempten, Germany
                [13 ]Medizinische Klinik 2, Klinikum Mittelbaden, Standort Balg , Baden-Baden, Germany
                [14 ]Klinik für Onkologie/Hämatologie, Kantonsspital , St Gallen, Switzerland
                [15 ]Innere Medizin 1, Klinikum Mutterhaus der Borromäerinnen , Trier, Germany
                [16 ]Mannheimer Onkologie Praxis , Mannheim, Germany
                [17 ]Medizinische Klinik III, Krankenhaus , Düren, Germany
                [18 ]Praxis für Innere Medizin, Nephrologie, Hämatologie und Onkologie , Trier, Germany
                [19 ]Klinik für Innere Medizin II, Universitätsklinikum , Jena, Germany
                Author notes
                [* ]III. Medizinische Klinik, Medizinische Fakultät Mannheim der Universität Heidelberg , Pettenkoferstrasse 22, Mannheim 68169, Germany. E-mail: Susanne.Saussele@ 123456medma.uni-heidelberg.de
                [20]

                These authors contributed equally to this work.

                Article
                leu201620
                10.1038/leu.2016.20
                4895174
                26859076
                c33a00cc-73f3-4e7f-8191-2f12a7658e0e
                Copyright © 2016 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                Categories
                Original Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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