Turkish Journal of Hematology Volume: 37 Issue: 1 / 2020

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PERSPECTIVES IN HEMATOLOGYDOI: 10.4274/tjh.galenos.2019.2019.0241Turk J Hematol 2020;37:42-47WHO 2016 Definition of Chronic Myeloid Leukemia and TyrosineKinase InhibitorsKronik Myeloid Lösemi WHO 2016 Tanımlaması ve Tirozin Kinaz İnhibitörleriİbrahim C. Haznedaroğlu 1 , Işınsu Kuzu 2 , Osman İlhan 31Hacettepe University Faculty of Medicine, Department of Hematology, Ankara, Turkey2Ankara University Faculty of Medicine, Department of Pathology, Ankara, Turkey3Ankara University Faculty of Medicine, Therapeutic Apheresis Unit, Department of Hematology, Ankara, TurkeyAbstractPhiladelphia (Ph*)/BCR-ABL1-positive chronic myeloid leukemia(CML) is considered as a chronic life-long disease, which could bemanageable with tyrosine kinase inhibitor (TKI) drugs. The aim of TKIdrug treatment is to provide age- and sex-matched duration of lifein a given patient with CML. Personalized CML treatment with TKIdrugs is the key strategy. Individual treatment approach includes theharmonization of CML disease characteristics, clinical experience, andbest available clinical evidence. Specific CML disease characteristicsin a given patient include; CML disease risk, comorbidities, molecularprofile, compliance, lifestyle, and drug off-target risk profile. CMLresearch evidence includes; randomized clinical trials indicatingthe data on the efficacy, safety, tolerability, toxicity, possible longtermadverse events, and pharmacoeconomy of TKIs. Clinical andphysician experience includes TKI availability, TKI reimbursability, drugexperience, adherence, and BCR-ABL1 monitorization facilities. Thekey decision of choosing a TKI of choosing TKIs for CML should bemade via the consideration of these variables. The aim of this paperis to outline the latest 2016 World Health Organization definition ofCML and its proper management with TKI-class drugs.Keywords: Chronic myeloid leukemia, CML, Tyrosine kinase inhibitor,TKIÖzPhiladelphia (Ph*)/BCR-ABL1 (+) kronik myeloid lösemi (KML), tirozinkinaz inhibitörleri (TKİ) grubundan ilaçlarla yaşam boyu yönetilebilecekkronik bir hastalıktır. TKİ ilaç tedavisinin hedefi, herhangi bir KMLhastasında aynı yaş ve cinsiyette sağlıklı bireylerde beklenen yaşamsüresi idamesini sağlamak olmalıdır. KML tedavisinde bireyselleştirilmişTKİ ilaç kullanımı anahtar stratejidir. Bireysel tedavi yaklaşımı; KMLhastalık özelliklerini, klinik deneyimi ve mevcut en iyi kanıtı uyguncabirleştirme esaslıdır. Herhangi bir KML hastasında özgül hastalıközellikleri; KML hastalık riski, komorbiditeler, moleküler profil, hastauyumu, yaşam tarzı, ve ilaç temelli yan etki profilleridir. KML’de kritikaraştırma kanıtları; TKİ etkinlik, güvenilirlik, tolerabilite, toksisite,uzun-dönem ilaç yan etkileri ve farmakoekonomi parametreleri içinkarar verdirici nitelikte olan randomize klinik çalışmalardır. Klinik vehekim deneyimi; TKİ mevcudiyeti, TKİ geriödenebilirliği, ilaç deneyimi,ilaca uyum ve izleyen klinikte BCR-ABL1 izlem olanakları olaraközetlenebilir. KML seyrinde ana kritik TKİ kararına esas olarak sayılan budeğişkenlerin dikkate alınması sonrasında ulaşılır. Bu makalenin amacı,KML tanımlamasında en son kullanılan Dünya Sağlık Örgütü-2016kriterleri eşliğinde TKİ grubu ilaçlar ile uygun KML yönetimi ilkelerinitartışmaktır.Anahtar Sözcükler: Kronik myeloid lösemi, KML, Tirozin kinazinhibitör, TKİIntroductionPhiladelphia (Ph*)/BCR-ABL1-positive chronic myeloid leukemia(CML) is a chronic neoplastic disease, which can be functionallycured via the administration of tyrosine kinase inhibitor(TKI) drugs [1]. The overall aim of TKI therapy in CML is toprovide normal life duration and quality to the patient. Theharmonization of CML disease characteristics, physician/clinicfacilities, and best clinical evidence is vital to reach this ultimateaim [2,3]. The disease characteristics of a given patient includeCML disease risk, comorbidities, molecular profile, compliance,lifestyle, and drug off-target risk profile. CML research evidenceincludes randomized clinical trials indicating data on the safety,efficacy, tolerability, toxicity, possible long-term adverse events,and pharmacoeconomy of TKIs. Clinical experience involves TKIavailability, TKI reimbursability, drug experience, adherence, and©Copyright 2020 by Turkish Society of HematologyTurkish Journal of Hematology, Published by Galenos Publishing HouseAddress for Correspondence/Yazışma Adresi: İbrahim C. Haznedaroğlu, M.D., Hacettepe University Faculty ofMedicine, Department of Hematology, Ankara, TurkeyPhone : +90 312 305 15 43E-mail : haznedar@yahoo.com ORCID: orcid.org/0000-0001-8028-9462Received/Geliş tarihi: June 27, 2019Accepted/Kabul tarihi: October 15, 201942
Turk J Hematol 2020;37:42-47Haznedaroğlu İC, et al: Tyrosine Kinase Inhibitorsmonitorization facilities. The critical decision regarding TKIs forCML should be done via the optimization of those variables forevery single CML patient (Figure 1) [3]. The aim of this paperis to outline the proper TKI treatment for the management ofCML, as described in the 2016 World Health Organization (WHO)classification [3].2016 WHO Definition of Chronic Myeloid LeukemiaThe essential clinicopathological characteristics of Ph*(+) CMLin the 2016 WHO classification are defined as follows [4];Chronic Phase CMLThis is a myeloproliferative neoplasm characterized by thechromosomal translocation t(9;22) (q34.1;q11.2), resulting inthe BCR-ABL1 fusion gene and formation of the Philadelphiachromosome (Ph*), which causes an increase in bloodgranulocytes and bone marrow myeloid precursors as themajor proliferative component. Cryptic and variant forms ofthe Philadelphia chromosome as well as additional cytogeneticabnormalities may complicate the disease pathobiology.Therefore, interphase fluorescence in situ hybridization (FISH),chromosome banding analysis, and PCR should be integrated forthe diagnosis and follow-up of CML [5,6].The disease is described in three main clinical phases, whichwere significantly prognostic before the TKI treatment era. Thechronic phase is the initial phase. Disease progression is thendescribed in two phases as the accelerated phase (AP) andblastic phase (BP). AP disease is characterized by 10%-19%blasts in the bone marrow or peripheral blood. The criterion fortransformed BP is more than 20% blasts either in the blood orin the bone marrow, or at extramedullary sites [4].Typical peripheral blood findings in CP-CML are characterizedby increased neutrophils with various early-stage granulocyticprecursors. The diagnosis needs to be proven by demonstratingthe molecular abnormality of BCR-ABL1 fusion. Typical bonemarrow (BM) histopathology is demonstrated in Figures 2A-2D.The presence of t(9;22) (q34.1;q11.2) or BCR-ABL1 abnormalitycould be demonstrated by karyotype analysis, FISH, or PCRbasedmethods. The most reliable and sensitive method is realtimePCR. This method is important and should be preferredespecially for routine monitoring for the evaluation of theresponse to TKI treatment [7].Complete responders to TKI treatment are defined by <10x109/Lblood cell count and <450x109/L platelet count without anyimmature granulocytes in differentiation and nonpalpablespleen [4]. The bone marrow features and cellular compositionsare normal with the appearance of erythrocytic precursors. Sucha case is demonstrated in Figures 2E-2H.Accelerated Phase CMLThe typical BM histopathology for AP was described before theTKI treatment era. Following the start of the TKI era, the criteriawere modified considering the therapy. Cases responding to TKItreatment are characterized by normalization of the cellularcomposition of the bone marrow as demonstrated in Figures 2I-2M. Abnormal megakaryocytes associated with marked reticulinor collagen fibrosis in accordance with typical AP-CML could bepresent (Figure 2K). The AP criteria are listed below [4].• The presence of t(9;22)(q34.1;q11.2) or BCR-ABL1 (viamolecular biology or karyotype analyses) together with genomiccytogenetic evolution and/or TKI resistance.• Genomic evolution may include second Ph*, trisomy 8,isochromosome 17q, trisomy 19, complex karyotype, or 3q26.2abnormalities.• Persistent or increasing abnormal blood counts despiteTKI treatment (leukocytosis (>10x109/L), thrombocytosis(>1000x109/L), or thrombocytopenia (<100x109/L) unrelated totherapy, 20% or more basophils, 10%-19% blasts)• Persistent or increasing splenomegaly.Figure 1. The harmonization of individual disease characteristics,the experience of physician/clinical facilities, and best clinicalevidence is essential for clinical decision-making in chronicmyeloid leukemia (CML).CML: Chronic myeloid leukemia, TKI: Tyrosine kinase inhibitor.• Occurrence of clinically significant driver mutations in BCR-ABL1 during TKI therapy (particularly T315I).• Additional clonal chromosomal abnormalities such as trisomy8, isochromosome 17q, trisomy 19, or any new entity of complexkaryotype and 3q26.2 abnormalities or any new chromosomal43
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