Case Reports in Hematology 3. Discussion Herein, we described an aggressive course of CML progressed despite the administration of almost all available TKIs, namely, bosutinib, imatinib mesylate, nilotinib, and dasa- tinib. Furthermore, other available anti-CML approaches including aIFN, cytotoxic chemotherapy, and allo-HSCT had failed to produce a satisfactory response in our CML patient. The striking ﬁnding of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course. Most patients (90%) present with CML in CP as in our case. In CP patients, well diﬀerentiated leukemic cells proliferate relatively slow. CP is followed by AP, and white blood cell counts are poorly controlled and the numbers of immature blasts in the peripheral blood are increased. After 1 to 2 years, AP may transit into BP. In this phase, cytopenias, infections, bleeding, organ failure, and death can occur. The transition occurs as rapidly as 3 years in the absence of treatment. Our patient has lived all these disease states. The median survival for patients with untreated BP CML is 3 to 6 months. The goals of CML treatment are to achieve normal blood count values, reduction and elimination of the Philadelphia chromosome, and reduction and elimination of BCR-ABL transcripts. Introduction of the ﬁrst TKI, imatinib mesylate, into clinical practice after IRIS trial [17], the treatment, and monitorisation of CML, has dramatically changed [1, 17]. TKIs speciﬁcally target tyrosine kinase activity of the oncogenic protein encoded by BCR/ABL gene. Chronic phase CML patients are treated with imatinib as the ﬁrst-line treatment agent. Indications for changing therapy to a second-generation TKI should be considered in imatinib intolerance, imatinib resistance, and suboptimal response to imatinib. Currently, two more powerful second generation TKIs are available in the market for the clinical management of CML, namely, dasatinib [18] and nilotinib [19]. The European Leukemia Net (ELN) 2009 recommendations have placed second-generation TKIs for the second-line treatment of imatinib-intolerant or imatinib-resistant CML [20, 21]. However, two recently published Phase III randomized clinical trials, Dasatinib versus Imatinib Study in Treatment- Naive CML patients (DASISION) [18] and Evaluating Nilo- tinib Eﬃcacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) [19], have led to approval of second- generation TKIs for the ﬁrst-line management of newly diagnosed CML. Dasatinib and Nilotinib produced superior results, such as earlier cytogenetic response and a deeper and durable molecular response in comparison to imatinib in the DASISION [9] and ENESTnd [19] trials. The elucidation of the superiority of frontline Dasatinib or Nilotinib could be possible with the upcoming three-year follow-up of the DASISION [18] and ENESTnd [19] trials. Our patient had been a part of BELA trial, but frontline bosutinib failed to produce a sustainable remission. Imatinib, dasatinib, or nilotinib have also failed (Table 1). There are problems in the management of “suboptimal response to imatinib” [9, 22]. This gray-zone concept has been generated without long-term follow-up data on ima- tinib and in the absence of second-generation TKIs [20]. 3 High-dose imatinib, which had inferior eﬃcacy when com- pared to dasatinib and nilotinib, is not superior to standard dose imatinib too [23]. Increased ratio of complete cyto- genetic response and faster, earlier, deeper, durable, more common sustained major molecular response obtained via second generation TKIs prompted the earlier administration of Dasatinib or Nilotinib during the clinical course of CML. More powerful TKIs shall be given at the earlier sign(s) of resistance and/or intolerance to frontline imatinib [24]. We could not increase the dose of imatinib in our present patient due to myelosuppressive eﬀects of the drug. Likewise, more powerful TKIs have also failed in our patient. There are many diﬀerent pathophysiologic mechanisms for imatinib resistance, including BCR-ABL kinase domain (KD) mutations preventing imatinib binding, clonal evolu- tion, BCR-ABL ampliﬁcation/overexpression, and decreased imatinib bioavailability/cell exposure. BCR-ABL KD muta- tions are detected in approximately 45% of patients with imatinib-resistant CML [25]. Although many imatinib- resistant mutations respond well to second-generation TKIs, the mutation at codon 315 of the BCR-ABL KD (T315I) is insensitive to all currently available TKIs [26]. However, no mutation against TKIs was present in our patient. The current treatment of chronic phase CML is the chronic in- hibition of tyrosine kinases and the regular follow-up of the CML patient with appropriate essential interventions [24]. However, the selections of second-generation TKIs [27], their long-term adverse eﬀects with proper follow-up and management [28], treatment of advanced-phase CML with focus on transplantation [29] represent the current problems in the management of CML [30]. Near future holds promise for the better CML management, operational cure of CML, or even cure of the disease with the discontinuation of TKI and/or targeting CML stem cell. Meanwhile, challenging cases will always be present despite the hope and progress in CML [31]. Elimination of the leukemic stem cell is the ultimate goal of treatment and the only potential for a CML cure [28]. References [1] Y. Buyukasik, I. C. Haznedaroglu, and O. 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