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Treatment-Free Remission by Tyrosine Kinase Inhibitor for Patients with Chronic Myeloid Leukemia

Naoto Takahashi* Department of Hematology, Nephrology, and Rheumatology, Akita University, Japan Published: 08 July 2014 ABBREVIATIONS: CML: Chronic Myeloid Leukemia; TKIs: Tyrosine Kinase Inhibitors; CCyR: Complete Cytogenetic Remission; MMR: Major Molecular Response; ELN; European Leukemia Net; STIM: Stop Imatinib; bcr-abl: breakpoint cluster region-Abelson 1; PCR: Polymerase Chain Reaction; ASH: American Society of Hematology; TFR: Treatment-Free Remission; QOL: Quality Of Life; MRD: Minimal Residual Disease; BCRP: Breast Cancer Resistance Protein; SNPs: Single Nucleotide Polymorphisms; GIST: Gastrointestinal Stromal Tumor; BIM: BCL2-Like INTRODUCTION Treatment of Chronic Myeloid Leukemia (CML) with Tyrosine Kinase Inhibitors (TKIs) such as imatinib has dramatically improved the prognosis of this condition. However, the cessation of TKI treatment is considered impossible, because in vitro assays show that CML stem cells cannot be eliminated [1]. Clinically, neither Complete Cytogenetic Remission (CCyR) nor a Major Molecular Response (MMR) is sufficient to prevent recurrence after the cessation of medication [2,3]. Furthermore, progression from chronic to acute-phase disease is considered a major risk factor for treatment cessation. Such a progression is difficult to treat with TKI alone; the European Leukemia Net (ELN) guidelines and the hematopoietic tumor guidelines of the Japanese Society of Hematology prohibit TKI treatment cessation in daily practice outside planned clinical research settings [4,5]. On the other hand, treatment effects are reported to be sometimes maintained after incidental or planned treatment cessation prompted by side effects or pregnancy [6-11].

However, the cessation of TKI treatment is considered impossible, because in vitro assays show that CML stem cells cannot be eliminated [1]. Clinically, neither Complete Cytogenetic Remission (CCyR) nor a Major Molecular Response (MMR) is sufficient to prevent recurrence after the cessation of medication [2,3]. Furthermore, progression from chronic to acute-phase disease is considered a major risk factor for treatment cessation. Such a progression is difficult to treat with TKI alone; the European Leukemia Net (ELN) guidelines and the hematopoietic tumor guidelines of the Japanese Society of Hematology prohibit TKI treatment cessation in daily practice outside planned clinical research settings [4,5]. On the other hand, treatment effects are reported to be sometimes maintained after incidental or planned treatment cessation prompted by side effects or pregnancy [6-11].

Previous prospective imatinib cessation trials
The Stop Imatinib (STIM) prospective cessation trial was announced in 2010 by a French group led by Mahon [12]. The subjects were 100 patients with CML maintaining Complete Molecular Response (CMR) without the breakpoint cluster region-Abelson 1 (bcr-abl) mRNA detected by high-sensitivity quantitative Polymerase Chain Reaction (PCR) for over 2 years. Among them, 39% had long-term CMR after imatinib cessation.
In contrast, molecular genetic evidence of recurrence was found in 61% of patients within 6 months after imatinib cessation. However, re-administration of imatinib in patients with recurring disease resulted in a rapid molecular genetics effect without disease progression. Follow-up data were published by the
American Society of Hematology (ASH) annual meeting in 2013, but no new relapses or disease progressions were observed [13].

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