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  • ISSN: 2333-6684
    Special Issue on The Future Aspects of Chronic Myeloid Leukemia Treatment
    Special Issue on The Future Aspects of Chronic Myeloid Leukemia Treatment
    Naoto Takahashi, MD, PhD
    Department of Hematology
    Akita University
    Hondo 1-1-1
    Akita, Japan
    Review Article
    Shinya Kimura*, Toshihiko Ando and Kensuke Kojima
    Abstract: Most newly diagnosed CML patients in the Chronic Phase (CP), when treated with imatinib, achieve durable responses. However, a small percentage of these patients as well as most advanced-phase patients relapse on imatinib therapy. Among several resistant mechanisms, “point mutation within the BCR-ABL kinase domain” that interferes with imatinib binding is most important. To overcome imatinib-resistance, four second generation ABL Tyrosine Kinase Inhibitors (TKIs) such as dasatinib, nilotinib, bosutinib and bafetinib were developed. Since there are slight differences in the strong and weak points for each mutation among each TKI, it is very important to identify the type of bcr-abl mutationpresent in ABL TKI-resistant patients. Unfortunately, none of second generation BCR-ABL TKIs can inhibit T315I clone. Thus, a third-generation BCR-ABL TKI, ponatinib was developed and had been already used in clinic. Furthermore, a lot of novel agents which can override BCR-ABL KD mutations including T315I are being developed.
    Noriko Usui*
    Abstract: More than 10 years has passed since the first BCR-ABL Tyrosine Kinase Inhibitor (TKI), imatinib, introduced into clinical practice in treatment for Chronic Myeloid Leukemia (CML). Addition to the development and clinical usage of more potent second generation TKIs, majority of patients with CP-CML can excellently control their disease and enjoy good quality of life. Recent prospective and retrospective discontinuation trials for imatinib suggested that roughly 40% of patients achieved Complete Molecular Response (CMR) for more than 2 years (or 24 months) would continue their CMR without relapse. Three female patients achieved long-term deep molecular response received planned pregnant management involving careful molecular monitoring with or without interefone-α (IFN-α) during her pregnancy after stopping imatinib in our institute. Fortunately all patients delivered healthy babies, however, a patient with Sokal high risk at initially diagnosed lost her molecular, cytogenetic and hematologic response in spite of receiving IFN-α.
    It would seem reasonable to recommend female patients who wish to become pregnant to wait until they have achieved CMR and sustained this for at least 2 years. Currently the proportion of patients obtaining prolonged and deep MR by treatment with imatinib is less than 10%, however, the use of second generation TKIs as first-line therapy will increase this percentage in near future. And continuing effort should be made to find optimal management for pregnant female patients with CP-CML.
    Izuru Mizoguchi1, Takayuki Yoshimoto1*, Seiichiro Katagiri2, Jun-ichi Furusawa1, Yukino Chiba1, Junichiro Mizuguchi3, Tetsuzo Tauchi1, Junko H Ohyashiki4 and Kazuma Ohyashiki2
    Abstract: Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells caused by a formation of the BCR-ABL1 chimeric gene, which encodes an aberrant tyrosine kinase with oncogenic activity. Despite the introduction of Tyrosine Kinase Inhibitors (TKIs) such as imatinib that dramatically improved the treatment of CML, CML remains incurable for the most part, and only allogeneic hematopoietic stem cell transplantation can eradicate and cure CML. This is probably because quiescent leukemic stem cells are resistant to TKIs. However, some CML patients are able to discontinue imatinib treatment after achieving a durable deep molecular response, although they still have very low levels of residual leukemic cells. This implies that immunological control also plays a critical role in minimizing CML cells and helps maintain a complete molecular response. Indeed, recent clinical trials have suggested that the combination of imatinib with interferon-α yields stronger molecular response rates and an improved possibility of treatment-free remission. Moreover, identification of several leukemia-specific antigens is promising for the development of vaccination against CML. As a specific prognostic factor that could determine which patients can safely discontinue the treatment, natural killer cells were recently revealed to be critically important. However, cytotoxic T lymphocytes specific for CML cells could also be a good candidate for this purpose. This review summarizes the recent advances in the novel immunological aspects of CML therapy leading to treatment-free remission under immunological control of CML.
    Naoto Takahashi*
    Abstract: The prospective French cessation trial, Stop Imatinib trial (STIM) represents a breakthrough in Treatment-Free Remission (TFR) research in Chronic Myeloid Leukemia (CML) treatment with Tyrosine Kinase Inhibitors (TKIs). About 40% had long-term complete molecular response (CMR) after imatinib cessation in STIM trial. It demonstrated that imatinib cessation might be possible in monotherapy if CMR can be achieved and maintained for a certain period of time. TFR is targeted to avoid late side effects and allow fertile females to become pregnant and bear children as well as to save the treatment costs and health economics of TKI treatment. The predictive factors contributing to the success of TFR were reported in prospective clinical trials and retrospective observations. They are as follows: (1) Sokal score, (2) imatinib treatment duration, (3) history of interferon-α treatment, and (4) the duration of CMR before cessation. In addition, (5) polymorphisms of ABCG2 421A/C, (6) the BIM common deletion polymorphism, and (7) the increase in the proportion of NK cells or reduction of regulatory T cells are potential biomarkers for predicting TFR. In this review, we discussed TFR as a treatment target of CML, and some conditions for successful TFR in CML treatment with TKIs.
    Mini Review
    Yosuke Minami*
    Abstract: Chronic Myeloid Leukemia (CML) is effectively treated with Tyrosine Kinase Inhibitors (TKI) such as Imatinib Mesylate (IM) targeted against BCR-ABL, however, several mathematical models and ex vivo-examinations suggested that IM does not eradicate CML stem cells. We previously reported the investigation of residual CML diseases during TKI treatment using FACS-sorting and quantitative RT-PCR of BCR-ABL among each population; total mononuclear cells, hematopoietic stem cells, and myeloid progenitors. Our observations were supportive of the mathematical model that consists of the initial rapid α-slope and the consequent β-slope correspondent to kinetics of residual cells. The observations also implied that the second-generation of ABL-tyrosine kinase inhibitors (2nd TKIs), dasatinib or nilotinib therapy can be more promising approach for efficient reduction of the CML stem cells.Moreover, we need to develop the evaluation method of the residual CML stem cells to establish rational TKI-cessation strategies in CML.
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