br Discussion The main goal of CML therapeutic strategies is

Discussion The main goal of CML therapeutic strategies is the safe discontinuation of TKIs; however withdrawal syndrome is a noteworthy phenomenon after TKI cessation. Although approximately 30% of patients who cease IM reportedly proceed to develop musculoskeletal pain or pruritus [2–5], it is not yet known which factors can predict musculoskeletal pain after the discontinuation of TKIs. In current study, we focused upon patient physical size parameters such as BW, BMI and BSA. The International Randomized Study of Interferon Versus STI571 (IRIS) study also identified weak correlations between steady-state trough levels of IM and both BW and BSA [6]. Breccia et al. further showed that patients with higher BMIs (25–40kg/m2) took significantly longer to achieve complete cytogenetic response and major molecular response than those with lower BMIs (<25kg/m2) [7]. In a prospective Japanese multicenter phase Ⅱ study, patients receiving 300mg of IM as tolerable daily doses had a lower BW and BSA than those who could tolerate daily doses of 400mg although mean trough levels did not differ between these groups [8]. Kim et al. further showed that the pharmacokinetic profile of IM in Korean patients was similar in caucasians [9] and these reports suggested that physical size is related to the pharmacokinetics of IM and associated with treatment effects or adverse reactions. In a previous report, it was speculated that withdrawal syndrome after IM cessation was related to a loss of blocking tyrosine kinases, such as c-kit and platelet-derived growth factor receptor (PDGFR) [2]. The inhibition of c-kit and PDGFR by IM reduces and increases the number of osteoclasts and osteoblasts, respectively; thus, long-term IM therapy can exert influence over bone DMXAA and leads to an increased bone volume [10]. In the current study, newly developed joint pain, including the fingers and wrist, was observed following IM cessation. Based upon our findings, we thus hypothesize that patients with a lower BW and BMI may be easily affected by blocking tyrosine kinases, such as c-kit and PDGFR, and these factors are linked to withdrawal syndrome following the discontinuation of IM. By carrying our additional research, and collating as much information as possible, it may be possible to identify positive factors with which to predict withdrawal syndrome following TKI cessation.
Disclosure of interest
Author\'s contributions
Acknowledgements This research was supported by a research grant from Tokyo Medical University.
Introduction Acute myeloid leukemia (AML) accounts for 80% of acute leukemia in adults with a median age at diagnosis of 65 years [1]. The standard upfront induction regimen for fit adult individuals remains “7+3”, consisting of 7 days of continuous infusion cytarabine and 3 days of an anthracycline, either daunorubicin or idarubicin [2]. Variations of induction and re-induction regimens in the refractory/relapsed disease setting often include either idarubicin or mitoxantrone in conjunction with high dose cytarabine and sometimes purine analogues. Medical comorbidities, specifically cardiovascular morbidity, have been shown to negatively impact the clinical outcomes of AML induction therapy in older adults. Cardiotoxicity constitutes the most frequently feared adverse event associated with the use of anthracyclines (>10%), and compromised cardiac function may compromise the use of potentially curative upfront and subsequent AML regimens in a patient\'s course. Prevention or mitigation of anthracycline-induced cardiotoxicity, particularly in older adults who constitute the majority of new AML diagnoses, is therefore an area of tremendous clinical relevance. Cardiotoxicity of anthracyclines is dose-dependent and can occur at any time in the treatment course with acute, subacute, and late-onset presentations. Clinical symptoms include arrhythmias, myopericarditis, cardiomyopathy, and congestive heart failure with reduced left ventricular ejection fraction (LVEF) [3–5]. For example, the incidence of cardiotoxic events with use of doxorubicin was less than 5% at a cumulative dose of 400mg/m2, but increased in a dose-dependent manner to 16% at a cumulative dose of 500mg/m2, 26% at 550mg/m2, and 48% at 700mg/m2[6,7]. For this reason, current recommendations limit the cumulative lifetime dose of doxorubicin to no more than 450mg/m2. Although the precise mechanisms of anthracycline-induced cardiac toxicities are not well elucidated, the most commonly proposed mechanism is drug-induced generation of iron-anthracycline complex mediated reactive oxygen species (ROS) which cause mitochondrial dysfunction leading to adenosine triphosphate depletion, lipid peroxidation, DNA damage, and subsequent myocardial injury [4,8]. Dexrazoxane (Cardioxane®; Zinecard®, Pfizer Inc., NY, NY) is a cyclic derivative of a strong metal-chelating agent which interferes with site-specific iron-based oxidative damage to cardiac mitochondria to exert its cardioprotective activity. By chelating free iron, dexrazoxane prevents the formation of iron-anthracycline complexes that lead to the formation of superoxide free radicals during redox reactions, thereby limiting cardiac injury [7]. Dexrazoxane was approved by the U.S. Food and Drug Administration (FDA) in 1995 for use as a cardioprotective agent in the treatment regimen of patients with metastatic or advanced breast cancer who have reached a cumulative anthracycline dose of 300mg/m2 and who are continuing to receive doxorubicin. Additionally, dexrazoxane was approved in 2007 by the FDA to decrease damage that may occur in the setting of inadvertent extravasation of anthracyclines into skin and subcutaneous tissue. Although not approved in the pediatric setting, dexrazoxane has also been extensively utilized in children with leukemia and lymphoma in order to mitigate the long-term cardiovascular effects of intensive chemotherapy regimens incorporating anthracyclines. Despite case reports of AML and myelodysplastic syndrome (MDS) developing in some children receiving dexrazoxane in conjunction with chemotherapy, the Children\'s Oncology Group recently reported that dexrazoxane did not appear to compromise long term survival of over 1000 pediatric patients treated with this agent on multiple clinical trials [9,10].