CML in pregnancy and childhood.
ABSTRACT With the improved survivals offered by the tyrosine kinase inhibitors has come the necessity to address issues relating to quality of life and one such area is that of fertility and parenting. Animal data suggest that imatinib at standard dosages is unlikely to impair fertility in either adult males or females but human data remain limited. Children born to men who are actively taking imatinib at the time of conception appear healthy and current advice is not to discontinue treatment. In contrast the data relating to children born to women exposed to imatinib during pregnancy are less encouraging. Although numbers are small there has been a disturbing cluster of rare congenital malformations such that imatinib cannot be safely recommended, particularly during the period of organogenesis. The appropriate management of children with CML has also been radically changed by the advent of imatinib. The features of the disease at presentation, the natural history and the response to therapy seem to be identical in children to that seen in adults. Now that imatinib has been in clinical use for almost ten years without severe long-term side effects, most physicians are now comfortable advising a trial of imatinib prior to consideration of transplant. Data relating to the efficacy and safety of second generation tyrosine kinase inhibitors in childhood is entirely absent and transplant remains the first choice for patients failing imatinib and perhaps also for young patients with sub-optimal responses.
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ABSTRACT: Childhood chronic myelogenous leukemia (CML) is a rare hematologic disease, with limited literature on the methods of treatment. Previously, allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment for this disease. Treatment with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase (TKI), has resulted in prolonged molecular response with limited drug toxicity. Imatinib is now implemented in the primary treatment regimen for children, but the paucity of evidence on its ability to result in permanent cure and the potential complications that may arise from long-term treatment with TKIs have prevented imatinib from superseding HSCT as the primary means of curative treatment in children. The results of allogeneic HSCT in children with CML are similar to those observed in adults; HSCT-related complications such as transplant-related mortality and graft-versus-host disease remain significant challenges. An overall consensus has been formed with regards to the need for HSCT in patients with imatinib resistance or those with advanced-phase disease. However, issues such as when to undertake HSCT in chronic-phase CML patients or how best to treat patients who have relapsed after HSCT are still controversial. The imatinib era calls for a reevaluation of the role of HSCT in the treatment of CML. Specific guidelines for the treatment of pediatric CML have not yet been formulated, underscoring the importance of prospective studies on issues such as duration of imatinib treatment, optimal timing of HSCT and the type of conditioning utilized, possible treatment pre- and post-HSCT, and the role of second-generation TKIs.Korean Journal of Pediatrics 03/2011; 54(3):111-6. DOI:10.3345/kjp.2011.54.3.111
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ABSTRACT: Introduction Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasms of the hematopoietic stem cells characterized by a triphasic clinical presentation, and the presence of a reciprocal translocation between chromosomes 9 and 22 or the Philadelphia chromosome (Ph). The juxtaposition of the breakpoint cluster region (BCR) on chromosome 22 with the Abelson gene (ABL) on chromosome 9 leads to a dys-regulation of the ABL intrinsic non receptor tyrosine kinase activity. By controlling downstream pathways involved in cell proliferation, adhesion, and survival, the hybrid oncogene BCR-ABL is considered as a major driver of leukemogenesis in CML. The therapeutic approach for CML has undergone a revolutionary change during the last 2 decades with the Abstract Objective: The introduction of several classes of targeted therapeutics for the treatment of chronic myelogenous leukemia (CML) raises the question of whether male fertility is affected and the degree of this affection, if any, among the different generations of tyrosine kinase inhibitors (TKIs). Additionally, when two drugs are equally effective, the drug with less toxic effect on fertility is favourable. Our aims were to evaluate semen parameters and pituitary gonadal function before and four months after starting TKIs namely, dasatinib, nilotinib, and imatinib in patients with CML. Design: Prospective study. Setting, patients and interventions: We studied the effect of TKIs' first generation (imatinib) and second generation (dasatinib and nilotinib) on semen parameters and endocrine functions in 20 eugonadal male patients with CML, aged between 35 to 51 years. They were receiving imatinib (400 mg) once daily, dasatinib (100 mg) once daily or nilotinib (300 mg) twice daily as upfront therapy. We assessed the serum gonadotropins (LH and FSH) and testosterone (T) secretion and sperm parameters before and after four months of using these TKIs. Results: Four months after starting TKIs, serum testosterone, LH and FSH concentrations decreased significantly. The total sperm count (SC), total and rapid progressive sperm motility, and % sperms with normal morphology decreased significantly versus pre-treatment. After 4 months of therapy, dasatinib had comparatively the least deleterious effects on SC, ejaculate volume (SV), sperm motility and % of sperms with normal morphology (%NM) compared to imatinib and nilotinib. Significant correlations were found between serum T concentrations and semen parameters before and after TKIs therapy including SC (r 0.658 and r 0.73 respectively, p 0.001), rapid progressive motility (r 0.675 and r 0.758, respectively; p 0.001), and the % NM (r 0.752 and r 0.834, respectively; p 0.001). After TKIs therapy, LH were correlated significantly with T concentrations, SV and SC (r 0.434, 0.439 and 0.376, respectively; p: 0.01). Conclusions: Our study showed that CML patients treated with TKIs have significant decrease of sperm parameters and decreased serum concentrations of serum T, LH and FSH. These potentially toxic effects on spermatogenesis are less prominent in patients treated with dasatinib compared to imatinib and nilotinib. The mechanisms and pathways for these effects need further human and/ or experimental studies. Citation: Yassin MA, Soliman AT, Sanctis VD (2014) Effects of tyrosine kinase inhibitors on spermatogenesis and pituitary gonadal axis in males with chronic myeloid leukemia. J Cancer Res Ther 2:116-121. Copyright: 2014 Yassin MA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited. Open Access introduction of the tyrosine kinase inhibitors. The use of these agents has changed overall survival as well as the08/2014; 2:116-121. DOI:10.14312/2052-4994.2014-18
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ABSTRACT: Elucidation of the pathogenesis of chronic myeloid leukemia (CML) and the introduction of tyrosine kinase inhibitors (TKIs) has transformed this disease from being invariably fatal to being the type of leukemia with the best prognosis. Median survival associated with CML is estimated at > 20 years. Nevertheless, blast crisis occurs at an incidence of 1%-2% per year, and once this has occurred, treatment options are limited and survival is short. Due to the overall therapeutic success, the prevalence of CML is gradually increasing. The optimal management of this disease includes access to modern therapies and standardized surveillance methods for all patients, which will certainly create challenges. Furthermore, all available TKIs show mild but frequent side effects that may require symptomatic therapy. Adherence to therapy is the key prerequisite for efficacy of the drugs and for long-term success. Comprehensive information on the nature of the disease and the need for the continuous treatment using the appropriate dosages and timely information on efficacy data are key factors for optimal compliance. Standardized laboratory methods are required to provide optimal surveillance according to current recommendations. CML occurs in all age groups. Despite a median age of 55-60 years, particular challenges are the management of the disease in children, young women with the wish to get pregnant, and older patients. The main challenges in the long-term management of CML patients are discussed in this review.Hematology 12/2011; 2011:128-35. DOI:10.1182/asheducation-2011.1.128 · 2.86 Impact Factor