br Conclusion br Authors contribution br Competing interests

Conclusion
Authors’ contribution
Competing interests
Acknowledgments
Case report Imatinib has radically changed prognosis in chronic-phase Chronic Myeloid Leukemia (CML), with 90% overall survival rate at 8yrs, and 40–70% of patients achieving a stable MMR [1]. Even better results have been reported in terms of cytogenetic and molecular responses and the rate of progression to accelerated/blast phase using second-generation tyrosine-kinase inhibitors (TKI) first-line [2,3]. Physicians are no longer familiar with resistant chronic-phase CML and are particularly frustrated when facing primary resistance to TKIs, as it methysergide is quite uncommon and related to still poorly understood mechanisms. Point mutations within the BCR-ABL kinase domain account for 50–60% of cases of secondary resistance to Imatinib and to a lesser extent to secondary resistance to second-generation TKIs [4]. However, ABL mutations are less frequently detected in primary resistant patients and mutational analysis is not required by European LeukemiaNet (ELN) Recommendations at diagnosis [5]. We report a CML patient who showed resistance to multiple TKIs because of different emerging ABL mutations, but who showed an admirable and incredible perseverance in the pursuit of her personal aims. In this case we had to face two serious concurrent problems: refractory CML and conception under second-line TKI. Primary resistance to TKIs entails a very dismal prognosis. In our case ABL mutations selected in sequence by the TKI in use were apparently responsible for resistance to multiple TKI, but in addition genetic instability typical of a more advanced phase might be hypothesized in a patient who had most likely ignored her disease for months. Ponatinib has been proven to be effective in heavily pretreated CML patients independent of the presence of ABL mutations [6]. However, genetic instability makes a long lasting response quite unlikely. Allogeneic stem cell transplantation seems to be the only meaningful option in this case, but we do not know if our patient will ever undergo the procedure. Whereas some reassuring data exists on unplanned conception under Imatinib treatment [7,8], very little information is available about the safety of conception under Nilotinib [9,10], and female patients in reproductive age are strongly advised to use effective methods of contraception while receiving TKIs. Fortunately, the child is healthy and developing normally. In our case the management of the pregnancy posed challenges to both the patient and the physicians, as our patient became pregnant on Nilotinib while strictly requiring treatment to control her disease. Moreover, it required delicate attention to important ethical and psychosocial issues, including as well as cultural sensibilities. So far, the patient has been confident in the good outcome of the whole clinical course, often reassuring her increasingly worried physicians with a smile and pictures of her son. This case reminds us that (i) CML is still a life-threatening disease and we should not to lower our guard, despite excellent results in the majority of patients and multiple TKIs available; (ii) patients\' personal social contexts and wishes have to be respected, even if they contrast with rational adherence to the treatment guidelines; and (iii) a patient\'s perseverance and optimism are invaluable in the fight against leukemia.
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Introduction The introduction of risk-adapted intensified combination therapy has markedly improved outcomes for children with acute lymphoblastic leukemia (ALL). Unfortunately, disease recurrence and treatment-induced toxicity remain clinically relevant risks [1]. Candidate gene studies previously reported that polymorphisms in genes encoding for enzymes in folate metabolism and drug detoxification pathways (e.g. TPMT, MTHFR, CBS, MTR, and DHFR) may modify relapse and treatment toxicity risk [2,3]. We sought to evaluate single nucleotide polymorphism (SNPs) in these pathways to validate previous reports. We expanded our previous candidate gene genotyping efforts to include 24 SNPs in 17 genes (MTHFR, MTR, PTH1R, ABCG2, MTRR, TPMT, SOD2, ABCB1, GGH, ENOSF1, GSTP1, LRP5, NQO1, SHMT1, TYMS, SLC19A1, and CBS) in the folate and drug metabolizing pathway for their association with risk of relapse in 714 children who had been treated in the CCG-1952 study [4]. Between 1996 and 2000, a total of 2027 pediatric patients were enrolled in the CCG-1952 study. This study compared the use of intrathecal (IT) methotrexate to IT triple (ITT) chemotherapy (methotrexate, cytarabine, and hydrocortisone sodium succinate) and oral mercaptopurine to thioguanine in treating children with standard-risk ALL. Guardians provided written informed consent and permission for the use of archived samples in accordance with National Institutes of Health guidelines.