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An observational study on risk of secondary cancers in chronic myeloid leukemia patients in the TKI era in the United States.

ABSTRACT: Introduction:The treatment with tyrosine kinase inhibitors (TKIs) has drastically improved the outcome of chronic myeloid leukemia (CML) patients. This study was conducted to examine the risk of secondary cancers (SCs) in the CML patients who were diagnosed and treated in the TKI era in the United States. Methods:The surveillance epidemiology and end results (SEER) database was used to identify CML patients who were diagnosed and received treatment during January 2002-December 2014. Standardized incidence ratios (SIRs) and absolute excess risks (AER) were calculated. Results:Overall, 511 SCs (excluding acute leukemia) developed in 9,200 CML patients followed for 38,433 person-years. The risk of developing SCs in the CML patients was 30% higher than the age, sex and race matched standard population (SIR 1.30, 95% CI: 1.2-1.40; p < 0.001). The SIRs for CLL (SIR 3.4, 95% CI: 2-5.5; p < 0.001), thyroid (SIR 2.2, 95% CI: 1.2-3.5; p < 0.001), small intestine (SIR 3.1, 95% CI: 1.1-7; p = 0.004), gingiva (SIR 3.7, 95% CI: 1.2-8.7; p = 0.002), stomach (SIR 2.1, 95% CI: 1.1-3.5; p = 0.005), lung (SIR 1.4, 95% CI: 1.1-1.7; p = 0.006) and prostate (SIR 1.3, 95% CI: 1.02-1.6; p = 0.026) cancer among CML patients were significantly higher than the general population. The risk of SCs was higher irrespective of age and it was highest in the period 2-12 months after the diagnosis of CML. The risk of SCs in women was similar to that of the general population. Conclusion:CML patients diagnosed and treated in the TKI era in the United States are at an increased risk of developing a second malignancy. The increased risk of SCs in the early period after CML diagnosis suggests that the risk of SCs may be increased due to the factors other than TKIs treatment.

SUBMITTER: Kumar V

PROVIDER: S-EPMC5813591 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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An observational study on risk of secondary cancers in chronic myeloid leukemia patients in the TKI era in the United States.

Kumar Vivek V Garg Mohit M Chaudhary Neha N Chandra Abhinav Binod AB

PeerJ 20180212

<h4>Introduction</h4>The treatment with tyrosine kinase inhibitors (TKIs) has drastically improved the outcome of chronic myeloid leukemia (CML) patients. This study was conducted to examine the risk of secondary cancers (SCs) in the CML patients who were diagnosed and treated in the TKI era in the United States.<h4>Methods</h4>The surveillance epidemiology and end results (SEER) database was used to identify CML patients who were diagnosed and received treatment during January 2002-December 201 ...[more]

PMID: 29456888

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Project description:Background:Imatinib and second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib have statistically significantly improved the life expectancy of chronic myeloid leukemia (CML) patients; however, resistance to TKIs remains a major clinical challenge. Although ponatinib, a third-generation TKI, improves outcomes for patients with BCR-ABL-dependent mechanisms of resistance, including the T315I mutation, a proportion of patients may have or develop BCR-ABL-independent resistance and fail ponatinib treatment. By modeling ponatinib resistance and testing samples from these CML patients, it is hoped that an alternative drug target can be identified and inhibited with a novel compound. Methods:Two CML cell lines with acquired BCR-ABL-independent resistance were generated following culture in ponatinib. RNA sequencing and gene ontology (GO) enrichment were used to detect aberrant transcriptional response in ponatinib-resistant cells. A validated oncogene drug library was used to identify US Food and Drug Administration-approved drugs with activity against TKI-resistant cells. Validation was performed using bone marrow (BM)-derived cells from TKI-resistant patients (n?=?4) and a human xenograft mouse model (n?=?4-6 mice per group). All statistical tests were two-sided. Results:We show that ponatinib-resistant CML cells can acquire BCR-ABL-independent resistance mediated through alternative activation of mTOR. Following transcriptomic analysis and drug screening, we highlight mTOR inhibition as an alternative therapeutic approach in TKI-resistant CML cells. Additionally, we show that catalytic mTOR inhibitors induce autophagy and demonstrate that genetic or pharmacological inhibition of autophagy sensitizes ponatinib-resistant CML cells to death induced by mTOR inhibition in vitro (% number of colonies of control[SD], NVP-BEZ235 vs NVP-BEZ235+HCQ: 45.0[17.9]% vs 24.0[8.4]%, P = .002) and in vivo (median survival of NVP-BEZ235- vs NVP-BEZ235+HCQ-treated mice: 38.5 days vs 47.0 days, P = .04). Conclusion:Combined mTOR and autophagy inhibition may provide an attractive approach to target BCR-ABL-independent mechanism of resistance.

Project description:Children with acute myeloid leukemia are at risk for sepsis and organ failure. Outcomes associated with intensive care support have not been studied in a large pediatric acute myeloid leukemia population. Our objective was to determine hospital mortality of pediatric acute myeloid leukemia patients requiring intensive care.Retrospective cohort study of children hospitalized between 1999 and 2010. Use of intensive care was defined by utilization of specific procedures and resources. The primary endpoint was hospital mortality.Forty-three children's hospitals contributing data to the Pediatric Health Information System database.Patients who are newly diagnosed with acute myeloid leukemia and who are 28 days through 18 years old (n = 1,673) hospitalized any time from initial diagnosis through 9 months following diagnosis or until stem cell transplant. A reference cohort of all nononcology pediatric admissions using the same intensive care resources in the same time period (n = 242,192 admissions) was also studied.None.One-third of pediatric patients with acute myeloid leukemia (553 of 1,673) required intensive care during a hospitalization within 9 months of diagnosis. Among intensive care admissions, mortality was higher in the acute myeloid leukemia cohort compared with the nononcology cohort (18.6% vs 6.5%; odds ratio, 3.23; 95% CI, 2.64-3.94). However, when sepsis was present, mortality was not significantly different between cohorts (21.9% vs 19.5%; odds ratio, 1.17; 95% CI, 0.89-1.53). Mortality was consistently higher for each type of organ failure in the acute myeloid leukemia cohort versus the nononcology cohort; however, mortality did not exceed 40% unless there were four or more organ failures in the admission. Mortality for admissions requiring intensive care decreased over time for both cohorts (23.7% in 1999-2003 vs 16.4% in 2004-2010 in the acute myeloid leukemia cohort, p = 0.0367; and 7.5% in 1999-2003 vs 6.5% in 2004-2010 in the nononcology cohort, p < 0.0001).Pediatric patients with acute myeloid leukemia frequently required intensive care resources, with mortality rates substantially lower than previously reported. Mortality also decreased over the time studied. Pediatric acute myeloid leukemia patients with sepsis who required intensive care had a mortality comparable to children without oncologic diagnoses; however, overall mortality and mortality for each category of organ failure studied was higher for the acute myeloid leukemia cohort compared with the nononcology cohort.

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An observational study on risk of secondary cancers in chronic myeloid leukemia patients in the TKI era in the United States.

Publications

An observational study on risk of secondary cancers in chronic myeloid leukemia patients in the TKI era in the United States.

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