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Importance: The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuing therapy with this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up., Objective: To determine features associated with discontinuation of ibrutinib therapy and outcomes., Design, Setting, and Participants: A total of 308 patients participating in 4 sequential trials of ibrutinib at The Ohio State University Comprehensive Cancer Center were included. These clinical trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014., Main Outcomes and Measures: Patients were evaluated for time to therapy discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued therapy because of disease progression, targeted deep sequencing was performed in samples at baseline and time of relapse., Results: With a median follow-up of 20 months, 232 patients remained on therapy, 31 had discontinued because of disease progression, and 45 had discontinued for other reasons. Disease progression includes Richter's transformation (RT) or progressive CLL. Richter's transformation appeared to occur early and CLL progressions later (cumulative incidence at 12 months, 4.5% [95% CI, 2.0%-7.0%] and 0.3% [95% CI, 0%-1.0%], respectively). Median survival following RT was 3.5 months (95% CI, 0.3-6.0 months) and 17.6 months (95% CI, 4.7 months-"not reached") following CLL progression. Sequencing on peripheral blood from 8 patients with RT revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCG2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCG2 mutations in all. These mutations were not identified before treatment in any patient., Conclusions and Relevance: This single-institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib therapy discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with RT. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCG2 with progression and clearly show that CLL progressions are associated with these mutations, while RT is likely not., Trial Registrations: clinicaltrials.gov Identifiers:NCT01105247, NCT01217749, NCT01589302, and NCT01578707.

Purpose: Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors., Experimental Design: Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies., Results: Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1-24). Total doses ranged from 40 to 105 mg/m(2). The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 μM. Area under the concentration-versus-time curve ([Formula: see text]) ranged from 4.31 to 32.2 μM[Symbol: see text]hr with an overall mean of 13.6 ± 7.0 μM[Symbol: see text]hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes., Conclusions: The maximum-tolerated dose of flavopiridol is 20 mg/m(2) bolus followed by 20 mg/m(2) infusion over 4 h given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.

Background: Hyperglycemia is often observed in medically ill patients. Previous studies have shown that patients with hyperglycemia during induction therapy for acute lymphoblastic leukemia develop more infections and have shorter disease-free survival. The authors hypothesized that hyperglycemia may be associated with adverse outcomes in patients with acute myeloid leukemia (AML) and sought to determine whether this association exists in this population., Methods: The authors performed a retrospective cohort study to examine the relation between hyperglycemia and hospital mortality in patients with the diagnosis of AML. Two hundred eighty-three adult patients were treated over a 3-year period. All hospitalizations were reviewed during the study period, and glucose exposure and outcomes were quantified., Results: Hyperglycemia during a patient's hospitalization was associated with increased hospital mortality (OR, 1.38; 95% CI, 1.23-1.55; P < .001) after adjusting for covariates, including disease state, treatment type, and response. The rise in mortality was evident at even mild levels (110-150 mg/dL) of glucose elevation. Although the odds of developing severe sepsis (OR, 1.24; 95% CI, 1.13.-1.38; P < .001) or severe sepsis with respiratory failure (OR, 2.04; 95% CI, 1.44-2.91; P < .001) were increased with hyperglycemia, sepsis did not appear to be the main factor responsible for the negative impact of hyperglycemia on hospital mortality., Conclusions: This study demonstrated an association between hospital mortality and even modest levels of hyperglycemia in AML patients. Prospective studies are needed to confirm this association and to discern causal pathways that mediate this effect., (Copyright (c) 2007 American Cancer Society.)