Risk of molecular recurrence after tyrosine kinase inhibitor discontinuation in chronic myeloid leukaemia patients: a systematic review of literature with a meta-analysis of studies over the last ten years

More than 10 years ago, the first pilot observational study of imatinib discontinuation was reported in chronic myeloid leukaemia (CML) patients in deep molecular response (DMR). Several studies have been published since then, in patients treated with frontline imatinib, or second-generation tyrosine kinase inhibitors (TKI) in first or second line but also on second attempt of TKI discontinuation. Our objective was to estimate, through meta-analyses of the literature data, the probability of molecular recurrence (MolRec) in the time periods of 0–6, 6–12, 12–18 and 18–24 months after a first and second TKI discontinuation and the probability of re-acquisition of DMR after MolRec. The Medline and Scopus databases were searched up to April 2019. The studies were selected by three independent reviewers. Random-effect meta-analyses were conducted using the MetaXL software. The probability of MolRec in the time periods 0–6, 6–12, 12–18 and 18–24 months after the first attempt was respectively 35%, 8%, 3% and 3%, whereas the probability of MolRec in the time periods 0-6, 6-12 and 12-18 after the second attempt was 48%, 27% and 12% respectively. Re-acquisition of a DMR was observed in 90% of patients. Most of the MolRec occur during the first six months in case of a first attempt, whereas the second MolRec occurs over a larger window of time.     

Sudden death in hypertrophic cardiomyopathy: identification of high risk patients

OBJECTIVES

We sought to identify patients with hypertrophic cardiomyopathy (HCM) at high risk of sudden death (SD).

BACKGROUND

Relatively low mortality rates in HCM make conventional analysis of multiple clinical risk markers for SD problematic. This study used a referral center registry to investigate a smaller number of generally accepted noninvasive risk markers.

METHODS

We studied 368 patients (14 to 65 years old, 239 males) with HCM. There were five variables: nonsustained ventricular tachycardia (NSVT), syncope, exercise blood pressure response (BPR), family history of sudden death (FHSD) and left ventricular wall thickness (LVWT).

RESULTS

During follow-up (3.6 ± 2.5 years [range 2 days to 9.6 years]), 36 patients (9.8%) died, 22 of them suddenly. Two patients received heart transplants. The six-year SD-free survival rate was 91% (95% confidence interval [CI] 87% to 95%). In the Cox model, there was a significant pairwise interaction between FHSD and syncope (p = 0.01), and these were subsequently considered together. The multivariate SD risk ratios (with 95% CIs) were 1.8 for BPR (0.7 to 4.4) (p = 0.22); 5.3 for FHSD and syncope (1.9 to 14.9) (p = 0.002); 1.9 for NSVT (0.7 to 5.0) (p = 0.18) and 2.9 for LVWT (1.1 to 7.1) (p = 0.03). Patients with no risk factors (n = 203) had an estimated six-year SD-free survival rate of 95% (95% CI 91% to 99%). The corresponding six-year estimates (with 95% CIs) for one (n = 122), two (n = 36) and three (n = 7) risk factors were 93% (87% to 99%), 82% (67% to 96%) and 36% (0% to 75%), respectively. Patients with two or more risk factors had a lower six-year SD survival rate (95% CI) compared with patients with one or no risk factors (72% [56% to 88%] vs. 94% [91% to 98%]) (p = 0.0001).

CONCLUSIONS

This study demonstrates that patients with multiple risk factors have a substantially increased risk of SD sufficient to warrant consideration for prophylactic therapy.     

Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study

Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.     

Patient-related risk factors for infection following knee arthroscopy: An analysis of over 700,000 patients from two large databases

Background

To determine patient-related risk factors for infection following knee arthroscopy using two large databases.

Testing the validity of categories in a theoretical perspective on chronic illness

The purpose of this study was to analyze differences in future time perspective, loneliness and perceived maternal expressiveness between adolescents who were chronically ill with cystic fibrosis and adolescents who were reportedly healthy. The sample consisted of 30 adolescents with cystic fibrosis who were matched on selected variables with 30 healthy adolescents. They responded to the Heimberg Future Time Perspective Inventory, the Revised UCLA Loneliness Scale, and the Perceived Maternal Expressiveness Scale. The three hypotheses were tested using the t-test. Since none of the hypotheses was supported, the validity of the categories was questioned. Theoretical and practical implications are addressed.     

Lipid-like materials for low-dose,in vivo gene silencing

Significant effort has been applied to discover and develop vehicles which can guide small interfering RNAs (siRNA) through the many barriers guarding the interior of target cells. While studies have demonstrated the potential of gene silencing in vivo, improvements in delivery efficacy are required to fulfill the broadest potential of RNA interference therapeutics. Through the combinatorial synthesis and screening of a different class of materials, a formulation has been identified that enables siRNA-directed liver gene silencing in mice at doses below 0.01 mg/kg. This formulation was also shown to specifically inhibit expression of five hepatic genes simultaneously, after a single injection. The potential of this formulation was further validated in nonhuman primates, where high levels of knockdown of the clinically relevant gene transthyretin was observed at doses as low as 0.03 mg/kg. To our knowledge, this formulation facilitates gene silencing at orders-of-magnitude lower doses than required by any previously described siRNA liver delivery system.