ABSTRACT
Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).
Subject(s)
Antineoplastic Agents/therapeutic use , Dasatinib/therapeutic use , Drug Monitoring , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Pleural Effusion/chemically induced , Protein Kinase Inhibitors/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Dasatinib/administration & dosage , Dasatinib/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Pleural Effusion/prevention & control , Prospective Studies , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Treatment Outcome , Young AdultSubject(s)
Blast Crisis , Fusion Proteins, bcr-abl , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Oncogene Proteins, Fusion , Proto-Oncogene Proteins c-kit , Pyrimidines/administration & dosage , Adult , Blast Crisis/drug therapy , Blast Crisis/genetics , Blast Crisis/metabolism , Blast Crisis/pathology , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolismABSTRACT
Many cases reported as 'chronic neutrophilic leukaemia' have had an associated plasma cell neoplasm. Recent evidence suggests that the great majority of such cases represent a neutrophilic leukaemoid reaction to the underlying multiple myeloma or monoclonal gammopathy of undetermined significance. We have analysed all accessible reported cases to clarify the likely diagnosis and to ascertain whether toxic granulation, Döhle bodies and an increased neutrophil alkaline phosphatase score were useful in making a distinction between chronic neutrophilic leukaemia and a neutrophilic leukaemoid reaction. We established that all these changes occur in both conditions. Toxic granulation and Döhle bodies are more consistently present in leukaemoid reactions but also occur quite frequently in chronic neutrophilic leukaemia. The neutrophil alkaline phosphatase score is increased in both conditions and is of no value in making a distinction.
Subject(s)
Cell Degranulation , Leukemia, Myeloid, Acute , Leukemia, Neutrophilic, Chronic , Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Neoplasms, Second Primary , Female , Humans , Inclusion Bodies/metabolism , Inclusion Bodies/pathology , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Leukemia, Neutrophilic, Chronic/diagnosis , Leukemia, Neutrophilic, Chronic/metabolism , Leukemia, Neutrophilic, Chronic/pathology , Male , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Monoclonal Gammopathy of Undetermined Significance/metabolism , Monoclonal Gammopathy of Undetermined Significance/pathology , Multiple Myeloma/diagnosis , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Neoplasms, Second Primary/diagnosis , Neoplasms, Second Primary/metabolism , Neoplasms, Second Primary/pathologyABSTRACT
BACKGROUND: Leukaemia is the eleventh commonest UK cancer. The four main subtypes have different clinical profiles, particularly between chronic and acute types. AIM: To identify the symptom profiles of chronic and acute leukaemia in adults in primary care. DESIGN AND SETTING: Matched case-control studies using Clinical Practice Research Datalink records. METHOD: Putative symptoms of leukaemia were identified in the year before diagnosis. Conditional logistic regression was used for analysis, and positive predictive values (PPVs) were calculated to estimate risk. RESULTS: Of cases diagnosed between 2000 and 2009, 4655 were aged ≥40 years (2877 chronic leukaemia (CL), 937 acute leukaemia (AL), 841 unreported subtype). Ten symptoms were independently associated with CL, the three strongest being: lymphadenopathy (odds ratio [OR] 22, 95% confidence interval [CI] = 13 to 36), weight loss (OR 3.0, 95% CI = 2.1 to 4.2), and bruising (OR 2.3, 95% CI = 1.6 to 3.2). Thirteen symptoms were independently associated with AL, the three strongest being: nosebleeds and/or bleeding gums (OR 5.7, 95% CI = 3.1 to 10), fever (OR 5.3, 95% CI = 2.7 to 10), and fatigue (OR 4.4, 95% CI = 3.3 to 6.0). No individual symptom or combination of symptoms had a PPV >1%. CONCLUSION: The symptom profiles of CL and AL have both overlapping and distinct features. This presents a dichotomy for GPs: diagnosis, by performing a full blood count, is easy; however, the symptoms of leukaemia are non-specific and of relatively low risk. This explains why many leukaemia diagnoses are unexpected findings.