Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.

Dose-Dense Mini-Hyper-CVD, Inotuzumab Ozogamicin and Blinatumomab Achieves Rapid MRD-Negativity in Philadelphia Chromosome-Negative B-cell Acute Lymphoblastic Leukemia.

BACKGROUND: The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, "dose-dense" administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes. PATIENTS AND METHODS: We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL. RESULTS: Twenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10-6, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen. CONCLUSION: Dose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings.

Incidence of adverse effects in patients receiving ponatinib with concomitant azole antifungals.

Ponatinib plus Hyper-CVAD yields a five-year overall survival of 73% in patients with Philadelphia-positive acute lymphoblastic leukemia. Ponatinib dose intensity is associated with increased incidence of adverse effects (AEs), including vascular events. Ponatinib combined with azole antifungals may further increase the risk of AEs due to increased ponatinib exposure. We reviewed 53 patients who received ponatinib with intensive (n = 39; 74%) or low-intensity chemotherapy (n = 14; 26%). Forty-eight patients (91%) received concomitant azole. Ponatinib was commonly initiated at 30 mg (n = 30; 57%) or 45 mg daily (n = 21; 40%). Twenty-six patients (49%) experienced at least one grade ≥3 AE possibly related to ponatinib; 19 (73%) were receiving a ponatinib dose equivalent ≥30mg and 58% >45mg. Eight patients (15%) experienced 10 vascular events, including 1 arterial event; 9 occurred on a ponatinib dose equivalent ≥30mg and 5 occurred while on an azole. Vascular events pose a clinical challenge with the risk potentially increasing with concomitant azoles.

Duration of cytopenias with concomitant venetoclax and azole antifungals in acute myeloid leukemia.

BACKGROUND: Venetoclax (VEN) combined with the hypomethylating agent (HMA) azacitidine improves survival in patients aged ≥75 years with newly diagnosed acute myeloid leukemia (AML). VEN and HMA treatment can result in prolonged and often profound neutropenia, and this warrants antifungal prophylaxis. Azole antifungals inhibit cytochrome P450 3A4, the primary enzyme responsible for VEN metabolism; this results in VEN dose reductions for each concomitant antifungal. Limited clinical data exist on outcomes for patients treated with VEN, an HMA, and various azoles. METHODS: The time to neutrophil recovery (absolute neutrophil count [ANC] > 1000 cells/mm3 ) and platelet (PLT) recovery (PLT count > 100,000 cells/mm3 ) in 64 patients with newly diagnosed AML who achieved a response after course 1 of VEN plus an HMA were evaluated. HMA therapy included azacitidine (75 mg/m2 intravenously/subcutaneously for 7 days) or decitabine (20 mg/m2 intravenously for 5 or 10 days). RESULTS: Forty-seven patients (73%) received an azole: posaconazole (n = 17; 27%), voriconazole (n = 9; 14%), isavuconazole (n = 20; 31%), or fluconazole (n = 1; 2%). The median time to ANC recovery were similar for patients who did receive an azole (37 days; 95% confidence interval [CI], 34-38 days) and patients who did not receive an azole (39 days; 95% CI, 30 days to not estimable; P = .8). The median time to PLT recovery was significantly longer for patients receiving azoles (28 vs 22 days; P = .01). The median times to ANC recovery (35 vs 38 days) and PLT recovery (26 vs 32 days) were similar with posaconazole and voriconazole. CONCLUSIONS: VEN plus an HMA resulted in neutropenia and thrombocytopenia, with the latter prolonged in patients receiving concomitant azoles. Concomitant posaconazole or voriconazole and VEN (100 mg) resulted in similar ANC and PLT recovery times, suggesting the safety of these dosage combinations during course 1.

Inotuzumab ozogamicin for the treatment of acute lymphoblastic leukemia.

Therapy for adult acute lymphoblastic leukemia (ALL) with multiagent cytotoxic chemotherapy has not been as successful as that for pediatric patients. The advent of targeted monoclonal antibodies against common cell surface antigens (i.e. CD19, CD20, and CD22) has resulted in improved outcomes without additional toxicities. Inotuzumab ozogamicin is an anti-CD22 antibody-drug conjugate approved for the treatment of relapsed or refractory B-cell precursor ALL. It improved outcomes compared with standard salvage chemotherapy. Its combination with low-intensity chemotherapy in the relapse setting and in frontline elderly patients is promising.

Ion exchange at the critical point of solution.

A mixture of isobutyric acid (IBA)+water has an upper critical point of solution at 26.7°C and an IBA concentration of 4.40M. We have determined the Langmuir isotherms for the hydroxide form of Amberlite IRN-78 resin in contact with mixtures of IBA+water at temperatures, 27.0, 29.0, 31.0 and 38.0°C, respectively. The Langmuir plot at 38.0°C forms a straight line. At the three lower temperatures, however, a peak in the Langmuir plot is observed for IBA concentrations in the vicinity of 4.40M. We regard this peak to be a critical effect not only because it is located close to 4.40M, but also because its height becomes more pronounced as the temperature of the isotherm approaches the critical temperature. For concentrations in the vicinity of the peak, the data indicate that the larger isobutyrate ion is rejected by the resin in favor of the smaller hydroxide ion. This reversal of the expected ion exchange reaction might be used to separate ions according to size. Using the Donnan theory of ion exchange equilibrium, we link the swelling pressure to the osmotic pressure. We show that the peak in the Langmuir plot is associated with a maximum in the "osmotic" energy. This maximum has its origin in the concentration derivative of the osmotic pressure, which goes to zero as the critical point is approached.

[Madelung disease and obstructive sleep apnea syndrome: apropos of a case]. / Maladie de Madelung et syndrome obstructif avec apnées du sommeil: à propos d'un cas.

Madelung's disease, or benign symmetric lipomatosis, is an uncommon disease. It is an unencapsulated fatty infiltration which in rare cases extends into the perilaryngeal space and mediastinum. The authors present a case complicated by an obstructive syndrome and sleep apnoea syndrome, which was successfully treated by continuous positive airway pressure. The literature is reviewed.

[Management of opiate-dependent adolescents in the Vaud canton. Reflections on the indication for treatment with methadone]. / Prise en charge des adolescents dépendants des opiacés dans le canton de Vaud. Réflexion sur l'indication d'un traitement par la méthadone.

Based on our clinical practices with opiate-dependent adolescents living in the area of Lausanne (Switzerland), our observations are focused tend on the particularities, on the current and future means of treatment for these patients. The use of methadone is being discussed.

[A brief plea against the use of guidelines in medicine]. / Petit plaidoyer contre l'emploi des lignes directrices en médecine.

The use of guidelines in medical practice may be dangerous since it limits the art of medicine to the mere observance of rules. Some aspects of guidelines do not rely on scientific knowledge, but on a democratic approach (panel of specialist!). Finally, guideline users expose themselves to the pressure of communities, health care systems or possible legal action. These are risks which cannot justifiably be incurred.

[Is non-allergenic bronchial hyperreactivity a good diagnostic test for asthma?]. / Hyperréactivité bronchique non allergénique: est-ce un bon test diagnostique pour l'asthme?

The measurement of non-allergic bronchial hyperreactivity brings limited information in the diagnosis of asthma, whether for epidemiological purposes or for an individual patient. Its sensitivity and specificity in the general population amount to 46 and 89% respectively. It follows that the positive and negative predictive values are of little use when the prevalence of asthma lies between 1 and 10%. The situation is different, more complex, but not necessarily more favorable when one deals with one given patient. The characteristics of the test may vary as a function of the severity of the disease (concept of spectrum bias). Furthermore, the differential diagnosis will be made for other diseases that can also be associated with bronchial hyperreactivity. The negative and positive predictive values of this test will therefore be sufficiently informative only when the diagnosis is already certain.

[Spirometry in the physician's office]. / La spirométrie au cabinet du praticien.

Spirometry is a valuable tool for the estimation of lung function in the daily practice. Some basic criteria for its use, its interpretation, as well as for the selection of a good spirometer are shortly discussed.

[The effects of smoke on airways]. / Effets de la fumée sur les voies aériennes.

Among the numerous effects of tobacco smoke on airway mucosa, the best known and the most frequent are those leading to chronic bronchitis (CB) or chronic obstructive pulmonary disease (COPD). Recent studies suggest that inflammation is central to these disorders. If predominant in larger airways (diameter greater than 4 mm), inflammation is associated with CB. When predominant in small airways (diameter less than 2 mm), it can induce COPD. The exact mechanisms remain unknown. There is no useful way in early detecting evolution toward COPD in asymptomatic smokers.

[Motility of the bronchi]. / Bronchomotricité.

Airway diameter depends on bronchial smooth muscle tone which is regulated via complex nervous influences including afferent and efferent vagal fibers, sympathetic agonists and the so called 'third nervous system' (non adrenergic non cholinergic), as recently described. Additionally, various mediators of inflammation and epithelium derived factors contribute to the regulation of bronchi motility in health and disease.

[Nonspecific bronchial reactivity]. / Réactivité bronchique non spécifique.

Nonspecific bronchial reactivity is defined as the ability of bronchial smooth muscles to contract in response to non-allergenic (nonspecific) stimuli. Recent techniques for its measurement in different experimental and clinical situations have opened up new avenues in the understanding of asthma, airway infection, cough, and effects of pollution. The most recent data suggest that airway inflammation is the central mechanism of bronchial hyperreactivity, but the cells and mediators involved remain to be discovered. Bronchial reactivity as a test for clinical purposes needs standardization, careful establishment of normal values and assessment of validity in terms of the decision-making process.