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.

Monoclonal antibodies in frontline acute lymphoblastic leukemia.

The recent development of monoclonal antibodies targeting CD19, CD20, and CD22 has significantly improved long-term survival in patients with acute lymphoblastic leukemia (ALL), both in the frontline and relapsed and refractory setting. The incorporation of CD20 monoclonal antibodies (e.g. rituximab) has improved cure rates from 35% to 50% in those with precursor B-cell ALL and from 40 to 80% in those with Burkitt leukemia. More novel antibodies, such as drug conjugates antibodies (e.g. inotuzumab ozogamicin) and bispecific T-cell engagers (e.g. blinatumomab), have shown significant promise in improving outcomes in the relapsed and refractory setting and are currently being studied in the frontline setting, with hopes to further improve long-term outcomes. In this chapter, we will review the role of monoclonal antibodies and how the incorporation of these agents has revolutionized and changed the treatment management of ALL in the frontline setting.

Antibody based therapy in relapsed acute lymphoblastic leukemia.

Outcomes for relapsed and refractory acute lymphoblastic leukemia (ALL) remain poor. With the advent of targeted monoclonal antibodies and antibody constructs, these outcomes have been significantly improved both in the frontline and salvage setting. These targets include a bispecific antibody that targets both CD3 and CD19, known as blinatumomab, as well as a conjugated antibody that targets CD22, known as inotuzumab ozogamicin. These agents have been thoroughly studied and successively approved for use as monotherapy, however, more recently they have been incorporated in combination or sequentially with cytotoxic chemotherapy. In this chapter, we will discuss the role that these monoclonal antibodies play as monotherapy and in combination in the treatment of ALL in the salvage setting, and how they continue to transform the treatment management of relapsed and refractory ALL.

Gilteritinib in the treatment of relapsed and refractory acute myeloid leukemia with a FLT3 mutation.

Acute myeloid leukemia (AML) is a malignancy of uncontrolled proliferation of immature myeloid blasts characterized by clonal evolution and genetic heterogeneity. FMS-like tyrosine kinase 3 (FLT3) mutations occur in up to a third of AML cases and are associated with highly proliferative disease, shorter duration of remission, and increased rates of disease relapse. The known impact of activating mutations in FLT3 in AML on disease pathogenesis, prognosis, and response to therapy has led to the development of tyrosine kinase inhibitors targeting FLT3. Gilteritinib is a potent, second generation inhibitor of both FLT3 and AXL, designed to address the limitations of other FLT3 inhibitors, particularly in targeting mechanisms of resistance to other drugs. In this review, we present comprehensive data on recent and ongoing studies evaluating the role of gilteritinib in the relapsed and refractory FLT3 mutated AML setting.

Continuous thermoregulatory responses to mass-participation distance running in heat.

PURPOSE: To continuously measure core temperature (T(c)) and heart rate(HR), and quantify fluid balance during a 21-km mass-participation road racein warm, humid environmental conditions. METHODS: Eighteen heat-acclimatized male soldiers ingested a telemetric Tc sensor on the evening prior to the race and wore an ambulatory T(c) data recorder and HR monitor during the race. Pre- to postrace changes in nude body mass quantified fluid balance. RESULTS: Environmental wet bulb globe temperature averaged 26.5 degrees C. All runners finished the race asymptomatic of heat illness in a mean +/- SD (range) time of 118 +/- 13 (105-146) min, corresponding to an average running speed of 10.8 +/- 1.1 (8.6-12.0) km.h(-1). All runners recorded peak T(c) > 39 degrees C; 56% (N = 10) > 40 degrees C; and 11% (N = 2) > 41 degrees C. Peak T(c) was 40.1 +/- 0.7 (39.3-41.7) degrees C at 86 +/- 36 (13-130) min, with T(c) 39.9 +/- 0.8 (38.3-41.7) degrees C at race finish. The magnitude of T(c) response was unrelated (P > 0.05) to running time or fluid balance (e.g., fluid intake, % dehydration). Cumulative heat strain index was 2790 +/- 1112 (1046-5144) units at race finish. CONCLUSION: Ingestible telemetric temperature sensors demonstrated utility for continuous measurement of T(c) during mass-participation running. Successful application of this technology has highlighted the magnitude and duration of T(c) elevation that runners will voluntarily achieve during mass-participation distance races in heat and high humidity without medical consequence.

Water versus carbohydrate-electrolyte fluid replacement during loaded marching under heat stress.

This study compared the effectiveness of carbohydrate-electrolyte (CHO-E) fluid replacement versus water (WAT) on hydration status, physiological and subjective responses, and exercise performance during a 3 x 60-minute loaded (14 kg) treadmill walk in 35 degrees C ambient temperature and 55% humidity. CHO-E did not affect urine loss, plasma volume change (WAT = -3.0 +/- 1.6% vs. CHO-E = -1.1 +/- 1.6%), dehydration (WAT = 0.4 +/- 0.3% vs. CHO-E = 0.4 +/- 0.3% of body mass), or core body temperature (Tc) and heart rate (HR) responses. Endurance time was greater but not significantly different with CHO-E (WAT = 134 +/- 9 vs. CHO-E = 146 +/- 9 minutes). CHO-E increased the frequency of task completion (WAT = 21% vs. CHO-E = 50%), elevated blood glucose, and reduced perceived exertion. CHO-E offers potential to enhance exercise capacity by elevating blood glucose and thereby preventing hypoglycemia, maintaining high rates of carbohydrate oxidation, and/or preventing central fatigue; but provided no additional benefits with regard to hydration status and physiological function during loaded walking under heat stress.

Leukocyte subset responses during exercise under heat stress with carbohydrate or water intake.

PURPOSE: This study investigated leukocyte subset responses to moderate-intensity exercise under heat stress, with water (W) or carbohydrate (CHO) drink ingestion. METHODS: In repeated trials, 13 soldiers consumed either a W or CHO drink during 3 h of walking at 4.4 km x h(-1) with a 5% gradient (15 min rest per hour) under heat stress (35 degrees C and 55% relative humidity). The soldiers wore combat uniforms and carried water bottles and dummy rifles and ammunition, altogether weighing about 11.5 +/- 1.0 kg. RESULTS: Plasma glucose concentration was significantly higher with CHO than W ingestion during exercise (p < 0.01). There were no significant differences between W and CHO conditions in exercise performance, plasma cortisol concentration, heart rate, or core temperature. CHO ingestion significantly moderated the increases in leukocyte (83% in W, 28% in CHO; p < 0.001), monocyte (60% in W, 34% in CHO; p < 0.05), and granulocyte counts (120% in W, 30% in CHO; p < 0.001), but not in lymphocyte count (41% in W, 25% in CHO). CONCLUSIONS: The increases in leukocyte and subset counts during moderate-intensity exercise under heat stress may be comparable to those observed during intense exercise in cool conditions. The response of immune cell counts is blunted by CHO intake during moderate-intensity exercise in the heat, and may not occur through the cortisol pathway.