Comparison of Mold Active Triazoles as Primary Antifungal Prophylaxis in Patients With Newly Diagnosed Acute Myeloid Leukemia in the Era of Molecularly Targeted Therapies.

BACKGROUND: Multiple factors influence the choice of primary antifungal prophylaxis (PAP) in patients with acute myeloid leukemia (AML) undergoing remission induction chemotherapy (RIC) given the recent incorporation of targeted leukemia therapies into these regimens. METHODS: We evaluated the incidence and characteristics of breakthrough invasive fungal infections (bIFI) in 277 adult patients with newly diagnosed AML undergoing RIC with high-intensity, or low-intensity venetoclax-containing therapy. Patients receiving posaconazole (PCZ), voriconazole (VCZ), or isavuconazole (ISA) for > 5 days as PAP during RIC were included. Echinocandin use prior to, but not concomitantly with, the PAP azole was allowed. IFI (modified EORTC/MSG criteria) occurring after > 5 days of continuous azole exposure or within 14 days of discontinuation were considered bIFI. RESULTS: Proven or probable bIFI were observed in 11 patients (4%). The incidence of bIFI was 2.9% for PCZ, 4.8% for VCZ, and 5.7% for ISA (P = .55). In total, 161 patients (58%) received echinocandin prophylaxis prior to azole initiation. Neither echinocandin exposure nor chemotherapy intensity impacted bIFI rate. Patients with bIFI had a lower rate of absolute neutrophil count recovery > 1000 cells/µL (64% vs 90%, P = .021) or complete remission (CR; 18% vs 66%, P = .002) after RIC. Thirty-eight patients (14%) discontinued PAP due to toxicity, most often hepatotoxicity. Discontinuation due to hepatotoxicity was similar among azoles (PCZ: 13%; VCZ: 15%; ISA: 13%). CONCLUSIONS: The rate of bIFI is low during RIC in patients with newly diagnosed AML receiving any of the mold-active triazoles as PAP. Neutrophil recovery and achievement of CR are important for bIFI risk.

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.

Effect of High-Dose Posaconazole on Serum Levels in Adult Patients with Hematologic Malignancy.

Posaconazole (POS) appears to have dose-proportional pharmacokinetics; however, there is a paucity of real-life data. We retrospectively evaluated 67 patients with hematologic cancer who had POS dose increases from 300 mg/day to either 400 mg/day (n = 52) or 300 mg twice daily (BID) (n = 15) and for whom POS serum levels were measured. Median POS levels were 840 ng/ml, 1,625 ng/ml, and 2,710 ng/ml for the dosages of 300 mg/day, 400 mg/day, and 300 mg BID, respectively. Significant interpatient variability in serum levels was noted.

Non-Aspergillus invasive mould infections in patients treated with ibrutinib.

BACKGROUND: Invasive mould infections (IMIs) are very rare in patients with lymphoid malignancies. However, IMIs, mostly due to Aspergillus species, have been increasingly reported in such patients receiving ibrutinib (IBR). There is paucity of information regarding non-Aspergillus invasive mould infections (NAIMIs) in this setting, OBJECTIVES: To review our recent experience and the published literature on the topic. PATIENTS/METHODS: We present a case of invasive sinusitis caused by Fusarium in a patient with refractory chronic lymphocytic leukaemia (CLL) who was treated with IBR and review the 12 published cases of NAIMIs during IBR. RESULTS: Nearly all cases of NAIMIs in the setting of IBR use were encountered in patients with CLL. Mixed fungal infections, brain involvement and late-onset infections were common. CONCLUSIONS: Although rare, NAIMIs should be considered in patients who receive IBR.

Lack of Toxicity With Long-term Isavuconazole Use in Patients With Hematologic Malignancy.

Prolonged courses of isavuconazole (ISA) are increasingly utilized in immunocompromised patients. Toxicities have been reported with long-term use of the other triazoles. We report the first real-life tolerability data in 50 patients with hematologic malignancy receiving ≥6 months of ISA. ISA was well tolerated in our ill patient population.

Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint.

BACKGROUND: Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (>8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. METHODS: Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a ß-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. RESULTS: Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC >27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%-5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%-97.9% when the MIC was 1 mg/L. CONCLUSIONS: For enterococcal bacteremia, a daptomycin fAUC/MIC >27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

Quizartinib in the treatment of FLT3-internal-tandem duplication-positive acute myeloid leukemia.

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.

Tolerability of isavuconazole after posaconazole toxicity in leukaemia patients.

BACKGROUND: Posaconazole (PCZ) is widely used for prophylaxis or treatment of invasive fungal infections (IFIs) in leukaemia patients. However, issues with PCZ tolerability can result in treatment interruption. Isavuconazole (ISA) has a similar broad spectrum of activity to PCZ; however, real-world data regarding the tolerability of ISA after PCZ toxicity are lacking. OBJECTIVES: To describe the tolerability of ISA after PCZ toxicity in leukaemia patients. PATIENTS/METHODS: We retrospectively assessed tolerability of ISA after PCZ toxicity in adult leukaemia patients (March 2015 to November 2017). We included all patients who received ≥7 days of ISA within 48 hours of PCZ discontinuation. Laboratory markers for liver toxicity were collected at three time points: prior to PCZ, at switch to ISA and after ISA therapy. RESULTS: We identified 23 such patients. Increased liver function tests (LFTs) were noted in 20 patients on PCZ, while three patients had Grade 3/4 QTc prolongation. No patient discontinued subsequent ISA due to toxicity. Grade 3/4 elevations in LFTs were decreased after changing to ISA (30% after PCZ vs 5% after ISA). No patient had significant QTc prolongation after switching to ISA. CONCLUSIONS: Isavuconazole was well-tolerated in patients discontinuing PCZ due to toxicity, with no patient discontinuing ISA due to toxicity.

Breakthrough Fungal Infections in Patients With Leukemia Receiving Isavuconazole.

We retrospectively assessed breakthrough invasive fungal infections (b-IFIs) in 100 consecutive patients with leukemia receiving single-agent isavuconazole; 13 had documented b-IFIs (candidiasis in 6, mucormycosis in 4). All b-IFIs were observed in patients with prolonged neutropenia and active leukemia.

Targeting CD123 in BPDCN: an emerging field.

INTRODUCTION: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with historically poor outcomes for patients, often refractory to traditional chemotherapy. Recent research has focused on targeted therapy to improve responses and limit potential toxicity. AREAS COVERED: CD123 (also known as IL-3 Rα) is a cell surface marker and attractive therapeutic target for many myeloid malignancies, particularly BPDCN, whose cells ubiquitously overexpress CD123. We review the history of CD123 research regarding BPDCN, recent advances including FDA approval of tagraxofusp (formerly SL-401) for BPDCN, and ongoing clinical studies utilizing novel therapeutic strategies to target CD123. EXPERT OPINION: The approval of tagraxofusp for the treatment of BPDCN in December 2018 drastically changed the treatment landscape for patients with this rare neoplasm. While tagraxofusp is better tolerated than traditional multi-agent chemotherapy regimens, it requires close monitoring and sound clinical judgment by providers to prevent and mitigate severe treatment-related complications with special attention to the recognition and management of capillary leak syndrome (CLS). Several other promising strategies for targeting CD123 in BPDCN are currently under investigation, including antibody-drug conjugates, T-cell engagers, and CAR-T cellular therapeutics. These CD123 targeted approaches may soon become standard of care for patients with this difficult to treat malignancy.

Pharmacodynamics of daptomycin in combination with other antibiotics for the treatment of enterococcal bacteraemia.

Daptomycin is commonly prescribed in combination with other antibiotics for treatment of enterococcal bacteraemia. Whilst a free drug area under the concentration-time curve to minimum inhibitory concentration (fAUC/MIC) ratio >27.4 is associated with 30-day survival with daptomycin monotherapy, it is unknown whether receipt of other antibiotics affects this threshold. Data were pooled from seven published trials assessing outcomes in daptomycin-treated enterococcal bacteraemia, including patients receiving daptomycin (≥72 h) and any ß-lactam, intravenous aminoglycoside, linezolid, tigecycline and/or vancomycin. Exposures were calculated using a published population pharmacokinetic model based on creatinine clearance, 90% protein binding and daptomycin Etest MIC. The fAUC/MIC threshold predictive of 30-day survival was determined by classification and regression tree analysis. Following pooling of data, 240 adults were included; 137 (57.1%) were alive at 30 days. A majority of patients were immunosuppressed (65.8%) and received a ß-lactam (94.6%). Examining the threshold in low-acuity patients (n = 135) to control for co-morbidities, these patients were more likely to survive when fAUC/MIC >12.3 was achieved (63.2% vs. 20.0%; P = 0.015). The difference remained significant in a multivariable logistic regression model that controlled for infection source and immunosuppression (P = 0.017). This threshold is 2-fold lower than that observed with daptomycin monotherapy. Probabilities of threshold attainment using a 10 mg/kg/day dose were 100% for isolates with MICs ≤ 2 mg/L and 95.2% for a 12 mg/kg/day dose for MICs of 4 mg/L. These data support the use of high-dose daptomycin in combination with another antibiotic for treatment of enterococcal bacteraemia.

Evolving Treatment Strategies for Elderly Leukemia Patients with IDH Mutations.

Acute myeloid leukemia (AML) is a debilitating and life-threatening condition, especially for elderly patients who account for over 50% of diagnoses. For over four decades, standard induction therapy with intensive cytotoxic chemotherapy for AML had remained unchanged. However, for most patients, standard therapy continues to have its shortcomings, especially for elderly patients who may not be able to tolerate the complications from intensive cytotoxic chemotherapy. New research into the development of targeted and alternative therapies has led to a new era in AML therapy. For the nearly 20% of diagnoses harboring a mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2), potential treatment options have undergone a paradigm shift away from intensive cytotoxic chemotherapy and towards targeted therapy alone or in combination with lower intensity chemotherapy. The first FDA approved IDH2 inhibitor was enasidenib in 2017. In addition, IDH1 inhibitors are in ongoing clinical studies, and the oral BCL-2 inhibitor venetoclax shows preliminary efficacy in this subset of patients. These new tools aim to improve outcomes and change the treatment paradigm for elderly patients with IDH mutant AML. However, the challenge of how to best incorporate these agents into standard practice remains.

Daptomycin non-susceptible Enterococcus faecium in leukemia patients: Role of prior daptomycin exposure.

OBJECTIVES: We sought to determine the association between previous daptomycin exposure and daptomycin non-susceptible Enterococcus faecium (DNSEf) bloodstream infections (BSI) in adult leukemia patients. METHODS: We retrospectively identified adult (≥18 years old) leukemia patients with Enterococcus spp. bacteremia at The University of Texas MD Anderson Cancer Center (MDACC) from 6/1/2013 to 7/22/2015. Antimicrobial susceptibility and previous antibiotic exposure within the 90 days prior to bacteremia were collected. Classification and Regression Tree (CART) analysis was used to identify the most significant breakpoint between daptomycin exposure and DNSEf. RESULTS: Any amount of daptomycin received within the 90 days preceding BSI was significantly associated with isolation of DNSEf compared to daptomycin susceptible E. faecium (DSEf) (88% vs. 44%, respectively, p < 0.01). CART analysis identified receiving ≥13 days of daptomycin in the preceding 90 days as most significantly correlated with DNSEf (60% vs. 11%, relative risk [RR] 5.31, 95% Confidence interval [CI] 2.36-11.96, p < 0.01). CONCLUSIONS: Prior daptomycin exposure for ≥13 days within 90 days preceding BSI was significantly associated with isolation of DNSEf BSI in adult leukemia patients at our institution. Antimicrobial stewardship initiatives aimed at minimizing daptomycin exposure in high-risk patients may be of significant benefit in limiting the emergence of DNSEf.

Cyclin-Dependent Kinase Inhibitors for the Treatment of Breast Cancer: Past, Present, and Future.

Treatment of metastatic breast cancer (MBC) that is resistant to endocrine therapy presents a significant clinical challenge. The well-known role of cell cycle dysregulation in these patients is partly mediated by cyclin-dependent kinase (CDK) activity. Specific cyclin and CDK complexes regulate cell cycle progression by managing the transition through the cell cycle, and inhibition of CDKs represents an important target for novel agents. First-generation CDK inhibitors (e.g., flavopiridol) were relatively nonselective and had an unacceptable toxicity profile in early trials. Second-generation CDK inhibitors were designed to target the CDK4 and CDK6 (CDK4/6) pathway and have shown promising clinical activity with an acceptable toxicity profile in patients with MBC. Palbociclib is a first-in-class CDK4/6 inhibitor that was granted accelerated U.S. Food and Drug Administration approval in combination with letrozole for the treatment of MBC in the first-line setting (February 2015) as well as in combination with fulvestrant for MBC that had progressed on previous endocrine therapy (February 2016). Other CDK4/6 inhibitors, including ribociclib and abemaciclib, are under investigation as monotherapy and in combination with endocrine or anti-human epidermal growth receptor 2 therapy for the treatment of MBC. Ongoing clinical trials should provide additional information to guide the appropriate use of these agents and identify patient populations that could derive the most benefit.