Nearly four decades after their conceptualization, antibody-based therapies are slowly being added to the treatment landscape of acute myeloid leukemia (AML). While the antibody–drug conjugate gemtuzumab ozogamicin is the only antibody-based therapy that has been approved for AML treatment thus far, several bispecific antibodies have been developed and shown early encouraging results. Bispecific antibodies comprise a wide variety of constructs that share the common concept of simultaneous binding of a surface target on malignant cells and most commonly CD3 on T cells leading to an endogenous, HLA-independent, immune response against malignant cells. However, the use of bispecific antibodies in AML has been limited by the absence of highly specific leukemia-associated antigens leading to on-target, off-leukemia side effects as well as reduced efficacy due to antigen escape. Herein, we discuss the history and evolution of bispecific T cell engagers as well as various adaptations such as dual affinity retargeting antibodies, bi- and tri-specific killer engager antibodies. Common side effects including cytokine release syndrome and management thereof are highlighted. Lastly, we expound on the future direction and integration of such antibody-based therapies with other immunotherapies (programmed cell death-1 inhibitors and chimeric antigen receptor T cells).
Hydralazine is used in the treatment of essential hypertension and is under investigation for epigenetic therapy in the treatment of neoplastic and renal diseases. -acetyltransferase (NAT) 2 exhibits a common genetic polymorphism in human populations. After recombinant expression in yeast, human NAT2 exhibited an apparent Lineweaver-Burk constant () value (20.1 ± 8.8 M) for hydralazine over 20-fold lower than the apparent value (456 ± 57 M) for recombinant human NAT1 ( = 0.0016). The apparent value for recombinant human NAT1 (72.2 ± 17.9 nmol acetylated/min/mg protein) was significantly ( = 0.0245) lower than recombinant human NAT2 (153 ± 15 nmol acetylated/min/mg protein), reflecting 50-fold higher clearance for recombinant human NAT2. Hydralazine NAT activities exhibited a robust acetylator gene dose response in cryopreserved human hepatocytes both in vitro and in situ. Hydralazine NAT activities in vitro differed significantly with respect to NAT2 genotype at 1000 ( = 0.0319), 100 ( = 0.002), and 10 M hydralazine ( = 0.0029). Hydralazine NAT activities differed significantly ( < 0.001) among slow acetylator hepatocytes, (******). The in situ hydralazine -acetylation rates differed significantly with respect to NAT2 genotype after incubation with 10 ( = 0.002) or 100 M ( = 0.0015) hydralazine and were higher after incubation with 100 M (10-fold) than with 10M (4.5-fold) hydralazine. Our results clearly document NAT2 genotype-dependent -acetylation of hydralazine in human hepatocytes, suggesting that hydralazine efficacy and safety could be improved by NAT2 genotype-dependent dosing strategies.
Up to 80% of patients with acute myeloid leukemia (AML) have pulmonary complications in the course of their illness. Historically, pneumonia was considered the most common cause of respiratory illness in this population (Hildebrand, 1990). However, recent literature has indicated a lower frequency of microbiologically proven infection in AML patients, even in the presence of radiographic infiltrates (Garcia, 2013). Neutropenic fever (NF) is frequently encountered in AML patients. Standard diagnostic evaluation of NF often includes chest computed tomography (CT), which offers high sensitivity, but carries the risk of false positive diagnosis of pneumonia. Here, we evaluated the prevalence of confirmed pneumonia in AML patients with NF and positive pulmonary infiltratesa group traditionally considered high risk for pneumonia. METHODS:We conducted a retrospective cohort study of adult patients >18 years old with active AML (defined as having a circulating blast count >3%), admitted to Yale-New Haven Hospital between 2015-2019. This cohort was narrowed to patients with NF (temperature greater than 100.4 F and an absolute neutrophil count [ANC] less than 1.5) and positive chest CT findings. Demographics, medications, labs, microbiological studies (respiratory cultures, viral panels, and fungal markers), and CT scan results were extracted through manual chart review.RESULTS: Among 626 inpatient hospital encounters of AML patients, 72 (11.5%, 70 unique patients) were identified as having both NF and infiltrates on chest CT. The average age was 61.9 years (AE14.3); 48.6% were male. The average white blood cell count was 27.5 x1000/mL (AE54.5), ANC was 0.02 x1000/mL (AE0.14), and maximum circulating blast count was 43.4% (AE33.1). Of the 72 encounters, 45 cases (62.5%) had hypoxemia. A comprehensive respiratory infectious evaluation yielded a positive result in only 8 (11.1%) cases: 3 (4.2%) positive lower respiratory bacterial cultures, 4 (5.5%) positive respiratory viral polymerase chain reaction test, and 1 (1.4%) positive fungal marker. Rates of positive respiratory infectious work-up in patients with and without hypoxemia during the hospital admission were 13.3% and 7.4% respectively.CONCLUSIONS: Among neutropenic AML patients a respiratory infectious source was rarely identified, despite the presence of cardinal features of pneumonia including fever and pulmonary infiltrates.CLINICAL IMPLICATIONS: While positive CT chest findings are common in AML patients with NF, diagnosis of pneumonia in this patient population is challenging, even in the setting of new hypoxemia. A streamlined diagnostic workup and criteria for treatment with antimicrobials should be established to prevent further development of drug resistance and potential misdiagnosis of the multitude of other noninfectious respiratory illnesses.
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