A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial).

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

A Higher Neutrophil Count Is Associated with Favorable Achievement of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Who Received Second Generation Tyrosine Kinase Inhibitor as Frontline Treatment.

BACKGROUND: ABL1 tyrosine kinase inhibitor discontinuation securely became among the therapeutic goal for chronic myeloid leukemia chronic phase patients (CML-CP). To establish successful prognostic factors for treatment-free remission (TFR), it is necessary to diagnose the patients with high-risk molecular relapse, however, a biomarker for the achievement of TFR has not been completely elucidated. Recent investigations have determined that neutrophils function crucially in cancer immunology. PATIENTS AND METHODS: The research was a multicenter retrospective observational study to examine the correlation between TFR and neutrophil counts before TKI discontinuation. The investigation included patients having Philadelphia chromosome-positive CML-CP who attempted the discontinuation of TKIs after a durable deep molecular response between January 2012 and July 2021 at four institutions in Japan. RESULTS: 118 CML-CP patients in total discontinued TKIs and an estimated 36-month TFR rate was 65.1%. 52 patients received second-generation TKIs as frontline. Higher neutrophil count (>3210/µL) at TKIs discontinuation was determined as an independent prognostic variable for TFR in patients who received second-generation TKIs as frontline [(HR, 0.235 (95%, confidence interval (CI) 0.078-0.711); p = 0.010]. CONCLUSIONS: The neutrophil-mediated immunomodulation can be a significant component for the effective achievement of TFR in CML supported by our clinical observation.

Reprogramming of pyrimidine nucleotide metabolism supports vigorous cell proliferation of normal and malignant T cells.

ABSTRACT: Adult T-cell leukemia/lymphoma (ATL) is triggered by infection with human T-cell lymphotropic virus-1 (HTLV-1). Here, we describe the reprogramming of pyrimidine biosynthesis in both normal T cells and ATL cells through regulation of uridine-cytidine kinase 2 (UCK2), which supports vigorous proliferation. UCK2 catalyzes the monophosphorylation of cytidine/uridine and their analogues during pyrimidine biosynthesis and drug metabolism. We found that UCK2 was overexpressed aberrantly in HTLV-1-infected T cells but not in normal T cells. T-cell activation via T-cell receptor (TCR) signaling induced expression of UCK2 in normal T cells. Somatic alterations and epigenetic modifications in ATL cells activate TCR signaling. Therefore, we believe that expression of UCK2 in HTLV-1-infected cells is induced by dysregulated TCR signaling. Recently, we established azacitidine-resistant (AZA-R) cells showing absent expression of UCK2. AZA-R cells proliferated normally in vitro, whereas UCK2 knockdown inhibited ATL cell growth. Although uridine and cytidine accumulated in AZA-R cells, possibly because of dysfunction of pyrimidine salvage biosynthesis induced by loss of UCK2 expression, the amount of UTP and CTP was almost the same as in parental cells. Furthermore, AZA-R cells were more susceptible to an inhibitor of dihydroorotic acid dehydrogenase, which performs the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis, and more resistant to dipyridamole, an inhibitor of pyrimidine salvage biosynthesis, suggesting that AZA-R cells adapt to UCK2 loss by increasing de novo pyrimidine nucleotide biosynthesis. Taken together, the data suggest that fine-tuning pyrimidine biosynthesis supports vigorous cell proliferation of both normal T cells and ATL cells.

Second Treatment-Free Remission Attempt in Patients with Chronic Myeloid Leukemia.

Long-term survival outcomes of patients with chronic myeloid leukemia in the chronic phase are now similar to those of the general population, following the introduction of ABL1 tyrosine kinase inhibitors (TKIs). Approximately 40% to 80% of patients with chronic myeloid leukemia successfully achieved treatment-free remission after the first attempt of TKI discontinuation (TFR1), after achieving a durable deep molecular response. However, the possibility of achieving treatment-free remission after a second attempt of TKI discontinuation (TFR2) remains unclear. Therefore, we reviewed current TFR2 studies to clarify the feasibility of achieving TFR2. We identified 5 TFR2 clinical trials and 2 real-world reports. TFR2 attempt may be feasible after retreatment with imatinib, nilotinib, or dasatinib. Patients who have achieved MR4.0 or deeper durable molecular remission are eligible to enter the TFR2 phase. Imatinib is well tolerated and can be administered for consolidative treatment before the TFR2 attempt, whereas drug-related adverse effects of nilotinib or dasatinib affect their tolerability and might lead to discontinuation. Late onset relapse (> 1 year or > 2 year) was often reported, thus careful monitoring is needed.

Thymic stromal lymphopoietin contributes to ozone-induced exacerbations of eosinophilic airway inflammation via granulocyte colony-stimulating factor in mice.

BACKGROUND: Ozone is one of the triggers of asthma, but its impact on the pathophysiology of asthma, such as via airway inflammation and airway hyperresponsiveness (AHR), is not fully understood. Thymic stromal lymphopoietin (TSLP) is increasingly seen as a crucial molecule associated with asthma severity, such as corticosteroid resistance. METHODS: Female BALB/c mice sensitized and challenged with house dust mite (HDM) were exposed to ozone at 2 ppm for 3 h. Airway inflammation was assessed by the presence of inflammatory cells in bronchoalveolar lavage fluid and concentrations of cytokines including TSLP in lung. Anti-TSLP antibody was administered to mice to block the signal. Survival and adhesion of bone marrow-derived eosinophils in response to granulocyte colony-stimulating factor (G-CSF) were evaluated. RESULTS: Ozone exposure increased eosinophilic airway inflammation and AHR in mice sensitized and challenged with HDM. In addition, TSLP, but not IL-33 and IL-25, was increased in lung by ozone exposure. To confirm whether TSLP signaling is associated with airway responses to ozone, an anti-TSLP antibody was administered, and it significantly attenuated eosinophilic airway inflammation, but not AHR. Interestingly, G-CSF, but not type 2 cytokines such as IL-4, IL-5, and IL-13, was regulated by TSLP signaling associated with eosinophilic airway inflammation, and G-CSF prolonged survival and activated eosinophil adhesion. CONCLUSIONS: The present data show that TSLP contributes to ozone-induced exacerbations of eosinophilic airway inflammation and provide greater understanding of ozone-induced severity mechanisms in the pathophysiology of asthma related to TSLP and G-CSF.

Localization of Sites of Osimertinib Action in Rat Intestine, Skin, and Lung by Immunohistochemistry.

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations and has shown efficacy in patients with non-small-cell lung cancer. In this study, we created osimertinib-specific antibodies and developed an immunohistochemistry (IHC) for locating the sites of osimertinib action. Moreover, we located osimertinib-protein conjugates in intestinal, dermal, and lung tissues of rats, thereby using our IHC to visualize the sites of the adverse effects of osimertinib, including diarrhea, skin disorder, and interstitial pneumonia. This report is the first to elucidate the localization of the sites of action of osimertinib in the rat intestine, skin, and lung and is expected to help clarify the mechanism of osimertinib-induced adverse effects.

Absence of multiple sleep-onset rapid eye movement periods (SOREMPs) is not a specific feature of patients with pathological sleep prolongation.

Purpose: Multiple sleep-onset rapid eye movement periods (SOREMPs) are involved in the pathophysiology of narcolepsy, but it is not clear whether the lack of multiple SOREMPs is associated with the pathophysiology of idiopathic hypersomnia or not. We examined the significance of multiple SOREMPs in patients with pathological sleep prolongation. Methods: Participants were consecutive patients complaining of unexplained sleepiness and agreed to a 3-day-sleep studies; 24 h polysomnography (PSG) followed by standard PSG and multiple sleep latency test (MSLT). Forty-one (26 females, 21.9 ± 8.1 years old, BMI 20.4 ± 2.3 kg/m2) of 54 eligible patients without other sleep pathologies showed pathological sleep prolongation. We subdivided them into those with and without multiple SOREMPs on MSLT and compared clinical and PSG variables between groups. Results: Six of 41 (14.6%) patients showed multiple SOREMPs on MSLT. There were almost no differences in sleep variables between those with and without multiple SOREMPs. We only found shorter mean sleep latency on MSLT and more REM cycles on 24 h PSG in those with multiple SOREMPs (adjusted p = 0.016 and 0.031). The frequencies of REM-related phenomena and clinical symptoms related to idiopathic hypersomnia were not different between groups. Conclusion: Our results indicated that patients with pathological sleep prolongation had the same clinical profiles regardless of the status of SOREMPs, suggesting the absence of multiple SOREMPs, prerequisite for the diagnosis of idiopathic hypersomnia, is not a specific feature of pathological sleep prolongation. Confirmation of sleep prolongation alone could be a diagnostic tool for idiopathic hypersomnia.