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Zhongguo Shi Yan Xue Ye Xue Za Zhi Apr 2024To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are...
OBJECTIVE
To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy.
METHODS
The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively.
RESULTS
After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred.
CONCLUSION
VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.
Topics: Humans; Leukemia, Myeloid, Acute; Sulfonamides; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Remission Induction; Treatment Outcome; Male; Adult; Female; Middle Aged
PubMed: 38660834
DOI: 10.19746/j.cnki.issn.1009-2137.2024.02.003 -
Journal of Clinical Pharmacology Apr 2024Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in...
Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in adult patients with extensive-stage small cell lung cancer receiving a platinum/etoposide-containing or topotecan-containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open-label, parallel-group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child-Pugh B, n = 8) and severe (Child-Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m. The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration-time curve) in participants with moderate and severe HI was ∼40% and ∼60% higher, respectively, compared with healthy matched controls based on Child-Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration-approved trilaciclib dose of 240 mg/m should be reduced by ∼30%, to 170 mg/m, for patients with moderate or severe HI.
PubMed: 38639103
DOI: 10.1002/jcph.2435 -
Clinical Nuclear Medicine Jul 2024The primary endpoints were objective response rate (ORR) and disease control rate (DCR). Secondary endpoints were duration of response, blood pressure control, safety,...
PATIENTS AND METHODS
The primary endpoints were objective response rate (ORR) and disease control rate (DCR). Secondary endpoints were duration of response, blood pressure control, safety, overall and progression-free survival rates, MIBG uptake, and correlations with genetic background.
RESULTS
The study included 25 patients. Twenty-four patients had distant metastases, 17 (68%) had hormonally active tumors, and 13 (52%) had previously received antineoplastic treatment. In 24 evaluable patients, the ORR was 38%, including 2 patients with complete response, and the DCR was 83%; median time to response was 12.5 months (95% confidence interval, 4.6-25.1). Twelve patients had sporadic disease, among whom the ORR was 25% and DCR was 83%. Twelve patients had hereditary disease ( SDHB , VHL , RET ); among these, the ORR was 50%, and DCR was 83%. Plasma metanephrines normalized in 30% of patients and improved by greater than 50% in 46%. Sixteen patients had hormonally active tumors and hypertension; in 9 (56%) of these, blood pressure normalized, leading to discontinuation of antihypertensive therapy.The most common adverse events were grades 1-2 nausea/vomiting and transient bone marrow suppression. One patient developed premature ovarian failure. Reversible grades 3-4 myelosuppression were seen in 7 patients (28%). One patient had fatal pneumonitis.
CONCLUSIONS
HSA- 131 I-MIBG is associated with a high DCR in patients with MPPGL, regardless of underlying genetic mutation.
Topics: Humans; Pheochromocytoma; Female; Male; Paraganglioma; Adult; Middle Aged; Adrenal Gland Neoplasms; 3-Iodobenzylguanidine; Aged; Young Adult; Treatment Outcome; Adolescent; Iodine Radioisotopes
PubMed: 38630996
DOI: 10.1097/RLU.0000000000005184 -
Frontiers in Oncology 2024Anemia is common in cancer patients and impacts on quality of life and prognosis. It is typically multifactorial, often involving different pathophysiological... (Review)
Review
Anemia is common in cancer patients and impacts on quality of life and prognosis. It is typically multifactorial, often involving different pathophysiological mechanisms, making treatment a difficult task. In patients undergoing active anticancer treatments like chemotherapy, decreased red blood cell (RBC) production due to myelosuppression generally predominates, but absolute or functional iron deficiency frequently coexists. Current treatments for chemotherapy-related anemia include blood transfusions, erythropoiesis-stimulating agents, and iron supplementation. Each option has limitations, and there is an urgent need for novel approaches. After decades of relative immobilism, several promising anti-anemic drugs are now entering the clinical scenario. Emerging novel classes of anti-anemic drugs recently introduced or in development for other types of anemia include activin receptor ligand traps, hypoxia-inducible factor-prolyl hydroxylase inhibitors, and hepcidin antagonists. Here, we discuss their possible role in the treatment of anemia observed in patients receiving anticancer therapies.
PubMed: 38628673
DOI: 10.3389/fonc.2024.1380358 -
British Journal of Clinical Pharmacology Apr 2024Pre-emptive prediction to avoid myelosuppression and harmful sequelae is difficult given the complex interplay among patients, drugs and treatment protocols. This study...
Administration mode matters for 5-fluorouracil therapy: Physiologically based pharmacokinetic evidence for avoidance of myelotoxicity by continuous infusion but not intravenous bolus.
AIMS
Pre-emptive prediction to avoid myelosuppression and harmful sequelae is difficult given the complex interplay among patients, drugs and treatment protocols. This study aimed to model plasma and bone marrow concentrations and the likelihood of myelotoxicity following administration of 5-fluorouracil (5-FU) by diverse intravenous (IV) bolus or continuous infusion (cIF) regimens.
METHODS
Using physicochemical, in vitro and clinical data obtained from the literature consisting of various regimens and patient cohorts, a 5-FU physiologically based pharmacokinetic (PBPK) model was developed. The predicted and observed PK values were compared to assess model performance prior to examining myelotoxicity potential of IV bolus vs. cIF and DPYD wild type vs. genetic variant.
RESULTS
The established model was verified by utilizing 5-FU concentration-time profiles of adequate heterogeneity contributed by 36 regimens from 15 studies. The study provided corroborative evidence to explain why cIF (vs. IV bolus) had lower myelotoxicity risk despite much higher total doses. The PBPK model was used to estimate the optimal dosage in patients heterozygous for the DPYD c.1905 + 1G > A allele and suggested that a dose reduction of at least 25% was needed (compared to the dose in wild-type subjects).
CONCLUSION
A verified PBPK model was used to explain the lower myelotoxicity risk of cIF vs. IV bolus administration of 5-FU and to estimate the dose reduction needed in carriers of a DPYD variant. With appropriate data, expertise and resources, PBPK models have many potential uses in precision medicine application of oncology drugs.
PubMed: 38627941
DOI: 10.1111/bcp.16061 -
Expert Opinion on Pharmacotherapy Apr 2024Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the... (Review)
Review
INTRODUCTION
Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation.
AREAS COVERED
This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia. MMB inhibits type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2), with consequent rebalancing of the SMAD pathways and reduced transcription of hepcidin. Moreover, it seems that MMB could reduce the serum levels of several inflammatory cytokines responsible for anemia. Clinical trials have demonstrated MMB's efficacy in reducing spleen size, alleviating symptoms, and improving anemia, with a favorable safety profile compared to other JAK inhibitors, both in treatment-naïve and in pre-treated patients.
EXPERT OPINION
Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies.
Topics: Humans; Primary Myelofibrosis; Pyrimidines; Animals; Benzamides; Janus Kinase Inhibitors; Anemia; Bridged-Ring Compounds
PubMed: 38623844
DOI: 10.1080/14656566.2024.2343780 -
Translational Cancer Research Mar 2024Programmed cell death protein 1 (PD-1) or its ligand (PD-L1) monoclonal antibody combined with bevacizumab (a monoclonal antibody targeting vascular endothelial growth...
Liver-directed moderately hypo-fractionated radiotherapy combined with pembrolizumab and bevacizumab for advanced hepatocellular carcinoma: a retrospective observational study of 23 cases.
BACKGROUND
Programmed cell death protein 1 (PD-1) or its ligand (PD-L1) monoclonal antibody combined with bevacizumab (a monoclonal antibody targeting vascular endothelial growth factor) has been established as first-line systemic treatment for advanced hepatocellular carcinoma (HCC). Radiotherapy is a crucial local treatment for HCC. Mutual efficacy enhancement has been reported between radiotherapy, anti-angiogenesis therapy and immunotherapy in preclinical researches, but not been validated in clinical practice. Whether radiotherapy can enhance efficacy of anti-PD-1 immunotherapy plus bevacizumab for HCC remains unclear. This retrospective observational study aimed to appraise efficacy and safety of the combination of radiotherapy with pembrolizumab (a PD-1 monoclonal antibody) and bevacizumab for advanced HCC for the first time.
METHODS
Patients with advanced HCC treated by intrahepatic tumor-directed moderately hypo-fractionated radiotherapy combined with pembrolizumab and bevacizumab were consecutively included. Clinicopathological characteristics, therapeutic outcomes and treatment-related adverse events (TRAEs) were recorded and evaluated.
RESULTS
A total of 23 patients were eventually enrolled. Median cycles of pembrolizumab and bevacizumab were 4 (median, 1-8) and 4 (median, 1-9) cycles. The objective response rates and disease control rates of irradiated intrahepatic HCC and non-irradiated extrahepatic HCC were 34.8% [95% confidence interval (CI), 16.4-57.3%] 10.0% (95% CI, 1.2-31.7%), and 91.3% (95% CI, 72.0-98.9%) 70.0% (95% CI, 45.7-88.1%), respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.6 (95% CI, 4.7-8.5) and 18.3 (95% CI, 8.2-33.6) months, and 12-month PFS and OS rates were 17.5% (95% CI, 7.0-28.0%) and 60.9% (95% CI, 50.7-71.1%). Two patients (8.7%) with locally advanced, unresectable HCC eventually underwent curative resection of tumors after this trimodal treatment. Eighteen patients (78.3%) had ≥ grade 3 TRAEs, with myelosuppression and transaminase increase as the most common.
CONCLUSIONS
This study firstly reported that combining radiotherapy with pembrolizumab and bevacizumab was preliminarily a feasible and effective therapeutic choice for advanced HCC in despite of more TRAEs. This tri-modal regimen may be a potential conversion therapy for unresectable, locally advanced HCC. The limitations of this study are its retrospective nature and small sample size; therefore, big-sample prospective studies are warranted to further investigate this tri-modal regimen.
PubMed: 38617508
DOI: 10.21037/tcr-23-1333 -
Cancers Mar 2024A retrospective analysis of 20 adult patients with histopathological and clinical diagnoses of ECD was conducted at a single institution over a twenty-year period...
A retrospective analysis of 20 adult patients with histopathological and clinical diagnoses of ECD was conducted at a single institution over a twenty-year period (2002-2022). Clinical responses were compared on the basis of treatments rendered, which included chemotherapy, immunotherapy, systemic corticosteroids, surgery and radiation, or targeted agents, referring to any small molecular inhibitors. Treatment response evaluation varied by the anatomic site(s) of disease, the extent of disease at diagnosis, and the imaging modality employed. In this analysis, patients were treated with a combination of targeted agents, myelosuppressive therapies, and radiation at various points in their disease courses. Of these, the most common treatment modality rendered was targeted therapy, employed in 11 of 20 patients. Partial responses or better were observed in 15 of 20 patients. Rates of stable disease trended towards being more frequent with targeted therapy versus conventional therapy but did not reach significance ( = 0.2967). Complete response rates trended towards being more common with conventional therapy than molecular ( = 0.5) but were equivocal overall. Trends of peripheral blood absolute monocytes with relation to disease activity were reviewed as recent literature implied that monocyte levels surrounding disease progression were of potential prognostic significance in histiocytic diseases. Amongst the patients who progressed at any point during their treatment course, absolute monocyte count (in K/µL) was identified at the closest available timepoint prior to or following disease progression and at the lowest value (nadir) following re-institution of therapy prior to any additional agent(s) being employed. There was no statistically significant difference in either of these monocyte values nor in disease outcomes with respect to treatments rendered within our cohort. However, our cohort consists of a heterogenous population of patients with ECD with data that highlights several trends over a longitudinal period, spanning the advent of targeted therapy. Significant differences are anticipated in ongoing analyses.
PubMed: 38610977
DOI: 10.3390/cancers16071299 -
Medicine Apr 2024This study aimed to investigate the clinical predictors, including traditional Chinese medicine tongue characteristics and other clinical parameters for... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to investigate the clinical predictors, including traditional Chinese medicine tongue characteristics and other clinical parameters for chemotherapy-induced myelosuppression (CIM), and then to develop a clinical prediction model and construct a nomogram. A total of 103 patients with lung cancer were prospectively enrolled in this study. All of them were scheduled to receive first-line chemotherapy regimens. Participants were randomly assigned to either the training group (n = 52) or the test group (n = 51). Tongue characteristics and clinical parameters were collected before the start of chemotherapy, and then the incidence of myelosuppression was assessed after treatment. We used univariate logistic regression analysis to identify the risk predictors for assessing the incidence of CIM. Moreover, we developed a predictive model and a nomogram using multivariate logistic regression analysis. Finally, we evaluated the predictive performance of the model by examining the area under the curve value of the receiver operating characteristic, calibration curve, and decision curve analysis. As a result, a total of 3 independent predictors were found to be associated with the CIM in multivariate regression analysis: the fat tongue (OR = 3.67), Karnofsky performance status score (OR = 0.11), and the number of high-toxic drugs in chemotherapy regimens (OR = 4.78). Then a model was constructed using these 3 predictors and it exhibited a robust predictive performance with an area under the curve of 0.82 and the consistent calibration curves. Besides, the decision curve analysis results suggested that applying this predictive model can result in more net clinical benefit for patients. We established a traditional Chinese medicine prediction model based on the tongue characteristics and clinical parameters, which could serve as a useful tool for assessing the risk of CIM.
Topics: Humans; Lung Neoplasms; Models, Statistical; Prognosis; Bone Marrow Diseases; Tongue; Antineoplastic Agents
PubMed: 38608065
DOI: 10.1097/MD.0000000000037636 -
European Heart Journal May 2024Low-dose colchicine (0.5 mg daily) is now FDA-approved for secondary prevention in patients with coronary disease and will be increasingly prescribed in clinical... (Review)
Review
Low-dose colchicine (0.5 mg daily) is now FDA-approved for secondary prevention in patients with coronary disease and will be increasingly prescribed in clinical practice. In this State-of-the-Art Review, data were collated from contemporary systemic reviews of case reports, drug registries, and placebo-controlled trials that assessed specific issues of safety related to the continuous use of colchicine in a range of clinical settings to inform physicians, pharmacists, and patients of the absolute risks of continuous use of low-dose colchicine, including among individuals taking statin therapy. Based upon these collective data, it is concluded that aside mild diarrhoea on initiation of colchicine that typically subsides in the vast majority of patients within a week of therapy, continuous use of low-dose colchicine is well tolerated and very safe. It does not affect renal, liver, or cognitive function, has no adverse effects on bleeding, wound healing, fertility, or pregnancy, and does not increase risks of cancer, serious infection, or cause-specific mortality. When appropriately prescribed to patients without significant renal or hepatic impairment, reports of myelosuppression, myotoxicity, and serious drug-drug interactions are rare and no more frequent than placebo, including in patients taking statin therapy. Physicians, pharmacists, and patients can be reassured that in the absence of significant renal or hepatic impairment continuous use of low-dose colchicine can be used safely in patients with atherosclerosis for the purpose of reducing cardiovascular risk.
Topics: Colchicine; Humans; Atherosclerosis; Drug Interactions; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 38596868
DOI: 10.1093/eurheartj/ehae208