ABSTRACT
BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.
Subject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Piperazines , Purines , Pyridines , Receptor, ErbB-2 , Receptors, Estrogen , Humans , Piperazines/administration & dosage , Piperazines/adverse effects , Piperazines/therapeutic use , Female , Pyridines/administration & dosage , Pyridines/therapeutic use , Pyridines/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Aminopyridines/adverse effects , Purines/administration & dosage , Purines/adverse effects , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Retrospective Studies , Thailand/epidemiology , Aged , Receptor, ErbB-2/metabolism , Adult , Receptors, Estrogen/metabolism , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/therapeutic use , Receptors, Progesterone/metabolism , Progression-Free SurvivalABSTRACT
Palbociclib and ribociclib an orally bioavailable, potent cyclin-dependent kinase 4/6 inhibitors, with low oral bioavailability due to substrate specificity towards CYP3A and P-glycoprotein. Thus, current research aims to examine the effect of a bioenhancer (naringin), on oral pharmacokinetics of palbociclib and ribociclib. Naringin's affinity for CYP3A4 and P-glycoprotein was studied using molecular docking; its impact on palbociclib/ribociclib CYP3A metabolism and P-glycoprotein-mediated efflux was examined using in vitro preclinical models; and its oral pharmacokinetics in rats were assessed following oral administration of palbociclib/ribociclib in presence of naringin (50 and 100 mg/kg). Naringin binds optimally to both proteins with the highest net binding energy of - 1477.23 and - 1607.47 kcal/mol, respectively. The microsomal intrinsic clearance of palbociclib and ribociclib was noticeably reduced by naringin (5-100 µM), by 3.0 and 2.46-folds, respectively. Similarly, naringin had considerable impact on the intestinal transport and efflux of both drugs. The pre-treatment with 100 mg/kg naringin increased significantly (p < 0.05) the oral exposure of palbociclib (2.0-fold) and ribociclib (1.95-fold). Naringin's concurrent administration of palbociclib and ribociclib increased their oral bioavailability due to its dual inhibitory effect on CYP3A4 and P-glycoprotein; thus, concurrent naringin administration may represent an innovative strategy for enhancing bioavailability of cyclin-dependent kinase inhibitors.
Subject(s)
Biological Availability , Cyclin-Dependent Kinase 6 , Flavanones , Protein Kinase Inhibitors , Animals , Humans , Rats , Administration, Oral , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Aminopyridines/administration & dosage , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Bioenhancers/pharmacology , Caco-2 Cells , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Flavanones/administration & dosage , Flavanones/pharmacology , Molecular Docking Simulation , Permeability , Piperazines/pharmacokinetics , Piperazines/pharmacology , Piperazines/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Purines/pharmacokinetics , Purines/administration & dosage , Purines/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Pyridines/administration & dosage , Rats, Sprague-DawleyABSTRACT
BACKGROUND: The MONALEESA7 and 2 phase 3 randomized trials demonstrated a statistically significant progressionfree survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre and postmenopausal patients with hormone receptorpositive (HR+)/human epidermal growth factor receptor 2negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre and postmenopausal patients with HR+/HER2 ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA7 and 2 studies. METHODS: Patients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigatorassessed PFS. RESULTS: As of April 25, 2022, the median followup was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies. CONCLUSIONS: These data demonstrate a favorable benefitrisk profile for ribociclib + ET in Chinese patients.
Subject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Letrozole , Postmenopause , Purines , Receptor, ErbB-2 , Receptors, Estrogen , Humans , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Aminopyridines/adverse effects , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Purines/administration & dosage , Purines/adverse effects , Middle Aged , Receptor, ErbB-2/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Receptors, Estrogen/metabolism , Letrozole/administration & dosage , Letrozole/therapeutic use , Adult , China , Aged , Receptors, Progesterone/metabolism , Premenopause , Progression-Free Survival , Goserelin/administration & dosage , Goserelin/therapeutic use , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/therapeutic use , East Asian PeopleSubject(s)
Aminopyridines , Benzamides , Cyclopropanes , Humans , Aminopyridines/adverse effects , Aminopyridines/administration & dosage , Cyclopropanes/administration & dosage , Cyclopropanes/adverse effects , Cyclopropanes/therapeutic use , Benzamides/administration & dosage , Benzamides/adverse effects , Female , Phosphodiesterase 4 Inhibitors/administration & dosage , Phosphodiesterase 4 Inhibitors/adverse effects , Skin Cream/administration & dosage , Skin Cream/adverse effects , Photosensitivity Disorders/drug therapy , Photosensitivity Disorders/diagnosis , Photosensitivity Disorders/chemically induced , Male , Middle AgedABSTRACT
Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including abemaciclib, have been approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced, and metastatic breast cancer. Despite the high therapeutic efficacy of CDK4/6 inhibitors, they are associated with various adverse effects, including potentially fatal interstitial lung disease. Therefore, a combination of CDK4/6 inhibitors with letrozole or fulvestrant has been attempted but has demonstrated limitations in reducing adverse effects, highlighting the need to develop new combination therapies. This study proposes a combination strategy using CDK4/6 inhibitors and tricyclic antidepressants to enhance the therapeutic outcomes of these inhibitors while reducing their side effects. The therapeutic efficacies of abemaciclib and desipramine were tested in different cancer cell lines (H460, MCF7, and HCT-116). The antitumor effects of the combined abemaciclib and desipramine treatment were evaluated in a xenograft colon tumor model. In vitro cell studies have shown the synergistic anticancer effects of combination therapy in the HCT-116 cell line. The combination treatment significantly reduced tumor size compared with control or single treatment without causing apparent toxicity to normal tissues. Although additional in vivo studies are necessary, this study suggests that the combination therapy of abemaciclib and desipramine may represent a novel therapeutic approach for treating solid tumors.
Subject(s)
Aminopyridines , Benzimidazoles , Desipramine , Drug Synergism , Xenograft Model Antitumor Assays , Humans , Benzimidazoles/pharmacology , Benzimidazoles/administration & dosage , Aminopyridines/pharmacology , Aminopyridines/administration & dosage , Animals , Mice , Desipramine/pharmacology , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cell Proliferation/drug effects , Mice, Nude , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , MCF-7 Cells , HCT116 Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Mice, Inbred BALB CABSTRACT
OBJECTIVE: We aimed to evaluate cardiac safety profile of ribociclib with 24-h rhythm Holter ECG. MATERIAL AND METHOD: Forty-two female metastatic breast cancer patients were included in the study. Rhythm Holter ECG was performed before starting treatment with ribociclib and after 3 months of the treatment initiation. RESULTS: The mean age of the patients was 56.36 ± 12.73. 52.4% (n = 22) of the patients were using ribociclib in combination with fulvestrant and 47.6% (n = 20) with aromatase inhibitors. None of the patients developed cardiotoxicity. When the rhythm Holter results before and in third month of the treatment were compared, there was no statistically significant difference. CONCLUSION: This is the first study evaluating effects of ribociclib treatment on cardiac rhythm with Holter ECG. The findings suggested ribociclib has a low risk of causing early cardiotoxicity.
Subject(s)
Aminopyridines , Breast Neoplasms , Electrocardiography, Ambulatory , Purines , Humans , Female , Middle Aged , Breast Neoplasms/drug therapy , Electrocardiography, Ambulatory/methods , Purines/adverse effects , Purines/administration & dosage , Aged , Aminopyridines/adverse effects , Aminopyridines/administration & dosage , Adult , Cardiotoxicity/etiology , Antineoplastic Agents/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosageABSTRACT
PURPOSE: Incorporating adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitors abemaciclib and ribociclib along with endocrine therapy has been shown to improve invasive disease-free survival (iDFS) for hormone receptor-positive (HR+) human epidermal receptor 2-negative (HER2-) early breast cancer (EBC). This study assesses the cost-effectiveness of this strategy, along with adjuvant aromatase inhibitors from an Indian perspective. METHODS: A Markov chain model evaluated the cost-effectiveness of abemaciclib and ribociclib with letrozole compared with letrozole alone for HR+/HER2- EBC from a payer perspective in India. Key measures included lifetime quality-adjusted life-years (QALY), life-years (LY), and total costs. This study explores two scenarios for effectiveness: a best-case (BC) scenario, where the benefit of CDK4/6 inhibitors in improving iDFS lasts a lifetime, and a worst-case (WC) scenario, where benefits disappear after 5 years. Probabilistic sensitivity analyses (PSA) were used to account for simulation uncertainty. RESULTS: In the BC scenario, abemaciclib added 2.17 QALY and 4.96 LY, incurring â¹2,317,957.7 ($27,756.65 in US dollars [USD]) in additional costs. However, the incremental cost-effectiveness ratio (ICER) for abemaciclib exceeded India's willingness-to-pay threshold in the BC and WC scenarios. In the BC scenario, ribociclib added 0.98 QALY and 2.58 LY with added costs of â¹1,711,504.32 ($20,494.6 USD). The ICER for ribociclib also surpassed India's threshold in both scenarios. PSA showed that neither drug was cost-effective at the current market prices in either BC/WC scenario. The cost of abemaciclib and ribociclib needs to be reduced by at least 78.61% and 87.19%, respectively, to be cost-effective in the BC scenario. CONCLUSION: The combination of adjuvant abemaciclib or ribociclib with letrozole is not cost-effective for HR+/HER2- EBC in India in either the BC or WC scenario.
Subject(s)
Aminopyridines , Benzimidazoles , Breast Neoplasms , Cost-Benefit Analysis , Purines , Humans , Aminopyridines/economics , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Benzimidazoles/economics , Benzimidazoles/administration & dosage , Benzimidazoles/therapeutic use , Purines/economics , Purines/administration & dosage , Breast Neoplasms/drug therapy , Breast Neoplasms/economics , Female , India , Chemotherapy, Adjuvant/economics , Chemotherapy, Adjuvant/methods , Quality-Adjusted Life Years , Antineoplastic Combined Chemotherapy Protocols/economics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Markov Chains , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolismABSTRACT
Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH. Methods: An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators. Results: A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment. Conclusion: The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy.
Subject(s)
Aminopyridines , Benzamides , Etoposide , Glucocorticoids , Lymphohistiocytosis, Hemophagocytic , Humans , Etoposide/administration & dosage , Etoposide/adverse effects , Etoposide/therapeutic use , Male , Female , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/mortality , Adult , Middle Aged , Benzamides/administration & dosage , Benzamides/adverse effects , Benzamides/therapeutic use , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Glucocorticoids/adverse effects , Aminopyridines/administration & dosage , Aminopyridines/adverse effects , Aminopyridines/therapeutic use , Treatment Outcome , Aged , Drug Therapy, Combination , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/adverse effects , Histone Deacetylase Inhibitors/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
The aim of this study is to share real-life data on the increase in creatinine due to CDK 4/6 inhibitor treatment and patients diagnosed with HR+/HER2-MBC and treated with ribociclib or palbociclib combined with ET were included in the study. While creatinine increase was observed in 17.9% (n = 19) of the 106 patients in the study population, 8.5% (n = 9) had Grade 1, 8.5% (n = 8) had Grade 2, and % 0.9 (n = 1) had Grade 3 creatinine elevation. The increase in creatinine occurred in 25% (n = 12) of ribociclib users and 12.1% (n = 7) of palbociclib users. No patient required a dose reduction or discontinuation of treatment due to elevated creatinine. Of the patients with high creatinine levels, 36.8% (n = 7) were over 65 years of age. Those with multiple comorbidities, blood urea nitrogen (BUN) >13.5 mg/dl, creatinine >0.66 mg/dl, BUN/creatinine ratio >19.95, glomerular filtration rate (GFR) >96.05 ml/min, and uric acid >4.69mg/dl. It was observed that the increase in the creatinine level was statistically significant (p <0.001). In conclusion, this study revealed that the increase in the serum creatinine secondary to ribociclib and palbociclib treatments is associated with kidney function tests and the number of concomitant diseases. Key Words: CDK 4/6 inhibitor, Creatinine elevation, Palbociclib, Ribociclib.
Subject(s)
Aminopyridines , Creatinine , Cyclin-Dependent Kinase 4 , Piperazines , Purines , Pyridines , Humans , Purines/adverse effects , Purines/administration & dosage , Purines/therapeutic use , Creatinine/blood , Piperazines/adverse effects , Piperazines/administration & dosage , Piperazines/therapeutic use , Aminopyridines/adverse effects , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Female , Pyridines/adverse effects , Pyridines/administration & dosage , Middle Aged , Aged , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Adult , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/administration & dosage , MaleSubject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Purines , Female , Humans , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Purines/administration & dosage , Purines/therapeutic use , Chemotherapy, AdjuvantABSTRACT
This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08-0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11-1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.
Subject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Benzamides , Cyclophosphamide , Hematopoietic Stem Cell Transplantation , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Transplantation Conditioning , Humans , Male , Female , Transplantation Conditioning/methods , Adult , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Adolescent , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Middle Aged , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Benzamides/administration & dosage , Benzamides/therapeutic use , Young Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Busulfan/administration & dosage , Busulfan/therapeutic use , Survival Rate , Transplantation, Homologous , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Graft vs Host Disease/mortality , Disease-Free Survival , Retrospective Studies , AllograftsSubject(s)
Antineoplastic Agents, Hormonal , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Clinical Trials as Topic , Female , Humans , Age Factors , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Black People , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/ethnology , Clinical Trials as Topic/standards , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Purines/administration & dosage , Purines/therapeutic use , Race Factors , Research Design/standards , Time FactorsSubject(s)
Antineoplastic Agents, Hormonal , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Clinical Trials as Topic , Female , Humans , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/ethnology , Breast Neoplasms/pathology , Clinical Trials as Topic/standards , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Purines/administration & dosage , Purines/therapeutic use , Research Design/standards , Age Factors , Race Factors , Time Factors , Black PeopleSubject(s)
Antineoplastic Agents, Hormonal , Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Clinical Trials as Topic , Female , Humans , Age Factors , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Black People , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/ethnology , Breast Neoplasms/pathology , Clinical Trials as Topic/standards , Combined Modality Therapy , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Purines/administration & dosage , Purines/therapeutic use , Race Factors , Research Design/standards , Time FactorsABSTRACT
OBJECTIVES: T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) are highly malignant and aggressive hematologic tumors for which there is no standard first-line treatment. Chidamide, a novel histone deacetylase inhibitor, shows great promise. We assessed the efficacy and safety of an irradiation-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplantation chidamide maintenance in patients with T-ALL/LBL. METHODS: We retrospectively analyzed the clinical data of six patients with T-ALL/LBL who underwent allo-HSCT with a radiotherapy-containing pretreatment regimen and post-transplant chidamide maintenance therapy. The endpoints were relapse, graft-versus-host disease (GVHD), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). RESULTS: All of the patients had uneventful post-transplant hematopoietic reconstitution, and all achieved complete molecular remission within 30 days. All six patients survived, and two relapsed with a median relapse time of 828.5 (170-1335) days. The 1-year OS rate was 100%, the 2-year PFS rate was 66.7%, and the TRM rate was 0%. After transplantation, two patients developed grade I-II acute GVHD (2/6); grade III-IV acute and chronic GVHD were not observed. The most common AEs following chidamide administration were hematological AEs, which occurred to varying degrees in all patients; liver function abnormalities occurred in two patients (grade 2), and symptoms of malaise occurred in one patient (grade 1). CONCLUSION: Chidamide maintenance therapy after T-ALL/LBL transplantation is safe, but the efficacy needs to be further investigated.
Subject(s)
Aminopyridines , Benzamides , Hematopoietic Stem Cell Transplantation , Transplantation Conditioning , Humans , Retrospective Studies , Male , Female , Aminopyridines/therapeutic use , Aminopyridines/administration & dosage , Adult , Benzamides/therapeutic use , Transplantation Conditioning/methods , Hematopoietic Stem Cell Transplantation/methods , Middle Aged , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Young Adult , Adolescent , Graft vs Host Disease/etiologyABSTRACT
BACKGROUND: A significant decline in pulmonary exacerbation rates has been reported in CF patients homozygous for F508del treated with lumacaftor/ivacaftor. However, it is still unclear whether this reduction reflects a diminished microbiological burden. OBJECTIVES: The aim of this study was to determine the impact of lumacaftor/ivacaftor on the bacterial and fungal burden. DESIGN: The study is a prospective multicenter cohort study including 132 CF patients homozygous for F508del treated with lumacaftor/ivacaftor. METHODS: Clinical parameters as well as bacterial and fungal outcomes 1 year after initiation of lumacaftor/ivacaftor were compared to data from 2 years prior to initiation of the treatment. Changes in the slope of the outcomes before and after the onset of treatment were assessed. RESULTS: Lung function measured as ppFEV1 (p < 0.001), body mass index (BMI) in adults (p < 0.001), and BMI z-score in children (p = 0.007) were improved after initiation of lumacaftor/ivacaftor. In addition, the slope of the prevalence of Streptococcus pneumoniae (p = 0.007) and Stenotrophomonas maltophilia (p < 0.001) shifted from positive to negative, that is, became less prevalent, 1 year after treatment, while the slope for Candida albicans (p = 0.009), Penicillium spp (p = 0.026), and Scedosporium apiospermum (p < 0.001) shifted from negative to positive. CONCLUSION: The current study showed a significant improvement in clinical parameters and a reduction of some of CF respiratory microorganisms 1 year after starting with lumacaftor/ivacaftor. However, no significant changes were observed for Pseudomonas aeruginosa, Staphylococcus aureus, or Aspergillus fumigatus, key pathogens in the CF context.
Subject(s)
Aminophenols , Aminopyridines , Benzodioxoles , Cystic Fibrosis , Drug Combinations , Quinolones , Humans , Cystic Fibrosis/drug therapy , Cystic Fibrosis/microbiology , Cystic Fibrosis/physiopathology , Male , Prospective Studies , Female , Aminophenols/therapeutic use , Benzodioxoles/therapeutic use , Child , Adult , Young Adult , Adolescent , Aminopyridines/pharmacology , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Aminopyridines/adverse effects , Quinolones/pharmacology , Sweden , Treatment Outcome , Mycoses/microbiology , Mycoses/drug therapy , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/drug therapy , Respiratory Tract Infections/diagnosis , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Lung/microbiology , Lung/physiopathology , Lung/drug effects , Chloride Channel Agonists/therapeutic use , Time Factors , Fungi/isolation & purification , Bacterial Infections/microbiology , Bacterial Infections/drug therapyABSTRACT
Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.
Subject(s)
Aminopyridines , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols , Benzamides , Histone Deacetylase Inhibitors , Lymphoma, Extranodal NK-T-Cell , Humans , Male , Female , Middle Aged , Benzamides/administration & dosage , Benzamides/therapeutic use , Benzamides/adverse effects , Aged , Lymphoma, Extranodal NK-T-Cell/drug therapy , Lymphoma, Extranodal NK-T-Cell/pathology , Histone Deacetylase Inhibitors/therapeutic use , Histone Deacetylase Inhibitors/administration & dosage , Histone Deacetylase Inhibitors/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Adult , Aminopyridines/administration & dosage , Aminopyridines/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunologyABSTRACT
PURPOSE: To assess the real-world efficacy and safety of flumatinib as first-line and post-line treatments for chronic myeloid leukemia in the chronic phase (CML-CP). RESULTS: Among 141 patients receiving flumatinib as first-line and post-line treatment, the 12-month major molecular response (MMR) rates were 69.4% and 67.6%, respectively. The median time to response was 6 and 10.5 months, respectively. In post-line treatment, the early molecular response (EMR) of flumatinib as second-line is significantly superior to that of third-line treatment (3-month EMR rate: 79.2% vs. 39.3%, P<0.001; 3-month MMR rate: 45.8% vs. 21.4%, P=0.033). Contrastively, patients who switched to flumatinib due to intolerance had significantly higher MMR rates at 3, 6, and 12 months compared to patients who switched due to inadequate response (60.6% vs. 24.2%, P=0.003; 66.7% vs. 36.0%, P=0.027; 84.2% vs. 50.0%, P=0.038). Premature drug discontinuation was observed in 28.4% of the patients. Grades 3-4 hematologic adverse events (AEs) were identified as independent risk factors for premature drug discontinuation. Patients who discontinued treatment and those who previously received only imatinib therapy had a poorer molecular response and failure-free survival. CONCLUSIONS: Flumatinib demonstrates favorable efficacy and safety. Treatment discontinuation can result in a poorer molecular response and long-term prognosis.
Subject(s)
Aminopyridines , Humans , Female , Male , Middle Aged , Retrospective Studies , Aged , Adult , Aminopyridines/adverse effects , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Benzamides/adverse effects , Benzamides/therapeutic use , Young Adult , Aged, 80 and over , Treatment Outcome , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Survival RateABSTRACT
BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) with disease progression on prior endocrine therapy. In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase III study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival was an exploratory endpoint. RESULTS: A total of 493 women were randomized 2 : 1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease, there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% confidence interval 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and chemotherapy-free survival numerically improved with the addition of abemaciclib. No new safety signals were observed. CONCLUSIONS: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (intent-to-treat population: 13.1 months; subgroup with visceral disease: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.
Subject(s)
Aminopyridines , Antineoplastic Combined Chemotherapy Protocols , Aromatase Inhibitors , Benzimidazoles , Breast Neoplasms , Letrozole , Receptor, ErbB-2 , Receptors, Estrogen , Receptors, Progesterone , Humans , Female , Aminopyridines/administration & dosage , Aminopyridines/therapeutic use , Benzimidazoles/administration & dosage , Benzimidazoles/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Double-Blind Method , Letrozole/administration & dosage , Letrozole/therapeutic use , Aromatase Inhibitors/therapeutic use , Aromatase Inhibitors/administration & dosage , Middle Aged , Aged , Receptors, Progesterone/metabolism , Receptors, Estrogen/metabolism , Anastrozole/therapeutic use , Anastrozole/administration & dosage , Adult , Aged, 80 and over , Progression-Free SurvivalABSTRACT
PURPOSE: A head-to-head comparison of efficacy between a cyclin-dependent kinase 4/6 inhibitor plus endocrine therapy (ET) versus combination chemotherapy (CT) has never been reported in patients with clinically aggressive hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). METHODS: In this open-label, multicenter, randomized phase II trial, pre/perimenopausal women with clinically aggressive HR+/HER2- ABC were randomly assigned 1:1 to first-line ribociclib (600 mg once daily; 3 weeks on, 1 week off) plus letrozole/anastrozole and goserelin or investigator's choice of combination CT (docetaxel plus capecitabine, paclitaxel plus gemcitabine, or capecitabine plus vinorelbine). The primary end point was progression-free survival (PFS). RESULTS: Among 222 patients randomly assigned to ribociclib plus ET (n = 112) or combination CT (n = 110), 150 (67.6%) had symptomatic visceral metastases, 41 (18.5%) had rapid disease progression per investigator's judgment, and 31 (14.0%) had symptomatic nonvisceral disease. Overall, 106 (47.7%) patients had investigator-assessed visceral crisis. The median follow-up time was 37.0 months. At data cutoff, 31.3% (ribociclib arm) and 15.5% (CT arm) of patients had completed study treatment and transitioned to post-trial access. The median PFS was 21.8 months (ribociclib plus ET; [95% CI, 17.4 to 26.7]) and 12.8 months (combination CT; [95% CI, 10.1 to 18.4); hazard ratio, 0.61 [95% CI, 0.43 to 0.87]; P = .003. The overall response rates and the median time to response in the ribociclib versus CT arms, respectively, were 66.1% and 61.8% and 4.9 months and 3.2 months (hazard ratio, 0.76 [95% CI, 0.55 to 1.06]). Lower rates of symptomatic adverse events were observed in the ribociclib versus CT arm. CONCLUSION: First-line ribociclib plus ET showed a significant PFS benefit, similar response rates, and better tolerability over combination CT in patients with clinically aggressive HR+/HER2- ABC.