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1.
N Engl J Med ; 388(4): 319-332, 2023 01 26.
Article in English | MEDLINE | ID: mdl-36511784

ABSTRACT

BACKGROUND: In a multinational, phase 3, head-to-head trial, ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, was compared with zanubrutinib, a BTK inhibitor with greater specificity, as treatment for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). In prespecified interim analyses, zanubrutinib was superior to ibrutinib with respect to overall response (the primary end point). Data from the final analysis of progression-free survival are now available. METHODS: We randomly assigned, in a 1:1 ratio, patients with relapsed or refractory CLL or SLL who had received at least one previous course of therapy to receive zanubrutinib or ibrutinib until the occurrence of disease progression or unacceptable toxic effects. In this final analysis, progression-free survival (a key secondary end point) was assessed with the use of a hierarchical testing strategy to determine whether zanubrutinib was noninferior to ibrutinib. If noninferiority was established, the superiority of zanubrutinib was assessed and claimed if the two-sided P value was less than 0.05. RESULTS: At a median follow-up of 29.6 months, zanubrutinib was found to be superior to ibrutinib with respect to progression-free survival among 652 patients (hazard ratio for disease progression or death, 0.65; 95% confidence interval, [CI], 0.49 to 0.86; P = 0.002), as assessed by the investigators; the results were similar to those as assessed by an independent-review committee. At 24 months, the investigator-assessed rates of progression-free survival were 78.4% in the zanubrutinib group and 65.9% in the ibrutinib group. Among patients with a 17p deletion, a TP53 mutation, or both, those who received zanubrutinib had longer progression-free survival than those who received ibrutinib (hazard ratio for disease progression or death, 0.53; 95% CI, 0.31 to 0.88); progression-free survival across other major subgroups consistently favored zanubrutinib. The percentage of patients with an overall response was higher in the zanubrutinib group than in the ibrutinib group. The safety profile of zanubrutinib was better than that of ibrutinib, with fewer adverse events leading to treatment discontinuation and fewer cardiac events, including fewer cardiac events leading to treatment discontinuation or death. CONCLUSIONS: In patients with relapsed or refractory CLL or SLL, progression-free survival was significantly longer among patients who received zanubrutinib than among those who received ibrutinib, and zanubrutinib was associated with fewer cardiac adverse events. (Funded by BeiGene; ALPINE ClinicalTrials.gov number, NCT03734016.).


Subject(s)
Antineoplastic Agents , Heart Diseases , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Disease Progression , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Heart Diseases/chemically induced
2.
Nucleic Acids Res ; 52(5): 2260-2272, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38109289

ABSTRACT

Intrinsically disordered regions (IDRs) are abundant in eukaryotic proteins, but their sequence-function relationship remains poorly understood. IDRs of transcription factors (TFs) can direct promoter selection and recruit coactivators, as shown for the budding yeast TF Msn2. To examine how IDRs encode both these functions, we compared genomic binding specificity, coactivator recruitment, and gene induction amongst a large set of designed Msn2-IDR mutants. We find that both functions depend on multiple regions across the > 600AA IDR. Yet, transcription activity was readily disrupted by mutations that showed no effect on the Msn2 binding specificity. Our data attribute this differential sensitivity to the integration of a relaxed, composition-based code directing binding specificity with a more stringent, motif-based code controlling the recruitment of coactivators and transcription activity. Therefore, Msn2 utilizes interwoven sequence grammars for encoding multiple functions, suggesting a new IDR design paradigm of potentially general use.


Subject(s)
DNA-Binding Proteins , Intrinsically Disordered Proteins , Saccharomyces cerevisiae Proteins , Transcription Factors , Gene Expression Regulation , Intrinsically Disordered Proteins/genetics , Intrinsically Disordered Proteins/metabolism , Mutation , Transcription Factors/chemistry , Transcription Factors/metabolism , Saccharomyces cerevisiae , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/metabolism , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism
3.
Future Oncol ; : 1-10, 2024 Jul 29.
Article in English | MEDLINE | ID: mdl-39072392

ABSTRACT

Aim ASPEN is a randomized, open-label, Phase III study comparing zanubrutinib and ibrutinib in patients with Waldenström macroglobulinemia (WM). Materials & methods: Patient-reported outcomes were exploratory end points assessed using the EORTC QLQ-C30 and EQ-5D-5L VAS scores. Results: Overall, 201 patients (102 zanubrutinib; 99 ibrutinib) were enrolled. Clinically meaningful differences were observed in diarrhea and nausea/vomiting in both the intent-to-treat population and in patients attaining very good partial response (VGPR) in earlier cycles of treatment, as well as in long-term physical functioning and fatigue in patients achieving VGPR. Conclusion: Treatment with zanubrutinib was associated with greater improvements in health-related quality of life compared with ibrutinib in patients with WM and MYD88 mutations.Clinical Trial Registration: NCT03053440 (ClinicalTrials.gov).


Patient quality of life is importantWhat is this article about? This article talks about a study called the ASPEN trial, which compares two medicines used for treating a rare blood cancer that doctors call Waldenström macroglobulinemia. The medicines are called zanubrutinib (ZAN) and ibrutinib (IBR). They work in the same way, by blocking a protein called Bruton tyrosine kinase. When patients take medicines for an illness, it is important to learn about their physical, social, emotional and mental well-being (quality of life). In this study, we asked patients to fill out questionnaires about their well-being before starting the study treatment for their blood cancer, and again a few times while taking the medication, to see if there were any changes.What were the results of the study? There were two groups of patients. One group took ZAN and the other took IBR. The patients could not choose which medicine they were going to take. Results from both groups of patients were compared. Patients taking ZAN did not feel worse or better about their diarrhea and sickness, but those taking IBR said these symptoms had become worse. Both medicines improved how patients were feeling. However, improvement in tiredness and physical ability was larger in patients taking ZAN than those on IBR, especially for the patients whose cancer was getting better.What do the results mean? For patients with a rare blood cancer in this study, those taking ZAN had a better quality of life than those taking IBR.

4.
Future Oncol ; 20(12): 717-726, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38088119

ABSTRACT

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of a research study called ALPINE. The study involved people who had been diagnosed with, and previously treated at least once for, relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Lymphocytes help to find and fight off viruses and infections in the body, but when someone has CLL or SLL, the body creates abnormal lymphocytes, leaving the patient with a weakened immune system and susceptible to illness. In CLL, these lymphocytes are in the bone marrow and bloodstream, whereas for SLL, they are mostly found in the lymph nodes, such as those in the neck. HOW WAS THE RESEARCH DONE?: The ALPINE study was designed to directly compare the cancer-fighting effects and side effects of zanubrutinib and ibrutinib as treatment for patients with relapsed or refractory CLL/SLL. WHAT WERE THE RESULTS?: After 30 months, zanubrutinib was more effective than ibrutinib at reducing and keeping the cancer from coming back. Clinical Trial Registration: NCT03734016 (ClinicalTrials.gov).


Subject(s)
Adenine/analogs & derivatives , Leukemia, Lymphocytic, Chronic, B-Cell , Lymphoma, B-Cell , Pyrimidines , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Piperidines/therapeutic use , Pyrazoles/adverse effects , Lymphoma, B-Cell/drug therapy
5.
Lancet Oncol ; 23(8): 1031-1043, 2022 08.
Article in English | MEDLINE | ID: mdl-35810754

ABSTRACT

BACKGROUND: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. METHODS: We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13·1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13·1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided α of 0·05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. FINDINGS: Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13·1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26·2 months (IQR 23·7-29·6), median progression-free survival per independent review committee was not reached in either group (group A 95% CI not estimable [NE] to NE; group B 28·1 months to NE). Progression-free survival was significantly improved in group A versus group B (HR 0·42 [95% CI 0·28 to 0·63]; two-sided p<0·0001). The most common grade 3 or worse adverse event was neutropenia (27 [11%] of 240 patients in group A, 116 [51%] of 227 in group B, and 17 [15%] of 111 patients in group C). Serious adverse events occurred in 88 (37%) of 240 patients in group A, 113 (50%) of 227 patients in group B, and 45 (41%) of 111 patients in group C. Adverse events leading to death occurred in 11 (5%) of 240 patients in group A, 12 (5%) of 227 patients in group B, and three (3%) of 111 patients in group C, most commonly due to COVID-19 (four [2%] of 240 patients in group A), diarrhoea, and aspiration pneumonia (two each [1%] of 227 patients in group B). INTERPRETATION: Zanubrutinib significantly improved progression-free survival versus bendamustine-rituximab, with an acceptable safety profile consistent with previous studies. These data support zanubrutinib as a potential new treatment option for untreated CLL and SLL. FUNDING: BeiGene.


Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Sequoia , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bendamustine Hydrochloride , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Piperidines , Pyrazoles , Pyrimidines , Rituximab
6.
Blood ; 136(18): 2038-2050, 2020 10 29.
Article in English | MEDLINE | ID: mdl-32731259

ABSTRACT

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Adenine/administration & dosage , Adenine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Piperidines/administration & dosage , Prognosis , Pyrazoles/administration & dosage , Pyrimidines/administration & dosage , Survival Rate , Waldenstrom Macroglobulinemia/pathology
8.
Haematologica ; 106(9): 2354-2363, 2020 10 13.
Article in English | MEDLINE | ID: mdl-33054121

ABSTRACT

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Aged , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Piperidines , Pyrazoles , Pyrimidines/adverse effects
9.
Future Oncol ; 16(10): 517-523, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32207333

ABSTRACT

Treatment standards for chronic lymphocytic leukemia (CLL) have been transformed with the advent of effective inhibitors of B-cell receptor signaling such as ibrutinib - a first-in-class inhibitor of BTK. Off-target kinase inhibitions by ibrutinib are thought to contribute to its adverse events. Zanubrutinib is a next-generation BTK inhibitor with minimal off-target effects, sustained BTK occupancy in peripheral blood mononuclear cells and lymph nodes from patients with B-cell malignancies and promising responses in patients with CLL. Described here is a head-to-head Phase III study comparing the efficacy and safety of zanubrutinib with those of ibrutinib in patients with CLL/small lymphocytic lymphoma in the relapsed/refractory setting.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Chronic Disease , Clinical Trials, Phase III as Topic , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Outcome Assessment, Health Care , Piperidines/adverse effects , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Pyrimidines/adverse effects , Randomized Controlled Trials as Topic , Safety
11.
Haematologica ; 109(7): 2284-2289, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38268449
12.
Future Oncol ; 14(22): 2229-2237, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29869556

ABSTRACT

Waldenström macroglobulinemia (WM), an incurable B-cell malignancy, is sensitive to Bruton tyrosine kinase (BTK) inhibition with ibrutinib, a first-generation BTK inhibitor. Off-target effects of ibrutinib against TEC- and EGFR-family kinases are implicated in some adverse events. Patients with CXCR4WHIM and MYD88L265P mutations or who are MYD88WT have less sensitivity to ibrutinib than those with MYD88L265P and CXCR4WT disease. Zanubrutinib, a next-generation BTK inhibitor with potent preclinical activity in WM and minimal off-target effects, showed sustained BTK occupancy in peripheral blood mononuclear cells from patients with B-cell malignancies and promising responses in advanced WM. Described here is a head-to-head Phase III study comparing efficacy and safety of zanubrutinib and ibrutinib in WM patients. Effect of MYD88 and CXCR4 mutation status will be assessed.


Subject(s)
Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Humans , Mutation , Myeloid Differentiation Factor 88/genetics , Treatment Outcome
13.
Blood Adv ; 8(10): 2478-2490, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38502198

ABSTRACT

ABSTRACT: First-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.


Subject(s)
Piperidines , Pyrazoles , Pyrimidines , Humans , Pyrimidines/therapeutic use , Pyrimidines/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/adverse effects , Piperidines/therapeutic use , Piperidines/adverse effects , Male , Aged , Female , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/adverse effects , Middle Aged , Cardiovascular Diseases/etiology , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Adenine/analogs & derivatives , Adenine/therapeutic use , Adenine/adverse effects , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Incidence , Atrial Fibrillation/drug therapy , Aged, 80 and over
14.
J Consult Clin Psychol ; 92(4): 249-259, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38127575

ABSTRACT

OBJECTIVE: Positive and negative affect play critical roles in depression and anxiety treatment, but the dynamic processes of how affect changes over treatment in relation to changes in symptoms is unclear. The study goal was to examine relationships among changes in positive and negative affect with changes in depression and anxiety symptoms. METHOD: This secondary analysis used a combined sample (N = 196) of two trials (Craske et al., 2019, 2023) comparing positive affect treatment (PAT) to negative affect treatment. Longitudinal cross-lag panel models explored whether changes in positive and negative affect (Positive and Negative Affect Schedule; Watson et al., 1988) predicted subsequent changes in depression and anxiety symptoms (Depression Anxiety Stress Scales; Lovibond & Lovibond, 1995), whether symptoms predicted subsequent changes in affect, and whether treatment condition moderated these relationships. RESULTS: Increases in positive affect predicted subsequent decreases in depression and anxiety symptoms, regardless of treatment condition. Symptoms did not reciprocally predict changes in positive affect. For individuals in PAT, decreases in negative affect predicted subsequent decreases in symptoms. Moreover, decreases in symptoms predicted subsequent decreases in negative affect, regardless of treatment condition. CONCLUSIONS: Results did not support a reciprocal relationship between positive affect and symptoms of depression and anxiety since positive affect predicted depression and anxiety symptoms but not vice versa. Results supported a reciprocal relationship between negative affect and symptoms of depression and anxiety since negative affect predicted depression and anxiety symptoms in PAT, and depression and anxiety symptoms predicted negative affect in both treatment conditions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Subject(s)
Anxiety , Depression , Humans , Depression/therapy , Depression/complications , Anxiety/therapy , Anxiety/complications , Anxiety Disorders , Psychotherapy
15.
Blood Adv ; 8(7): 1639-1650, 2024 Apr 09.
Article in English | MEDLINE | ID: mdl-38315878

ABSTRACT

ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.


Subject(s)
Adenine/analogs & derivatives , Piperidines , Pyrazoles , Pyrimidines , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/drug therapy , Waldenstrom Macroglobulinemia/genetics , Myeloid Differentiation Factor 88/genetics , Biomarkers
16.
Br J Haematol ; 162(2): 250-62, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23682827

ABSTRACT

Single cell network profiling (SCNP) is a multi-parameter flow cytometry technique for simultaneous interrogation of intracellular signalling pathways. Diagnostic paediatric acute myeloid leukaemia (AML) bone marrow samples were used to develop a classifier for response to induction therapy in 53 samples and validated in an independent set of 68 samples. The area under the curve of a receiver operating characteristic curve (AUC(ROC)) was calculated to be 0·85 in the training set and after exclusion of induction deaths, the AUC(ROC) of the classifier was 0·70 (P = 0·02) and 0·67 (P = 0·04) in the validation set when induction deaths (intent to treat) were included. The highest predictive accuracy was noted in the cytogenetic intermediate risk patients (AUC(ROC) 0·88, P = 0·002), a subgroup that lacks prognostic/predictive biomarkers for induction response. Only white blood cell count and cytogenetic risk were associated with response to induction therapy in the validation set. After controlling for these variables, the SCNP classifier score was associated with complete remission (P = 0·017), indicating that the classifier provides information independent of other clinical variables that were jointly associated with response. This is the first validation of an SCNP classifier to predict response to induction chemotherapy. Herein we demonstrate the usefulness of quantitative SCNP under modulated conditions to provide independent information on AML disease biology and induction response.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Adolescent , Child , Child, Preschool , Cytarabine/administration & dosage , Daunorubicin/administration & dosage , Female , Flow Cytometry/methods , Humans , Infant , Intracellular Signaling Peptides and Proteins , Male , Neoadjuvant Therapy , Prognosis , Prospective Studies , Remission Induction , Retrospective Studies , Single-Cell Analysis/methods , Thioguanine/administration & dosage , Treatment Outcome
17.
Clin Pharmacol Drug Dev ; 12(8): 832-838, 2023 08.
Article in English | MEDLINE | ID: mdl-37145975

ABSTRACT

Zanubrutinib is a second-generation Bruton tyrosine kinase inhibitor that is primarily metabolized by CYP3A enzymes. Previous drug-drug interaction (DDI) studies have demonstrated that co-administration of zanubrutinib with rifampin, a strong CYP3A inducer, reduces zanubrutinib plasma concentrations, potentially impacting activity. The impact of the co-administration of zanubrutinib with less potent CYP3A inducers is unclear. This phase 1, open-label, fixed-sequence DDI study evaluated the pharmacokinetics, safety, and tolerability of zanubrutinib when co-administered with steady-state rifabutin, a known CYP3A inducer less potent than rifampin, in 13 healthy male volunteers (NCT04470908). Co-administration of zanubrutinib with rifabutin resulted in a less than 2-fold reduction of zanubrutinib exposures. Overall, zanubrutinib was well tolerated. The results of this study provide useful information for the evaluation of the DDI between rifabutin and zanubrutinib. In conjunction with safety and efficacy data from other clinical studies, these results will be taken into consideration to determine the appropriate dose recommendation of zanubrutinib when co-administered with CYP3A inducers.


Subject(s)
Cytochrome P-450 CYP3A Inducers , Rifampin , Humans , Male , Cytochrome P-450 CYP3A Inducers/adverse effects , Cytochrome P-450 CYP3A Inducers/pharmacokinetics , Rifabutin/adverse effects , Healthy Volunteers , Cytochrome P-450 CYP3A/metabolism , Drug Interactions
18.
J Consult Clin Psychol ; 91(6): 350-366, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36892884

ABSTRACT

OBJECTIVE: Determine whether a novel psychosocial treatment for positive affect improves clinical status and reward sensitivity more than a form of cognitive behavioral therapy that targets negative affect and whether improvements in reward sensitivity correlate with improvements in clinical status. METHOD: In this assessor-blinded, parallel-group, multisite, two-arm randomized controlled clinical superiority trial, 85 treatment-seeking adults with severely low positive affect, moderate-to-severe depression or anxiety, and functional impairment received 15 weekly individual therapy sessions of positive affect treatment (PAT) or negative affect treatment (NAT). Clinical status measures were self-reported positive affect, interviewer-rated anhedonia, and self-reported depression and anxiety. Target measures were eleven physiological, behavioral, cognitive, and self-report measures of reward anticipation-motivation, response to reward attainment, and reward learning. All analyses were intent-to-treat. RESULTS: Compared to NAT, individuals receiving PAT achieved superior improvements in the multivariate clinical status measures at posttreatment, b = .37, 95% CI [.15, .59], t(109) = 3.34, p = .001, q = .004, d = .64. Compared to NAT, individuals receiving PAT also achieved higher multivariate reward anticipation-motivation, b = .21, 95% CI [.05, .37], t(268) = 2.61, p = .010, q = .020, d = .32, and higher multivariate response to reward attainment, b = .24, 95% CI [.02, .45], t(266) = 2.17, p = .031, q = .041, d = .25, at posttreatment. Measures of reward learning did not differ between the two groups. Improvements in reward anticipation-motivation and in response to reward attainment correlated with improvements in the clinical status measures. CONCLUSIONS: Targeting positive affect results in superior improvements in clinical status and reward sensitivity than targeting negative affect. This is the first demonstration of differential target engagement across two psychological interventions for anxious or depressed individuals with low positive affect. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Subject(s)
Cognitive Behavioral Therapy , Depressive Disorder , Adult , Humans , Depressive Disorder/therapy , Anhedonia , Cognitive Behavioral Therapy/methods , Reward , Psychotherapy
19.
Suicide Life Threat Behav ; 53(3): 457-469, 2023 06.
Article in English | MEDLINE | ID: mdl-36942926

ABSTRACT

INTRODUCTION: Depression and anxiety are implicated in suicide risk, but the contributionof specific symptom dimensions within these disorders is not well understood. The present study examined longitudinal associations of transdiagnostic symptoms (General Distress[GD]) and unique symptom dimensions (Anhedonia-Apprehension [AA], Fears, and Narrow Depression [ND]) of depression and anxiety and suicidal ideation (SI). METHODS: Data from 551 adolescents oversampled on high neuroticism were examined in a series of discrete-time survival analyses to predict first SI onset over an 8-year period. RESULTS: Results indicate that GD, AA, and ND were independent predictors of increased likelihood of SI onset and remained significant when controlling for effects of fears. Furthermore, AA and GD remained significant when controlling for one another. ND effects reduced by 24% when adjusting for AA and 74% when adjusting for GD. Fears did not significantly predict SI onset. CONCLUSION: Results suggest that broad levels of distress across depression and anxiety, deficits in positive affect, and elevated negative affect specific to depression increase the likelihood of suicidal thoughts. As such, attention to broader distress and a lack of pleasure, interest, and motivation-potentially more so than negative affect characterizing depression-are particularly important for addressing suicide risk in adolescents.


Subject(s)
Depression , Suicidal Ideation , Humans , Adolescent , Depression/diagnosis , Anxiety/diagnosis , Anxiety Disorders , Anhedonia , Risk Factors
20.
J Psychopathol Clin Sci ; 132(6): 645-656, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37261781

ABSTRACT

This study aimed to characterize within-person pre-COVID-19 and coronavirus pandemic (COVID-19) transdiagnostic anxiety and depression symptom trajectories in emerging adults and determine the roles of neuroticism and behavioral activation in predicting these COVID-19-related changes. We recruited a sample of 342 emerging adults (aged 18-19 at baseline) who were screened on neuroticism and behavioral activation and completed symptom questionnaires on multiple occasions before and after the start of the pandemic. We examined estimates of the symptom factors of General Distress, Anhedonia-Apprehension, and Fears at each wave. The stress amplification model predicts a multiplicative neuroticism-adversity interaction with those high on neuroticism showing the greatest symptom increases to the pandemic. The stably elevated negative affect model is an additive model and predicts that persons high on neuroticism will display elevated symptoms at every wave. General Distress and Anhedonia-Apprehension showed large increases from the pre-COVID-19 to COVID-19 transition then decreased thereafter. The increase brought the average General Distress score to clinical levels at the first COVID-19 wave. There was a small decrease in Fears from the pre-COVID-19 to COVID-19 transition followed by a large increase. Thus, COVID-19 was associated with both increases in psychological symptoms and some resilience. Neuroticism positively predicted the pre-COVID-19 to COVID-19 transition change in Fears but was associated with a dampening of increases in General Distress and Anhedonia-Apprehension. The results disconfirmed the stress amplification model of neuroticism but partially supported the stably elevated negative affect model. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Subject(s)
COVID-19 , Adult , Humans , COVID-19/epidemiology , Depression/diagnosis , Depression/epidemiology , Depression/psychology , Anhedonia , Anxiety/diagnosis , Anxiety/psychology , Personality
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