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Blood Advances Jan 2022The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by... (Clinical Trial)
Clinical Trial
The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
Topics: Acute Disease; Adult; Dasatinib; Humans; Imatinib Mesylate; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 34516628
DOI: 10.1182/bloodadvances.2021004607 -
Nature Communications Nov 2022The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as...
The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as senolytics, have proven beneficial for health; however, the biomarkers that label in vivo senescence at systemic levels are lacking, thus hindering anti-aging applications. In this study, we generate a Glb1‒Glb1-2A-mCherry (GAC) reporter allele at the Glb1 gene locus, which encodes lysosomal β-galactosidase-an enzyme elevated in tissues of old mice. A linear correlation between GAC signal and chronological age is established in a cohort of middle-aged (9 to 13 months) Glb1 mice. The high GAC signal is closely associated with cardiac hypertrophy and a shortened lifespan. Moreover, the GAC signal is exponentially increased in pathological senescence induced by bleomycin in the lung. Senolytic dasatinib and quercetin (D + Q) reduce GAC signal in bleomycin treated mice. Thus, the Glb1-2A-mCherry reporter mice monitors systemic aging and function decline, predicts lifespan, and may facilitate the understanding of aging mechanisms and help in the development of anti-aging interventions.
Topics: Animals; Mice; Aging; Bleomycin; Cellular Senescence; Dasatinib; Longevity; Genes, Reporter; Glycoside Hydrolases
PubMed: 36396643
DOI: 10.1038/s41467-022-34801-9 -
Molecular Therapy : the Journal of the... Jan 2023Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR...
Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the ex vivo expansion of unedited CD7 CAR T cells and allowed regaining full CAR-mediated cytotoxicity in vitro and in vivo on withdrawal of the inhibitors. The unedited CD7 CAR T cells persisted long term and mediated sustained anti-leukemic activity in two mouse xenograft models of human T cell acute lymphoblastic leukemia (T-ALL) by self-selecting for CD7, fratricide-resistant CD7 CAR T cells that were transcriptionally similar to control CD7-edited CD7 CAR T cells. Finally, we showed feasibility of cGMP manufacturing of unedited autologous CD7 CAR T cells for patients with CD7 malignancies and initiated a phase I clinical trial (ClinicalTrials.gov: NCT03690011) using this approach. These results indicate pharmacologic inhibition of CAR signaling enables generating functional CD7 CAR T cells without additional engineering.
Topics: Mice; Animals; Humans; T-Lymphocytes; Immunotherapy, Adoptive; Dasatinib; Feasibility Studies; Receptors, Chimeric Antigen; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36086817
DOI: 10.1016/j.ymthe.2022.09.003 -
GeroScience Jun 2023Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and...
Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated β-galactosidase (SA-β-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury.
Topics: Female; Animals; Mice; Senotherapeutics; Quality of Life; Cellular Senescence; Doxorubicin; Dasatinib; Fibrosis
PubMed: 36648735
DOI: 10.1007/s11357-023-00728-2 -
JAMA Oncology Mar 2020A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).
OBJECTIVE
To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation.
DESIGN, SETTING, AND PARTICIPANTS
This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019.
INTERVENTIONS
Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy.
MAIN OUTCOMES AND MEASURES
The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival.
RESULTS
Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups.
CONCLUSIONS AND RELEVANCE
Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.
TRIAL REGISTRATION
Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.
Topics: Antineoplastic Agents; Child; Child, Preschool; Dasatinib; Female; Humans; Imatinib Mesylate; Infant; Male; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 31944221
DOI: 10.1001/jamaoncol.2019.5868 -
Journal of Clinical Pathology Mar 2023Dasatinib is a second-generation multityrosine kinase inhibitor used in the first-line and second-line treatment of Philadelphia chromosome-positive leukaemia. The most...
Dasatinib is a second-generation multityrosine kinase inhibitor used in the first-line and second-line treatment of Philadelphia chromosome-positive leukaemia. The most frequent type of Dasatinib-induced intestinal injury is haemorrhagic colitis; other morphologic patterns include apoptotic colopathy, CD8+ T-cell-mediated colitis and non-specific colitis. Aim of this study is to describe a novel Crohn's-like histopathologic pattern of Dasatinib-induced colitis. Four patients developed diarrhoea during Dasatinib treatment; colonoscopy was performed and biopsy sets were taken for histological analysis. All patients showed patchy, chronic active inflammation with cryptitis and microgranulomas (two patients). Ileal and rectal biopsies showed either no or mild, focal inflammation. An increase in lamina propria eosinophils was seen (two patients) and apoptoses were seen (three patients). Complete remission was observed after interruption of treatment. Dasatinib-induced colitis and Crohn's disease may share histologic features including microgranulomas, which can potentially lead to misdiagnosis if no information on treatment is provided.
Topics: Humans; Crohn Disease; Dasatinib; Colitis; Inflammation; Biopsy; Colitis, Ulcerative; Intestinal Mucosa
PubMed: 35701140
DOI: 10.1136/jclinpath-2022-208340 -
Nature Cancer Mar 2021T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug...
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, and novel therapeutics are much needed. Profiling patient leukemia' drug sensitivities , we discovered that 44.4% of childhood and 16.7% of adult T-ALL cases exquisitely respond to dasatinib. Applying network-based systems pharmacology analyses to examine signal circuitry, we identified preTCR-LCK activation as the driver of dasatinib sensitivity, and T-ALL-specific LCK dependency was confirmed in genome-wide CRISPR-Cas9 screens. Dasatinib-sensitive T-ALLs exhibited high BCL-XL and low BCL2 activity and venetoclax resistance. Discordant sensitivity of T-ALL to dasatinib and venetoclax is strongly correlated with T-cell differentiation, particularly with the dynamic shift in LCK vs. BCL2 activation. Finally, single-cell analysis identified leukemia heterogeneity in LCK and BCL2 signaling and T-cell maturation stage, consistent with dasatinib response. In conclusion, our results indicate that developmental arrest in T-ALL drives differential activation of preTCR-LCK and BCL2 signaling in this leukemia, providing unique opportunities for targeted therapy.
Topics: Cell Line, Tumor; Dasatinib; Humans; Network Pharmacology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; T-Lymphocytes
PubMed: 34151288
DOI: 10.1038/s43018-020-00167-4 -
The Journal of Clinical Investigation Apr 2022Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated...
Cellular senescence plays an important role in human diseases, including osteoporosis and osteoarthritis. Senescent cells (SCs) produce the senescence-associated secretory phenotype to affect the function of neighboring cells and SCs themselves. Delayed fracture healing is common in the elderly and is accompanied by reduced mesenchymal progenitor cells (MPCs). However, the contribution of cellular senescence to fracture healing in the aged has not to our knowledge been studied. Here, we used C57BL/6J 4-month-old young and 20-month-old aged mice and demonstrated a rapid increase in SCs in the fracture callus of aged mice. The senolytic drugs dasatinib plus quercetin enhanced fracture healing in aged mice. Aged callus SCs inhibited the growth and proliferation of callus-derived MPCs (CaMPCs) and expressed high levels of TGF-β1. TGF-β-neutralizing Ab prevented the inhibitory effects of aged callus SCs on CaMPCs and promoted fracture healing in aged mice, which was associated with increased CaMPCs and proliferating cells. Thus, fracture triggered a significant cellular senescence in the callus cells of aged mice, which inhibited MPCs by expressing TGF-β1. Short-term administration of dasatinib plus quercetin depleted callus SCs and accelerated fracture healing in aged mice. Senolytic drugs represent a promising therapy, while TGF-β1 signaling is a molecular mechanism for fractures in the elderly via SCs.
Topics: Animals; Cellular Senescence; Dasatinib; Fracture Healing; Fractures, Bone; Mice; Mice, Inbred C57BL; Quercetin; Transforming Growth Factor beta1
PubMed: 35426372
DOI: 10.1172/JCI148073 -
Blood Advances Jun 2020Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer... (Meta-Analysis)
Meta-Analysis
Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk [RR], 4.28; 95% confidence interval [CI], 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities.
Topics: Adult; Antineoplastic Agents; Dasatinib; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase
PubMed: 32559295
DOI: 10.1182/bloodadvances.2019001329 -
Journal of Clinical Oncology : Official... Mar 2024JCO We report the long-term results of the frontline trial with dasatinib and blinatumomab in induction/consolidation (GIMEMA LAL2116, D-ALBA) for adult...
JCO We report the long-term results of the frontline trial with dasatinib and blinatumomab in induction/consolidation (GIMEMA LAL2116, D-ALBA) for adult Philadelphia-positive ALL (Ph+ ALL), which enrolled 63 patients of all ages. At a median follow-up of 53 months, disease-free survival, overall survival, and event-free survival are 75.8%, 80.7%, and 74.6%, respectively. No events have occurred among early molecular responders. A significantly worse outcome was recorded for patients. Twenty-nine patients-93.1% being in molecular response (ie, complete molecular response or positive nonquantifiable) after dasatinib/blinatumomab-never received chemotherapy/transplant and continued with a tyrosine kinase inhibitor only; 28 patients remain in long-term complete hematologic response (CHR). An allogeneic transplant was carried out in first CHR mainly in patients with persistent minimal residual disease; 83.3% of patients are in continuous CHR. The transplant-related mortality was 12.5% for patients transplanted in first CHR and 13.7% overall. Nine relapses and six deaths have occurred. mutations were found in seven cases. The final analysis of the D-ALBA study shows that a chemotherapy-free induction/consolidation regimen on the basis of a targeted strategy (dasatinib) and immunotherapy (blinatumomab) is effective in inducing durable long-term hematologic and molecular responses in adult Ph+ ALL, paving the way for a new era in the management of these patients.
Topics: Adult; Humans; Dasatinib; Treatment Outcome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasm Recurrence, Local; Antibodies, Bispecific
PubMed: 38127722
DOI: 10.1200/JCO.23.01075