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Objective: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette‐Guérin (BCG) or immediate radical cystectomy (iRC). Materials and Methods: We performed an institutional review board‐approved retrospective study analysing non‐muscle‐invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan–Meier method was used to calculate overall survival (OS), cancer‐specific survival (CSS) and metastasis‐free survival (MFS). Multivariable Cox models were used to determine the association between progression‐free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. Results: A total of 411 T1 high‐grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow‐up was 53 (32–96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG‐treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2–13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82–12.12; P = 0.095). Conclusions: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non‐muscle‐invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette–Guérin (BCG). Patients and Methods: We performed an Institutional Review Board‐approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re‐induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing‐risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high‐grade (HG) recurrence and cancer‐specific mortality (CSM). Results: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing‐risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub‐standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87–2.81, P = 0.134; and SHR 1.05, 95% CI 0.77–1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). Conclusion: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options. [ABSTRACT FROM AUTHOR]

Keywords: bacillus Calmette-Guérin; bladder cancer; bladder-sparing treatment; refractory; relapsing; outcomes EN bacillus Calmette-Guérin bladder cancer bladder-sparing treatment refractory relapsing outcomes 384 386 3 09/25/23 20231001 NES 231001 Abbreviations BST bladder-sparing treatment CIS carcinoma in situ FDA United States Food and Drug Administration HG high grade HR hazard ratio (N)MIBC (non-)muscle-invasive bladder cancer In recent years, BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) has gained recognition and acceptance as a disease entity in which single-arm studies are allowed by regulatory bodies, such as the United States Food and Drug Administration (FDA), for the evaluation of novel therapies [[1]]. The definition adopted by the FDA includes patients who are refractory as well as those who are disease free but relapse early following adequate BCG; however, it is well known that the natural history of patients with disease recurrence after BCG immunotherapy can vary [[4]]. Bacillus Calmette-Guérin (BCG) unresponsive non-muscle-invasive bladder cancer: are the subgroups equal?. [Extracted from the article]

Objective: To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non‐muscle‐invasive bladder cancer (NMIBC) treated with adequate bacille Calmette–Guérin (BCG). Patients and Methods: We performed an Institutional Review Board‐approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence‐ and progression‐free survival were analysed using Kaplan–Meier methods and Cox proportional hazard models. Results: Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence‐ or progression‐free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. Conclusion: The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of one‐third‐dose (1/3D) bacillus Calmette‐Guérin (BCG) on oncological outcomes in a large cohort of patients with non‐muscle‐invasive bladder cancer (NMIBC) treated with adequate BCG (as defined by the US Food & Drug Administration (FDA)) in a real‐world setting. Patients and Methods: We performed an institutional review board‐approved review of patients with NMIBC treated with adequate BCG at our institution between 2000 and 2020. Patients were stratified according to whether they had received 1/3D BCG or full‐dose (FD) BCG. Time to recurrence, time to progression and cancer‐specific survival were estimated using Kaplan–Meier methods. Results: Of 563 patients with NMIBC treated with adequate BCG, 150 (26.6%) received 1/3D and 413 (73.4%) received FD. The use of 1/3D BCG did not adversely affect time to recurrence (P = 0.449) or time to progression (P = 0.716), and this remained consistent when patients were stratified by individual 2021 European Association of Urology (EAU) prognostic factor risk groups. Cancer‐specific survival was similar in patients receiving 1/3D and those receiving FD BCG (P = 0.320). Conclusion: The use of 1/3D BCG was not associated with adverse oncological outcomes in a large cohort of patients receiving adequate BCG for intermediate‐ and high‐risk NMIBC. Based on this real‐world experience, risk‐stratified split‐vial dosing may represent a valuable approach for other institutions facing BCG shortages whilst also providing reassurance to patients who may be concerned about suboptimal outcomes. [ABSTRACT FROM AUTHOR]

Background: Nilotinib is a potent, second-generation inhibitor of BCR-ABL1 tyrosine kinase and has been approved as frontline and salvage therapy for patients with chronic-phase chronic myeloid leukemia (CP-CML).Methods: In this single-institution, phase 2 study, 122 patients with newly diagnosed CP-CML received nilotinib 400 mg twice daily. The median follow-up on study was 78.3 months (interquartile range, 58.4-96.5 months).Results: Fifty-six percent of patients remained on therapy at the last follow-up. Both the complete cytogenetic response rate and the major molecular response (MR) rate were 91%. Seventy-five percent and 59% of patients achieved a ≥4.5-log reduction in BCR-ABL1 transcripts (MR4.5) and a sustained MR4.5 beyond 2 years, respectively. The estimated event-free survival and overall survival rates at 5 years were 89% and 93%, respectively, and the corresponding rates at 10 years were 85% and 88%, respectively. Treatment discontinuation due to toxicity occurred in 19% of patients, mostly because of cardiovascular events (10%) and biochemical abnormalities (6%). The top 3 nonhematologic toxicities were rash (55%), elevated bilirubin (57%), and elevated aminotransferases (48%). Hematologic toxicity was transient and mild. Ischemic cardiovascular adverse events occurred in 8% of patients. Four patients (3%) progressed to accelerated or blast phase while on therapy, and 7 patients (6%) died on study.Conclusions: The current data confirm the long-term efficacy of nilotinib 400 mg twice daily in patients with CP-CML. A majority of patients can achieve sustained MR4.5. [ABSTRACT FROM AUTHOR]

Summary: Programmed cell death protein 1 (PD‐1) and PD‐ligand 1 (PD‐L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti‐PD‐1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow‐up of 12·8 months. For the HMA‐failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow‐up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune‐related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher‐risk MDS. This combined therapy may have anti‐tumour activity in a subset of patients and merits further studies in the front‐line setting. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of upper tract urothelial carcinoma (UTUC) on bacillus Calmette‐Guerin (BCG) response and progression in patients with non‐muscle‐invasive bladder cancer (NMIBC). Patients and Methods: We performed an institutional review board‐approved review of patients with NMIBC treated with adequate intravesical BCG, as defined by the US Food and Drug Administration, at our institution between 2000 and 2018. Patients were stratified by presence of any UTUC and time of UTUC diagnosis (preceding vs synchronous to NMIBC diagnosis or metachronous disease after NMIBC diagnosis). Descriptive statistics were used to summarize the data overall and by groups, and t‐tests or Wilcoxon's rank sum tests and Pearson's chi‐squared or Fisher's exact tests were used to analyse continuous and categorical data, respectively. Results: Of 541 patients with NMIBC treated with adequate BCG, 59 (10.9 %) were diagnosed with UTUC. Of these, 34 had a history of UTUC prior to NMIBC (UTUC‐P; median [interquartile range {IQR}] 13.1 [7.4–27.6] months prior), while 25 developed UTUC after diagnosis of NMIBC (six synchronous and 19 metachronous; median [IQR] 12.1 [1.7–28.1] months after). Compared to the non‐UTUC group, patients with UTUC‐P were more likely to exhibit Tis without papillary tumour in the bladder (20.6% vs 5.0%; P < 0.001), but were less likely to have T1 disease on index transurethral resection (8.8% vs 49.4%; P < 0.001). Patients with UTUC‐P developed more recurrences (55.9% vs 34.0%; P = 0.010), any stage/grade progression (23.5% vs 9.8%; P = 0.012) and progression to muscle‐invasive or metastatic disease (17.6% vs 6.4%; P = 0.014). The presence of high‐grade UTUC‐P compared to low‐grade UTUC‐P was associated with increased NMIBC recurrence (68.2% vs 25.0%; P = 0.049). There was no significant difference in rates of recurrence or progression based on timing of UTUC with respect to the index bladder tumour, although this analysis was limited by small numbers. Conclusions: Presence of UTUC prior to a diagnosis of NMIBC was associated with an almost twofold increased recurrence and progression rates after adequate BCG therapy. This should be considered when counselling patients and designing cohorts for clinical trials. [ABSTRACT FROM AUTHOR]

Background: The impact of the allelic burden of ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations on survival remains unclear in patients with newly diagnosed acute myeloid leukemia (AML).Methods: The authors assessed bone marrow aspirates from 421 patients with newly diagnosed AML using next-generation sequencing for ASXL1, DNMT3A, JAK2, TET2, and TP53 mutations, defined as the presence of mutations in ASXL1, DNMT3A, JAK2, TET2, or TP53 with a minimum variant allele frequency (VAF) of 5%.Results: A total of 71 patients (17%) had ASXL1 mutations, 104 patients (25%) had DNMT3A mutations, 16 patients (4%) had JAK2 mutations, 82 patients (20%) had TET2 mutations, and 86 patients (20%) had TP53 mutations. Among patients with each mutation, the median VAF of ASXL1 was 34.31% (range, 1.17%-58.62%), the median VAF of DNMT3A was 41.76% (range, 1.02%-91.66%), the median VAF of JAK2 was 46.70% (range, 10.4%-71.7%), the median VAF of TET2 was 42.78% (range, 2.26%-95.32%), and the median VAF of TP53 was 45.47% (range, 1.15%-93.74%). The composite complete response rate was 60%, and was 77% in patients with AML with and without ASXL1, DNMT3A, JAK2, TET2, or TP53 mutations, respectively (P = .006); the median overall survival was 11 months and 27 months, respectively (P < .001). Multivariate analysis identified age; an antecedent history of dysplasia; white blood cell count; adverse cytogenetic risk; previous treatment with an FLT3 inhibitor; and the VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations by next-generation sequencing as prognostic factors for overall survival.Conclusions: The VAF of ASXL1, DNMT3A, JAK2, TET2, TP53, and NPM1 mutations is associated with worse prognosis in patients with newly diagnosed AML. [ABSTRACT FROM AUTHOR]

Background: Some patients with chronic myeloid leukemia (CML) have a history of previous malignancies. To the authors' knowledge, outcomes for CML diagnosed in these patients have not been well described. The current study was conducted to determine the outcome of patients with CML and a history of prior malignancies.Methods: The current study included patients who were enrolled in clinical trials of tyrosine kinase inhibitors as initial therapy for CML in chronic phase from July 2000 to January 2014.Results: Of the 630 patients with CML who were treated with frontline tyrosine kinase inhibitors, 626 had a known prior malignancy status. Of these, 45 patients (7%) had a prior malignancy other than nonmelanoma skin cancer whereas 17 patients (3%) had a history of nonmelanoma skin cancers alone. Characteristics of CML were similar between the patients with no prior malignancy, those with a prior malignancy, and those with nonmelanoma skin cancer. Patients with a prior malignancy were found to have an older median age compared with the other 2 groups. The most common prior malignancies were nonmelanoma skin cancer in 20 patients, breast cancer in 11 patients, melanoma in 7 patients, prostate cancer in 6 patients, and colorectal cancer in 5 patients. With regard to CML, the event-free survival, transformation-free survival, and failure-free survival rates were found to be similar between the groups. There was a statistically significantly decreased survival in the group with a prior malignancy versus the group with no prior malignancy versus the group with nonmelanoma skin cancer. In a multivariate analysis, advanced age and an elevated creatinine level were found to be associated with worse survival after a diagnosis of CML.Conclusions: Patients with CML with a history of prior malignancies appear to have the same excellent outcome as patients with no prior malignancies. In the few instances in which concomitant therapy for other malignancies was required during therapy with tyrosine kinase inhibitors, this was able to be accomplished without significant toxicity. Cancer 2017;123:609-616. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS.Methods: This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities.Results: Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3α (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival.Conclusions: In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS. [ABSTRACT FROM AUTHOR]

Background: The prognosis is poor for patients who have relapsed-refractory acute myelogenous leukemia (AML). Most published reports analyzed results from therapies in first-salvage AML or in studies that were conducted before 2000. Several novel agents and strategies are being tested for potential approval as treatment for patients with relapsed-refractory AML in second salvage. Therefore, it is important to establish the historic results of anti-AML therapies in this setting in the modern era. The objective of the current study was to analyze the results from second salvage therapies in patients with AML since 2000 with regard to response and survival.Methods: In total, 673 patients who received second salvage therapies for AML since 2000 were analyzed. Their median age was 60 years (range, 18-89 years). Salvage therapy consisted of cytarabine-based regimens in 267 patients, noncytarabine combinations in 37, hypomethylating agent-based regimens in 136, and phase 1 and 2 single agents in 233.Results: Eighty-six of the 673 patients (13%) achieved a complete response (CR) or a CR with low platelet count (CRp). The median duration of CR-CRp was 7.2 months. The median survival was 4.4 months (95% confidence interval, 4.0-4.8 months), and the 1-year survival rate was 16% (95% confidence interval, 14%-19%). Multivariate analysis identified the following as independent adverse factors for achievement of CR-CRp: platelets < 50 × 109 /L (P < .001), complex karyotype with ≥3 chromosomal abnormalities (P = .02), regimens that did not include cytarabine or hypomethylating agents (P = .014), and no prior CR lasting ≥12 months with frontline or salvage 1 therapies (P < .001). The independent adverse factors associated with worse survival were age ≥60 years (P = .01), platelets < 50 × 109 /L (P = .02), peripheral blasts ≥ 20% (P = .03), albumin ≤ 3 g/dL (P = .04), and complex karyotype (P = .003). The authors also applied and validated, in the current population, the 2 multivariate-derived prognostic models for CR and survival developed in their previous study of 594 patients who received treatment for second salvage AML from the previous 2 decades.Conclusions: This large-scale analysis establishes the modern historic results of second salvage therapy in AML and validates the prognostic models associated with outcome. These data could be used to analyze the differential benefits of current or future investigational strategies under evaluation in this setting and for the purpose of potential approval of new agents in the United States and the world. Cancer 2018;124:2534-40. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

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Background: Outcomes in patients with chronic myeloid leukemia in blast phase (CML-BP) are historically dismal. Herein, the authors sought to analyze the characteristics, prognostic factors, and survival outcomes in patients with CML-BP in the tyrosine kinase inhibitor (TKI) era.Methods: A total of 477 patients with CML-BP were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics that were predictive of survival. Overall survival and failure-free survival were assessed. Optimal cutoff points for specific parameters were identified using classification and regression tree (CART) analysis.Results: The median age of the patients was 53 years (range, 16-84 years) and 64% were male. Approximately 80% of patients initially were diagnosed in the chronic phase of CML at a median of 41 months (range, 0.7-298 months) before transformation to CML-BP. De novo CML-BP occurred in 71 patients. Approximately 72% of patients received TKI therapy before CML-BP. The initial therapy for CML-BP included a TKI alone (35%), a TKI with chemotherapy (46%), and non-TKI therapies (19%). The median overall survival was 12 months and the median failure-free survival was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, lactate dehydrogenase level ≥1227 IU/L, platelet count < 102 K/μL, no history of stem cell transplantation, transition to BP from chronic phase/accelerated phase, and the presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first-line treatment was found to be predictive of better survival. The combination of a TKI with intensive chemotherapy followed by stem cell transplantation appeared to confer the best outcome.Conclusions: Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes, and require newer treatment approaches. Cancer 2017;123:4391-402. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

This study assessed the relevance of 2013 European LeukaemiaNet ( ELN) response categories on patients treated with common frontline tyrosine kinase inhibitors ( TKI) in chronic myeloid leukaemia in chronic phase ( CML- CP). Four hundred and eighty-seven patients treated with imatinib (400 mg; IM 400, n = 70; 800 mg; IM800, n = 201), dasatinib ( n = 107) or nilotinib ( n = 109) were analysed. Intention to treat ( ITT) analysis indicated that the proportion of patients falling into optimal, warning and failure ELN categories were 89%, 6%, 6% at 3 months, 78%, 17% and 6% at 6 months, and 75%, 13% and 13% at 12 months, respectively. Rates of optimal response at 3 months were 75% for IM400, 90% for IM800, 89% for dasatinib and 97% for nilotinib; 41%, 80%, 86% and 89% at 6 months; and 47%, 77%, 76% and 87% at 12 months, respectively. Patients achieving optimal response had longer eventfree ( EFS), failurefree ( FFS), transformationfree ( TFS) and overall survival ( OS) compared to warning and failure responses at all-time points. Treatment with imatinib 800, dasatinib or nilotinib predicted for achieving an optimal response. Optimal response predicted for significantly longer EFS, FFS, TFS and OS at 3, 6 and 12 months, irrespective of the TKI modality used. ELN response categories reliably predicted outcomes in CML patients receiving commonly used TKIs. [ABSTRACT FROM AUTHOR]

The article examines the prognostic factors in patients with marginal zone lymphoma (MZL). The patients in the study were divided into three groups according to the type of MZL such as extranodal, nodal and splenic. The results of the study revealed that splenic MZL patients had the best prognosis among the three groups despite the increased prevalence of negative prognostic indicators. The patients with extranodal and nodal MZL had similar prognosis. The study was able to provide a prognostic scoring system for patients with extranodal MZL.