scholarly journals The Observed and Expected Incidence of Cardiovascular (CV) Ischemic Events in Dasatinib (DAS)-Treated Patients (pts) Across a Clinical Trial Program

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4534-4534 ◽  
Author(s):  
Giuseppe Saglio ◽  
Philipp le Coutre ◽  
Jorge E. Cortes ◽  
Jiří Mayer ◽  
Philip A. Rowlings ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Factors ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Phase 3 ◽  
Population Total ◽  
Total N ◽  
Ischemic Events

Abstract Background: The safety profile of each BCR-ABL1– targeted tyrosine kinase inhibitor (TKI) used to treat chronic myeloid leukemia (CML) is unique and should be considered when choosing therapy. Although rare, potentially severe adverse events have been reported in CML pts treated with TKIs, particularly pulmonary arterial hypertension with DAS (Montani, Circulation 2012), peripheral arterial occlusive disease with nilotinib (Kim, Leukemia 2013), and arterial and venous occlusive events with ponatinib (Cortes, N Engl J Med 2013). The incidence of CV ischemic events in DAS-treated pts from clinical trials was assessed. Standardized incidence rates (SIRs) were calculated to determine if the number of observed events was different than expected compared with reference populations. Methods: Incidence of CV ischemic events (Table 1) were assessed in a pooled population of DAS-treated pts with any phase CML or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia from 11 first- and second-line clinical trials (N=2712; median age, 54 years [y]), newly diagnosed CML pts treated with DAS (n=258; median age, 46 y) or imatinib (IM; n=258; median age, 49 y) from the phase 3 DASISION trial only (CA180-056, NCT 00481247), and prostate cancer pts from the phase 3 READY trial treated with DAS or placebo in combination with docetaxel and prednisone (CA180-227, NCT 00744497; N=1518; about 66% of pts were >65 y of age). Reference populations for SIR analyses were a general population (total N=116,000,000; males N=56,000,000), CML pts (N=16,000), and prostate cancer pts (N=530,000) derived from Truven's MarketScan Commercial Claims and Medicare Supplemental database, 2008–2013, narrowed to mimic clinical trial eligibility. SIRs were calculated by dividing the observed number of events in DAS-treated pts by the expected number of events, based on the DAS exposure and reference population event rates. Results: Within the pooled population, 96 pts (4%) had CV ischemic events. In DASISION, 10 DAS- and 4 IM-treated pts had any grade CV ischemic events. In READY, 18 pts in the DAS arm and 9 pts in the placebo arm had any grade CV ischemic events. The majority of pts with a CV event had a history and/or risk factors for atherosclerosis (77/96 [80%] in the pooled population; 8/10 with DAS and 3/4 with IM in DASISION). Time-to-event analysis revealed that, in the pooled population, CV ischemic events occurred in 69/96 pts (72%) within 1 y, 11 pts (11%) in 1–2 y, and 16 pts (17%) in 3–7 y. Over 70% tolerated continued DAS therapy without a recurrent CV event. In DASISION, CV events occurred in 7/10 pts within 1 y of DAS initiation, 2 pts in 1–3 y, and 1 pt after 5 y. Based on SIRs, the observed number of CV events in DAS-treated pts was not higher than expected, given the rates of reference populations (Table 1). SIR results should be interpreted with caution due to the limitations of the indirect comparison between clinical data and claims data (eg, coding differences and surveillance bias). Conclusion: CV ischemic events were reported in 4% of DAS- and 2% of IM-treated pts in DASISION, 4% of DAS-treated pts in the pooled population, and 2% of DAS- and 1% of placebo-treated pts in READY. In all populations, among pts who experienced an event, the majority had a history of arterial ischemic events and/or risk factors for atherosclerosis, and most events occurred early. SIRs suggest that the total number of CV ischemic events among DAS-treated pts was not higher than expected, and in contrast to what has been observed with other TKIs, largely restricted to 1 y after initiating therapy. Disclosures Saglio: Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; BMS: Consultancy, Fees for occasional speeches Other. Off Label Use: Dasatinib is approved for first line use in adults with chronic phase Ph+ CML, and in adult AP- or BP-CML, and Ph+ ALL patients who are resistant or intolerant to prior therapy. le Coutre:ARIAD: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria. Cortes:Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Mayer:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Mahon:ARIAD: Consultancy, Research Funding; Pfizer : Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Kroog:Bristol-Myers Squibb: Employment. Gooden:Bristol Myers Squibb: Employment. Subar:Bristol Myers Squibb: Employment. Preston:Bristol-Myers Squibb: Employment. Shah:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding.

Peripheral Arterial Occlusive Disease (PAOD) In Patients (Pts) Receiving Dasatinib: Experience Across Multiple Clinical Trials

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1489-1489 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Timothy P. Hughes ◽  
Francois-Xavier Mahon ◽  
Dong-Wook Kim ◽  
Juan Luis Steegmann ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Second Line ◽  
Related Event ◽  
First Line ◽  
Phase 3 ◽  
Advisory Committees ◽  
Dasatinib Treatment

Abstract Background The introduction of BCR-ABL inhibitors revolutionized the treatment of chronic myeloid leukemia (CML) which is now a manageable, chronic disease. As BCR-ABL inhibitors are used more widely and for longer, some distinctly different or late occurring adverse events (AEs) have become apparent from clinical studies and literature reports (e.g. pulmonary arterial hypertension, PAOD). PAOD has been described in a varying percentage of pts receiving nilotinib across the ENESTnd phase 3 trial of nilotinib versus imatinib (1.2%) and the literature (0.5%–12.5%). Arterial thrombotic events have also been reported in pts receiving ponatinib (11%). To assess whether PAOD may be a class effect, a pooled database of over 2700 pts in clinical trials of dasatinib was assessed. Methods Bristol-Myers Squibb clinical trial safety databases were examined using specific search-terms to identify cases of PAOD or PAOD-related events based on the mapped MedDRA preferred terms. In total, 11 clinical trials of first-line (n=2) and second-line (n=9) single-agent dasatinib in pts with CML (any phase) or Philadelphia chromosome-positive acute lymphoblastic leukemia were evaluated. Dasatinib 100 mg once daily (QD) was received in first-line trials while doses received in second-line trials varied: 15–240 mg QD or twice daily (BID), 20 mg BID, 50 mg BID, 70 mg BID, 100 mg QD, 140 mg QD. Results Across 11 clinical trials, 2705 pts received dasatinib with a cumulative 5890 pt years exposure. 6 pts (0.2%) were identified with either PAOD (n=1) or a PAOD-related event (n=5). See Table for details. In the dasatinib and imatinib arms of the phase 3 DASISION study (the only study with an imatinib control arm using the standard 400 mg QD dose) no cases of PAOD or related events were identified. For the 6 pts receiving dasatinib with PAOD or a related event the median age was 67.5 years (range: 54.0–80.0). All pts received dasatinib following imatinib resistance (n=4) or intolerance (n=2) after 20.0 months median duration of prior imatinib therapy (range: 2.4 – 53.1). Pts received dasatinib treatment for a median of 39.1 months (range: 9.9 – 74.4); 5/6 received a starting dose of 70 mg BID. All of the 6 PAOD or related events were grade 3 or lower in severity; no grade 4 or serious AEs were reported. None of the 6 pts discontinued dasatinib due to PAOD or a related event. Dose interruptions occurred in 2/6 pts; the remaining pts continued to receive dasatinib. All pts had risk factors for PAOD including cardiovascular events (n=3) such as coronary/ischemic heart disease, tricuspid regurgitation, hypertension, and heart failure; endocrine/metabolic events (n=2) such as obesity and diabetes mellitus; or other events such as hyperlipidemia (n=1). 3/6 pts were or had been smokers. PAOD or related events were newly diagnosed in 5/6 pts; 1 pt with femoral artery occlusion had a prior history of right leg angioplasty indicating a preexisting condition (pt 5 in the Table). Common concomitant medications included acetylsalicylic acid (n=3) and erythropoietin (n=3). Conclusion The incidence of PAOD in pts receiving dasatinib is low and as expected for the target population. In the dasatinib clinical trials assessed here, PAOD occurred in pts who had received prior imatinib treatment and had significant predisposing risk factors for PAOD. These results suggest that PAOD is most likely not an effect of dasatinib treatment. In conclusion, confronting possible vascular AEs, pt baseline risk factors, AE profiles, and off-target profiles of therapeutic alternatives should be considered individually when choosing the most appropriate BCR-ABL inhibitor. Disclosures: le Coutre: Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Hughes:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Mahon:Ariad: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Kim:Ilyang: Research Funding, Speakers Bureau; Ariad: Research Funding; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Support for travel to meetings Other. Steegmann:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Wallis:Bristol-Myers Squibb: Employment. Cortes:Novartis: Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding; Tragara: Membership on an entity’s Board of Directors or advisory committees; Ambit: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Arog: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding.

scholarly journals Aggressive Smoldering Curative Approach Evaluating Novel Therapies (ASCENT): A Phase 2 Trial of Induction, Consolidation and Maintenance in Subjects with High Risk Smoldering Multiple Myeloma (SMM): Initial Analysis of Safety Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Shaji K. Kumar ◽  
Al-Ola Abdallah ◽  
Ashraf Z. Badros ◽  
Betsy Laplant ◽  
Binod Dhakal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
High Risk ◽  
Research Funding ◽  
Advisory Board ◽  
Phase 2 ◽  
Phase 3 ◽  
Phase 2 Trial ◽  
Risk Of Progression ◽  
M Spike

Background: Smoldering multiple myeloma (SMM) represents an intermediate stage between monoclonal gammopathy of undetermined significance and active myeloma with a high risk of progression to active MM, especially during the initial years after diagnosis. Available clinical risk factors have enabled development of risk stratification systems that allow for identification of patients at the highest risk of progression, opening opportunities for early intervention. Two phase 3 trials using lenalidomide with dexamethasone or lenalidomide alone have both shown benefit for early intervention by decreasing the risk of progression and improving the overall survival in the former. It remains unknown if an approach using a single active drug to delay progression, or one that uses therapies like active myeloma, represent a better approach; both are being studied in phase 3 trials. We designed this phase 2 trial to examine if an intense but limited duration therapy can possibly provide a significant elimination of the tumour burden that can potentially lead to long term responses. Patients and Methods: Patients with SMM (per updated IMWG definition of SMM) with high risk disease (defined by the IMWG updated risk stratification criteria- presence of any two of the following: Serum M spike > 2 gm/dL OR an involved to uninvolved FLC ratio > 20 OR bone marrow PC% > 20%) or a score of ≥9 using the risk scoring system using FLC ratio, serum M spike, marrow plasma cell% and presence of high risk FISH were enrolled provided they had adequate marrow and organ function. Patients with significant comorbidities such as heart disease were excluded from the trial. Treatment consisted of three phases: induction, consolidation and maintenance. Patients received carfilzomib (36 mg/m2 twice weekly or as per updated protocol 56mg/m2 weekly for 2 weeks), lenalidomide (25 mg daily for three weeks), daratumumab (weekly for 8 doses, every other week for 16 weeks) and dexamethasone 40 mg weekly, in 4 week cycles for 6 cycles as part of induction, the same regimen was administered with daratumumab every 4 weeks and dexamethasone 20 mg weekly for another 6 cycles for consolidation. This was followed by 12 cycles of maintenance therapy with lenalidomide (10 mg daily for three weeks), daratumumab (day 1 every other cycle) of a 4-week cycle. Appropriate antiviral, and thrombosis prophylaxis were mandated. The primary endpoint of this trial is the rate of confirmed sCR as best response across all cycles of treatment. We plan to accrue 83 patients to this trial with one-stage binomial trial design to test the null hypothesis that the true success (sCR) proportion is at most 65% and the alternate hypothesis of 80%. Results: Forty-six patients have been accrued to the trial as of July 14, 2020. The median age of the study population is 63 years (range 47 - 76); 70% are male. Overall, 2% have completed the maintenance, 50% have completed the consolidation, 80% have completed the induction and 15% are in the induction phase; only two patients have gone off treatment. The reasons for going off treatment were patient preference. At least one patient needed a dose modification for each drug; 17%, 2%, 13% and 7% required dose reductions for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively. The relative median dose intensity for the drugs were 85%, 92%, 80% and 98% for carfilzomib, daratumumab, lenalidomide and dexamethasone respectively across the delivered cycles. The adverse events seen in at least 5% of the patients are as shown in the figure. A grade 3 or higher AE was seen in 52% of patients. There were no treatment related deaths observed. Response rate and depth have been as expected for this regimen in myeloma and analysis is pending completed accrual. Figure 1 Disclosures Kumar: Adaptive Biotechnologies: Consultancy; Sanofi: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Novartis: Research Funding; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Carsgen: Other, Research Funding. Badros:Amgen: Consultancy; University of Maryland: Current Employment. Dhakal:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Other: AdvIsory Board, Research Funding; Janssen: Consultancy, Other: Advisory Board, Research Funding; Takeda: Consultancy, Other: Advisory Board; GSK: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding. Abonour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; Takeda: Consultancy; BMS: Consultancy, Research Funding. Rosenbaum:Celgene: Honoraria; Akcea: Honoraria; Amgen: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Research Funding. Bensinger:GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bhutani:Prothena: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute; BMS: Other: Clinical trial funding to institute, Speakers Bureau; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Takeda: Other: Clinical trial funding to institute, Speakers Bureau. Jakubowiak:AbbVie, Amgen, BMS/Celgene, GSK, Janssen, Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive, Juno: Consultancy, Honoraria. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

scholarly journals A Review of Phase III Clinical Trials of Prostate Cancer Chemoprevention

2007 ◽  
Vol 89 (3) ◽  
pp. 207-211 ◽  
Author(s):  
JF Thorpe ◽  
S Jain ◽  
TH Marczylo ◽  
AJ Gescher ◽  
WP Steward ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Age Of Onset ◽  
Cancer Chemoprevention ◽  
Phase Iii ◽  
Phase Iii Clinical Trials ◽  
Prostate Cancer Prevention ◽  
Phase Iii Trials

INTRODUCTION Prostate cancer is an excellent target for chemoprevention strategies; given its late age of onset, any delay in carcinogenesis would lead to a reduction in its incidence. This article reviews all the completed and on-going phase III trials in prostate cancer chemoprevention. PATIENTS AND METHODS All phase III trials of prostate cancer chemoprevention were identified within a Medline search using the keywords ‘clinical trial, prostate cancer, chemoprevention’. RESULTS In 2003, the Prostate Cancer Prevention Trial (PCPT) became the first phase III clinical trial of prostate cancer prevention. This landmark study was terminated early due to the 24.8% reduction of prostate cancer prevalence over a 7-year period in those men taking the 5α-reductase inhibitor, finasteride. This article reviews the PCPT and the interpretation of the excess high-grade prostate cancer (HGPC) cases in the finasteride group. The lack of relationship between cumulative dose and the HGPC cases, and the possible sampling error of biopsies due to gland volume reduction in the finasteride group refutes the suggestion that this is a genuine increase in HGPC cases. The other on-going phase III clinical trials of prostate cancer chemoprevention – the REDUCE study using dutasteride, and the SELECT study using vitamin E and selenium – are also reviewed. CONCLUSIONS At present, finasteride remains the only intervention shown in long-term prospective phase III clinical trials to reduce the incidence of prostate cancer. Until we have the results of trials using alternative agents including the on-going REDUCE and SELECT trials, the advice given to men interested in prostate cancer prevention must include discussion of the results of the PCPT. The increased rate of HGPC in the finasteride group continues to generate debate; however, finasteride may still be suitable for prostate cancer prevention, particularly in men with lower urinary tract symptoms.

Predictors of clinical trial enrollment and impact on outcome in children and adolescents with acute lymphoblastic leukemia: A population based study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7031-7031
Author(s):  
Paul James Gibson ◽  
Uma H. Athale ◽  
Vicky Rowena Breakey ◽  
Nicole Mittmann ◽  
Mylene Bassal ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Acute Lymphoblastic Leukemia ◽  
Health System ◽  
Children And Adolescents ◽  
Lymphoblastic Leukemia ◽  
Income Quintile ◽  
Factors Associated ◽  
Income Status ◽  
Single Payer

7031 Background: Outcomes in pediatric acute lymphoblastic leukemia (ALL) have shown remarkable improvements in large part due to sequential clinical trials. Concerns however persist around whether access to clinical trials is equitable. It is also unclear whether patient outcomes are improved simply by enrolling on a clinical trial. Our objective was to therefore determine which patient and disease-related factors are associated with enrollment, and whether enrollment was associated with clinical outcomes among children and adolescents with ALL in a single-payer health system in Ontario, Canada. Methods: We included all Ontario patients diagnosed with ALL between 0-18 years of age from 2002-2012 treated at a pediatric center, identified through a provincial pediatric cancer registry. Clinical trial availability was determined by whether each patient’s primary institution had an open frontline trial for which the patient was eligible at the time of their diagnosis, considering individual disease characteristics such as lineage, central nervous system (CNS) status and risk group. Demographic, disease, trial enrolment, and outcome data were obtained through chart abstraction. Logistic regression models determined factors associated with trial enrolment, while Cox proportional hazard models determined factors associated with event-free and overall survival (EFS, OS). Results: Of 858 patients, 693 (81%) were eligible for an open clinical trial at their time of diagnosis. 476 (69%) enrolled on a trial. In adjusted analyses, age > 15 years (odds ratio 0.4 vs. age 5-9, 95th confidence interval (95CI) 0.2-0.8; p = 0.01) and CNS3 disease (OR 0.38 vs. CNS1, 95CI 0.17-0.83; p = 0.01) were significantly associated with decreased likelihood of enrolment, while sex and neighborhood income quintile were not associated with enrolment. Adjusted for disease and demographic factors, clinical trial enrolment was not significantly associated with either EFS (hazard ratio (HR) 1.1, 95CI 0.7-1.7; p = 0.83) or OS (HR 1.3, 95CI 0.7-2.5; p = 0.44). Conclusions: The majority of patients with ALL eligible for available clinical trials at their time of diagnosis were enrolled. While no disparities in enrolment by income status were noted, adolescents were substantially less likely to participate in trials even within pediatric centers. Studies of mechanisms underlying this disparity are warranted in order to design and implement effective interventions targeting increased enrolment rates in this patient population. Our results however also suggest that clinical trial enrolment on its own is not associated with improved outcomes in the context of a single payer health system.

Chromosome 1q Amplification Is Associated with a History of Prior Malignancies Among Patients Newly Diagnosed with Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2193-2193
Author(s):  
Elizabeth B Lamont ◽  
Andrew J. Yee ◽  
Stuart L. Goldberg ◽  
Andrew D Norden
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Usual Care ◽  
Real World ◽  
Research Funding ◽  
Newly Diagnosed ◽  
History Of ◽  
Equity Ownership ◽  
Prior Malignancy

Background: Over the past 20 years, observational data from usual care clinical oncology settings has been leveraged to inform estimates of cancer treatment-associated benefits and risks among patients not treated on clinical trials. Increasing genomic testing to inform treatment decisions in usual care settings now meaningfully augments traditional observational data, positioning it to provide insights beyond clinical care into tumor biology. We studied patients with newly diagnosed multiple myeloma (MM), comparing cytogenetic test patterns according to history of prior malignancy. Methods: In this retrospective cohort study, we identified 2,380 patients from the COTA real-world database (RWD) who were newly diagnosed with MM in the years 2010-2018. The COTA RWD is a de-identified composite of both abstracted electronic health record and administrative data pertaining to patients receiving their cancer care at one of COTA's clinical oncology practice partners. Among these patients, 1769 (74%) had evidence of MM-associated cytogenetic testing with fluorescent in-situ hybridization (FISH) within the 120 days surrounding their date of diagnosis. The 1,769 patients form the analytic cohort. We compared patients' FISH results for t(4;14), deletion(17p), t(14;16), deletion(13), t(14;20), t(6;14), t(11;14), deletion (1p), and amplification(1q) according to their history of prior malignancy. Results: Within the cohort, 263 prior malignancies were identified in 241 patients (14%, 241/1,769). Two-hundred and twenty-one patients (92%) had one prior malignancy, 28 (7.9%) had two prior malignancies, and one (<1%) had four prior malignancies. The most common prior malignancies were prostate (n=50), breast (n=19), melanoma (n=14), skin (n=13), and cervix (n=6). Amplification of the long arm of chromosome one (amp(1q)) was noted in 31% of patients (75/241) with a prior malignancy vs. 24% of patients (370/1,528) without (chi2 test p=0.02). Overall 25% of patients had amp(1q). No other translocations, amplifications, deletions were associated with prior cancers. A non-parametric test for trend revealed a strong positive association between patients' malignancy count (range 0-4) and amp1q (p<0.01). MM patients with prior lymphomas and prior melanomas also had high rates of amp(1q), though these were not significantly different from patients without these prior malignancies. In a multivariable logistic regression model that adjusted for patient demographic attributes, other known potentially collinear MM poor prognostic factors (i.e., revised ISS stage, IgA sub-type, lambda light chains) and adjusted standard errors for clustering of patients within treatment settings, a history of prostate cancer remained clinically and statistically significantly positively associated with amp(1q) (OR 2.1, 95% CI: 1.9-2.2) as did history of two or more prior malignancies (OR 2.8, 95% CI: 2.3-3.3). Of note, amp(1q) was positively associated with IgA subtype (OR 1.5, 95% CI: 1.3-1.6) and the presence of lambda subtype (OR 1.3, 95%CI: 1.3-1.4). Conclusions: Using RWD, we found that newly diagnosed MM patients with histories of prostate cancer and those with two or more prior malignancies were more likely to have amp(1q), a poor prognostic marker in MM. Gains in 1q have previously been identified among patients with prostate and lymphoid cancers, but to our knowledge this is the first study to identify an association with a prior history of cancer, especially prostate cancer, and amp(1q) in MM. This relationship is worth further exploration of whether there is a common pathway associated with for example risk of prostate cancer and amp(1q) in MM. Clinical trials are less likely to answer this question as patients with prior malignancies are often excluded from enrollment. Overall, the results reported suggest that RWD is an efficient and comparatively inexpensive tool to support research in cancer biology through hypothesis generating and testing analyses of linked real-world phenotypic and genotypic data. Disclosures Lamont: COTA: Employment. Yee:Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Norden:COTA: Employment, Equity Ownership.

Toxicity and Risk Factors Contributing to Delayed Methotrexate (MTX) Elimination in Adult/Elderly Patients (pts) Treated with High-Dose Methotrexate Therapy (HDMTX), a 2-Year, Single Center Survey.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2439-2439
Author(s):  
Stefan Schwartz ◽  
Peter Martus ◽  
Wolf-Dieter Ludwig ◽  
Renate Arnold ◽  
Markus Ruhnke ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Serum Creatinine ◽  
Liver Toxicity ◽  
Lymphoblastic Leukemia ◽  
Advanced Age ◽  
High Dose ◽  
Severe Toxicity ◽  
Urine Ph ◽  
Grade 3

Abstract HDMTX is a well-established regimen used in a variety of neoplasms, including acute lymphoblastic leukemia (ALL) or lymphoma (NHL). Risk factors contributing to a delayed MTX-elimination and toxicity have been studied in pediatric pts with HDMTX (Relling MV, J Clin Oncol 1994, 12: 1667–72). However, data are scarce on risk factors contributing to delayed MTX elimination in adult pts, on toxicities in elderly pts and from pts treated with HDMTX outside clinical trials. We assessed toxicities and risk factors in all non-pediatric pts treated with HDMTX at the Charité in 2003/04. 141 pts (age 16–81y, median 44y) received 614 HDMTX cycles (median dose MTX/m2: 3000mg, range 320–12000mg) for ALL (39), NHL (38), CNS-NHL (36), sarcoma or other solid tumor (28) within (69) or outside (72) clinical trials. In 99/614 (16%) of HDMTX cycles a 15–85% (median 50%) dose reduction was carried out due to renal dysfunction (58), severe toxicity of prior chemotherapy (18) or other reasons (23). Toxicities in 62/614 (10%) HDMTX cycles caused delays of 1–50 days (median 7 days) of scheduled therapy. 61/614 (10%) HDMTX cycles resulted in an increase of serum creatinine values above the upper limit of normal (ULN) (median of 112μmol/L, range 81–386μmol/L). Delayed MTX-elimination (MTX blood level >150μM 24h, >3μM 36h, >1μM 42h, >0.4μM 48h or >0.1μM 68h) occurred in 156/614 (25%) HDMTX cycles. Grade 3/4 toxicities were recorded in 224 (36%) cycles for leukopenia, 127 (21%) cycles for liver toxicity, 116 (19%) cycles for thrombocytopenia, 88 (14%) cycles for fever with neutropenia and 63 (10%) cycles for mucositis/gastrointestinal toxicity. Presence of a 3rd space and comedications with known interference with MTX elimination or nephrotoxic potential were associated with a delayed MTX elimination (p<0.01). Overweight (BMI≥25kg/m2), urine pH<7 at some time after HDMTX and presence of a 3rd space were associated with an increase of serum creatinine values above ULN (p≤0.05). Pts with delayed MTX elimination or an increase of serum creatinine above ULN were older compared to pts with regular MTX elimination (median age 51y vs. 30y and 54y vs. 35y, p<0.01). Pts receiving HDMTX outside clinical trials more frequently experienced delayed MTX elimination (p<0.01). HDMTX frequently causes grade 3/4 hematotoxicity and increases of serum creatinine. Delayed MTX elimination is associated with advanced age and therapy outside clinical trials. Improved supportive care strategies are needed, especially in pts with advanced age, to ensure predictable MTX-elimination and reduce toxicities associated with HDMTX.

Mortality and Morbidities During Long-Term Follow-up After Recovery From Thrombotic Thrombocytopenic Purpura (TTP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 362-362 ◽  
Author(s):  
Jessica A. Reese ◽  
Zayd L. Al-Nouri ◽  
Cassandra C. Deford ◽  
Lauren M. Stewart ◽  
Deirdra R. Terrell ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trial ◽  
Relative Frequency ◽  
Research Funding ◽  
Population Data ◽  
Term Survival ◽  
The Us ◽  
Initial Episode

Abstract Abstract 362 Introduction Since recovery from an acute episode of TTP is typically assumed to be complete, subsequent survival has been commonly assumed to be normal except for the risk of death with relapse. However we have observed unexpectedly high mortality among patients in the Oklahoma TTP-HUS Registry who had recovered from their initial episode of TTP. Therefore we documented long-term survival and compared the mortality of our patients to the US population data. To investigate possible risk factors for increased mortality, we documented the frequency of common risk factors for poor health outcomes: abnormal renal function, increased body mass index (BMI), hypertension (HTN) and diabetes (DM). Methods We included all 68 Oklahoma TTP-HUS Registry patients whose initial episode was associated with severe ADAMTS13 deficiency (<10%), 1995–2010. Health outcome measures for renal function were glomerular filtration rate (GFR) and urine albumin-creatinine ratio (ACR). BMI and HTN and DM preceding TTP were documented at the time of the initial episode. HTN, DM, GFR, and ACR were documented on patients who survived their initial episode at the time of their last follow-up. HTN and DM were documented by the use of regularly prescribed medication. GFR was estimated by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. ACR was quantified on a random urine sample. Population data were obtained from the National Health and Nutrition Examination Survey (NHANES); we calculated expected proportions based on the age, race, and gender composition of our patient group. We used survival data analysis to compare the mortality of the patients to the U.S. population; we used one way chi-square to compare the relative frequency of BMI, GFR, ACR, HTN and DM of the patients to the expected proportions from the US population. Results Fifty-five of the 68 consecutive patients survived their initial episode of TTP. At the time of their initial episode, the median age of the 55 patients was 39 years (range 9–71); 44 (80%) were women; 20 (36%) were black. Median follow-up to August 1, 2012 was 9.5 years (range, 2.3–16.7 years). At the time of their initial episode, BMI was significantly greater than the US population (p<0.001); in 15 (27%) of the 55 patients, BMI was >40 kg/m2, indicating morbid obesity. Although the relative frequency of hypertension (16%) and diabetes (9%) was not different from the US population preceding the initial episode of TTP, the relative frequencies were significantly greater than the US population at the time of their last follow-up (hypertension, 47%, p<0.001; diabetes, 22%, p=0.003). The GFR (measured in all 55 patients) and ACR (measured in 37 patients) were not different from the US population (p=0.374 and p=0.053). Nineteen (35%) patients have had 1–4 subsequent episodes of TTP. Eleven (20%) of the 55 patients have died (median age at death, 51 years; range, 41–82), a mortality proportion significantly greater than the age/race/gender matched U.S. population (Table). Two of the 11 patients died during their first relapse. Although relapsed TTP was not an apparent cause of death in the remaining 9 patients, 2 deaths were sudden and unexpected; 7 followed prolonged illnesses: congestive heart failure/myocardial infarction (3), sepsis (2), respiratory failure, ovarian cancer. Conclusion Long-term survival after recovery from an acute episode of TTP is significantly less than the age/race/gender-matched US population. Although relapse contributes to increased mortality, the significantly increased relative frequency of hypertension and diabetes are important and previously unrecognized risk factors for poor health outcomes in TTP survivors. Disclosures: Terrell: Baxter, Inc.: Consultancy; Amgen, Inc.: Consultancy. Kremer Hovinga:Baxter Healthcare: Consultancy, Research Funding. George:Alexion, Inc.: Consultancy; Baxter, Inc.: Consultancy; Amgen, Inc.: Consultancy, PI for clinical trial involving romiplostim, PI for clinical trial involving romiplostim Other, Research Funding.

Distribution and geographic accessibility of prostate cancer clinical trials in the United States.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 59-59 ◽  
Author(s):  
Matt D. Galsky ◽  
Asma Latif ◽  
Kristian D. Stensland ◽  
Erin L. Moshier ◽  
Russell McBride ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
United States ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Geographic Distribution ◽  
The United States ◽  
First Line ◽  
Trial Site ◽  
Lorenz Curves ◽  
Number Of Patients

59 Background: An extremely small proportion of patients with cancer in the United States (US) enroll in clinical trials. While several barriers to trial accrual have been described, the geographic distribution and accessibility of clinical trial sites has not been comprehensively explored. Methods: ClinicalTrials.gov was queried to identify all active US clinical trials exploring first-line therapies for metastatic prostate cancer (PCa) on 9/16/2012. We evaluated the geographic distribution of trial sites and determined the relationship between the number of sites and the number of patients with advanced PCa per county and evaluated heterogeneity using Lorenz curves. We also estimated the minimum driving distance required to access a clinical trial site from each ZIP code in the continguous US; a distance >30 miles was defined as high travel burden consistent with prior studies. Results: We identified 958 sites associated with 42 PCa clinical trials (Table). The geographic distribution of clinical trial sites was very inhomogeneous with several states having only 1-2 trial sites. Among 3185 US counties, 2,669 (83.8%) had no clinical trials available for first-line treatment of metastatic PCa. Counties with larger populations of patients with advanced PCa had significantly higher numbers of clinical trial sites. For every 100 additional patients with advanced PCa per county, the number of available trial sites increased by 21.0% (95% CI: 16.5-25.7%). However, Lorenz curves indicated a high degree of inequality in trial accessibility (Gini index 0.71). Approximately 31% of the US population resided >30 miles from a PCa trial site. Conclusions: Clinical trials sites are poorly accessible, geographically, to a large subset of US PCa patients, a finding that likely contributes to dismal accrual. Innovative solutions are required to address geographic barriers to access. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document