Racial Disparities and Their Impact on Knowledge, Behavioral Patterns, and Preferences Towards Participation in Clinical Trials Among Cancer Patients

Background: Clinical trials are critical to drug development and the formulation of evidence-based guidelines which are essential to providing crucial and often life-saving treatment to cancer patients. Clinical trial participation is very poor in the United States overall, with a dismal representation of racial minorities. While this has been a focus of several efforts focused on education, targeted enrollment etc., there is a lack of understanding of the patient's knowledge and preferences, and how that may be shaping their decision to consider participation in clinical trials. We undertook a patient-reported survey to explore these factors and understand any underlying disparities. Methods: A 15-question paper-based anonymous questionnaire addressing the cancer patient's knowledge about their disease and clinical trials, as well as factors that may shape their understanding of, or may be barriers to their participation in clinical trials was used. This was administered to adult patients with lymphoid malignancies at the Mayo Clinic in Florida. Categorical and continuous variables between white and minority respondents were compared using the Chi-square test and U Mann Whitney with a significance level of 0.05. Results: The survey was completed by 203 cancer patients. Of these, 3 patients did not report race and ethnicity and so responses from 200 patients were included in the final analysis. Of the respondents, 73% (n=146) were white and 27% (n=54) were minorities. Whites were older than minorities, although not statistically significant (median 67 vs. 61.5 yrs, p=0.06). Minority patients had lower education level with 41% having ≤high school education as compared to 16% whites (p<0.001). Majority of white patients (53%) reported their physicians as the highest ranked source of information for cancer vs. 33% minority patients (p=0.01). Other sources of information explored were internet, nurses, family/friends, books/flyers or other patients. A higher number of white patients reported treatment and its side effects to be the topic of most importance to them at the time of cancer diagnosis as compared to minorities (33% vs. 15%, p=0.01). Similarly, prognosis was more important for a higher number of whites than minorities (21% vs. 15%, p=0.03). Understanding of the diagnosis and financial impact were also explored but not found to have any significant difference. Understanding their treatment and long-term treatment plan was the most frequent knowledge gap reported by whites (81%) vs. minorities (54%, p=0.004). Minorities had several knowledge gap areas (understanding the diagnosis, treatment, side effects, long-term treatment plan, financial impact, survival) more evenly distributed. Regarding clinical trials, minorities were more likely to agree that clinical trials were of benefit for patients (42% vs. 28%, p=0.05) and that in a clinical trial the experimental drug always works better than the one it is being compared to (65% vs. 38%, p<0.001). Minority patients were less likely to agree to participating in clinical trials just based on their doctor's recommendation and judgement (83% vs. 93%, p=0.03). A higher number of minority patients felt that pharmaceutical companies have a big influence on the result of a clinical trial (83% vs. 65%, p=0.01). Fear of not benefiting from clinical trials was the reason for not participating among a higher number of whites (36% vs. 19%, p=0.02) while minorities more frequently reported fear of being a guinea pig (22% vs. 14%) and fear of financial burden (17% vs. 8%) although these were not statistically significant. Conclusions: Racial disparities exist at various aspects of cancer-related knowledge resources, gaps and needs. Minorities have more widespread knowledge gaps and depend on more resources for cancer-related knowledge, which may affect their clinical trial participation and preferences. There appears to be mistrust and misinformation guiding minority patient's understanding, leading to more widespread fears of clinical trials. Knowledge gaps and misinformation needs to be addressed in order to achieve higher participation in clinical trials in general, and among minority patients in particular. Disclosures Manochakian: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Guardant health: Membership on an entity's Board of Directors or advisory committees; Novocure: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ailawadhi:Phosplatin: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Takeda: Honoraria; Amgen: Research Funding; Celgene: Honoraria.

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Long Term Treatment and Prevention Of Recurrent VTE In Cancer Patients: Results Of The Canadian Proact Survey

Blood ◽

10.1182/blood.v122.21.5581.5581 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5581-5581

Author(s):

Normand Blais ◽

Charles A. Butts ◽

Mark A. Crowther ◽

Nanette Cox-Kennett ◽

Josée Martineau

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Research Funding ◽

Term Treatment ◽

Advisory Committees ◽

Extended Treatment ◽

Treatment And Prevention ◽

Long Term Treatment ◽

Recurrent Vte

Abstract Introduction Cancer associated thrombosis (CAT) is the second leading cause of death in cancer patients after death from cancer. Despite multiple available guidelines for CAT management, there remains variability in treatment practices. In order to gain insight on this variability in Canada, a survey was conducted to identify the perceived importance of managing CAT, identify differences in the pharmacological management of CAT, highlight the main barriers to optimal extended treatment and prevention of recurrent venous thromboembolism (VTE), outline challenges associated with long term treatment adherence, and identify predictors of patient non-adherence. Methods A survey was designed targeting physicians involved in the management of CAT. The questionnaire included queries on physician practice, 37 items related to beliefs and attitudes about extended treatment for prevention of recurrence of VTE, and a 30-item patient-specific profile. Results Responses were obtained from 21 professionals from four Canadian provinces (Nova Scotia, Quebec, Ontario, and Alberta); 76% were hematologists and/or oncologists, 14% were internists and 10% were pharmacists. Community and academic centers were well represented. Specific management profiles were obtained for 131 patients. Most care givers felt that VTE recurrence was an important issue deserving extended therapy for most patients. Although more than 90% believed bleeding and recurrent VTE risk should influence the length of treatment, only 62% believe that VTE recurrence risk should modify the type of treatment and 52% were concerned of the risk of bleeding with long term therapy (≥6 months). 71% of respondents believed patients’ lack of awareness of the risk of recurrent VTE reduces adherence to anticoagulant therapy for extended treatment of VTE. Although 100% of respondents detailed giving verbal patient counseling, only 19% provided written information to patients. 95% stated they assessed compliance verbally; less than 20% used more objective measures (pharmacy records, laboratory monitoring). Participants admitted to using results of clinical trials (95%) more than clinical guidelines (48%) as most felt that the published guidelines contained conflicting recommendations. The main drivers of treatment choice were clinical evidence, efficacy, and personal experience. No respondents indicated they preferred to use oral anticoagulants for extended therapy of CAT and 43% believed that LMWHs should not be used interchangeably. Most (95%) stated they follow-up with patients directly to reassess therapy after 3-6 months of treatment. The patient profile information showed the median age of patients was 62 years and 60% were female. Lung cancer, colon cancer, breast cancer, and lymphoma were the most common tumor sites and accounted for 50% of described cases. Cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) were evenly represented and 82% were symptomatic. Most events were temporally related to cancer therapy (69%), presence of a central venous catheter (18%), and recent surgery (17%). Less than 5% of these cases presented with a contraindication to anticoagulation therapy (severe thrombocytopenia, active bleeding) at CAT diagnosis. Most patients were treated in the outpatient setting. Nonetheless, hospitalization was required in 33% of cases with an average patient stay of 10.8 days. Hospitalized patients were preferentially treated with LMWH (84%) and usually stayed on the same regimen upon discharge (8.3 ± 6.4 months). Long term treatment was largely managed with LMWHs (most frequently dalteparin – 80% of all treated patients) while few were managed with vitamin K antagonists (6%) or novel direct antithrombotics (2%). Anticoagulant therapy for outpatients was prescribed for 9.0 ± 7.7 months after the most recent VTE episode. Conclusion In Canada, CAT is believed to be an important complication of cancer. Extended therapy is indicated for most patients with CAT. Although bleeding risk is perceived as an important reason to modify therapy, contraindications to LMWHs were rare in the reported cases. Uptake of outpatient therapy of CAT is widespread in this country, yet hospitalization is still frequently required at diagnosis and is associated with prolonged inpatient stays. Even if non-adherence to antithrombotic therapy was believed to be rare among patients with CAT, this was rarely rigorously monitored. Disclosures: Blais: Pfizer: Consultancy; Sanofi: Consultancy; Leo: Consultancy. Butts:Pfizer: Consultancy, Honoraria, Speakers Bureau. Crowther:Pfizer: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees. Cox-Kennett:Pfizer: honorarium as a speaker Other. Martineau:Pfizer: honorarium as a speaker Other; Boehringer: honorarium as a speaker, honorarium as a speaker Other; Bayer: honorarium as a speaker, honorarium as a speaker Other; Sanofi: honorarium as a speaker and participated in clinical trial, honorarium as a speaker and participated in clinical trial Other; BMS: honorarium as a speaker Other.

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Determinants of Clinical Trial Participation and Impact on Survival Outcomes Among Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-131776 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5833-5833

Author(s):

Gabriella C Malave ◽

Prashant Kapoor ◽

Angela Dispenzieri ◽

Morie A. Gertz ◽

Martha Q. Lacy ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Trial Participation ◽

Newly Diagnosed ◽

Clinical Trial Participation ◽

Advisory Committees ◽

Baseline Characteristics

Background: The overall participation of cancer patients in interventional clinical trials in the United States remains very low, with ~5% of patients being enrolled in clinical trials nationwide. The outcomes of patients with MM have improved significantly over the past decade, but available data suggest that the participation rates for patients with MM is comparable to other cancers. The drivers of participation and the potential impact of clinical trial participation have not been systematically studied in MM. Patients and Methods: We identified 228 patients who were enrolled into clinical trials for initial therapy of newly diagnosed MM between 2004 and 2018, and 4 controls for each of these patients. Controls were patients with NDMM, who were diagnosed closest in time to the index patients and did not participate in an interventional treatment trial. Various baseline characteristics as well as overall survival were compared between the two groups. Results: The baseline characteristics of the two groups are as shown in the Table. Patients who entered clinical trials were more likely to be female, resided closer to the clinic, and were more likely to have a prior history of MGUS. They were more likely to have higher ISS Stage, and a higher serum LDH, but there was no difference in the FISH risk status. Other indices of disease burden such as lower hemoglobin and platelets, higher serum creatinine were all seen more often in the control group, but may have been influenced by the trial entry criteria. Looking at the outcomes, the overall survival was longer among those enrolled into clinical trials compared to those who did not [median 103 (95% CI; 86, 136) vs. 63 (95% CI; 53, 69) months, p<0.001 (Figure). Conclusions: The current study provides important clues regarding demographic determinants of trial participation and disease biology related features that reflect likelihood of trial participation. Overall survival was significantly longer among the trial participants, which likely represent a mix of reasons including baseline status of patients, intensity of monitoring and efficacy of novel treatment approaches. Table Disclosures Kapoor: Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding. Dispenzieri:Alnylam: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Akcea: Consultancy; Intellia: Consultancy. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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Sickle-Cell Disease in Greece: Patient Reported Outcomes Related to Clinical Complications, Treatment Choices and Attitudes, Beliefs and Trends Affecting Potential Participation in Clinical Trials - a Greek National Multicentric Study

Blood ◽

10.1182/blood-2019-127966 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4838-4838

Author(s):

Sophia Delicou ◽

Michael D. Diamantidis ◽

Konstantinos Manganas ◽

Eftychios Eftychiadis ◽

Despoina Pantelidou ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Educational Status ◽

Current Treatment ◽

Advisory Committees ◽

Chi Square ◽

Clinical Complications

Background: Sickle cell disease (SCD) is an autosomal recessive disorder caused by a point mutation in the β-globin chain of hemoglobin that forms hemoglobin S. It is clinically characterized by complicated episodes of veno-occlusive crises (VOC), emergency room (ER) visits and uncomplicated inpatient admissions. Aim: We investigated the clinical complications and treatment choices of a large cohort of Greek SCD patients, representative of the whole country. Most importantly, this study aimed to assess patients' attitudes and beliefs regarding their enrollment in clinical trials testing new drugs. We examined the factors influencing such a participation. Patients and Methods: A total of 254 patients from 10 Thalassemia and Sickle Cell Departments across Greece (110 men/144 women), aged 18 - over 65, 210 (82.7%) with β-thalassemia/sickle cell trait and 44 (17.3%) with homozygous SCD participated in the study. The participants had variable educational and socioeconomic background. They all answered an anonymous self-report questionnaire during their medical evaluations between November 2018 and May 2019, including their demographic and clinical characteristics, their current treatment and their opinion regarding a possible participation in a clinical trial for SCD. Descriptive statistical analysis using calculated scale variables and Chi-square test were performed. Results: All participants completed the survey. During the previous year, 64 patients (25.3%) had no admissions for VOC, 128 (50.6%) had 1-5, whereas 21 (8.3%) had 5-10 and 40 (15.8%) more than 10. Except for acute pain crises, the most frequent complications were chronic pain (59%), liver/spleen dysfunction (32.4%), infectious episodes (29.5%), iron overload (23.8%) and pulmonary hypertension (20.1%). In addition to hematological care, patients seeked medical attention from expert physicians for disease complications; 77.6% of the patients reported that they yearly visited a cardiologist, 42.4% an ophthalmologist, 31.9% an orthopedic, 28.4% a pneumonologist, 28.9% a hepatologist, 12.6% an urologist, 14% a nephrologist, 11.9% an infectious disease doctor, 10.1% a pain management specialist and 8.1% a neurologist. The therapeutic approaches included daily folic acid supplementation (86.1%), vaccines (68.3%), hydroxyurea (66.3%), antibiotics (57.1%), simple pain moderators (52.4%), opioids (48.8%) and iron chelators (30.2%). Previous experience in clinical trials was reported by only 17 patients (6.9%). Regarding the patients' attitudes towards a probable clinical trial, 41.3% were positive to try new therapies, 28.3% negative and 30.4% neutral. 67.2% were satisfied with their current treatment, without excluding a potential participation in clinical trials; such treatment satisfaction correlated significantly with older age, lower income and secondary hemochromatosis under chelation treatment (p<0.05). 40% reported that they had been waiting for years for a new treatment, but 43.2% strongly denied becoming an experimental mouse model, whereas 47.3% mentioned that they would trust their doctors' advice correlating positively with male gender and higher income (p<0.05). Lower educational status, prior intake of hydroxyurea and residence/origin in the capital in contrast to the countryside (chi-square, p<0.05) significantly correlated with a potential clinical trial participation. Internet and television information motivated patients to seek more details from their doctor. Concerning the factors rated as the most important for a potential participation in a clinical trial, 7 out of 10 patients of our cohort considered of utmost equal importance the effectiveness of a probable treatment and the relative toxicity. Conclusions: Most SCD patients have chronic complications and visit specialized physicians. Since the participation of larger number of patients in clinical trials is essential for the application of novel drugs, the most important factors of our cohort are the effectiveness of a probable treatment and the relative toxicity, along with the trust to the doctor. These factors are crucial, influencing patients' decision. Even though a proportion of our patients remain skeptical towards clinical trials, an increasing number is willing to participate, which correlates positively with residence in the capital, lower educational status and prior intake of hydroxyurea. Disclosures Kattamis: Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Development and Testing of a Lymphoma Clinical Trials Specific Frailty Index: A Secondary Analysis of the LY.12 Clinical Trial

Blood ◽

10.1182/blood-2021-153037 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4076-4076

Author(s):

Abi Vijenthira ◽

Xinzhi Li ◽

Michael Crump ◽

Annette E. Hay ◽

Lois E. Shepherd ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Frailty Index ◽

Secondary Analysis ◽

Advisory Committees ◽

Frail Patients ◽

The Impact

Abstract Background: Frailty is common in older patients with lymphoma. However, it remains unknown whether frailty is prevalent in patients included in clinical trials of lymphoma, as those with frailty may meet inclusion criteria of a trial which do not include functional information beyond performance status (PS). Understanding the prevalence and impact of frailty in clinical trials is important to direct future stratification criteria, as well as to have robust data to counsel frail patients on their potential outcomes. Methods: We conducted a secondary analysis using data from the phase III LY.12 clinical trial in which patients with relapsed aggressive non-Hodgkin lymphoma were randomized to gemcitabine-dexamethasone-cisplatin or dexamethasone-high dose cytarabine-cisplatin chemotherapy prior to autologous stem cell transplant. The primary objective of our study was to construct a lymphoma clinical trials specific frailty index (FI) using previously described methods (Searle. BMC Geriatr. 2008;8:24). Secondary objectives were to describe the association of frailty (binary variable) with overall survival (OS), event-free survival (EFS), hospitalization, adverse events (AE), serious adverse events (SAE), and proceeding to transplant, and to describe the association of frailty with these outcomes, controlling for important covariates (age, sex, immunophenotype, revised international prognostic index score (rIPI), Eastern Cooperative Oncology Group (ECOG) PS, stage, and response to previous chemotherapy). Results: 619 patients in the LY12 trial were used to construct the frailty index (Table 1). Using a binary cut-off for frailty (<0.2), 15% (N=93) of patients were classified as frail. There were no differences in age or sex between frail and non-frail patients; however they differed in terms of other lymphoma-related characteristics (Table 2). Frailty was strongly associated with OS (HR 2.012, 95% CI 1.57-2.58), EFS (HR 1.94, 95% CI 1.53-2.46), frequency of the worst overall Grade >3 AE (OR 2.65 (15% vs. 6%), p=0.003), and likelihood of proceeding to ASCT (OR 0.26, 95% CI 0.15-0.43), but not hospitalization (OR 1.52, 95% CI 0.97-2.40) or SAE (6% vs. 4%, p=0.3). In multivariable analysis, frailty was not significantly associated with OS, EFS, likelihood of proceeding to ASCT, nor hospitalization (Table 3), though there was a trend to significance for ASCT. However, rIPI remained significantly associated with OS and EFS, ECOG remained significantly associated with OS (Table 3) Conclusion: A potentially broadly applicable lymphoma clinical trials specific FI was constructed through secondary analysis of LY12 data. 15% of patients were classified as frail. Frailty was significantly associated with OS, EFS, frequency of grade >3 AE and likelihood of proceeding to transplant. However, this relationship no longer was significant when controlling for lymphoma-related prognostic variables, suggesting that the impact of poor prognostic features of lymphoma supersede the impact of frailty alone in this younger clinical trial population. Interestingly, rIPI and ECOG demonstrated their value as simple predictors that are highly associated with OS and/or EFS even when controlling for other important covariates including frailty. These findings require further testing in an external data set, and would be particularly valuable to test in an older population. Calibration of the FI against clinical frailty assessment (e.g. Clinical Frailty Scale, Comprehensive Geriatric Assessment) would also be meaningful to confirm its ability to classify frail versus non-frail patients. Figure 1 Figure 1. Disclosures Crump: Epizyme: Research Funding; Roche: Research Funding; Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hay: Merck: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Karyopharm: Research Funding; Seattle Genetics: Research Funding. Prica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria.

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Does Trial Participation Improve Outcomes for Higher-Risk Myelodysplastic Syndromes (MDS) Patients Treated at Specialty Centers?

Blood ◽

10.1182/blood-2018-99-117174 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3096-3096

Author(s):

Sudipto Mukherjee ◽

David P. Steensma ◽

Rami S. Komrokji ◽

Amy E. DeZern ◽

Gail J. Roboz ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Wald Test ◽

Genetic Alterations ◽

Cancer Center ◽

Trial Participation ◽

Advisory Committees ◽

Risk Categories

Abstract Background: For some rare cancers, better outcomes have been reported for patient (pts) treated at high volume or specialty centers compared to pts who did not receive such care. Greater availability of interventional clinical trials may be one of the drivers of better outcomes in specialty centers. However, not all pts referred to specialty centers are eligible or willing to participate in trials, and it is not known how outcomes compare for pts treated at specialty centers on clinical trials versus standard of care. In this study, we compared the outcomes of higher-risk MDS pts treated in and out of clinical trials at MDS specialty centers. Methods: Pts treated at MDS Clinical Research Consortium institutions (Moffitt Cancer Center, Cleveland Clinic, MD Anderson Cancer Center, Cornell University, Dana-Farber Cancer Institute, and Johns Hopkins) from 2006-2016 were included. Pts were diagnosed with MDS according to 2008 WHO criteria and identified as having "higher-risk" disease based on the revised IPSS (IPSS-R) criteria that included Intermediate, High and Very high risk categories. All pts treated outside clinical trials received hypomethylating agents (HMAs), either azacitidine (AZA) or decitabine (DAC). Trial and non-trial pts were matched 1:1 based on age, sex, number of treatment regimens prior to HMA (for non-trial pts) or experimental regimen (for trial pts) and IPSS-R categories. All non-trial pts included in the analysis received at least 4 cycles of AZA or DAC at the same institution. Transplant rates and overall survival (OS) were evaluated for association with trial participation. OS was estimated by the Kaplan-Meier method and compared using Cox proportional hazard regression with two-sided Wald test with adjustment for matching variables. The relative odds of transplant following initial treatment were estimated using logistic regression and compared with two-sided Wald test. Results: Of 774 pts in the MDS CRC database for whom complete data were available, 323 were treated in clinical trials and 451 were treated with AZA or DAC. The trial and non-trial MDS cohorts were well matched with regards to median age (68.5 vs 68.2 yrs; P=0.65), females (28.4% vs 29.9%, P=0.75), numbers of regimens (3 vs 3, P=0.77) and IPSS-R risk categories (P=0.86). Estimated median OS of pts treated in and out of clinical trials was 44.5 and 50.6 months (P=0.67), respectively. Compared to standard of care, trial participation was not associated with any survival advantage [Hazard ratio (HR), 95% CI, 0.94 (0.72-1.24), P=0.67] (Figure 1). Clinical trial participation did not significantly increase the odds of proceeding to transplant [Odds Ratio (OR) (95% CI), 1.5 (0.68, 1.61), P = 0.83)]. As shown in Table 1, in multivariate analyses, among all factors, increasing number of regimens received was significantly associated with better survival, possibly reflecting a bias towards healthier pts who survived longer to receive multiple regimens. Conclusions: In a matched-pair analysis, we found comparable survival outcomes between trial and non-trial higher-risk MDS pts treated at specialty centers. Our matched analysis failed to identify any statistical evidence to suggest that an average patient benefited from trial participation within the MDS CRC sites. Additional research is necessary to interrogate these comparisons for specific patient subpopulations by genetic alterations, co-morbidities and regimen sequence, for which trial participation may have been beneficial. Based on the population-average findings, however, we expect any improvement in survival to be modest. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Orsenix: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Celgene Corporation: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Otsuka: Consultancy; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Cellectis: Research Funding. Nazha:MEI: Consultancy. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

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Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A Large Single-Center Experience: Analysis of Clinical and Molecular Characteristics and Patient Outcomes

Blood ◽

10.1182/blood.v126.23.3746.3746 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3746-3746 ◽

Cited By ~ 5

Author(s):

Naveen Pemmaraju ◽

Hagop M. Kantarjian ◽

Jorge E. Cortes ◽

Madeleine Duvic ◽

Joseph D Khoury ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Dendritic Cell ◽

Board Of Directors ◽

Research Funding ◽

Plasmacytoid Dendritic Cell ◽

Cell Transplant ◽

Advisory Committees ◽

Significant Difference ◽

Cell Neoplasm

Abstract Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with heterogeneous clinical presentation and no available standard therapy. Little is known about the clinical characteristics, molecular characterization, and outcomes of patients (pts) with BPDCN. Methods: We conducted a retrospective review of pts age ≥18 years with a confirmed pathological diagnosis of BPDCN. Results: 37 pts evaluated at our institution between October 1998-June 2015 were identified. Table 1 shows baseline pt characteristics. Bone marrow (BM) was involved in 23 (62%), skin in 26(70%), lymph nodes in 11(30%), central spinal fluid (CSF) in 3 (8%) and 1 (3%) pt each had disease involving brain, uterus/ovary, elbow/soft tissue, and pleural fluid. Tumor immunophenotype demonstrated: CD4+ (31/32), CD56+ (29/32), TCL-1+ (19/21), CD 123+ (22/23). Additionally, CD22 was expressed in 3/9 pts. Frontline therapies received: 19 (51%) HCVAD; 5 (14%) CHOP, 5 (14%) clinical trials, 2 (5%) bortezomib-based, 1 AML induction with daunorubicin+ARAC, 1 oral MTX, 1 IFN-based therapy, 3 other regimens. 5 (14%) pts received radiation (XRT) as part of their therapy. Median follow-up time was 7 months [1-27 mo]. Median number of chemotherapy regimens was 1 [1-6]. Complete remission (CR1) (by standard AML criteria) was achieved in 19 pts (51%) with a median CR1 duration of 19 mo [1-39 mo]. Median overall survival (OS) was 23 mo [6-45 mo]. 23 (69%) pts died, the most common cause of death being multi-organ failure. Among 14 (38%) pts without BM involvement at diagnosis, all 14 had skin involvement. Comparison of pts with BM involvement versus skin-only showed no difference in outcomes. For pts with BM disease, median OS and median CR1 were 23 mo [1-45 mo] and 21 mo [1-39 mo], respectively. For pts with skin-only disease,median OS and median CR1 were 18 mo [1-31 mo] and 19 mo [1-23 mo], respectively, p =0.43 (OS), p=0.78 (CR1). 10 pts (27%) received stem cell transplant (SCT) [7 allogeneic (including 3 cord blood) and 3 autologous). The median OS for pts receiving SCT (n=10) was 18 mo [8-40 mo] versus 23 mo [1-45] for non-SCT group (n=27), p = 0.98. 19 pts (51%) received HCVAD as part of first-line therapy: median OS was 18 mo [1-45 mo] and median CR1: 21 mo [1-39 mo]. Out of 16 pts evaluable for response, 15 achieved CR1; 1 pt died at day 15 (pneumonia). A clinically validated 28-gene molecular panel (next-generation sequencing for commonly mutated genes in myeloid malignancies) is now being performed prospectively on all new pts with BPDCN seen at our institution (thus far, n=9); notably, all 9 have expressed some form of TET2 mutation [ordered mutations=3(c.1648C>T p.R550; c.3781C>T p.R1261C; c.4365del p.M1456fs*2)], ordered+variant=2,variants=4], confirming our earlier finding of occurrence of TET2 mutations in pts with BPDCN (Alayed K, et al Am J Hematol 2013). Thus far, there has been no statistically significant difference in terms of response rates in pts with known TET2 mutations/variants (n=9) vs all others/not done (n=26). Conclusions: Among patients with BPDCN, we observed an older, male predominance, a high incidence of TET2 mutations and, despite intensive chemotherapy and achievement of CR1 in many pts, most still experience relapse and short survival. Therefore, there is an urgent need for novel therapies. Therapies targeting cell surface CD123 and CD56, are available in 2 separate clinical trials at our institution: SL-401 (DT-IL3), which demonstrated 7/9 (78%) major responses including 5 CR, after a single cycle of therapy, (Frankel et al, Blood 2014) is currently being tested in an ongoing multicenter phase I/II trial (Stemline Therapeutics Inc, ClinicalTrials.gov Identifier: NCT02113982, refer to separate abstract ASH 2015) and Lorvotuzumab Mertansine (ImmunoGen, Inc), an antibody-drug conjugate targeting CD56 (ClinicalTrials.gov Identifier: NCT02420873), is in an ongoing ph II trial in CD56-expressing hematologic malignancies, including BPDCN. Table 1. Baseline characteristics (N = 37) Characteristic N (%) / [range] Median age, years 62[20 - 86] Male 33 (89) Median WBC x 109/L 5.9 [1.7-76.5] Median Hemoglobin g/dL 12.9 [6.8-17.1] Median Platelet x 109/L 130 [22-294] Median BM blast 13[0-95] Cytogenetics (n=27)DiploidComplexDeletion 12p13 17 8 1 Miscellaneous 1 28-gene profile (n=9); includes mutations& variantsTET2ASXL1MPLTP53IDH1IDH2 9 3 2 1 1 1 Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Off Label Use: No standard of care available. clinical trial drug therapies/investigation/trial only various cytotoxic chemotherapies used in ALL, AML, other blood cancers. Cortes:BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Duvic:Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding; Cell Medica Ltd: Consultancy; Array Biopharma: Consultancy; Oncoceutics: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Therakos: Research Funding, Speakers Bureau; Huya Bioscience Int'l: Consultancy; MiRagen Therapeutics: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Soligenics: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity's Board of Directors or advisory committees, Research Funding. Daver:ImmunoGen: Other: clinical trial, Research Funding. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Frankel:Stemline: Consultancy, Patents & Royalties, Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

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How Median Follow-up Time Informs Survival Outcomes: Lessons from a Trial of Acute Myeloid Patients Treated with Venetoclax and Azacitidine

Blood ◽

10.1182/blood-2019-126344 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5897-5897

Author(s):

Diana Abbott ◽

Andrew Hammes ◽

Jonathan A Gutman ◽

Daniel A Pollyea ◽

Clayton Smith

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Trial Data ◽

Time To Event ◽

Advisory Committees ◽

Kaplan Meier ◽

The Stability

Background: Follow-up time in clinical trials must leverage conflicting aims. To ensure patient safety, investigators often assess toxicity and efficacy endpoints at various times throughout a trial. Yet accurate analysis requires stable estimates of time-to-event outcomes, which can require longer follow-up than is observed in interim analyses. While median follow-up is routinely reported in clinical trials, the stability of time-to-event estimates and their relationship to follow-up times are rarely discussed. However, the potential follow-up of study participants who are censored in a clinical trial can impact time-to-event estimates (Betensky 2015). Methods: A clinical trial of venetoclax + azacitidine in 33 newly diagnosed older patients with AML was conducted at our institution and is described in detail elsewhere (Pollyea 2018). Trial data consisting of follow-up from January 2015 through February 2018 established promising results (overall response rate = 91%; median response duration, progression-free survival, and overall survival (OS) were not yet reached). Due to ongoing interest in median time-to-event patient outcomes that were not reached and thus could not be reported at the time of publication, the data have been re-analyzed on repeated occasions as follow-up has continued, with OS of particular interest. Median follow-up was calculated using the reverse Kaplan-Meier method. Median OS was calculated using Kaplan-Meier product limit estimates. Analysis of trial data has occurred at 6 different censoring time points: December 4, 2017; February 28, 2018; October 3, 2018; December 31, 2018; March 8, 2019; and May 20, 2019. Upper and lower limits of the Kaplan-Meier OS estimate were calculated to explore the stability of OS estimates over time (Betensky 2015). Analyses were performed using SAS version 9.4 (SAS Institute). Results: Median OS was not reached until analysis was conducted as of October 3, 2018. At this analysis the median OS (1130 days) exceeded the median follow-up time (867 days). This phenomenon also occurred for data censored on December 31, 2018, with the median OS (1130 days) also exceeding the median follow-up time (956 days). In the most recent two analyses of the data (March 8, 2019 and May 20, 2019), the median OS settled at a consistent value (880 days) that did not exceed the median follow-up times (1023 days and 1096 days, respectively). Exploration of the stability of OS estimates revealed that a single patient enrolled early in the study and died after 1130 days of follow-up skewed the median OS estimate upward. Conclusions: Interest in our clinical trial results motivated numerous follow-up analyses of our data. As such, we encountered a peculiar result in which median OS exceeded median follow-up. In investigating the stability of the OS K-M estimates, a single patient's study data was found to skew results in these instances. Removal of this patient's data in these instances (when the relationship between median follow-up and median OS suggest estimate instability) results in a median OS consistent with subsequent analyses at later censoring dates (880 days for the modified analysis). We therefore conclude that time-to-event estimate stability is informative and should be incorporated into survival analysis of clinical trial data. Disclosures Pollyea: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Tapering Eltrombopag in Patients with Chronic ITP: How Successful Is This and in Whom Does It Work?

Blood ◽

10.1182/blood.v126.23.1054.1054 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1054-1054 ◽

Cited By ~ 5

Author(s):

James B. Bussel ◽

Shah N. Mahmud ◽

Sophie L Brigstocke ◽

Sarah M Torneten

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Term Treatment ◽

Bleeding Events ◽

Advisory Committees ◽

Platelet Counts ◽

Need For Treatment ◽

Chronic Itp ◽

Long Term Treatment

Abstract Background: Thrombopoietin receptor agonists (TPO-RA) eg eltrombopag (Epag), are highly effective treatments of ITP as demonstrated in multiple randomized studies. Studies have shown effective and safe long-term use; toxicity appears tolerable with thromboembolism the most common serious adverse event. An important question is if there will be an indefinite long-term need for treatment with these agents once initiated. The aim of this study is to taper eltrombopag in a single arm study to determine how many and which patients will be able to discontinue treatment over time. It specifically targets patients with adequate counts ie 50-100,000/uL, not waiting for patients whose counts spontaneously increase to high levels and thus indicate that they are being over-dosed. Methods: All patients on eltrombopag at doses of 75 mg daily or less for at least 4 months were offered study entry; only one refused. Initially the study tapered Epag rapidly but then changed to slow tapering over up to 2 years. Patients whose platelet counts were >50,000/uL were tapered at 4 week intervals in 10-20% dose increments. Tapering could be postponed for clinical reasons ie impending procedure or trip, infection skewing count, sports or other physical activity, etc. Analysis was descriptive and t test comparisons used to assess variables associated with successful tapering. Results: Patients were divided into 3 groups: 10 responders (those able to discontinue eltrombopag completely within 2 years, fig 1A), 10 tapering (those still tapering who have reduced their medication but not discontinued it, fig 1B), and 12 non-responders (those who tried and failed to discontinue within 2 years). To complete being a responder required >12 weeks without any ITP treatment, platelet count > 30,000/uL and 20,000/uL more than baseline after the last dose of eltrombopag. Eight of the 10 responders have remained off therapy for more than 1 year with platelet counts consistently > 50,000/uL. No medication was provided in the study. No serious AEs occurred and no serious bleeding events were seen. Fig 1a illustrates the discontinuation of eltrombopag treatment in responders: 4 discontinued within 8 weeks while the longest discontinuation required a full 2 years. Fig 1b shows patients who are tapering eltrombopag but have not reached 2 years by indicating how many are on <70% and <40% of their starting doses; it shows that tapering is typically a slow process but that at least dose reduction can be achieved in many patients even if they do not discontinue their eltrombopag. Table 1 compares means and medians of the 3 groups for a number of clinical variables. While the numbers are small and the results preliminary, it surprisingly shows that patients who have been on eltrombopag longer prior to tapering and those who have received more treatments are more likely to successfully discontinue eltrombopag. In contrast, non-responders failed splenectomy and rituximab more often than did those tapering and responders. Finally AIPF at initiation of study did not predict a successful taper. Summary: A substantial fraction of patients with chronic ITP will be able to successfully taper off eltrombopag; the exact number (somewhere between 10 and 20 of the 32 patients) depends upon the group still tapering. The tapering schedule selected is slow and requires regular monitoring and individualization/flexibility. Even if patients do not fully taper off eltrombopag, they may be able to substantially reduce their dose. We speculate that tapering eltrombopag as outlined here may reduce the toxicity and costs of long-term treatment without diminishing hemostatic efficacy. Table 1. Comparison Table (Responders, Tapering, Non-Responders) Responders (n=10) Tapering (n=10) Non-Responders (n=12) Age (years) (median/average) 29/37.4 11/25.70 21/30.58 Gender (m/f) 3/7 6/4 5/7 Duration ITP (years) (median/average) 8.75/11.95 5.5/17.45 7/8.25 Duration of TPO-RA Therapy (years) (median/average) 5/4.2 5.5/7.45 2.5/3.38 # of prior ITP treatments (median/average) 4.5/5.5 2/2.14 3.5/3.83 # of patients with previous splenectomy 4 0 6 patients with previous Rituximab treatments 5 4 9 Baseline AIPF (tapering counts) (*10E2/uL) (median/average) 81.75/75.5 63/57.43 75/69 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Bussel: Immunomedics: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; BiologicTx: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Momenta: Membership on an entity's Board of Directors or advisory committees; Symphogen: Membership on an entity's Board of Directors or advisory committees; Protalex: Membership on an entity's Board of Directors or advisory committees.

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Efficacy and Safety of Deferasirox (Exjade®) in Patients with β-Thalassemia Major Treated for up to 5 Years.

Blood ◽

10.1182/blood.v114.22.4063.4063 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4063-4063 ◽

Cited By ~ 4

Author(s):

M. Domenica Cappellini ◽

Silverio Perrotta ◽

Leyla Agaoglu ◽

Yesim Aydinok ◽

Marcello Capra ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Iron Concentration ◽

Term Treatment ◽

Efficacy And Safety ◽

Advisory Committees ◽

Absolute Change ◽

Transfusion Requirements ◽

Long Term Treatment

Abstract Abstract 4063 Poster Board III-998 Background In a large, 1-yr Phase 3 clinical trial, patients (pts) with β-thalassemia (aged ≥2 yrs) were randomized to receive deferasirox (Exjade®) or deferoxamine (DFO), with doses assigned according to baseline liver iron concentration (LIC). Pts completing the 1-yr core were permitted to enter a 4-yr extension; those receiving deferasirox continued on this therapy (deferasirox cohort), while those receiving DFO crossed over to deferasirox (crossover cohort). This analysis evaluates the efficacy and safety of deferasirox over 5 yrs. Methods Based on analyses showing that iron burden and transfusional iron intake need to be considered for appropriate dosing of deferasirox, dose adjustments were permitted in the extension to ensure optimal dosing. Deferasirox dose in the extension was initially based on dose response in the core (deferasirox cohort only) and end-of-core LIC (biopsy or SQUID); subsequent adjustments in steps of 5–10 mg/kg/day were based on serum ferritin (SF) levels and safety markers. Efficacy was assessed by monthly SF levels and LIC at baseline, end of 1-year core and end of study (EOS) (or upon discontinuation). Safety was assessed by incidence and type of adverse events (AEs) and changes in laboratory parameters. Results 296 pts (deferasirox cohort) and 259 pts (crossover cohort) received ≥1 dose of deferasirox; 181 (61%) & 190 (73%) pts from each cohort respectively completed the extension. Most common reasons for discontinuation: consent withdrawal (n=62) and AEs (n=43). Most common AEs leading to discontinuation: increased ALT [n=5], increased transaminases [n=4], glycosuria [n=4]. 2 deaths occurred during the extension in the deferasirox cohort (cardiac failure, cardiomyopathy); 2 in the crossover cohort (cardio-respiratory arrest, road traffic accident); none considered to be related to study drug. Median duration of deferasirox treatment was 61.2 & 48.1 mths in deferasirox & crossover cohorts, respectively. At start of deferasirox, mean LIC was 14.0 ± 9.8 & 10.4 ± 7.6 mg Fe/g dry weight (dw) and median SF was 2211 & 1758 ng/mL in deferasirox and crossover cohorts, respectively. Transfusion requirements at start of deferasirox were comparable; most pts (81% & 83%, respectively) receiving 7–14 mL/kg/mth. Mean deferasirox dose during study: 21.6 ± 6.4 & 23.2 ± 5.9 mg/kg/d (final actual dose: 24.4 ± 8.7 & 27.0 ± 8.0 mg/kg/d) in deferasirox and crossover groups, respectively. Most pts were receiving 15–<35 mg/kg/day at EOS (75% & 78%, respectively); 11% & 17% were receiving ≥35 mg/kg/day. In pts who received at least 5 yrs of deferasirox and at least 4 yrs in the crossover group, mean absolute change in LIC were –5.3 ± 10.1 mg Fe/g dw (n=173; P<0.001) & –2.4 ± 7.6 mg Fe/g dw (n=99; P<0.001) and median absolute change in SF were –775 ng/mL (range: –10164–2572; n=182; P<0.001) & –371 ng/mL (range: –4498–2636; n=151; P<0.001), respectively (Figure). Percentage of pts with LIC<7 mg Fe/g dw increased from 35% to 45% & SF≤1000 ng/mL increased from 12% to 33% from the start of deferasirox to EOS (LIC: EOS, last available value; SF: EOS, average of at most 3 available values after start of deferasirox). Most common drug-related AEs (≥5% overall) after start of deferasirox in deferasirox & crossover cohort, respectively: increased blood creatinine (n=42, 14%; n=20, 8%), nausea (n=28, 10%; n=13, 5%), vomiting (n=18, 6%; n=17, 7%), diarrhea (n=13, 4%; n=15, 6%) & rash (n=17, 6%; n=19, 7%). Frequency of drug-related AEs decreased from year to year. In deferasirox & crossover cohorts, 26 (9%) & 11 (4%) pts had 2 consecutive serum creatinine increases >33% above baseline & upper limit of normal (ULN) & 3 (1%) & 2 (1%) pts had ALT >10 x ULN on 2 consecutive visits, respectively, after start of deferasirox. Conclusions Long-term treatment with deferasirox (for up to 5 yrs) significantly decreased iron burden in β-thalassemia pts aged ≥2 yrs with an increasing percentage of pts achieving therapeutic goals of LIC<7 mg Fe/g dw and SF≤1000 ng/mL. Significant improvements in LIC and SF were also observed after switching from DFO. Deferasirox was well tolerated over this long-term treatment, and the frequency of AEs decreased over time. Disclosures: Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Perrotta:Novartis: Consultancy, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Piga:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Griffel:Novartis Pharmaceuticals: Employment, Equity Ownership. Lagrone:Novartis Pharmaceuticals: Employment. Clark:Novartis Pharma AG: Employment. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau.

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Long Term Safety and Efficacy of Sustained Eculizumab Treatment In Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood.v116.21.4237.4237 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4237-4237 ◽

Cited By ~ 4

Author(s):

Robert A Brodsky ◽

Carlos de Castro ◽

Hubert Schrezenmeier ◽

Antonio M. Risitano ◽

Joerg Schubert ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Term Treatment ◽

Advisory Committees ◽

Serious Infections ◽

Long Term Treatment ◽

History Of ◽

Terminal Complement

Abstract Abstract 4237 PNH is a chronic, life-threatening, acquired disease associated with deficiency of GPI-anchored complement inhibitory proteins on blood cells. The resulting defective regulation of terminal complement activation is responsible for hemolysis and can lead to thromboembolism (TE), chronic kidney disease (CKD) and pulmonary hypertension. The risk of TE is high, with an observed 6.24 venous TE events per 100 patient years, or approximately 62-fold higher compared to the general population: in fact, TE accounts for 40–67% of PNH related deaths. The effectiveness of anticoagulation (AC) in PNH patients (pts) is uncertain, as AC treated PNH may still experience TE. The terminal complement inhibitor eculizumab reduces intravascular hemolysis rapidly and significantly; it also leads to a reduction in TE events, pulmonary hypertension and improvements in CKD and quality of life. Here, we report on prolonged treatment of PNH patients with eculizumab for safety and sustained patient outcomes. Methods: All pts (N=195) in the PNH eculizumab clinical trials (Pilot (N=11), TRIUMPH (N=87) and SHEPHERD (N=97)) and subsequent Extension studies were assessed for long term safety and efficacy. Median age was 40 yrs, 54% female, 29% had a history of aplastic anemia and 1.5% with history of myelodysplasia. TE was reported in 32% (63/195) of pts prior to eculizumab treatment. There was high adherence to long term treatment; 90% (175/195) of pts completed the parent and extension trials. Results: The median eculizumab treatment duration was 29 mo (1 -66; IQR:23-32m); with a total eculizumab exposure of 474.1 patient-years. Intravascular hemolysis was rapidly reduced in 100% of pts after eculizumab treatment. LDH was reduced from a median of 2,133 U/L (∼10x ULN) at baseline to 310 U/L at 1 month of treatment (P<0.0001) and was sustained at 272U/L at 36 months (P<0.0001). There was an 81% (P<0.0005) reduction in TE events from 52 pre treatment events to 10 trial events using a match time analysis (P<0.0005). Of the 7 (7/195) pts who experienced a TE on drug, 5 had a history of TE and 2 were concomitantly treated with AC. Of pts treated with AC, 59% (58/98) experienced at least 1 TE prior to treatment. In 11 pts who discontinued AC, there were no TE reported with eculizumab treatment during or following AC discontinuation. Prevalence of CKD was reduced from 69% of pts at baseline to 31% (n=29) after 36 months of treatment, consistent with previous results. A fraction of pts still require blood transfusions and a fraction of pts, even without need for blood transfusions, had no significant increase (>1gm/dL) in steady state hemoglobin level over baseline. Eculizumab was well tolerated. Twenty pts (∼10%) did not complete the trial including 9 pts following a reported adverse event (AE). In 16 week follow-up to the 20 pts who discontinued eculizumab treatment, TE was reported in 3 pts, including 1 death. Most AEs (95%) were mild or moderate in severity and 90.8% of adverse events were deemed unrelated to study drug. Frequent AEs were: nasopharyngitis, (40%); headache (37%) and upper respiratory tract infection, (31%). There were 2 cases of meningococcal sepsis and both were successfully treated without sequelae. Serious infections were reported in 21% of pts and 2 pts discontinued therapy due to infections (meningococcal, staphylococcal sepsis: both resolved). Most commonly reported serious infections included pyrexia (4.6%) and viral (3.1%), lower respiratory tract (1.5%) and urinary tract (1.5%) infections. There were 4 patient deaths during treatment. Three deaths were considered not related to study drug and 1 possibly related to study drug by the investigator. Causes of death were progression from myelodysplasia to chronic myelomonocytic leukemia, adenoma progressing to adenocarcinoma, brain herniation following trauma injury, and TE of the small bowel. Conclusion: Long term treatment of PNH pts with eculizumab is associated with a favorable benefit/risk ratio and the clinical benefits demonstrated at earlier timepoints are sustained over 36 months. Improvement in TE and CKD was maintained over 36 months when compared to baseline and previous published data. Considering that thrombosis and CKD have been demonstrated to be significant causes of death in PNH, it is reasonable to expect that eculizumab treatment, by decreasing the risk of thrombosis and improving renal function, may increase the life expectancy of PNH pts. Disclosures: Brodsky: Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion Pharmaceuticals, Inc: Speakers Bureau. Schrezenmeier:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schubert:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria. Maciejewski:Alexion Pharmaceuticals, Inc: Consultancy. Duehrsen:Alexion Pharmaceuticals, Inc: Honoraria, Research Funding. Luzzatto:Alexion Pharmaceuticals, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees. Muus:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding. Szer:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Socié:Alexion Pharmaceuticals, Inc: Consultancy. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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