scholarly journals Role of hnRNP K and Interacting mRNAs in Pathogenesis of AML with 9q Deletion

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1531-1531
Author(s):  
Kerstin Rahn ◽  
Isabel Naarmann-de Vries ◽  
Yvonne Sackmann ◽  
Felicitas Klein ◽  
Antje Ostareck-Lederer ◽  
...  
Keyword(s):  
Research Funding ◽  
Transcriptional Control ◽  
Mrna Level ◽  
Rna Seq ◽  
Employment Equity ◽  
Knock Out ◽  
Hnrnp K ◽  
Qpcr Analysis ◽  
Equity Ownership ◽  
The Impact

Abstract Introduction: Acute myeloid leukemia (AML) is characterized by heterogeneous cytogenetic and molecular aberrations. Deletions on the long arm of chromosome 9 (del(9q)) are observed in 2% of AML patients. In about 24% of the cases, del(9q) is observed as sole karyotypic abnormality, while in the remaining 76%, it is associated with a t(8;21) translocation or other aberrations. Among all del(9q) AML cases, 36%-50% exhibit an additional t(8;21), whereas 7%-14% of AML cases with t(8;21) show del(9q) as an additional aberration. A commonly deleted region (CDR) of del(9q) was defined and further analysis specified a minimally deleted region (MDR) composed of seven annotated genes (GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2) (Kronke J et al. Blood. 2013). However, the function of these genes and their impact on the pathogenesis of AML remain elusive. A recent study demonstrated that reduced expression of the HNRNPK gene product can contribute to leukemogenesis in AML (Gallardo M, Cancer Cell. 2015). The multifunctional protein hnRNP K interacts with other proteins, DNA and RNA, to modulate gene activity and gene expression on different levels. For example, hnRNP K not only regulates SRC gene transcription, but as well SRC mRNA translation and the activity of c-Src kinase. In the context of AML, hnRNP K was shown to interact with the mRNAs encoding C/EBPa (CEBPA) and p21 (CDKN1A). We analyzed a cohort of 31 del(9q) AML patients in order to further analyze the deleted region and to analyze the impact of HNRNPK deletion on leukemogenesis. Methods: 31 del(9q) patients were used for the characterization of the deleted region. mRNA level (determined by RT-qPCR analysis) and clinical parameters were compared with a cohort of 24 normal karyotype (NK) AML patients. HnRNP K immunoprecipitation was combined with RNA-Seq, a whole transcriptome shotgun sequencing application based on next generation sequencing and validated by RT-qPCR analysis. CRISPR-Cas9 genome editing has been applied to functionally characterize the impact of post-transcriptional control by hnRNP K in pathogenesis of AML. Results: Our analysis confirmed the MDR in a cohort of 31 AML del(9q) patients. Survival of patients and clinical parameters were not correlated with deletion size, further supporting the importance of the MDR, while other deleted genes seem to be less important for leukemogenesis. As demonstrated by qPCR analysis, the mRNA level of HNRNPK and other genes located in the MDR was reduced in patients carrying a del(9q) compared to NK patients. To further dissect a potential function of hnRNP K in AML del(9q), we characterized hnRNP K interacting mRNAs in the AML cell line KG-1a. Therefore, hnRNP K was immunoprecipitated from cytoplasmic extracts of KG-1a cells and interacting RNAs were identified by RNA-Seq analysis. This analysis revealed that 1076 RNAs are potentially associated with hnRNP K, among them the C/EBPa mRNA. Panther Protein Class analysis identified a high number of transcripts encoding nucleic acid binding proteins, mainly transcription factors. KG-1a cell lines harboring either a complete knock out of hnRNP K or a deletion of the RNA-binding KH-domain are currently generated by CRISPR-Cas9 genome editing to functionally analyze the impact of hnRNP K-mediated post-transcriptional control in AML. Conclusion and Outlook: The deletion of seven genes (GKAP1, KIF27, C9ORF64, HNRNPK, RMI1, SLC28A3 and NTRK2) in the MDR is indispensable, indicating a crucial function for the development of AML del(9q). Among them HNRNPK seems to be a particularly important factor in this process. The identification of hnRNP K interacting RNAs provides the basis to further improve our insight in molecular mechanisms, which drive the pathogenesis of AML del(9q). HNRNPK knock out cell lines will be used to analyze the effect of HNRNPK deletion on post-transcriptional control of identified target genes. Disclosures Ehninger: Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy. Rollig:Janssen: Research Funding; Bayer: Research Funding. Thiede:Novartis: Honoraria, Research Funding; AgenDix: Other: Ownership.

Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4591-4591 ◽  
Author(s):  
Chris L. Pashos ◽  
Christopher R Flowers ◽  
Mark Weiss ◽  
Nicole Lamanna ◽  
Charles M Farber ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Performance Status ◽  
Clinical Practices ◽  
Employment Equity ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Ecog Ps ◽  
The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4248-4248 ◽  
Author(s):  
Uwe Platzbecker ◽  
David P. Steensma ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Phase 2 ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Equity Ownership ◽  
The Impact ◽  
Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

Age Differences in Disease Characteristics, Patterns of Care, and Outcomes of Follicular Lymphoma (FL) in the United States (US): Report From the National Lymphocare Study (NLCS)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3708-3708
Author(s):  
Chadi Nabhan ◽  
Michelle Byrtek ◽  
Shadi Latta ◽  
Keith L Dawson ◽  
Xiaolei Zhou ◽  
...  
Keyword(s):  
Research Funding ◽  
Age Groups ◽  
Age Group ◽  
Employment Equity ◽  
Disease Characteristics ◽  
Baseline Factors ◽  
Equity Ownership ◽  
Grade 3 ◽  
The Impact ◽  
To Receive

Abstract Abstract 3708 Background: There are few prospective studies on disease characteristics, patterns of care, response, and outcomes in elderly FL patients (pts) in the US. The NLCS is a Genentech-sponsored prospective multicenter registry study that collects this information without study-specific treatment. We utilized the NLCS database to better understand the impact of age on FL outcome. Patients and Methods: All evaluable pts with FL histology in the NLCS were included except pts with FL plus other lymphoma histology or pts who progressed before first treatment or before being assigned to watchful waiting (WW). Using Pearson Chi-Square tests, associations of age groups (≤60, 61–70, >70) with disease characteristics and overall response (ORR) were examined. Median PFS and OS by treatment regimen were estimated using Kaplan-Meier methods for each age group. Cox proportional hazards regression adjusted for baseline factors (grade, number of nodal sites, LDH, Hgb, stage, performance status (PS), bone marrow (BM) involvement, race, and treatment center type) were used to assess treatment differences in PFS and OS and the significance of age by treatment interactions. Results: Of 2,647 pts, 47% (n=1,254) were ≤60 yrs, 25% (n=666) were 61–70 yrs, and 27% (n=727) were >70 yrs (min age of 22; max of 97). Compared with pts ≤60 yrs, pts 61–70 and >70 were more likely to be white (93% >70, 92% 61–70, and 88% ≤60, P=.02 and .02 respectively), have stage I/II disease (37% >70, 36% 61–70, and 29% ≤60, P=.0008 and .0003), have <5 nodal sites (73% >70, 69% 61–70, and 61% ≤60, P=.001 and <.0001), and have poor-risk FLIPI (53% >70, 51% 61–70, and 15% ≤60, P<.0001 and <.0001). Compared with pts ≤60, elderly pts (>70) were more likely to have FL grade 3 (24% vs 18%, P=.01). While there were no differences in geographic distribution by age, elderly pts were more likely to receive therapy at community practices (86%) versus academic institutions than pts ≤60 (77%, P<.0001) or 61–70 (81%, P=.004). Treatments varied significantly by age (P<.0001). More elderly pts were observed compared to pts ≤60 (23% vs19%). When treated, elderly pts (22%) were more likely to receive rituximab (R) monotherapy compared with patients aged 61–70 (12%) or ≤60 (10%). When chemotherapy alone or plus R was given, elderly pts were less likely to receive anthracyclines (45% vs 65% (61–70) and 68% (≤60)). Among all variables, only grade 3 histology predicted anthracycline use in all age groups. Lack of BM involvement predicted anthracycline use for younger pts (≤60 and 61–70). Of those ≤60, white pts were more likely to receive anthracyclines, and of those 61–70, those with ≥5 nodal sites were more likely to receive anthracyclines. ORRs were similar across age groups receiving similar regimens with R plus chemo providing the highest ORR. Adjusting for baseline factors, treatment (WW, R, R-Chemo, or other) benefit varied for each age group in terms of PFS (P=.02), with treatment outcomes being most differentiated among younger pts (Table). PFS appeared shorter in elderly pts regardless of the treatment received. No significant interaction between age and efficacy of anthracycline in terms of PFS or OS was observed (P-values >.65), but the overall effect of anthracycline for all pts was beneficial for PFS (HR=0.80, P=.02) and OS (HR=0.67, P=.003). Median OS was 8 years for elderly and not reached for others. After adjusting for baseline factors, no significant differences in treatment impact by age on OS were seen. Elevated LDH, reduced Hgb, stage III/IV, PS ≥1, and BM involvement were all significantly associated with shortened OS. These factors were also significantly associated with treatment choice, as worse-prognosis elderly pts were more likely to receive either R or R+chemo than WW or other treatment. Conclusions: FL pts >70 yrs more commonly received R alone and less commonly received anthracyclines when treated with chemotherapy. The impact of anthracyclines on PFS did not vary by age, but differences in PFS for other treatment regimens showed a stronger association among younger pts Disclosures: Nabhan: Genentech: Research Funding, Speakers Bureau. Byrtek:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Dawson:Genentech, Inc., a member of the Riche Group: Employment, Equity Ownership. Link:Genentech, Inc., a member of the Riche Group: Consultancy; Celgene: Consultancy; Spectrum: Consultancy. Friedberg:Genentech: Consultancy. Cerhan:Genentech: National LymphoCare Scientific Advisory Board Other. Flowers:Celgene: Consultancy; Prescription Solutions: Consultancy; Seattle Genetics: Consultancy; Millennium: Consultancy, Research Funding; Genentech: Consultancy; GIlead: Research Funding; Spectrum: Research Funding; Janssen: Research Funding; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees.

Safety and Efficacy of Venetoclax (ABT-199/GDC-0199) Monotherapy for Relapsed/Refractory Multiple Myeloma: Phase 1 Preliminary Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4219-4219 ◽  
Author(s):  
Shaji K. Kumar ◽  
Ravi Vij ◽  
Jonathan L. Kaufman ◽  
Joseph R. Mikhael ◽  
Thierry Facon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Abdominal Pain ◽  
Research Funding ◽  
Phase 1 ◽  
Cell Transplant ◽  
Brain Hemorrhage ◽  
Employment Equity ◽  
Equity Ownership ◽  
Upper Abdominal ◽  
The Impact

Abstract Background: The anti-apoptotic protein BCL-2 has been implicated in mediating the survival of multiple myeloma (MM) cells. Venetoclax is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Venetoclax induces cell death in MM cell lines in vitro and primary MM samples ex vivo. Certain genetic subtypes of MM cells are particularly sensitive to venetoclax, including t(11;14) cells, which express a high ratio of BCL2 to MCL1 (venetoclax resistance factor). The current Phase 1 study evaluates safety, efficacy, and pharmacokinetics (PK) in patients (pts) with relapsed/refractory MM. Methods: Primary objectives are to evaluate safety, PK, and recommended phase two dose; other objectives include assessing preliminary efficacy and the impact of chromosomal abnormalities. In dose-escalation (DE) cohorts, venetoclax was given orally daily at 300, 600, 900, or 1200 mg after a 2-week dose ramp-up (3+3 design). Patients in the safety expansion (SE) cohort received 1200 mg daily after ramp-up. All patients were monitored for tumor lysis syndrome (TLS). Results: As of June 17, 2015, 37 patients were enrolled in the study: 30 from DE cohorts and 7 from the SE. Median (range) age was 66 years; 19 (51%) were female. Fourteen were ISS stage I, 13 stage II, 8 stage III, 2 unknown. The median (range) number of prior lines of therapy was 6 (1-19). Thirty-two had prior bortezomib (20 refractory), 35 lenalidomide (18 refractory), and 26 had prior stem cell transplant. Fourteen patients had t(11;14), 4 had t(4;14), 5 had del 17p, and 17 had del 13q. Adverse events (AEs) in ≥20% of patients were nausea (49%), diarrhea (38%), vomiting (30%), anemia (27%), fatigue (24%). Grade 3/4 AEs (≥10%): thrombocytopenia (22%), anemia (19%), neutropenia (11 %). Serious AEs (≥2 patients): pyrexia (n=3), cough, malignant neoplasm progression, and sepsis (2 each); 2 (upper abdominal pain and anemia) were possibly related to venetoclax. Thirty (81%) patients have discontinued venetoclax: 24 due to PD, 3 for AEs (worsening shortness of breath, hypokalemia, and nausea), 2 withdrew consent, 1 due to death (brain hemorrhage following injury). Four deaths occurred (2 due to PD, 1 due to brain hemorrhage, 1 due to pneumopathy). Two of the 6 patients in the 600 mg cohort experienced DLTs of upper abdominal pain and nausea with abdominal pain. No patients met the criteria for laboratory or clinical TLS. Based on preliminary PK (n=21), the mean Cmax and AUC24 were ~dose-proportional at all studied doses (300, 600, 1200 mg) except 900 mg, and dose-normalized venetoclax exposure in MM was similar to that in CLL and NHL pts. Thirty-two of the 37 patients were evaluable for preliminary efficacy (Table). Two patients, both t(11;14), achieved a complete response (1 at 600 mg and 1 at 900 mg). Responses were first achieved at 1.8 and 1.1 months and were maintained for 9.7 and 9.0 months, respectively (900 mg pt remains in CR). Among the 16 patients receiving 1200 mg in the DE or SE cohort, 6 of whom had t(11;14), 5 achieved SD, 6 experienced PD, and 5 are not yet evaluable. Conclusions: Venetoclax monotherapy had a tolerable safety profile in heavily-pretreated relapsed/refractory MM, and no new safety signals were observed compared to other venetoclax studies. The study continues to enroll in the SE cohort at 1200 mg. Responses (including CR) and longer time on venetoclax were observed in t(11;14) patients. These early results suggest that venetoclax has single agent activity, most prominently in t(11;14) patients. Figure 1. Figure 1. Disclosures Kumar: Celgene: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Vij:Takeda, Onyx: Research Funding; Celgene, Onyx, Takeda, Novartis, BMS, Sanofi, Janssen, Merck: Consultancy. Kaufman:Janssen: Consultancy; Spectrum: Consultancy; Merck: Research Funding; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Onyx: Research Funding. Mikhael:Sanofi: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Onyx: Research Funding. Moreau:Takeda: Other: Adboard; Janssen: Other: Adboard; Celgene: Other: Adboard; Novartis: Other: Adboard; Amgen: Other: Adboard. Alzate:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Touzeau:AbbVie: Research Funding.

The Effect of Ruxolitinib on White Blood Cell Counts in Patients with Polycythemia Vera: Results from the RESPONSE Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4070-4070 ◽  
Author(s):  
Carole B. Miller ◽  
Jean-Jacques Kiladjian ◽  
Martin Griesshammer ◽  
Ahmad B. Naim ◽  
William Sun ◽  
...  
Keyword(s):  
Blood Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Thromboembolic Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
The Impact ◽  
Over Time ◽  
Response Trial

Abstract Background: Age, prior thrombotic events, and an elevated hematocrit are established risk factors for increased risk of thrombosis in patients with polycythemia vera (PV). Evidence also suggests that elevated white blood cell (WBC) counts ≥ 11×109/L are a significant independent risk factor for thrombosis in patients with PV (P =0.02; Barbui T, et al. Blood. 2015; 126:560-561). Therefore, this analysis was conducted to evaluate the impact of ruxolitinib (Rux) and best available therapy (BAT) treatment on WBC counts among patients with Baseline WBC counts ≥ 11×109/L in the RESPONSE trial. RESPONSE is a global, multicenter, open-label phase 3 trial investigating Rux and BAT in patients with PV who are resistant to or intolerant of hydroxyurea (HU). In the RESPONSE trial, Rux was associated with durable improvements in hematocrit control without phlebotomy compared with BAT as well as reductions in WBC counts. Methods: Changes from Baseline in WBC counts in the Rux arm (n=110), BAT arm (n=112), and HU subgroup of the BAT arm (n=66) were evaluated as part of an exploratory analysis using the RESPONSE 80-Week analysis dataset. Patient subgroups with Baseline WBC counts ≥ 11×109/L and < 11×109/L were analyzed for changes in WBC counts at Weeks 12, 32, and 80. For patients with Baseline WBC counts ≥ 11×109/L, the proportion of patients who achieved a decrease in WBC counts to ≤ 10×109/L or a ≥50% reduction at Week 12 and Week 32, respectively, was summarized; time to achieve the decrease was analyzed by Kaplan-Meier method. Results: Baseline mean WBC counts were generally similar among patients in the Rux arm, BAT arm, and HU subgroup (17.6×109/L, 19.0×109/L, and 17.4×109/L, respectively). The proportion of patients with Baseline WBC counts ≥ 11×109/L was also similar among the Rux arm, BAT arm, and HU subgroup (75%, 71%, and 70%, respectively). In patients with Baseline WBC counts ≥ 11×109/L, patients treated with Rux had greater mean reductions in WBC counts compared with the BAT arm and HU subgroups, and these reductions were maintained over time; mean changes from Baseline in WBC values at Week 12/Week 32 (×109/L) were -7.7/-7.2 for Rux, -3.2/-4.2 for BAT, and -1.2/-2.2 for HU. In patients with lower Baseline WBC counts, mean values remained stable over time. The change from Baseline to Week 12 for individual patients with Baseline WBC counts ≥ 11×109/L is shown in Figure 1. In patients with Baseline WBC counts ≥ 11×109/L, worsening WBC counts were observed in 10.8% of patients in the Rux arm vs 35.4% in the BAT arm (P =0.0002) and 47.8% in the HU subgroup (P <0.0001). In this same subgroup with elevated WBC counts, a greater proportion of patients in the Rux arm achieved WBC counts ≤ 10×109/L or a ≥50% reduction compared with the BAT arm or HU subgroup (Week 12: Rux, 41% vs BAT, 19% vs HU, 13%; Week 32: Rux, 45% vs BAT, 22% vs HU, 9%); median time to this reduction was 8 weeks in the Rux arm and was not reached in the BAT arm or HU subgroup. Conclusion: Rux treatment resulted in better control of WBC counts compared to BAT in patients with PV. These changes in the Rux arm occurred early after study initiation (within a median of 8 weeks) and were durable over time. Although RESPONSE was not powered to assess the impact of Rux on thromboembolic events, the lower rate of thromboembolic events observed in the Rux arm vs the BAT arm (1.8 vs 8.2 per 100 patient-years of exposure) is consistent with the observed effects of Rux on hematocrit, WBC counts, and C-reactive protein levels, which are all associated with thromboembolic risk. Disclosures Miller: Incyte Corporation: Honoraria, Research Funding. Kiladjian:Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy; Novartis: Consultancy. Naim:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Gadbaw:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau.

scholarly journals The Irish Personalized Approach to the Treatment of Haemophilia (iPATH) - Determinants of Inter-Individual Variation in FVIII Pharmacokinetics

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1190-1190
Author(s):  
Michelle Lavin ◽  
Niamh Larkin ◽  
Anjali Patel ◽  
Evelyn Singleton ◽  
Mary Byrne ◽  
...  
Keyword(s):  
Bayesian Analysis ◽  
Blood Group ◽  
Research Funding ◽  
Clinical Phenotype ◽  
Employment Equity ◽  
Limited Sampling ◽  
Bleeding Episodes ◽  
Equity Ownership ◽  
The Impact ◽  
Antihemophilic Factor

Abstract Introduction: Standard factor VIII (FVIII) prophylaxis aims to minimise bleeding episodes in people with haemophilia A (PWHA) using a weight based dosing strategy. However, it is well recognised that FVIII half-life (FVIII t1/2) varies markedly between individual PWHA. Consequently, some PWHA continue to experience repeated bleeding episodes even after commencing standard dose prophylaxis therapy. In essence, these patients 'bleed their way' to eventually reaching their required optimal FVIII prophylactic regimen. Given that even a small number of joint bleeds have been shown to represent a risk factor for hemophilic arthropathy, there is a clear unmet need for the development of personalised treatment approaches for PWHA that include consideration of individual FVIII pharmacokinetics (PK) to guide prophylaxis dosing. With the introduction of limited plasma FVIII sampling and Bayesian analysis, evaluation of FVIII pharmacokinetics (PK) are now possible in routine clinical practice. However, real life clinical experience to date has been limited to small cohorts of PWHA. Critically, the influence of PK in modulating clinical phenotype has not been systematically studied. As part of the Irish Personalised Approach to the Treatment of Haemophilia (iPATH) study, we integrated extensive clinical data and individual PK profiles to investigate modulators of FVIII PK, the role of limited versus extended sampling FVIII PK and the impact of PK on FVIII prophylaxis and clinical phenotype. Methods: Written informed consent was obtained prior to recruitment to the iPATH study. All PK samples were obtained following administration of a single rFVIII product (antihemophilic factor [recombinant]; ADVATE®, Shire, Lexington, MA, USA) and using myPKFiT™ software (Shire, Lexington, MA, USA). Utilising limited sampling (2 timed FVIII:C levels, taken at 3‒6 and 24‒32 hours post rFVIII administration) and Bayesian analysis, PK curves were constructed using myPKFiT™. For each individual the FVIII t1/2, Von Willebrand Factor antigen (VWF:Ag), blood group, weight, age at PK and Haemophilia Joint Health Score (HJHS) was recorded. rFVIII prescribed over the preceding 5 years was analysed; all patients used antihemophilic factor (recombinant) throughout this time period. Mann-Whitney analyses were used for non-parametric comparisons and correlations were performed using the Pearson test on Prism 7.0c for Mac OSX. Results: Complete PK profiles were available for 53 patients with FVIII deficiency recruited to the iPATH study (3 moderate, 50 severe FVIII deficiency). FVIII t1/2 varied considerably, ranging from 7.7‒20.1 hours (median=11.4 hours). Patients with blood group O had a significantly shorter FVIII t1/2 (n=31, median=10.9 hours) than non-O patients (n=22, median=12.2 hours, p=0.014). Both increased age (r2=0.2932, p<0.0001) and higher plasma VWF:Ag levels (r2=0.3, p<0.0001) at time of PK were associated with a significantly longer FVIII t1/2. HJHS significantly increased with age (r2=0.494, p<0.0001) but no significant correlation between FVIII t1/2 and HJHS was observed, likely reflecting the multifactorial nature of arthropathy in PWHA. In a subset of 10 PWHA we compared the FVIII t1/2 results generated from extended (10 point) to those from limited sampling (2 point) PK. Each limited sampling study included a 24 hour time point as well as either a 3, 4 or 6 hour sample. The 10 point results significantly correlated with limited sampling results using either the 3/24 hour (r2=0.9801, p<0.0001), 4/24 hour (r2=0.9762, p<0.0001) or 6/24 hour sampling combination (r2=0.9693, p<0.0001), underscoring the clinical utility of limited PK sampling. Prior to the introduction of routine PK-guided dosing in 2018, prescribed rFVIII dose was altered according to bleed rate at clinical review. Analysing the prescribed rFVIII dose over the past 5 years, a clear relationship to rFVIII t1/2 was identified (r2=0.3517, p<0.0001), suggesting that bleeding events in PWHA guided them towards their PK dose. Conclusions: This study highlights the accuracy of simplified vs extended sampling for generation of PK profiles on antihemophilic factor (recombinant) using myPKFiT™. Bleed rate adjusted prophylaxis was found to correlate with FVIII t1/2 in an Irish population of PWHA, suggesting that early evaluation of PK and implementation of PK guided dosing of prophylaxis may be of benefit in minimising bleeds in PWHA. Disclosures Lavin: Shire: Honoraria, Research Funding, Speakers Bureau. Reipert:Shire: Employment, Equity Ownership. Pipe:Shire: Consultancy, Research Funding; HEMA Biologics: Consultancy; Pfizer: Consultancy; Nove Nordisk: Consultancy; Bioverativ: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Ainylam: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Apcintex: Consultancy; Catalyst Biosciences: Consultancy; Spark Therapeutics: Consultancy; Freeline: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Biomarin: Consultancy; R2 Diagnostics: Research Funding; Siemens: Research Funding. Turecek:Shire: Employment, Equity Ownership. O'Donnell:Bayer: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Leo Pharma: Speakers Bureau; Octapharma: Speakers Bureau; CSL Behring: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Research Funding; Baxter: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau.

scholarly journals Venetoclax Improves Quality of Life for Patients with Elapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4858-4858 ◽  
Author(s):  
Tara Cochrane ◽  
Tatiana Chagorova ◽  
Tadeusz Robak ◽  
Su-Peng Yeh ◽  
Evgeny Nikitin ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Eortc Qlq ◽  
The Impact

Abstract INTRODUCTION: Patients with chronic lymphocytic leukemia (CLL) have significantly decreased health related quality of life (HRQoL), particularly related to severe and progressive fatigue. Side effects of chemotherapies and the emotional burden of living with an often poor prognosis disease also negatively impact patient HRQoL. Venetoclax, an oral agent that targets the anti-apoptotic protein BCL2, has demonstrated high rates of deep and durable response in patients with relapsed/refractory (R/R) CLL, including those with 17p deletions, and has been shown to facilitate clinically relevant improvement in several key aspects of functioning and HRQoL. We evaluated the impact of venetoclax monotherapy on the quality of life of patients with R/R CLL. METHODS: VENICE II is an ongoing open-label, phase 3b, multicenter study (NCT02980731) that assessed patient-reported HRQoL in patients who were ≥18 years old with R/R CLL, including those with 17p deletion, TP53 mutations, and/or prior experience with B-cell receptor pathway inhibitor-containing (BCRi) therapy, treated with venetoclax monotherapy (5-week dose-titration, starting at 20mg once daily, then increased weekly to 50 mg, 100 mg, 200 mg, and 400 mg, followed by 400mg once daily). The primary endpoint was the mean change from baseline to Week 48 in the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) subscale. HRQoL subscales analyzed included: Global Health Status, Role Functioning, Emotional Functioning, Cognitive Functioning, Social Functioning, and Fatigue. The impact on QoL was also assessed on the CLL Module (EORTC QLQ-CLL16). Relevance of mean changes in HRQoL measures from baseline were analyzed based on minimum important difference (MID); a 5-10 point change was defined as MID, and >10 points was considered clinically meaningful.(Osoba, D., et al. J Clin Oncol. 1998;16:139-44. Osoba, D., et al. Qual Life Res. 1994;3:353-64.) Safety and adverse events (AEs) were also monitored. RESULTS: As of the data cutoff, April 30, 2018, the median time on study was 28 weeks (range: 1 - 73) and the median time on therapy was 23 weeks (range: 0.1 - 69) in this ongoing study. Of the 169 treated patients, 70% were male; the median age was 65 years (range: 24 - 86). Among those with available data, 17p deletions and TP53 mutations were confirmed in 34% (41/122) and 38% (19/50) of patients, respectively. Overall, 38%, 20%, and 42% of patients had one, two, and three (or more) prior lines of therapy respectively; 21% of patients had prior BCRi therapy. Clinically meaningful improvements from baseline were observed by week 12 and were sustained through week 48 in the EORTC-QLQ-C30 global health status and the role function, social function, and fatigue subscales (Table and Figure 1A) and EORTC-QLQ-CLL16 future health and disease effect subscales (Table and Figure 1B). Eighty-two percent of patients had at least 1 AE; most commonly observed AEs (≥10% of patients) were neutropenia (35%), diarrhea (17%), thrombocytopenia (15%), anemia (12%), nausea (12%), and upper respiratory infection (11%). Twenty-eight percent of patients had a serious AE, of which the most common were pneumonia (5%), febrile neutropenia (4%) and pyrexia (3%). Five percent of patients discontinued the study due to an AE. CONCLUSIONS: Preliminary data from this ongoing study suggest that patients with R/R CLL experienced improvement in several key aspects of functioning and quality of life with venetoclax monotherapy within the first 12 weeks which is sustained over time. Venetoclax monotherapy was well tolerated in R/R CLL patients. These findings are consistent with previous studies of R/R CLL patients who received venetoclax monotherapy. Disclosures Cochrane: Janssen: Membership on an entity's Board of Directors or advisory committees; Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Calgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MSD: Honoraria. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Nikitin:AbbVie, Inc: Speakers Bureau. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Masud:AbbVie, Inc: Employment, Equity Ownership. Sail:AbbVie, Inc: Employment, Equity Ownership. Komlosi:AbbVie, Inc: Employment, Equity Ownership. Anderson:Walter and Eliza Hall: Employment, Patents & Royalties; AbbVie, Inc: Research Funding; Genentech: Research Funding.

scholarly journals Genetic and Transcript Changesin Cereblon in IMiD-Treated Myeloma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1793-1793
Author(s):  
Sarah Gooding ◽  
Naser Ansari-Pour ◽  
Fadi Towfic ◽  
Maria Ortiz ◽  
Dan Rozelle ◽  
...  
Keyword(s):  
Research Funding ◽  
E3 Ligase ◽  
Resistance Mechanisms ◽  
Response To Therapy ◽  
Employment Equity ◽  
Transcript Variants ◽  
Equity Ownership ◽  
The Right ◽  
The Impact ◽  
Exon 10

Myeloma survival has been significantly improved by novel therapies over the past two decades. Immunomodulatory agents (IMiDs, Lenalidomide (LEN) and Pomalidomide (POM)) are a backbone of current treatment strategies. But myeloma (MM) remains incurable, because patients ultimately relapse. IMiD drug resistance mechanisms are multifactorial, and can be either dependent or independent of IMiDs binding to Cereblon (CRBN) (a component of an E3 ligase) in tumor and immune cells. A small series of relapsed patients demonstrated sub-clonal mutation rates of 12% in CRBN and 10% in other CRBN pathway genes (Kortum et al, Blood 2016), but the clinical implication of this observation is unknown. In contrast, baseline gene expression of CRBN was not associated with clinical outcome to POM-DEX therapy (Qian et al, Leukemia & Lymphoma 2018). An integrated assessment of the burden of different mechanisms of CRBN function loss, the selective pressure for their survival, and their effects on response to CRBN-modulating agents, is lacking. For patients that progress on IMiD-based therapies, there is a need to develop drugs that will overcome their resistance. To appropriately target the right novel agents to the right patients, resistance mechanisms must be understood. A deeper understanding of the mechanistic basis for IMiD-specific resistance mechanisms is critical for differentiating new Cereblon modulating agents (eg CELMoDs) from the IMiDs. Here, we present the largest comprehensive analysis of the burden of CRBN mutation or transcript variants in relapsed refractory myeloma (RRMM) patients. We analysed WGS and RNASeq data from 298 MM samples from 268 patients across 4 clinical trials (CC-4047-MM-010 (N=226), CC-4047-MM-013 (N=17), CC-220-MM-001 (N=45) and CC-122-ST-001MM2 (N=10), for whom outcome data were available. All patients had been exposed to LEN-based therapy and a subset (69/268) were also exposed to POM-based therapy. The overall incidence of single nucleotide variants in CRBN was 17/298 (5.7%). The incidence of at least monoalleleic deletion at the CRBN gene locus was 21/298 (5.5%). CRBN has different transcript isoforms (Gandhi et al, BJHaem 2014). As high levels of isoform ENST00000424814.5, with deletion of exon 10, was previously correlated with poorer survival (Neri et al, Blood 2016), we assessed incidence of a high ratio (>2) of exon 10-deleted CRBN transcript to full length CRBN transcript. 92 samples had sufficient purity (>90% tumor cells) for this analysis. 13/92 samples (14.1%) had a high exon10-deleted transcript ratio. Overall, 43/268 (16.0%) patients had genetic or transcript variants in CRBN. In contrast, 27/514 (5.2%) newly diagnosed myeloma (NDMM) patients from the Myeloma Genome Project had genetic or transcript variants in CBRN; 2/514 (0.4%) had CRBN mutations, 11/514 (2.1%) had CRBN gene deletion and 14/514 (2.7%) had a high exon10-deleted transcript ratio. Thus, there was an increase in CRBN variants from NDMM to RRMM. In patients exposed to LEN but not POM (219/268), there were 5 CRBN mutations, 14 monoallelic CRBN deletions and 13/92 patients with high exon10-deleted transcript ratio. In 69/268 patients exposed to POM (baseline from CC-220-MM-001 (N=35), CC-122-ST-001MM2 (N=10), or follow up samples from CC-4047-MM-010 (N=24)), there were 12 CRBN mutations in 8 patients (11.6%) and 7 CRBN deletions (10.1%), approximately double the incidence seen in the whole cohort. 3 CRBN deletions were homozygous, which was not observed in non-POM-exposed individuals. Sample purity was insufficient to measure transcript ratios. In summary, 16.0% of RRMM patients that received LEN or POM have genetic or transcript variants in CRBN, a higher proportion than in NDMM. The impact of these aberrations on CRBN function, especially related to binding of CRBN-modulating drugs, remains to be ascertained. Analysis of the correlation between CRBN variation and response to therapy, clinical outcomes, and the incidence and effect of mutation or copy loss of CRBN interactors (E3 Ligase members and regulators, CRBN substrates) is underway and will be presented. Disclosures Gooding: Celgene: Research Funding. Ansari-Pour:Celgene Corporation: Consultancy. Towfic:Celgene Corporation: Employment, Equity Ownership. Ortiz:Celgene Corporation: Employment, Equity Ownership. Rozelle:Celgene Corporation: Other: Contractor for Celgene. Zadorozhny:Celgene Corporation: Other: Contractor for Celgene. Amatangelo:Celgene Corporation: Employment, Equity Ownership. Flynt:Celgene Corporation: Employment, Equity Ownership. Tsai:Celgene Corporation: Employment, Equity Ownership. Neri:Celgene, Janssen: Consultancy, Honoraria, Research Funding. Bahlis:AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Vyas:Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding. Thakurta:Celgene: Employment, Equity Ownership.

An Ethnographic Investigation Tracking the Experience of Chronic Myeloid Leukemia (CML) Patients on Tyrosine Kinase Inhibitor (TKI) Therapies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 394-394 ◽  
Author(s):  
François Guilhot ◽  
John Coombs ◽  
Tomasz Szczudlo ◽  
Oleg Zernovak ◽  
Nancy J. Macdonald ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Healthcare Providers ◽  
Work And Family ◽  
Employment Equity ◽  
Study Results ◽  
Equity Ownership ◽  
The Impact

Abstract Abstract 394 Background: The advent and approval of TKIs has dramatically improved the life expectancy of patients with CML. As treatment innovation has transformed CML into a chronically managed disease, we examined the impact of these changes on patients with CML in order to offer recommendations for healthcare providers (HCPs) to better support patients with CML. Method: 50 patients with CML from Brazil, France, Germany, Russia and Spain were included in this ethnographic investigation including: patients within 18 months of diagnosis and on frontline imatinib therapy (n = 20), patients with ongoing frontline treatment (> 18 months to 7 years, n = 20), and patients who were switched to second- or third-line TKI therapies (n = 10). Patients in all 5 countries participated in a 2.5-hour in-home interview, and patients in Brazil and France completed 7-day photo journals and an optional telephone debrief interview. Patients were asked to discuss and write about their perceptions and experiences regarding such issues as adherence, disease knowledge, disease management, and their relationship with HCPs. Result: This global ethnographic investigation generated a 5-stage, patient-centered model emphasizing emotions and experiences throughout the diagnosis, treatment and management of their disease: crisis, hope, adaption, normalcy, and uncertainty. Depending upon their circumstances, these experiential stages were found to be abbreviated or prolonged and influenced by patients having differentiating levels of knowledge about their disease, comfort levels with the treatment and/or their HCPs, as well as different degrees of optimism about their treatment and long-term prognosis. In addition, the study results showed that patients cycle through the various stages of the model throughout the course of their disease. The crisis phase occurred at diagnosis and tended to resolve upon HCP reassurance of the availability of successful treatments. Hope followed crisis when patients were educated about their disease and its treatments and responded to initial therapy. Adaption involved patients adjusting to any physical changes wrought by the disease, treatments, and associated adverse events. As well, they began to psychologically come to terms with the long-term nature of their disease and develop their drug-taking routines and compliance pattern. As patients attained stability in their disease and adapted to changes, a ‘new’ normal returned and patients began to refocus their life away from the disease back to social, work, and family matters. The uncertainty stage was found to be associated with drug resistance, disease progression, newly occurring adverse events, or due to limitations around access to therapy because of public health regulations or personal financial issues. While uncertainty arose for multiple reasons and could occur at any time after patients had advanced through the 4 preceding phases, patients who went through stages of uncertainty most often cycled back to phases of adaption or normalcy once the issues were resolved. Conclusions: Here, we have identified 5 common patient experience stages and we provide recommendations based on patient research for the management of CML. This investigation suggests that HCPs can help patients move through the early stages of crisis and hope by providing reassurance, along with information and resources regarding drug efficacy and product differentiation, while explaining the importance of speed and depth of responses. Once in the adaption/normalcy stages, HCPs should set expectations for the risk/benefits of long-term chronic drug therapy and long-term disease monitoring and continue to support patient compliance and adherence programs while helping patients achieve and maintain a normal lifestyle. Disclosures: Guilhot: Novartis: Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Coombs:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Zernovak:Novartis: Employment, Equity Ownership. Macdonald:Novartis: Consultancy. Shapiro:Novartis: Consultancy.

scholarly journals Systemic Mastocytosis Patient Experience from Mast Cell Connect, the First Patient-Reported Registry for Mastocytosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4783-4783 ◽  
Author(s):  
Philina Lee ◽  
Tracy I. George ◽  
Hongliang Shi ◽  
Erica K. Evans ◽  
Teghpal Singh ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mast Cell ◽  
Research Funding ◽  
Disease Burden ◽  
Systemic Mastocytosis ◽  
Employment Equity ◽  
New Therapies ◽  
Patient Reported ◽  
Equity Ownership ◽  
The Impact

Abstract Background: Systemic mastocytosis (SM) is a rare mast cell disorder associated with a range of debilitating symptoms and a shortage of effective treatment options. Little is known about the impact of the disease from the patients' perspective. Systematically characterizing the natural history of SM and its impact on patients will facilitate the development of new therapies. Registries that engage patients have proven valuable in other rare diseases by expanding knowledge of current treatment approaches, evaluating disease burden and accelerating clinical trials. Methods: Mast Cell Connect (NCT02620254, www.mastcellconnect.org) is an observational database that captures demographic, socioeconomic and disease information from patients with mastocytosis. It is the first patient-reported registry for mastocytosis to our knowledge. Key objectives are to improve collective understanding of the disease burden on patients and to facilitate development of new therapies by increasing participation in clinical trials. Enrollment is "site-agnostic" as participants register and take surveys on a secure online portal. Since many US patients are seen outside large clinical centers, this enables broader participation and collection of real-world data. Inclusion criteria are a diagnosis of SM or cutaneous mastocytosis (CM). Diagnoses are self-reported and participants are asked to provide medical reports that will be used to confirm diagnoses in the future. Informed consent is required to join this IRB-approved study. Results: Mast Cell Connect opened on December 1, 2015. As of May 31, 2016, 166 participants had registered, of whom 157 had responded to the online survey. Of the 153 participants who reported their diagnosis, 107 had SM and 38 had CM. Those who reported a diagnosis of SM were categorized as SM participants if they also reported other diagnoses. The current analyses are based on data provided by the 107 SM participants. Of the 107 SM participants, 60 (56%) had Indolent SM (ISM), 8 (7%) had Smoldering SM (SSM), 10 (9%) had Advanced SM (AdvSM, defined as aggressive SM, SM with an associated hematological neoplasm, and Mast Cell Leukemia) and 29 (27%) did not know their subtype. Median age was 50 years (range 4-77). More females participated (74%) than males (26%). Median time from symptom-onset to diagnosis was 7 years. Participants saw a median of 3 specialists prior to diagnosis, most frequently dermatology (67%), allergy/immunology (67%), hematology/oncology (63%) and general practitioner/internal medicine (63%). Specialists diagnosing SM most often included dermatology (36%), allergy/immunology (25%) and hematology/oncology (23%). AdvSM participants were typically diagnosed by hematology/oncology (70%). The medications taken most often at the time of survey were anti-histamines (85% H1 blockers, 72% H2 blockers), leukotriene inhibitors (38%) and cromolyn sodium (33%). Agents to reduce mast cell burden were taken less often (imatinib: 7%, interferon-α: 2%, hydroxyurea: 1% and investigational agents: 1%). Symptoms reported as moderately to severely bothersome included: fatigue (69%), difficulty concentrating (63%), abdominal pain (55%), pain in other locations (53%), difficulty sleeping (53%), itching (46%), diarrhea (45%), bloating (43%), nausea (42%), headache (40%), skin changes (40%), anxiety (39%) and flushing (37%). Participants reported being limited in work or other daily activities "quite a bit" to "very much" in 47% of ISM, 43% of SSM, and 70% of AdvSM cases. Participants' physical condition or medical treatment interfered with their family life "quite a bit" or "very much" in 59% of ISM, 43% of SSM, and 80% of AdvSM cases. Conclusions: Over 160 participants joined Mast Cell Connect in the first 6 months, indicating the mastocytosis community, including The Mastocytosis Society, is highly motivated to participate in research. SM participants reported a diagnostic odyssey, seeing multiple specialists over a median of 7 years prior to diagnosis. Despite frequent use of symptom-directed medications, symptom burden remains substantial and considerably impacts quality of life. Novel therapies targeting the underlying disease are needed. Establishing US centers of excellence may hasten the time to diagnosis. Continued collaboration between researchers, patient advocates and industry is needed to advance the care of patients with SM. Disclosures Lee: Blueprint Medicines: Employment, Equity Ownership. George:Allakos: Research Funding; Novartis: Consultancy; Blueprint Medicines: Consultancy; Allakos: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy; GLG: Consultancy; Wiley Blackwell: Consultancy; American Registry of Pathology: Patents & Royalties; Wolters Kluwer: Patents & Royalties; UpToDate: Patents & Royalties. Shi:Blueprint Medicines: Employment, Equity Ownership. Evans:Blueprint Medicines: Employment, Equity Ownership. Singh:Blueprint Medicines: Employment, Equity Ownership. Boral:Blueprint Medicines: Employment, Equity Ownership. Rangel Miller:PatientCrossroads: Employment, Equity Ownership.

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