scholarly journals U2AF1 Mutations in S34 and Q157 Create Distinct Molecular and Clinical Contexts

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3155-3155 ◽  
Author(s):  
Vera Adema ◽  
Cassandra M. Hirsch ◽  
Bartlomiej P Przychodzen ◽  
Aziz Nazha ◽  
Teodora Kuzmanovic ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Gene Mutations ◽  
Advisory Committees ◽  
Cross Sectional ◽  
Downstream Effects ◽  
Targeted Deep Sequencing ◽  
Sectional Analysis ◽  
The Impact

Abstract Background: U2AF1 forms a heterodimer for the recognition of the 3' splice site during pre-mRNA splicing. Somatic U2AF1 mutations are present in approximately 10% of MDS patients. Most U2AF1 mutations are recurrent at 2 highly conserved hotspots, while non-canonical mutations are rare. U2AF1S34 and U2AF1Q157 mutations map within the zinc finger domains of the protein, resulting in distinct downstream effects. We have previously shown that U2AF1Q157 mutant patients have distinct splicing patterns compared to U2AF1WT with a set of misspliced targeted genes, including ARID2 and EZH2. In contrast, recent work focusing on S34 suggests a distinct subset of misspliced genes, including ATG7 (Park SM, Molecular Cell, 2016). The biological and clinical implications of these 2 distinct mutations are unknown. We investigated the differences between these mutations with respect to clinical outcomes and molecular background, including their impact on clonal architecture. Methods: We first collected molecular and clinical data on a cohort of 1700 patients with myeloid neoplasms (median follow up 1.0 year, range 1-5 years), median age was 65 years (range, 11-93). Targeted deep sequencing of a panel of frequently mutated genes (64) was applied. Our analyses included somatic mutational patterns, clonal hierarchy, and mutational correlation of the cohort of patients with U2AF1S34 and U2AF1Q157 and those without mutations in this gene. U2AF1 mutations were found in 5% (78/1700) of patients, all of them were missense and in a heterozygous configuration. Results: Both mutations were equally distributed in the cohort: U2AF1S34 (45%, 35/78), and U2AF1Q157 (46%, 36/78). Other mutations (Q84, E124, E152, and R156) were detected at a lower frequency (9%). We then dissected the clonal hierarchy of both U2AF1 mutations and found that 44% (34/77) were ancestral while 56% (43/77) were secondary. In MDS, most U2AF1 mutations (77%, P=.002) were dominant, while subclonal U2AF1 mutations were evenly distributed between the subentities. U2AF1S34 or U2AF1Q157 were equally likely to be dominant (21% vs. 27%; ancestral events; P=.09, respectively). Similarly, S34 and Q157 mutant clones had similar median variant allele frequencies (3-52% vs. 8-64%). U2AF1 S34 mutant cases had similar OS to patients carrying U2AF1Q157 (N=35 vs. N=36; 10 vs. 15 months; P=.209; LogR=.65). When we compared the impact of ancestral vs. secondary U2AF1S34 and U2AF1Q157 we found that MDS patients carrying ancestral U2AF1 mutations had a shorter OS compared to MDS patients carrying secondary U2AF1 patients (N=26 vs. N=18; 13 vs. 34 months; LogR=.04). Of note, ancestral U2AF1S34 patients had shorter OS compared to ancestral U2AF1Q157 patients (13 vs.11; 10 vs.15 months; P=.03; LogR=.86). Given these differences, we also investigated the mutational spectrum of U2AF1MUT patients. Cross sectional analysis identified that the top genes mutated in the U2AF1 mutant cohort were: ASXL1 (26%), BCOR/L1 (15%), TET2 (13%), DNMT3A and PHF6 (12%), ETV6 (10%), RUNX1 and STAG2 (9%), and SETBP1 (8%). Transcriptional factor and DNA-methylation genes were predominantly mutated in U2AF1MUT patients (35% and 24%, respectively). Exploring the association between S34/Q157 vs. other gene mutations, S34 co-occurred with BCOR/L1 mutations (P=.007, 24%), while Q157 mutations co-occurred with ASXL1 (P=.003, 44%) irrespective of their rank in the clonal hierarchy. When S34 was the dominant mutation, secondary mutations included ETV6, BCOR, and CUX1. In contrast, when Q157 was the ancestral event, secondary mutations included ASXL1 and DNMT3A. Subclonal S34 occurred in the context of ancestral RUNX1, BCOR/L1, CUX1 and DNMT3A, while subclonal Q157 followed ancestral ASXL1, EZH2, PHF6 and TET2. Conclusion: In sum, U2AF1S34 and U2AF1Q157, consistent with their differential missplicing consequences, create a distinct molecular milieu leading to differences in clinical outcomes. Disclosures Makishima: The Yasuda Medical Foundation: Research Funding. Carraway:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Celgene: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Genetic Alterations at Diagnosis Predict Outcome of AML Patients Age 60 or Older Undergoing Allogeneic Transplantation in First Remission

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 48-48 ◽  
Author(s):  
H. Moses Murdock ◽  
Haesook T. Kim ◽  
Bryan Hambley ◽  
Pankit Vachhani ◽  
Nathan Denlinger ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Advisory Committees ◽  
Genetic Characteristics ◽  
The Impact ◽  
Advisory Role

Background: Older age is associated with inferior outcomes after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML). High risk genetic characteristics are common among older patients and linked to poor outcomes in the non-transplant setting. An enhanced understanding of genetic risk may thus provide a basis for improving transplant outcomes in these patients. We evaluated the impact of leukemia genetic characteristics at diagnosis on HSCT outcomes in a multi-center cohort of AML patients age 60 or older receiving HSCT in first complete remission (CR1). Methods: We performed targeted sequencing of 112 genes on diagnostic leukemia samples from 257 patients with AML age 60 or older who received allogeneic HSCT in CR1 at 5 US transplant centers. Median age at diagnosis and HSCT were 65 (range 59-76) and 66 (range 60-76), respectively. 31% had clinically defined secondary AML, 11% had therapy-related AML, and 23% had adverse cytogenetics by 2017 ELN classification. Most (84%) were treated with anthracycline-based induction chemotherapy, while 16% received non-intensive induction. Conditioning was either reduced-intensity or non-myeloablative in 94% of patients. Median follow-up for survivors was 3.7 years; 3-year overall survival (OS) and leukemia-free survival (LFS) were 48% and 44%, respectively. Results: All patients had recurrent genetic alterations at the time of diagnosis, including 251 (98%) with gene mutations and 6 with only cytogenetic abnormalities. The most frequent gene mutations were DNMT3A (25%), NPM1 (23%), FLT3-ITD (22%), ASXL1 (21%), TET2 (21%), RUNX1 (20%), and SRSF2 (18%). Secondary-type mutations associated with antecedent MDS occurred in 42%, and 10% had TP53 mutations. As expected, secondary-type and TP53 mutations were associated with clinically-defined secondary AML (p<0.001), need for reinduction (p=0.03), and CR with incomplete count recovery (p= 0.03). Despite the older age at leukemia diagnosis, putative germline pathogenic variants were identified in 22 (8.6%) patients, including 17 (6.6%) with DDX41 mutations (13/17 with somatic mutation of the second allele), and 5 with TERT or TERC variants not found in population databases. We evaluated the impact of gene mutations on LFS using univariable and multivariable Cox models and developed a hierarchical model of 3 molecular genetic risk groups according to the hazard ratios (Fig 1A): (1) patients with TP53 mutation or JAK2 mutation or FLT3-ITD/NPM1-WT (high risk), (2) patients without high risk mutations who have DNMT3A or GATA2 or DDX41 mutations (low risk) (3) patients without high- or low-risk mutations (intermediate risk), with 3-year LFS of 8%, 65%, and 47% (p<0.001), respectively. Next, we combined molecular genetic and cytogenetic risk to derive a final genetic model comprised of 4 groups with distinct 3-year LFS (69%, 50%, 27%, and 0%) (Fig 1B). Poor LFS in the very high-risk group was due almost entirely to relapse (3-year relapse rate > 90%), but was driven by a combination of relapse and non-relapse mortality in the intermediate and high-risk groups (Fig 2). Conclusion: Genetic characteristics at diagnosis are highly associated with OS and LFS in AML patients age 60 or older who undergo allogeneic transplantation in CR1. We identify patients with low genetic risk and remarkably good outcomes who may be candidates for strategies aimed at reducing toxicity, and those with very high-risk genetics who have limited benefit from current transplant approaches. Among intermediate and high-risk patients, the impact of disease genetics on LFS is mostly due to relapse, suggesting that a model incorporating measurement of residual disease in CR1 and after transplantation could enable a more dynamic estimation of risk. Disclosures Perales: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nektar Therapeutics: 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; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; NexImmune: Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Medigene: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyte/Gilead: Research Funding; Miltenyi: Research Funding. Koreth:Equillium: Consultancy; Amgen: Consultancy; Cugene: Consultancy. Ho:Jazz Pharmaceuticals: Consultancy. Soiffer:Mana therapeutic: Consultancy; Kiadis: Other: supervisory board; Juno, kiadis: Membership on an entity's Board of Directors or advisory committees, Other: DSMB; Gilead, Mana therapeutic, Cugene, Jazz: Consultancy; Jazz: Consultancy; Cugene: Consultancy. Carroll:Astellas Pharmaceuticals: Research Funding; Incyte: Research Funding; Janssen Pharmaceuticals: Consultancy. Vasu:Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Wang:Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding.

scholarly journals Restoring Functional Deficits in Older Adults with Hematologic Malignancy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4776-4776
Author(s):  
Ashley E. Rosko ◽  
Sarah A Wall ◽  
Robert A Baiocchi ◽  
Don M. Benson ◽  
Jonathan E. Brammer ◽  
...  
Keyword(s):  
Older Adults ◽  
Physical Function ◽  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Hematologic Malignancy ◽  
Exercise Program ◽  
Advisory Committees ◽  
The Impact

Background: Geriatric deficits in patients with malignancy are predictive of morbidity and mortality. Measuring geriatric deficits provides additional prognostic information not otherwise captured in routine oncology care. Currently, the gap in geriatric-care delivery is the paucity of data demonstrating effective interventions once geriatric deficits are identified. Older adults with hematologic malignancy are understudied and evaluating both the impact of geriatric factors and interventions to improve upon geriatric deficits are warranted. Here we demonstrate the impact of identifying functional impairment and an exercise program among older adults with hematologic malignancy. Methods: This was a single center prospective study of older patients (≥60 years) with hematologic malignancy. Patients actively receiving any therapeutic treatment (chemotherapy, immunotherapy, targeted agents) were enrolled in a six-month exercise program to attenuate functional decline. The Otago Exercise Program (OEP) has been found to be an effective exercise regimen to improve functional balance, muscle strength, and prevent fall-related injury and mortality.1 The OEP is a structured combination of physical therapist prescribed individualized exercise plans with home-based exercise targeted to improve balance and functional decline. Patients enrolled had mild or moderate impairments in physical function, as defined by a score ≤9 on the Short Physical Performance Battery (SPPB). Patients were evaluated at baseline for geriatric deficits (Visit 1), after four months of OEP training (Visit 2), and following two months of self-directed exercise (Visit 3 - end of study) using a standardized Geriatric Assessmpent (GA) tool (CARG GA). The relationship between geriatric deficits and mortality and hospital utilization were analyzed. The change in GA factors over 3 visits were evaluated through a linear mixed model. The proportional hazards model was built to assess the association between Visit 1 GA and overall survival (OS), where OS was defined as time from date of V1 to death, censoring patients who were still alive at time of last follow-up. The generalized linear models were used to link Visit 1 GA with other clinical outcomes such as hospital length of stay (LOS) and the probability of emergency room (ER) visit. Results: Older adults (median age: 75.5; range 62-83) actively receiving chemotherapy for hematologic malignancy were enrolled (n=30). Physical health scores as measured by the MOS-PFS increased significantly at the second visit. [Median MOS-PFS: V1=55 (0-100); V2=70 (30-100), p<.01; V3=57.5 (0-90), p=0.43], where patient reported KPS increased significantly and the improvement was sustainable [Median KPS: V1=80 (40-100); V2=90 (60-100), p=0.02; V3=90 (50-100), p=0.04]. Objective measures of physical function improved to normal scores by visit 2 and were sustained [Median SPPB: V1=7 (0-11); V2=11 (2-12), p<.01; V3=9 (2-12), p<0.01]. With a median follow-up of 21.4 months, 9 patients had died. Half of patients were hospitalized either once or multiple times with a median of 3 admissions (range 1-7).The total LOS ranged from 2 to 41 days with a median of 13 days. During the study period and 1-year follow up, 67% (20/30) patients had ER visits with a median count of 1.5 visits (range 1-6). The SPPB was the only tool that was associated with all three clinical outcomes; OS with a hazard ratio (HR) of 0.80 (95% confidence interval (CI) 0.65-0.97, p=0.03), LOS [Incidence Rate Ratio=0.86 (95% CI 0.75-0.98), p=0.02], and the odds of ER visit [odds ratio = 0.77 (95% CI 0.62-0.94), p=0.01]. Chronologic age had no relationship with OS, LOS, or ER utilization. Conclusions: Functional deficits of older patients with hematologic malignancy on active chemotherapy, both subjective and objective metrics, improved with the OEP exercise program. Objective markers of physical function (SPPB) correlated with mortality and hospital utilizations among this population. There was no significant relationship between age and clinical outcomes. Mitigating functional impairment among older adults with hematologic malignancy is important to improve clinical outcomes in this high-risk population. Disclosures Rosko: Vyxeos: Other: Travel support. Baiocchi:Prelude: Consultancy. Brammer:Celgene: Research Funding; Seatlle Genetics: Honoraria, Speakers Bureau. Byrd:Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau. Maddocks:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding. Rogers:Acerta Pharma: Consultancy; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding.

scholarly journals Survival Outcomes Following Idelalisib Interruption in the Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3149-3149 ◽  
Author(s):  
Shuo Ma ◽  
Rebecca J Chan ◽  
Wei Ye ◽  
Guan Xing ◽  
Carrie Ellen Brubaker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Treatment Interruption ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
The Impact

Abstract Introduction: Idelalisib (Zydelig®, IDELA) is a PI3Kδ inhibitor approved for treatment of relapsed or refractory (R/R) follicular lymphoma and in combination with anti-CD20 for R/R chronic lymphocytic leukemia (CLL). While IDELA is efficacious, emergence of adverse events (AEs) such as diarrhea, colitis, and transaminitis may limit its long-term administration. We hypothesize that IDELA dose interruption followed by re-initiation as a strategy to manage AEs will permit patients to remain on drug longer and improve clinical outcomes. Objective: To evaluate the impact of IDELA treatment interruption on duration of IDELA therapy (DoT), progression-free survival (PFS), and overall survival (OS) in patients with R/R indolent non-Hodgkin's lymphoma (iNHL) and R/R CLL. Methods: Using clinical outcomes data from Gilead-sponsored trials of patients with R/R iNHL treated with IDELA (101-09, N=125, Gopal et al., N. Engl. J. Med. 2014; 370:1008) or with R/R CLL treated with IDELA + anti-CD20 (312-0116/0117, N=110, Furman et al., N. Engl. J. Med. 2014; 370:997 and 312-0119, N=173, Jones et al., Lancet Haematol. 2017; 4:e114), the effect of IDELA interruption on DoT, PFS, and OS was evaluated retrospectively. Interruption was defined as missing at least one treatment day due to an AE. Patients were stratified according to number of treatment interruptions (0, 1, or ≥2) and by percentage of time off therapy (0, ≤8%, and >8%). The 8% threshold was based on the median (m) percentage of time off therapy in patients with ≥1 drug interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a stratified log-rank test. Results: Among patients with R/R iNHL, 49.6% interrupted therapy, with 31.2% experiencing 1 interruption and 18.4% ≥2 interruptions. Among patients with R/R CLL, 55.5% interrupted therapy, with 27.2% experiencing 1 interruption and 28.3% ≥2 interruptions. Baseline patient and disease characteristics were similar among the various treatment interruption groups (Table 1). The most common AEs (any grade) leading to any treatment interruption were diarrhea (iNHL, 14.5%; CLL, 28%), cytopenias or febrile neutropenia (iNHL, 4.8%; CLL, 22.3%), hepatic toxicity (elevated transaminases, alkaline phosphatase, or bilirubin; iNHL, 4.8%; CLL, 16.6%), and pneumonia (iNHL, 9.7%; CLL, 9.6%). iNHL and CLL patients without treatment interruption tended to have a shorter total DoT (iNHL, 3.8 months; CLL, 10.7 months) than patients with either 1 (iNHL, 12.7 months; CLL, 19 months) or ≥2 (iNHL, 12.2 months; CLL, 18.6 months) interruptions. iNHL and CLL patients with any treatment interruption achieved a longer PFS and OS than patients with no interruption (iNHL, mPFS=5.6 months, 14.2 months, and 16.5 months for 0, 1, and ≥2 interruptions, respectively [Fig. 1] and mOS=not reached (NR) for all groups; CLL, mPFS=13.9 months, 20.9 months, and 28.9 months [Fig. 2] and mOS=33.6 months, NR, and 47.4 months for 0, 1, and ≥2 interruptions, respectively). To account for differences in DoT across the treatment interruption groups, we compared PFS and OS based on percentage of time off therapy (no time off therapy, ≤8% time off therapy, and >8% time off therapy). Patients who interrupted with time off therapy ≤8%, but not >8%, had improved PFS and OS compared to patients who did not interrupt (iNHL, mPFS=5.6 months, 20.3 months, and 11.1 months for no, ≤8%, and >8% time off therapy, respectively [Fig. 3] and mOS=NR for all groups; CLL, mPFS=13.9 months, 28.9 months, and 16.2 months [Fig. 4] and mOS=33.6 months, 47.4 months, and NR for no, ≤8%, and >8% time off therapy, respectively). Conclusion/Discussion: In these clinical trials, approximately half the patients interrupted IDELA therapy due to AEs. Patients who interrupted therapy had a longer DoT and achieved longer PFS and OS than patients who did not interrupt. While limited time off therapy appeared to confer a clinical benefit, additional time off therapy (defined by an 8% threshold) did not provide a benefit beyond that achieved with no interruption. These findings suggest that management of IDELA AEs via treatment interruption and clinically appropriate re-initiation may benefit some patients by improving tolerability and prolonging PFS and OS. Additional analyses evaluating the influence of dose reductions are ongoing. The impact of IDELA treatment interruption on clinical outcomes should be confirmed with prospective clinical studies. Disclosures Ma: Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: 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. Ye:Gilead Sciences, Inc.: Employment, Equity Ownership. Xing:Gilead Sciences, Inc.: Employment. Brubaker:Gilead Sciences: Employment, Equity Ownership. Roudet:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:ASTEX: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; JUNO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

scholarly journals Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5468-5468
Author(s):  
Shuo Ma ◽  
Rebecca J Chan ◽  
Lin Gu ◽  
Guan Xing ◽  
Nishan Rajakumaraswamy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Treatment Interruption ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Impact of Additional Cytogenetic Alterations At Diagnosis on Prognosis of CML: Long-Term Observation From 1151 Patients of the Randomized CML Study IV

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 782-782
Author(s):  
Alice Fabarius ◽  
Armin Leitner ◽  
Andreas Hochhaus ◽  
Martin C Müller ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Y Chromosome ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Current Evidence ◽  
Prognostic Impact ◽  
Advisory Committees ◽  
Major Route ◽  
The Impact

Abstract Abstract 782 Introduction: Current evidence indicates that acquired genetic instability in chronic myeloid leukemia (CML) as a consequence of the t(9;22)(q34;q11) and the resulting BCR-ABL fusion causes the continuous acquisition of additional chromosomal aberrations (ACA) and mutations and thereby progression to accelerated phase and blast crisis (BC). Around 10 –12% of patients in chronic phase (CP) CML have ACA already at diagnosis. During the course of the disease this number rises to 80% in BC. Acquisition of ACA during treatment is considered as a poor prognostic indicator, whereas the impact of ACA at diagnosis is controversial. Patients and methods: Clinical and cytogenetic data of 1151 out of 1311 patients with Philadelphia and BCR-ABL positive CP CML randomized until 2009 to the German CML-Study IV were investigated in a prospective study. There were 459 females (40%) and 692 males (60%). Median age was 53 years (range, 16–88). All patients were treated with imatinib alone or in combination with interferon alpha or araC. The impact of ACA at diagnosis on time to complete cytogenetic and major molecular remission (CCR, MMR) and progression-free and overall survival (PFS, OS) was investigated. Written informed consent was obtained from all patients prior to entering the study. Results: At diagnosis 1003/1151 patients (87%) had the standard t(9;22)(q34;q11) only and 69 patients (6.0%) had a variant t(v;22). In 60 of 69 patients with t(v;22), only one further chromosome was involved in the translocation, in 7 patients two, and in 2 patients three further chromosomes were involved. Seventy-nine patients (6.9%) had ACA. Of these, 38 patients (3.3%) lacked the Y chromosome (-Y) and 41 patients (3.6%) had ACA except -Y. Sixteen of the 41 patients had major-route ACA (+8, i(17)(q10), +der(22)t(9;22)(q34;q11), ider(22)(q10)t(9;22)(q34;q11)) and 25 minor-route ACA [e.g. t(3;12), t(4;6), t(2;16), t(1;21)]. In patients with major-route ACA, trisomy 8 was the most frequent additional alteration (n=9). +der(22)t(9;22)(q34;q11) was observed in six patients, isochromosome (17)(q10) in five patients and ider(22)(q10)t(9;22)(q34;11) in three patients. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), -Y, minor- and major-route ACA median times to CCR were 1.01, 0.95, 0.98, 1.49 and 1.51 years, to MMR 1.40, 1.58, 1.65, 2.49 and > 7 years, 5-year PFS 90%, 81%, 88%, 96% and 50% and 5-year OS 92%, 87%, 91%, 96% and 53%, respectively. In patients with major-route ACA times to CCR and MMR were longer. PFS and OS were shorter (p<0.001) than with standard t(9;22)(q34;q11). Loss of Y chromosome had no influence on time to CCR or MMR, PFS and OS. Conclusion: We conclude that the prognostic impact of additional cytogenetic findings at diagnosis of CML is heterogeneous and consideration of their types may be important. Major-route ACA identify a small group of patients with significantly poorer prognosis as compared to all other patients requiring early and more intensive intervention such as stem cell transplantation. Disclosures: Hochhaus: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kneba:Hoffmann La Roche: Honoraria.

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.

Impact Of The Proportion Of Metaphases With Isolated Del(5q) On Clinical Outcomes In Lenalidomide (LEN)-Treated Patients With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) In MDS-003 and MDS-004

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1538-1538
Author(s):  
Aristoteles Giagounidis ◽  
Alan List ◽  
Eva Hellström-Lindberg ◽  
Mikkael A. Sekeres ◽  
Ghulam J. Mufti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Rank Test ◽  
Employment Equity ◽  
Advisory Committees ◽  
Log Rank Test ◽  
Equity Ownership ◽  
Baseline Characteristics ◽  
Rbc Transfusion

Abstract Introduction The proportion of aberrant metaphases is prognostic for overall survival (OS) in MDS patients with trisomy 8 (Mallo M, et al. Leuk Res. 2011;35:834-6). The impact of the proportion of metaphases with del(5q) on clinical outcomes, including OS, disease progression and response to therapy with LEN in MDS remains undefined. In two large multicenter studies of LEN (MDS-003 and MDS-004) in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk del(5q) MDS, RBC transfusion independence (TI) ≥ 8 weeks was achieved in 51–67% of patients (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). This retrospective analysis evaluated response to treatment, progression to acute myeloid leukemia (AML) and OS by proportion of del(5q) metaphases in patients with isolated del(5q) from the MDS-003 and 004 studies. Methods In order to allow sufficient patient numbers for analysis, ≥ 16 metaphases were evaluated for del(5q) by standard karyotyping (MDS-003 and MDS-004) and 200 interphase nuclei were evaluated by fluorescence in situ hybridization (FISH; MDS-004 only) using a probe for the commonly deleted region 5q31 (LSI EGR1/D5S721, Abbott, Wiesbaden, Germany). Patients received LEN on days 1–21 of each 28-day cycle (10 mg) or continuously (5 mg or 10 mg), or placebo. In MDS-004, patients randomized to placebo could cross over to LEN 5 mg by week 16. RBC-TI ≥ 26 weeks, time to AML progression and OS were analyzed by the proportion of del(5q) metaphases or interphases (≤ 60% vs > 60%) using standard karyotyping and FISH, respectively. Results Of the 353 patients from MDS-003 and MDS-004, 194 had isolated del(5q) by standard karyotyping; median proportion of del(5q) metaphases was 96% (range 4–100). Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, platelet and absolute neutrophil counts were comparable among patients with ≤ 60% (n = 21) and > 60% (n = 173) del(5q) metaphases. Rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 0.6515). Time to AML progression was comparable for patients in the ≤ 60% group versus the > 60% group (log-rank test P = 0.9802); 2-year rates were 22.2% (95% confidence interval [CI]: 7.7–54.5%) and 14.6% (95% CI: 9.9–21.2%), respectively. Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.5514). OS was longer in the > 60% versus the ≤ 60% group (log-rank test P = 0.0436); median OS was 3.7 years (95% CI: 3.0–4.2) and 2.4 years (95% CI: 1.5–4.9), respectively. In MDS-004, the proportion of del(5q) interphases was analyzed using FISH in 106 patients, including 46 with ≤ 60% and 60 with > 60%. When analyzed by FISH, rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 1.000). Time to AML progression and OS were similar across these groups (log-rank test P = 0.7311 and P = 0.8639, respectively) when analyzed by FISH. In the ≤ 60% and > 60% groups respectively, 2-year AML progression rates were 14.8% (95% CI: 6.9–30.1%) and 18.6% (95% CI: 10.4–32.0%), and median OS was 3.1 years (95% CI: 2.3–4.8) and 2.9 years (95% CI: 2.3–4.4). Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.8631). Conclusions In IPSS Low- or Int-1-risk MDS patients with isolated del(5q) treated with LEN in MDS-003 and MDS-004 studies, baseline characteristics, RBC-TI ≥ 26 weeks and AML progression were comparable in patients with > 60% versus ≤ 60% del(5q) metaphases. Although similar across groups when analyzed by FISH in a subset of patients, surprisingly, OS was longer in patients with > 60% del(5q) metaphases than in those with ≤ 60% del(5q) metaphases by standard karyotyping. However, the number of patients with ≤ 60% del(5q) metaphases was limited and no adjustment was made for multiple testing. These findings suggest that the number of cells with the isolated del(5q) abnormality measured by FISH does not impact clinical outcome in this RBC transfusion-dependent study population, but this finding could not be confirmed for OS by standard karyotyping. Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene: Consultancy. Morrill:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Celgene: Honoraria.

Impact Of Liver Iron Overload On Myocardial T2* Response In Transfusion-Dependent Thalassemia Major Patients Treated With Deferasirox For Up To 3 Years

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1016-1016 ◽  
Author(s):  
John Porter ◽  
Ali T Taher ◽  
Yesim Aydinok ◽  
Maria D Cappellini ◽  
Antonis Kattamis ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Iron Removal ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Significant Difference ◽  
Liver Iron Overload ◽  
The Impact

Abstract Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al., 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC <7, 7–≤15 and >15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p-values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC <7 mg/g), 38.0 ±3.4 (LIC 7–≤15 mg/g), and 37.6 ±3.1 (LIC >15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC <7 mg/g. After 36 months, a significant mean decrease from BL in LIC of -7.6 ±4.6 mg/g (p = 0.0049) and -16.8 ±14.0 mg/g (p <0.001) was observed in patients with LIC ≤15 and >15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p=0.0016) and 46% (7.3 ±7.3 ms, p<0.001), respectively. Patients with BL LIC ≤15 normalized mT2* in 24 months (Mean, 20.0 ±6.0 ms) versus 36 months for patients with BL LIC >15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC <7 mg/g (24% increase; mean abs. change, 3.5 ±2.3 ms), LIC 7–≤15 mg/g (19% increase; 3.4 ±5.2 ms) and those with LIC >15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC <7, LIC 7-≤15 and LIC >15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase (p <0.001), respectively. Similarly, at 36 months, the mT2* had increased by 71% (Mean abs. change, 10.3 ±6.6 ms) in the LIC <7 mg/g group; a 31% increase (5.3 ±5.0 ms) had occurred in the LIC 7– ≤15 mg/g group; and an 18% (3.3 ±6.0 ms) increase (p <0.001) had occurred in the LIC >15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher:Novartis Pharma: Honoraria, Research Funding. Aydinok:Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini:Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis:Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali:Novartis Pharma: Employment. Martin:Novartis Pharma: Employment. Pennell:Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria.

ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 92-92 ◽  
Author(s):  
Giuseppe Saglio ◽  
Andreas Hochhaus ◽  
Timothy P. Hughes ◽  
Richard E. Clark ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Eligibility Criterion ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Vascular Events ◽  
Advisory Committees ◽  
The Impact

Abstract Introduction Frontline NIL continues to show benefit over IM in pts with Philadelphia chromosome-positive (Ph+) CML-CP, with higher rates of major molecular response (MMR; BCR-ABLIS ≤ 0.1%) and MR4.5 (BCR-ABLIS ≤ 0.0032%), lower rates of progression to accelerated phase (AP)/blast crisis (BC) and fewer new BCR-ABL mutations on treatment in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts (ENESTnd) trial. Here, we report data with a minimum follow-up (f/u) of 4 y; updated data based on 5 y of f/u will be presented. Methods Adults with newly diagnosed Ph+ CML-CP (N = 846) were randomized to NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Progression and overall survival (OS) events were collected prospectively during study f/u, including after discontinuation of study treatment. Efficacy in the NIL 300 mg BID and IM arms was evaluated based on achievement of EMR (BCR-ABLIS ≤ 10% at 3 mo). Results At 4 y, ≥ 87% of pts remained on study in each arm and 57%-69% remained on core treatment (Table). Rates of MMR and MR4.5 by 4 y were significantly higher with NIL vs IM. Significantly fewer pts progressed to AP/BC on NIL vs IM (on core treatment: 0.7%, 1.1%, and 4.2%; on study: 3.2%, 2.1%, and 6.7% [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Of 17 pts across the 3 arms who progressed on core treatment, 11 (65%) had never achieved complete cytogenetic response and none had achieved MR4.5. Fewer mutations have emerged in the NIL arms vs the IM arm; in y 4, mutations emerged in 2 pts (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM). More pts achieved EMR in the NIL 300 mg BID arm vs the IM arm (91% vs 67%). Pts with EMR had significantly higher rates of progression-free survival (PFS) and OS at 4 y vs pts with BCR-ABL > 10% at 3 mo. Among pts with BCR-ABL > 10% at 3 mo, more progressions to AP/BC occurred in the IM arm (n = 14) vs the NIL 300 mg BID arm (n = 2); half of these pts progressed between 3 and 6 mo. In pts with intermediate or high Sokal risk, PFS and OS at 4 y were higher in both NIL arms vs the IM arm. No new safety signals were detected. Selected cardiac and vascular events were more common on NIL vs IM (by 4 y, peripheral arterial occlusive disease [PAOD] in 4 [1.4%], 5 [1.8%], and 0 pts; ischemic heart disease [IHD] in 11 [3.9%], 14 [5.1%,] and 3 [1.1%] pts; and ischemic cerebrovascular events in 3 [1.1%], 5 [1.8%], and 1 [0.4%] pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively). In the NIL 300 mg BID arm, 2 of 11 IHD events occurred between 3 and 4 y (all 4 PAOD events occurred in the first 2 y). In the NIL 400 mg BID arm, 2 of 5 PAOD events and 3 of 14 IHD events occurred between 3 and 4 y. Most pts (7 of 9) with a PAOD event on NIL were at high risk due to a combination of baseline risk factors. Conclusions NIL, a standard-of-care frontline therapy option for newly diagnosed CML-CP pts, affords superior efficacy compared with IM, including higher rates of EMR (which is associated with improved long-term outcomes), higher rates of MR4.5 (a key eligibility criterion for many studies of treatment-free remission), and a lower risk of disease progression. NIL continues to show good tolerability with long-term f/u. While selected cardiac and vascular events (including PAOD) are slightly more frequent on NIL vs IM, no increase in annual incidence of these events over time has been observed. Disclosures: Saglio: ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hochhaus:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL: Research Funding. Clark:Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Nakamae:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau, travel/ accomodations/ meeting expenses Other. Kim:BMS, Novartis,IL-Yang: Honoraria; Pfizer: Consultancy, Research Funding. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Flinn:Novartis: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Fan:Novartis: Employment. Menssen:Novartis: Employment. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; ARIAD: Research Funding. Larson:Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy.

Gene Mutations and Treatment Outcome in CLL Patients Treated with Chlorambucil (Chl) or Ofatumumab-Chl (O-Chl): Results from the Phase III Study COMPLEMENT1 (OMB110911)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1992-1992 ◽  
Author(s):  
Eugen Tausch ◽  
Christina Galler ◽  
Richard Schlenk ◽  
Peter Hillmen ◽  
Fritz Offner ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Gene Mutations ◽  
Phase Iii ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
Advisory Committees

Abstract BACKGROUND: Genomic aberrations and IGHV mutation status are established prognostic factors in CLL. With TP53, NOTCH1, SF3B1, ATM, MYD88, FBXW7, BIRC3 and POT1 recurrently mutated genes were found in CLL and were discussed to associate with disease characteristics and to affect therapy efficacy and outcome. METHODS: We assessed the incidence and impact of gene mutations in the COMPLEMENT1 trial (1st line Chl vs. O-Chl). Pretreatment samples were available from 376 patients (84.1%) and this cohort was representative of the full trial population. Mutations were analyzed by amplicon-based targeted NGS using Illumina Miseq for all coding exons (TP53, ATM, MYD88, FBXW7, BIRC3 and POT1) or hotspot exons (NOTCH1, SF3B1). Additionally, the exact variant frequency was determined. RESULTS: The incidences of gene mutations were: TP53 8.2%, NOTCH1 14.9%, SF3B1 14.1%, ATM 10.9%, MYD88 2.7%, FBXW7 3.5%, POT1 7.7%, and BIRC3 2.7%. Regarding baseline characteristics, we found significant associations: TP53mut with high ß2MG (p=0.01), 17p- (p<0.01), and unmutated IGHV (p=0.01); ATMmut with high WBC (p=0.02), and 11q- (p<0.01); MYD88mut with mutated IGHV (p=0.02); FBXW7mut with 17p- (p=0.02), and +12q (p<0.01). BIRC3mut was only present in IGHV unmutated cases (p<0.01), was more frequent in 11q- (p<0.01), +12q (p=0.05), and in cases with NOTCH1mut (p=0.05). POT1mut was more frequent in NOTCH1mut cases (p=0.02) without associations with any other baseline parameter. Regarding response to treatment, TP53mut was significantly associated with reduced ORR rate (p<0.01). CR rate was not correlated with mutations in the covered genes. At a median follow-up of 31.7 months, there were 249 (66%) events for PFS and 63 (16.8%) events for OS. O-Chl as compared to Chl resulted in significantly improved PFS (median 22.4 vs. 13.1 months, HR 0.54, p<0.01). In univariate analyses, TP53mut (HR 2.07, p<0.01), NOTCH1mut (HR 1.50, p=0.01) and SF3B1mut (HR 1.66, p=0.01) were associated with shorter PFS, whereas ATM and other candidate genes showed no association (ATMmut: HR 1.40, p=0.07). Analyzing both treatment arms separately, TP53mut had an impact on PFS with Chl and O-Chl treatment (HR 1.92, p=0.04 and HR 2.49, p<0.01). Notably, NOTCH1mut was associated with outcome in O-Chl only (HR 2.01, p<0.01 vs. HR 1.14, p=0.59) resulting in a reduced beneficial effect from the addition of Ofatumumab to Chlorambucil treatment. ATMmut and BIRC3mut mutations were only adverse prognostic factors with Chl monotherapy (ATMmut: HR 1.69, p=0.05 vs. HR 1.35, p=0.27; BIRC3mut: HR 2.84, p=0.04 vs. HR 0.99, p=0.99). OS was reduced significantly only in TP53mut cases (HR 3.69, p<0.01). Of note, none of the MYD88mut cases (n=10) had died within the follow-up period. To identify genomic factors of independent prognostic impact, we performed multivariable Cox regression analyses for PFS and OS including treatment arms, 11q-, +12q, 17p-, IGHV and all candidate gene mutations. For PFS, the following independent prognostic factors were identified: O-Chl (HR 0.46, p<0.01), 17p- (HR 3.14, p<0.01), 11q- (HR 1.57, p=0.01), unmutated IGHV (HR 1.43, p=0.02), TP53mut (HR 1.81, p=0.03), NOTCH1mut (HR 1.63, p<0.01) and SF3B1mut (HR 1.54, p=0.02). Regarding OS, only 17p- (HR 4.07, p<0.01), and unmutated IGHV (HR 1.81, p=0.05) were identified as independent adverse prognostic factors with TP53mut showing a trend (HR 2.14, p=0.10). CONCLUSION: We performed mutational analyses for the 8 most frequent mutated genes in CLL in the COMPLEMENT1 trial evaluating 1st line O-Chl against Chl. An independent prognostic impact was identified for TP53mut, NOTCH1mutand SF3B1mut regarding PFS. Notably, NOTCH1mut affected outcome mainly with O-Chl treatment, whereas ATMmut and BIRC3mut were associated with outcome with Chl monotherapy. In multivariate analysis for OS, none of the gene mutations, but the established parameters IGHV and 17p- had independent prognostic impact. Disclosures Tausch: GlaxoSmithKline: Research Funding, Travel support Other. Hillmen:GSK: Honoraria, Research Funding. Offner:GlaxoSmithKline: Honoraria, Research Funding. Janssens:GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Roche: Speakers Bureau; Mundipharma: Speakers Bureau. Mayer:Glaxo: Research Funding; Roche: Research Funding. Panagiotidis:GlaxoSmithKline: Consultancy, Honoraria. McKeown:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Stilgenbauer:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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