scholarly journals A Revised International Prognostic Scoring System of 3.5 Points Stratifies Patients with Myelodysplastic Syndromes into 2 Risk Categories

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Maria Julia Montoro ◽  
Margarita Ortega ◽  
Guillermo Villacampa ◽  
Teresa Bernal ◽  
Helena Pomares ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cox Model ◽  
Youden Index ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Travel Grant

Introduction: Although the IPSS-R stratifies patients with MDS in five risk groups and includes an intermediate-risk group, treatment options are commonly based on the division of the patients into low-risk MDS (LR-MDS) and high-risk MDS (HR-MDS). However, it is not well-defined which cut-off better classifies patients in LR-MDS vs. HR-MDS and, specifically, to which category belongs the intermediate IPSS-R group. A prior study from the International Working Group for the Prognosis of MDS suggested that a cut-off of ≤3.5 points was adequate to identify LR-MDS patients. The aim of the study was to establish the point of the IPSS-R that best divides patients in LR-MDS and HR-MDS and describe the clinical characteristics and outcomes of the intermediate-risk subgroup. Methods: All patients diagnosed with MDS according to the WHO 2008 from the Spanish Registry of Myelodysplastic Syndromes between 1980 and 2019 were included. Patients with an OS ≥30 months were defined as LR-MDS. The prognostic risk of the patients was performed according to the IPSS-R. The IPSS-R point that dichotomized the patients was obtained in agreement with the value that maximized the log-rank test in the overall survival (OS) analysis and the Youden index. Kaplan-Meier test was used for survival analysis, Cox model to obtain the hazard ratios (HR) and competing risk analysis for the evolution to acute myeloid leukemia (AML). Statistical analysis was performed by software R. Results: Among 8,107 MDS included in the registry, 4,103 had all the variables to be classified according to the IPSS-R (patients characteristics detailed in table 1). The median follow-up for survivors was 52.7 months (CI95% 49.9-56.5). Median OS was 52.9 months (CI95% 50.2-56). The IPSS-R cut-off that best identified LR-MDS patients was ≤3.5 (75% accuracy to predict OS ≥30 months). According to this value, 2,830 (69%) and 1,273 (31%) patients were classified as LR-MDS and HR-MDS, with a median OS of 75 months (CI95% 71.1-80.7) and 15.4 months (CI95% 14.5-17.4), respectively; [HR= 3.68 (95%CI 3.37-4.02); p<0.001] [Figure 1]. The 3-years cumulative incidence of AML evolution was 5.4% (IC95% 4.5-5.4) in the LR-MDS and 26.8% (IC95% 24.2-29.5) in the HR-MDS [HR= 6.1 (IC95% 4.9-7.5); p<0.001]. When the whole cohort was stratified into MDS with IPSS-R low (IPSS-R ≤3), intermediate (IPSS-R 3.5-4.5), and high (IPSS-R >4.5), median OS was 79, 30.8 and 12.1 months, respectively (Figure 2). Patients characteristics are detailed in table 2. Considering the point of 3.5, most of the intermediate IPSS-R patients (457 of 706, 65%) were upgraded to MDS-HR. Moreover, MDS with intermediate IPSS-R exhibited an OS and a 3 years cumulative incidence of AML evolution [20.7% (CI95% 17.7-24.3)] analogous to MDS with high IPSS-R. Conclusions: Our study supports the use of a cut-off of ≤3.5 to stratify MDS patients in low and high-risk subgroups, with significant differences in both OS and risk of AML transformation. Intermediate-risk IPSS-R group disclose a clinical outcome resembling more HR-MDS than LR-MDS. Thus, by using this cut-off most of the intermediate IPSS-R MDS patients are indeed considered as higher risk. These findings have relevant clinical implications, as they imply that intermediate-risk patients should be managed as high-risk MDS. Disclosures Villacampa: Merck Sharp & Dohme: Honoraria; AstraZeneca: Other: advisory role. Tormo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Ramos:Roche: Other: travel grant; Rovi: Other: travel grant; Merck-Sahrp & Dohme: Other: travel grant; Daiichi-Sankyo: Other: travel grant; Takeda: Consultancy, Other: travel grant ; Jannsen: Other: travel grant; Abbvie: Consultancy, Other: travel grant; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and research grants; Novartis: Consultancy, Other: travel grant; Amgen: Consultancy, Other: travel grant. Diez-Campelo:Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4304-4304
Author(s):  
Caspar Da Cunha-Bang ◽  
Rudy Agius ◽  
Arnon P. Kater ◽  
Mark-David Levin ◽  
Anders Österborg ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Severe Infection ◽  
Newly Diagnosed ◽  
Risk Of Infection ◽  
Advisory Committees ◽  
Educational Grant ◽  
Travel Grant ◽  
Grade 3

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (>65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

Targeted Genomic Mutation Panel (M3 P) Results from 504 Multiple Myeloma (MM) Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1795-1795
Author(s):  
K Martin Kortuem ◽  
Esteban Braggio ◽  
Pieter Sonneveld ◽  
Laura Ann Bruins ◽  
Santiago Barrio ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Clinical Care ◽  
Prognostic Significance ◽  
Gene Panel ◽  
Advisory Committees ◽  
P Gene ◽  
New Findings ◽  
Travel Grant

Abstract Introduction: Customized gene panel sequencing is an attractive approach to genomic tumor characterization in clinical care. Based on published MM exome data we developed a MM Mutation Panel (M3 P) that includes the most commonly mutated genes, actionable drug targets, genes targeted by current standard of care (SOC) therapies and which allows tracking of clonal evolution, copy number and sample purity. Methods and Material: M3 P (v3.0) covers 88 genes (1327 amplicons, 181kb). MM samples from 504 patients (pts) have been analyzed (corresponding germline in 81%) through collaborations between Mayo Clinic and Hospital-12-de-Octubre (Madrid, Spain), the DSMM and GMMG (Würzburg, Ulm, Freiburg and Heidelberg, Germany) and the HOVON trial groups (Rotterdam, The Netherlands). The investigated cohort includes 410 untreated pts (81%), which includes a high risk cohort of 72 pts with del17p, 25 paired samples with later follow up from the same cohort, and 94 relapsed patients, of which 50 were relapsed and refractory. Results: Overall coverage per mutation averaged >500x depth. We identified 945 variants (1.9 per pt) and in 83% of the pts a mutation was found. Clonal heterogeneity was assessed with mutations ranging from 3%-100% variant reads suggesting the presence of a significant number of subclones (e.g. 21% of mutations were in < 10% of reads). The mutation incidence was compared with and closely resembles the most recent MM comprehensive genomic data from the MMRF CoMMpass study: We compare here all pts sequenced by M3 P, untreated pts sequenced by M3 P and CoMMpass: KRAS (24%/23%/24%), NRAS (20%/20%/18%), DIS3 (13%/14%/10%), BRAF (9%/7%/6%), FAM46C (6%/6%/8%) and TRAF3 (6%/6%/7%). TP53 mutation incidence, however, was significantly increased in our cohort (14%/12%/4.2%), a difference explained by the inclusion of del17p (untreated) and relapsed refractory MM in panel sequenced pts, cohorts with elevated incidences of TP53 mutations (32% / 26% respectively). Potentially actionable targets include BRAF mutationsin 43 patients (9%), with druggable p.V600E in 19 or 5%, 8 pts (2%) with FGFR3 (p.R248C and p.G375C one patient each), p.R132 mutation in 4 out of 5 IDH1 (1%) and p.R172K IDH2 mutation in 1 of 3 (1%) pts. Mutations in the MAPK pathway (NRAS, KRAS, BRAF) were detected in 59% of pts, ranging from 36% untreated MM to 72% in refractory MM. Similarly, the CRBN/CUL4B/IKZF1/IKZF3/IRF4 pathway, important for IMiD function, harbored a significant enrichment of mutations in advanced disease (6% untreated vs 17% relapsed), including CRBN mutations (0.5% vs 7%). Nine of 17 IRF4 mutations were located at the p.K123R hotspot, with minor difference between early or late disease (1% vs 3%). Notably, in 8 of 9 pts with CRBN mutation and clinical information, all were unresponsive to IMiD therapy, supporting association of these mutations with resistance to IMiDs. Conversely, M3 P genes related to other SOC therapies, including NR3C1 (targeted by steroids) and 5 proteasome subunit genes (proteasome inhibitors), were rarely mutated across the cohorts not exceeding 1% mutation incidence for each gene. Significant differences in DIS3 and FAM46C mutation incidences were observed across cohorts: DIS3 mutations are more common in untreated pts with a 1.7 fold increased predominance (14% untreated and 8% treated). FAM46C has an expected incidence of 8% but was rarely mutated in untreated del17p high risk disease with only one of 100 patients harboring both mutations. The significance of this finding needs to be determined but implies a possible overlap in function. Finally we assessed impact on survival of the mutation variants identified in 142 untreated Mayo patients and found STAT3 mutations negatively impacting PFS (p=0.034) and OS (p=0.001). This gene is rarely mutated in MM (2% of the total cohort) thus the sample size was small and this finding needs further validation. Conclusion: We here describe 504 MM patients sequenced using the M3 P gene panel, which identified mutations in >80% of investigated patients, overlaps well with published whole exome sequence data and provides clinically relevant information. New findings were the high frequency of minor clones, the relative lack of overlap of del17 and FAM46C mutation, a higher frequency of DIS3 mutation at diagnosis compared to relapse, the prognostic significance of STAT3 mutation and the frequent presence of CRBN pathway mutation in drug resistant relapsed patients. Disclosures Sonneveld: Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Mai:Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Goldschmidt:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Knop:Celgene Corporation: Consultancy. Kull:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Novartis: Honoraria, Research Funding; Bristol-Meyer Squibb: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Einsele:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Raab:Novartis: Research Funding. Stewart:Oncospire Inc.: Equity Ownership; Celgene: Consultancy; Novartis: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Genomic Profiling of Smoldering Multiple Myeloma Classifies Molecular Groups with Distinct Pathogenic Phenotypes and Clinical Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 723-723
Author(s):  
Shankara Anand ◽  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Robert A. Redd ◽  
Eileen M Boyle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Molecular Classification ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Over Time

Abstract Introduction: Multiple Myeloma (MM) is an incurable plasma cell malignancy commonly preceded by the asymptomatic stage smoldering multiple myeloma (SMM). MM is characterized with significant genomic heterogeneity of chromosomal gains and losses (CNVs), translocations, and point mutations (SNVs); alterations that are also observed in SMM patients. However, current SMM risk models rely solely on clinical markers and do not accurately capture progression risk. While incorporating some genomic biomarkers improves prediction, using all MM genomic features to comprehensively stratify patients may increase risk stratification precision in SMM. Methods: We obtained a total of 214 patient samples at SMM diagnosis. We performed whole-exome sequencing on 166 tumors; of these, RNA sequencing was performed on 100. Targeted capture was done on 48 additional tumors. Upon binarization of DNA features, we performed consensus non-negative matrix factorization to identify distinct molecular clusters. We then trained a random forest classifier on translocations, SNVs, and CNVs. The predicted clinical outcomes for the molecular subtypes were further validated in an independent SMM cohort of 74 patients. Results: We identified six genomic subtypes, four with hyperdiploidy (&gt;48 chromosomes, HMC, HKR, HNT, HNF) and two with IgH translocations (FMD, CND) (Table 1). In multivariate analysis accounting for IMWG (20-2-20) clinical risk stages, high-risk (HMC, FMD, HKR) and intermediate-risk (HNT, HNF) genetic subtypes were independent predictors of progression (Hazards ratio [HR]: 3.8 and 5.5, P = 0.016 and 0.001, respectively). The low-risk, CND subtype harboring translocation (11;14) was enriched for the previously defined CD-2 MM signature defined by the B cell markers CD20 and CD79A (FDR = 0.003 ), showed upregulation of CCND1, E2F1, and E2F7 (FDR = 0.01, 0.0004, 0.08), and was enriched for G2M checkpoint, heme metabolism, and monocyte cell signature (FDR = 0.003, 0.003, 0.003, respectively). The FMD subtype with IgH translocations (4;14) and (14;16) was enriched for P53, mTORC1, unfolded protein signaling pathways and plasmacytoid dendritic cell signatures (FDR = 0.01, 0.005, 0.008, respectively). The HKR tumors were enriched for inflammatory cytokine signaling, MYC target genes, T regulatory cell signature, and the MM proliferative (PR) signatures (FDR = 0.02, 0.03, 0.007, 0.02, respectively). The APOBEC mutational signature was enriched in HMC and FMD tumors (P = 0.005), while there was no statistical difference across subtypes in the AID signature. The median follow-up for the primary cohort is 7.1 years. Median TTP for patients in HMC, FMD, and HKR was 3.8, 2.6, and 2.2 years, respectively; TTP for HNT and HNF was 4.3 and 5.2, respectively, while it was 11 years in CND patients (P = 0.007). Moreover, by analyzing the changes in MM clinical biomarkers over time, we found that patients from high-risk subgroups had higher odds of developing evolving hemoglobin and monoclonal protein levels over time (P = 0.01 and 0.002, respectively); Moreover, the absolute increase in M-protein was significantly higher in patients from the high-risk genetic subtypes at one, two, and five years from diagnosis (P = 0.001, 0.03, and 0,01, respectively). Applying the classifier to the external cohort replicated our findings where intermediate and high-risk genetic subgroups conferred increased risk of progression to MM in multivariate analysis after accounting for IMWG staging (HR: 5.5 and 9.8, P = 0.04 and 0.005, respectively). Interestingly, within the intermediate-risk clinical group in the primary cohort, patients in the high-risk genetic subgroups had increased risk of progression (HR: 5.2, 95% CI 1.5 - 17.3, P = 0.007). In the validation cohort, these patients also had an increased risk of progression to MM (HR: 6.7, 95% CI 1.2 - 38.3, P = 0.03), indicating that molecular classification improves the clinical risk-stratification models. Conclusion: We identified and validated in an independent dataset six SMM molecular subgroups with distinct DNA alterations, transcriptional profiles, dysregulated pathways, and risks of progression to active MM. Our results underscore the importance of molecular classification in addition to clinical evaluation in better identifying high-risk SMM patients. Moreover, these subgroups may be used to identify tumor vulnerabilities and target them with precision medicine efforts. Figure 1 Figure 1. Disclosures Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Casneuf: Janssen: Current Employment. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Davies: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria. Bergsagel: Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; GSK: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Yong: BMS: Research Funding; Autolus: Research Funding; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Prognostic Value of Cpss Cytogenetic Risk Classification in Patients with CMML after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Multicenter Study of the Chronic Malignancies Working Party of the EBMT

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2182-2182
Author(s):  
Christian Koenecke ◽  
Dirk-Jan Eikema ◽  
Sheree Hazelaar ◽  
Dietrich W. Beelen ◽  
Victoria Potter ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct

Abstract Introduction: The only curative treatment approach for patients with Chronic Myelomonocytic Leukemia (CMML) is allogeneic hematopoietic stem cell transplantation (HSCT), but disease relapse after transplantation is a major concern. Predictors for disease outcome after HSCT are limited. However, unfavorable cytogenetic abnormalities have been shown to serve as predictors for relapse after transplantation. The aim of this large multicentric, international study was to retrospectively determine the impact of cytogenetic information according to the CMML-specific prognostic scoring system (CPSS) on outcome after allogeneic HSCT. Patients and Methods: Patients were selected from the EBMT database who had received a first allogeneic HSCT for the treatment of CMML between 2000 and 2015. 268 centers participated into this study. In total, 1503 patients were included. Impact of CPSS-cytogenetic classification was analyzed regarding overall survival (OS) and cumulative incidence of relapse and non-relapse mortality after HSCT (gray test). Results: 488 female (32.5%) and 1013 male (67.5%) patients were included to the study. Median age at HSCT was 57.6 years (range 0.3-75.4). At time of HSCT, only 422 (28.1%) patients were in complete remission, whereas 1004 (66.8%) had active disease (77 missing). Matched related donor HSCT was performed in 35.7% of the patients, matched unrelated donor HSCT in 57.6%, mismatched related in 3.3% and mismatched unrelated in 3.4%. Bone marrow (12.6%), peripheral blood (84.3%), or both (0.3%) served as the stem cell graft. Cord blood was used as a graft in 2.8%. Myeloablative preparative regimens wereused in 223 patients (15.0%), and less intensive regimens were given to 1268 patients (85.0%). Median survival of patients included into this study was 52.2 months. 637 patients had sufficient cytogenetic information according to CPSS (866 missing), complete relapse information was available in 1385 patients. 143 patients could be categorized into CPSS-high, 85 in intermediate and 375 in low risk cytogenetics, respectively. In univariate analysis high risk CPSS cytogenetic information was found to be strongly associated with OS (low 38% (32-44%), intermediate 41% (30-53%), high 26% (18-34%)), and higher cumulative incidence of relapse (low 40% (35-46%), intermediate 42% (30-54%), high 48% (39-56%)), but not with non relapse mortality (low 28% (23-33%), intermediate 25% (16-35%), high 30% (22-38%)) at 60 months (Figure 1). Conclusion: In this international, multicentric analysis we show that CMML patients with high-risk cytogenetics had significantly worse OS after HSCT than patients with intermediate or low risk cytogenetics according to CPSS. New therapeutic strategies to prevent relapse after HSCT in CMML patients with high-risk cytogenetics are needed. Disclosures Koenecke: Amgen: Consultancy; abbvie: Consultancy; BMS: Consultancy; Roche: Consultancy. Beelen:Medac: Consultancy, Other: Travel Support. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding.

scholarly journals Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) and Validation of a Proposed Novel Risk Model (BALL Score) in Real-World Relapsed/Refractory (R/R) CLL Patients Receiving Idelalisib and Rituximab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5485-5485
Author(s):  
Massimo Gentile ◽  
Gianluigi Reda ◽  
Francesca Romana Mauro ◽  
Paolo Sportoletti ◽  
Luca Laurenti ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Low Risk ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

The CLL-IPI score, which combines genetic, biochemical, and clinical parameters, represents a simple worldwide model able to refine risk stratification for CLL patients. This score, developed in the era of chemo-immunotherapy, has not been gauged extensively in R/R-CLL patients treated with novel targeted agents, such as BCR and BCL2 inhibitors. Soumerai et al (Lancet Hematol 2019) assembled a novel risk model for OS in the setting of R/R-CLL receiving targeted therapies in clinical trials. This model, consisting of four accessible markers (β2M, LDH, Hb, and time from initiation of last therapy; BALL score), is able to cluster 3 groups of CLL patients with significantly different OS. This multicenter, observational retrospective study aimed to validate the proposed Soumerai (BALL) and/or CLL-IPI scores for R/R-CLL real-world patients treated with idelalisib and rituximab (IDELA-R). The primary objectives were to determine whether: i) the CLL-IPI retains its prognostic power also in R/R patients treated with IDELA-R; ii) the BALL score is of prognostic value for IDELA-treated R/R-CLL patients, and iii) the BALL score is predictive of PFS. This study, sponsored by Gilead (ISR#IN-IT-312-5339), included CLL patients collected from 12 Italian centers, who received IDELA-R (idelalisib 150 mg b.i.d. and a total of 8 rituximab infusions intravenously) outside clinical trials as salvage therapy with available data for the calculation of the CLL-IPI and BALL scores at the time of treatment start. OS was estimated for all subgroups of both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test, and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by Harrell's C-index. Overall, 120 CLL patients were included in this analysis. The majority of patients were Binet stage B and C (94.2%). The median age was 75 years and 83 cases (69.2%) were male. The median number of previous therapies was 3 (range 1-9) Baseline patient features are listed in Table 1. After a median follow-up of 1.6 years (1 month to 5.8 years), 33 patients had died and 39 experienced an event (death or progression). CLL-IPI scoring (115/120 evaluable cases) indicated that 6 patients (5.2%) were classified as low-risk, 24 (20.9%) as intermediate-risk, 58 (50.4%) as high-risk, and 27 (23.5%) as very high-risk. Stratification of patients according to the CLL-IPI score did not allow prediction of significant differences in OS. Thus, low-risk patients had a 2-year OS probability of 75% (HR=1), with an intermediate-risk of 68% (HR=2.9, 95%CI 0.37-23.3, P=0.3), high-risk of 83% (HR=1.58, 95%CI 0.2-12.5, P=0.66), and very high-risk of 63% (HR=5.9, 95%CI 0.78-45.2, P=0.86). Next, we tested a modified CLL-IPI by assigning a more balanced score to the original CLL-IPI variables (Soumerai et al, Leukemia Lymphoma 2019), partially overlapping previous results. Specifically, modified CLL-IPI high-risk group showed a significantly different OS as compared with intermediate- and low-risk groups. However, differently from the original report no difference was observed between low- and intermediate-risk). According to the BALL score (120/120 evaluable cases), 33 patients (27.5%) were classified as low-risk, 68 (56.7%) as intermediate-risk, and 19 (15.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 92% (HR=1), intermediate-risk of 76% (HR=5.47, 95%CI 1.3-23.7, P=0.023), and high-risk of 54% (HR=15.1, 95%CI 3.4-67, P<0.0001) (Figure 1). Harrell's C-statistic was 0.68 (P<0.001) for predicting OS. To note, BALL score failed to significantly stratify patients in terms of PFS. As for Soumerai et al (Leukemia Lymphoma 2019), the original CLL-IPI score did not retain discriminative power in term of OS in R/R-CLL patients receiving IDELA-R. The modified CLL-IPI failed to stratify low- and intermediate-risk groups, likely due to the number of cases analysed in the current cohort and the heterogeneous IDELA-containing regimens included in the Soumerai study (Soumerai et al, Leukemia Lymphoma 2019). The CLL-IPI was designed for CLL patients treated with first-line chemo-immunotherapy. Herein, we confirm the prognostic power of the BALL score in this real-world series for OS, while losing the predictive impact of patient outcomes in terms of PFS. Disclosures Mauro: Gilead: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Varettoni:ABBVIE: Other: travel expenses; Roche: Consultancy; Janssen: Consultancy; Gilead: Other: travel expenses. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Azacitidine in Patients with Acute Myeloid Leukemia: Impact of Intermediate-Risk Vs High-Risk Cytogenetics on Patient Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 955-955 ◽  
Author(s):  
Lisa Pleyer ◽  
Sonja Burgstaller ◽  
Reinhard Stauder ◽  
Michael Girschikofsky ◽  
Werner Linkesch ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Negative Impact ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Bone Marrow Blasts ◽  
Acute Myeloid

Abstract Background Several studies, including retrospective analyses of patient registries1,2 and a subanalysis of the phase III MDS-AZA-001 trial3 suggest that poor-risk cytogenetics negatively impact overall survival (OS) in patients with myelodysplastic syndrome (MDS) and World Health Organization (WHO)-defined acute myeloid leukemia (AML) treated with azacitidine (AZA). There are few data available to indicate whether AZA has improved clinical activity vs conventional care in AML patients with adverse cytogenetics. However, in a subanalysis of MDS-AZA-001 (MDS and AML [20–30% bone marrow blasts]) patients with –7/–7q abnormalities had better OS with AZA than low-dose cytarabine (21.4 vs 3.5 months, respectively) supporting significant activity of AZA in patients with adverse cytogenetics.4 Methods In this retrospective study of the Austrian AZA Registry (N=346), we compared patients with WHO-AML and intermediate- (n=228) vs high-risk (n=74) cytogenetics according to Medical Research Council (MRC) criteria. Outcomes were also assessed with respect to AZA treatment line. Results The intermediate-risk cytogenetics group comprised 228 patients (AZA 1st line, n=109; AZA ≥2nd line, n=119), and the high-risk cytogenetics group comprised 74 patients (AZA 1st line, n=39; AZA ≥2nd line, n=35; Figure 1). Comparison of baseline characteristics of both groups revealed significant differences with regard to prevalence of males and Eastern Cooperative Oncology Group Performance Status (ECOG PS) >2 for patients with high-risk cytogenetics receiving AZA 1st line, but not in those receiving AZA ≥2nd line. Peripheral blood blasts were present in a significantly larger proportion of high- than intermediate-risk patients (Figure 1). In patients who received AZA 1st line, median number of AZA cycles was 6 for both the intermediate- and high-risk cytogenetic groups (range: 1–46 and 1–25, respectively). Median time from diagnosis to AZA start was <1 month for AZA 1st line and >7.6 months for AZA ≥2nd line. Median time from AZA stop to death was <2 months in all cohorts. In the whole cohort, the overall response rate (ORR) according to International Working Group (IWG) 2003 criteria5 was similar for patients with intermediate- and high-risk cytogenetics (complete response [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR]: 32.0 vs 20.3%; p=0.106; Figure 1). Rates of hematologic improvement (HI) according to IWG 2006 criteria6 were also not significantly different (54.4 vs 75.6; p=0.063), and when ORR and HI were combined, the difference remained non-significant (47.4 vs 46.0%; p=0.885; Figure 1). Median OS was consistently higher in patients with intermediate- than high-risk cytogenetics (9.8 vs 5.4 months for the total cohort; p=0.046 [Figures 1 and 2a]; 13.5 vs 9.5 months for AZA 1st line [not significant]; and 7.6 vs 3.5 months for AZA ≥2nd line; p=0.005 [Figure 1]). However, median OS for responding patients (CR/CRi/PR/HI) was similar for patients with intermediate- and high-risk cytogenetics, irrespective of treatment line (19.9 vs 19.3 months for all responders; 20.5 vs 21.7 months for AZA 1st line; and 18.5 vs 15.0 months for AZA ≥2nd line). Furthermore, presence of a monosomal karyotype had a significant negative impact on OS (Figure 2b). None of the baseline factors analyzed had an impact on OS in patient subgroups with intermediate- or high-risk cytogenetics, except number of comorbidities >3. Conclusions Here, we compared outcomes of 302 WHO-AML patients with intermediate- vs high-risk cytogenetics treated with AZA. In line with recent data of MDS patients,1 baseline cytogenetics did not seem to have a significant effect on response to AZA. However, in agreement with other studies of AZA in MDS/WHO-AML patients,1–3 high-risk cytogenetics had a negative impact on survival compared with intermediate-risk cytogenetics in WHO-AML treated with AZA. 1. Sebert M, et al. Oral presentation at ASH 2013. Abstract 389 2. Thepot S, et al. Am J Hematol 2014;89:410–6 3. Fenaux P, et al. J Clin Oncol 2010;28:562–9 4. Fenaux P, et al. Br J Haematol 2010;149:244–9 5. Cheson BD, et al. J Clin Oncol 2003;21:4642–9 6. Cheson BD, et al. Blood 2006;108:419–25 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pleyer: AOP Orphan Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for haematopoietic stem cell transplantation with 20–30 % blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML-patients with >30% bone marrow blasts.. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy. Stauder:Novartis: Research Funding; Ratiopharm: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharm: Consultancy, Honoraria. Pfeilstöcker:Janssen-Cilag: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lang:Celgene: Consultancy. Sperr:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Phadia: Research Funding. Valent:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Greil:Sanofi Aventis: Honoraria; Roche: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; GSK: Research Funding; Ratiopharm: Research Funding.

Impact of Hypomethylating Agent Therapy in Myelodysplastic Syndromes with Chromosome 3 Abnormalities

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1705-1705
Author(s):  
David Sallman ◽  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Mikkael A. Sekeres ◽  
Amy E. DeZern ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Chromosome 3 ◽  
Advisory Committees ◽  
Monosomy 3 ◽  
Risk Patients

Abstract Background In myelodysplastic syndromes (MDS), abnormalities of chromosome 3 (i.e. inversion 3 (inv(3)), translocation 3q (t(3q)), or deletion 3q (del(3q)) represent a poor-risk karyotype in the Revised International Prognostic Scoring System (IPSS-R). In acute myeloid leukemia (AML) patients with 3q abnormalities, patients with inv(3)/t3;3 represented the most unfavorable group with a median overall survival (OS) of 10.3 months (Lugthart et al., 2010). We previously presented a single institution experience regarding outcomes of MDS patients with chromosome 3 abnormalities. Here, we sought to further define outcomes of chromosome 3 abnormalities in MDS and address the impact of hypomethylating agents (HMA) on outcome in multiple institutions. Patients and Methods Patients were identified through the MDS Clinical Research Consortium and were included if they had a WHO diagnosis of MDS, MDS/myeloproliferative neoplasm (MPN), therapy related MDS (t-MDS), or AML (20-30% myeloblasts) and had any karyotypic abnormality involving chromosome 3. Data analyzed included baseline demographics, disease characteristics, IPSS/IPSS-R scores, treatment and outcome. Responses to HMA therapy were evaluated using International Working Group (IWG) 2006 criteria. Kaplan-Meier estimates were used for overall survival. Results A total of 413 patients were identified with a median age at diagnosis of 67 years. WHO classification was as follows: 9% RA/RARS, 12% RCMD, 26% RAEB-1, 31% RAEB-2, 2% MDS/MPN, 7% MDS Unclassified, 13% AML; 34% had t-MDS. Overall, 97% of patients were higher risk by IPSS-R (i.e., intermediate to very high risk) with a median blast % in bone marrow of 8%. Distribution of cytogenetic abnormalities were inv(3) (10%), del(3q) (12%), t(3q) (18%), monosomy 3 (22%), 3p abnormalities (22%), and other chromosome 3 changes (17%). Median OS for the cohort was 12.0 months (95% C.I. 10.8 to 13.9 months) and 31% of patients without AML transformed to AML. IPSS-R was predictive of median OS across subgroups (P < 0.00001). The specific cytogenetic abnormality was predictive for survival (P < 0.00001) with median OS for t(3q) 19 months, inv(3) 13 months, del(3q) 13 months, 3p 10 months, monosomy 3 9 months, and other 3 abnormalities 11 months. There was no survival difference between patients with translocations of 3q21 versus 3q26 (median OS 18 months versus 18.6 months, P = 0.96). Patients with an isolated chromosome 3 abnormality had significantly improved OS (25.1 months versus 10.9 months (P < 0.00001). Complex karyotype (>/= 3 abnormalities) was observed in 74% of patients and was associated with decreased OS (11 months versus 21 months, P < 0.00001). Of patients who received HMA therapy (48%), the overall response rate was 46% (17% hematological improvement (HI), 7% PR, 20% CR, 2% marrow CR (CRm) with stable disease in 23%). Median OS with and without HMA was 15.5 months versus 8.4 months (p=0.038). In int-2/high risk patients by IPSS, HMA treated patient had a median OS of 14.0 months versus 7.6 months for patients not treated with HMAs (P = 0.005) with no benefit for HMAs in lower-risk patients (median OS 24.5 months with HMA versus 38.7 months without; P =0.41). Cox regression modeling with HMA therapy, IPSS and clinical site confirmed the HMA OS benefit in higher-risk patients (HR 0.69; 95% CI 0.53-0.89; P = 0.005), but showed decreased OS in lower-risk patients (HR 2.0; 95% CI 1.03-3.92; P = 0.04). Allogeneic transplantation was performed in 18% (n=75) of patients, with median OS of 18 months versus 10 months in non-transplanted patients (P < 0.00001). Conclusion In this large cohort of patients with MDS and oligoblastic AML associated with chromosome 3 abnormalities, survival was heterogeneous but overall poor, with isolated chromosome 3 abnormality and t(3q) patients having a more favorable OS than patients with other chromosome 3 anomalies. MDS patients with 3p changes have poor outcomes. Although some patients with chromosome 3 respond to HMA therapy, the overall survival remains poor and novel approaches are needed. Disclosures Sekeres: Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Steensma:Amgen: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Lancet:Boehringer-Ingelheim: Consultancy; Kalo-Bios: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy. List:Celgene Corporation: Honoraria, Research Funding. Komrokji:Incyte: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau.

Could Chronic Gvhd Overcome the Poor Prognosis of Patients with MDS and TP53 Undergoing Allogeneic HSCT?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2890-2890
Author(s):  
Juan Carlos Caballero ◽  
Mercedes Sánchez-Barba ◽  
Mónica Del Rey ◽  
Kamila Janusz ◽  
Eva Lumbreras ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Somatic Mutations ◽  
Advisory Committees ◽  
Poor Outcome

Abstract Background and Aim Although new agents have been approved for the treatment of MDS, the only curative approach for these patients is allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, in these patients this approach has only obtained 40-60% of overall survival. Somatic mutations in MDS have recently been analyzed in order to confirm clonally and also prognostic impact in MDS patients. In this regard, TP 53 mutated gene is present in MDS in less than 10% of patients and is associated with advanced disease and high-risk features. Recent studies confirms poor outcomes in patients with TP 53 mutated receiving allogeneic stem cell transplantation1,2. The present study try to analyze if the development of chronic graft versus host disease (cGVHD) could modify, due to graft versus leukemia effect, the adverse prognosis of these high-risk patients (TP53 mutated patients). Design and Methods <>Results of HSCT in 92 MDS patients from 5 centers in Spain were retrospectively studied. Samples were collected 1 month prior to transplant. 280ng of the genomic DNA from BM cells was screened for somatic mutations in TP53 gene. The study was done by NGS on a GS Junior Instrument (Roche) according to an amplicon sequencing design. For each sample, eight exons (4-11) were amplified with preconfigured primer plates provided within the IRON II study network. Data analysis, were carried out using the Sequence Pilot software version 3.5.2 (JSI Medical Systems) and GS Amplicon Variant Analyzer software, versions 2.7 and 2.9 (Roche Applied Science). Minimum coverage of sequenced exons was 100 reads and the sensitivity of variant detection was set to a lower limit of >2% for bidirectional reads. Only those variants that resulted in amino acid change in the protein sequence were considered. OS and RFS were calculated using the Kaplan-Meier method. The log-rank test was used for comparisons. All calculations were done using SPSS 18.0. Cumulative incidence of relapse was also calculated by xlstat version 2014 program. <>Results Median age was 54 years (17-69), 71.7% were "de novo" MDS and regarding IPSS, 53% were in the int-2/high-risk category. Other characteristics were in Table 1. In the pre-transplant evaluation, 15 patients out of 92 (16,3%) were TP 53 mutated. The mutations were located in exons 5, 6, 7, 8 and 10. These variations were present in a variable percentageof the cell population (3 to 84%). All mutations were specific nucleotide changes except for two cases. At the time of the last update, 16 patients had relapsed (17.4%) and 40 had died (43.5%). After a median follow up of 15.5 months, OS was 56.5%. Median OS for patients with mutated TP53 trend a toward to be shorter than survival for patients without mutated TP53 (median of 7 mo vs median not reached, respectively, p=0.156). Multivariate analysis for OS confirmed complex karyotype (HR 5,588, 95CI 1,794-17,407, p=0.003) and no developement of cGVHD (HR 3,531, 95IC 1,634-7,632, p=0.001) as predictors for poor outcome. Cumulative incidence of relapse was 20.3% (+/-4.3%) at 1 years. Mutational status of TP53 significantly influenced on relapse (53.3% +/-12.9% vs 13.7% +/-4% at 1 year for patients with vs without TP 53 mutation (Gray test=0.001, Figure 2). Regarding Relapse Free Survival (RFS), after a median of follow up of 17 months, RFS was 67.9% and as previously suggested, the presence of TP 53 mutation had an impact on RFS (41.7% for mutated (median RFS of 6 months) and 75% for non mutated patients (median RFS not reached), p=0.009). Multivariate analysis for RFS confirmed age (HR 1.054, 95CI 1.005-1.106, p=0.032) and TP 53 mutated (HR 3.054, 95IC 1.145-8.149, p=0.026) as predictors for lower RFS. Regarding 15 patients with mutated TP 53, 7 did relapsed and 9 had died. Developement of cGVHD showed a trend toward to improve outcome among TP 53 mutated patients, with a better OS and RFS for those developing cGVHD as compared to those who did not (OS of 55% vs 17% for patients with and without cGVHD, p=0.039, Figure 2 and RFS of 71% vs 50%, respectively, p=0.3). <>Conclusions Mutated TP53 pre-allo patients presents poor outcome as compared to not mutated, as previously described Bejar1 and Kim2. Nevertheless, the developement of cGVHD could overcome the adverse impact of this factor due to the developement of graft versus tumor efect, improving survival curves (OS and RFS) as compared to previous published results. Study supported by GRS-1033/A/14 P53. 1.-BŽjar, JCO 2014, 32(25). 2.-Kim, BBMT 2015, Epub ahead of print. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sanz: JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Valcarcel:AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Díez-Campelo:CELGENE: Research Funding, Speakers Bureau; JANSSEN: Research Funding; NOVARTIS: Research Funding, Speakers Bureau.

scholarly journals Use of Artificial Intelligence Electrocardiography to Predict Atrial Fibrillation (AF) in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-51
Author(s):  
Georgios Christopoulos ◽  
Zachi I. Attia ◽  
Peter A. Noseworthy ◽  
Timothy G. Call ◽  
Wei Ding ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
High Risk ◽  
Sinus Rhythm ◽  
Board Of Directors ◽  
Research Funding ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Increased Risk ◽  
Very High

Background: Clinical factors including previous history of AF, heart failure, hypertension, valvular heart disease, increased age and male gender increase the risk of AF in CLL patients (Shanafelt, Leukemia and Lymphoma 2017). Treatment with Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib has also been associated with an increased risk of AF in CLL. We evaluated the role of artificial intelligence electrocardiography (AI-ECG) in predicting ibrutinib-induced AF (and, for reference, AF unrelated to ibrutinib) in patients with CLL. Methods: We identified two cohorts of CLL patients using the Mayo Clinic CLL Database. Cohort 1 included patients evaluated within 12 months of CLL diagnosis who did not ever receive ibrutinib. Cohort 2 included patients who were treated with ibrutinib. The electrocardiographic signature of AF in sinus rhythm was detected by an AI-ECG algorithm previously developed using a convolutional neural network (Attia, Lancet 2019). The baseline AI-ECG AF score (positive defined as &gt;0.10 on a scale of 0-1 which offers best balance between sensitivity and specificity per Attia et al.) was computed based on ECGs obtained within 10 years prior to CLL diagnosis (Cohort 1) or 10 years prior to initiation of ibrutinib therapy (Cohort 2). Patients with AF at baseline, missing data, or with ECGs previously used to train the AI algorithm were excluded. Reverse Kaplan Meier diagrams were plotted for both cohorts grouped by AI-ECG positivity. Cox proportional hazards were fitted to assess the predictive ability of AI-ECG in both cohorts. Results: After screening 2,739 patients and applying exclusion criteria (126 patients had baseline AF) a total of 1,149 patients with median 4 (interquartile range [IQR] 2-9) baseline ECGs were included in the analysis (Figure 1A). Cohort 1 included 951 patients with a median follow up of 3.0 (IQR 0.6-7.0) years and positive baseline AI-ECG in 546 (57%) patients. Cohort 2 included 198 patients with a median follow up of 1.6 (IQR 0.7-3.2) years and positive baseline AI-ECG in 91 (46%) patients. In Cohort 1, the median age was 67 years (IQR 58-72), 681 (72%) of patients were men, 68% had low/intermediate risk CLL-International Prognostic Index (IPI), and 32% had high/very high-risk CLL-IPI. In Cohort 2, the median age was 69 years (IQR 62-75), 139 (70%) of patients were men, 13% had low/intermediate risk CLL-IPI, and 87% had high/very high-risk CLL-IPI. AF occurred during follow up in 164 patients (17%) in Cohort 1 and 46 patients (23%) in Cohort 2. In both Cohorts 1 and 2, a positive baseline AI-ECG significantly increased the incidence of AF during follow up (log rank &lt;0.001) (Figure 1B and C). Hazard ratios (for positive vs. negative AI-ECG) were 33.9 (95% confidence interval [CI] 15.0-76.6) for Cohort 1 and 14.8 (95% CI 5.3-41.3) for Cohort 2. Conclusion: The addition of AI to a standard 12-lead ECG obtained during normal sinus rhythm - an inexpensive and ubiquitous test - predicts the occurrence of future AF in patients with CLL. This holds true irrespective of BTKi -based therapy and has important implications for the management of CLL patients. Disclosures Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Kenderian:BMS: Research Funding; Gilead: Research Funding; Novartis: Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Juno: Research Funding; MorphoSys: Research Funding; Lentigen: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; Kite: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Torque: Consultancy. Wang:Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Kay:Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Abbvie: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Honoraria; GlaxoSmithKline: Research Funding. Parikh:MorphoSys: Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria, Research Funding.

scholarly journals Impact of Chronic Graft-Versus-Host Disease on Long-Term Outcomes of Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Adults with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3980-3980
Author(s):  
Jae-Ho Yoon ◽  
Sung-Soo Park ◽  
Young-Woo Jeon ◽  
Sung-Eun Lee ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Median Time ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Advisory Committees

Abstract Background : The role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC-HCT) in adult acute lymphoblastic leukemia (ALL) remains unclear because the interpretation of transplantation outcome is mainly limited by the small sample size, short follow-up duration, various regimens for conditioning and graft-versus-host disease (GVHD) prophylaxis, and the heterogeneity of the criteria used to select patients for RIC-HCT. Previously, we conducted a phase 2 trial of RIC-HCT in adults with high-risk ALL who were ineligible for myeloablative conditioning and showed the potential role of this strategy, especially in patients in first complete remission (CR1). Here, we report the long-term outcomes of RIC-HCT by analyzing 122 consecutive adults with high-risk ALL in CR1, particularly focusing on the prognostic relevance of chronic GVHD. Methods: During the period between 2000 and 2014, 122 patients in CR1 (median age, 52 years [range, 15-65 years]; 54 Ph-negative ALL and 68 Ph-positive ALL) were given an identical RIC regimen consisting of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2in total). The indications for RIC-HCT were advanced age (≥50 years; n=79; 64.8%) and comorbid conditions (n=43; 35.2%). Graft sources were peripheral blood stem cells (n=118; 66 matched sibling donor, 23 matched unrelated donor, 29 mismatched unrelated donor) and bone marrow (n=4; 1 matched sibling donor, 1 matched unrelated donor, 2 mismatched unrelated donor). The median time to transplantation was 155.5 days (range, 103-291 days). GVHD prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for sibling donor transplants, tacrolimus for unrelated donor transplants) plus methotrexate. Antithymocyte globulin was administered to the patients who received mismatched unrelated donor grafts. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued. Results: The median time for neutrophil and platelet recovery was 12 days (range, 8-30 days) and 13 days (range, 5-60 days) after RIC-HCT. Sixty-two patients developed acute GVHD (53 grade II, 5 grade III, 4 grade IV). The cumulative incidence of acute GVHD at 1 year was 50.8% (42.6% for Ph-negative and 57.4% for Ph-positive, P=0.152). Except for 11 patients with early deaths within 100 days, 77 developed chronic GVHD (30 mild, 29 moderate, 18 severe), resulting in a 5-year cumulative incidence of 63.6% (69.1% for Ph-negative ALL and 58.8% for Ph-positive ALL, P=0.319). The median time to onset of chronic GVHD was 140 days (range, 37-843 days) after transplantation. Cytomegalovirus reactivation >10,000 copies/mL was observed in 40.2% (44.4% for Ph-negative ALL and 36.8% for Ph-positive ALL, P=0.447). After a median follow-up duration of 57.9 months (range, 17.7-206.8 months), the 5-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 27.5% (23.9% for Ph-negative ALL and 30.2% for Ph-positive ALL) and 19.0% (17.4% for Ph-negative ALL and 20.3% for Ph-positive ALL), respectively, and the 5-year disease-free survival (DFS) and overall survival (OS) rates were 53.5% (58.4% for Ph-negative ALL and 49.7% for Ph-positive ALL) and 59.8% (60.2% for Ph-negative ALL and 59.3% for Ph-positive ALL). In multivariate analysis, the presence of chronic GVHD lowered CIR (HR, 0.23; 95% CI, 0.10-0.48; P<0.001), but severe chronic GVHD increased NRM (HR, 8.76; 95% CI, 3.39-22.6; P<0.001). Thus, the presence of mild to moderate chronic GVHD was closely related to better outcomes in terms of DFS (HR, 0.45; 95% CI, 0.32-0.64; P<0.001) and OS (HR, 0.44; 95% CI, 0.30-0.64; P<0.001) in all patients as well as in both subgroups of patients. In Ph-positive ALL subgroup of patients, patients without achievement of major molecular response until the time of transplantation had also significantly higher CIR (HR, 7.42; 95% CI, 3.04-18.10; P<0.001) and poorer DFS (HR, 3.47; 95% CI, 1.48-8.14; P=0.004) and OS (HR, 2.58; 95% CI, 1.03-6.47; P=0.043). Conclusion: Our long-term follow-up data with a uniform treatment strategy suggest that RIC-HCT is a valid alternative choice for providing a long-term disease control for adult high-risk ALL patients in CR1. Minimal residual disease-based treatment strategies to reduce leukemia cell burden before HCT and to enhance the graft-versus-leukemia effect are needed in the future. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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