Prognosis of Myelodysplastic Syndromes (MDS) in Patients in the Age of 80 Years and Older: Data from the Regular Care MDS Registry in Germany

Abstract The international prognosis scoring system (IPSS) and the revised-IPSS were generated with data from 816 and 7,019 patients (pts) from academic centers with a median age of 69 and 71 years (y) respectively. As the median age of pts with MDS receiving care in Germany is 74.9 y and around a quarter of pts are older than 80 y, the aim was to evaluate the meaning of the IPSS and additional risk factors in the older population group. Methods: Pts with written informed consent could be included in the online-registry. Pts were eligible if a bone marrow examination had been performed and if basic data and the quarterly course of the disease were documented. Statistical analysis: Depending on the distributions of each variable frequency tables, means (SD), medians were calculated overall and stratified by age classes. Corresponding overall tests were performed (Chi-square, Kruskal-Wallis). Time dependent survival probabilities from MDS diagnosis were estimated by Kaplan Meier curves (compared using log rank test). Multiple Cox regression models were used to investigate associations between mortality risk and baseline risk factors. Variable selection was performed in the subpopulation of elderly pts based on univariate models and models including all prespecified variables (IPSS, sex, transfusion dependent at diagnosis (Tx at d), primary or secondary MDS, comorbidities). Mortality of pts subgroups was compared and age-sex-standardized with the German population 2013 as given in the Human Mortality Database (www.mortality.org, University of California Berkeley, Max Planck Institute for Demographic Research). Standardized mortality rates (SMR) and 95%-confidence intervals were estimated. Results: Between July 2009 and March 2016 (81 months) 2,118 pts from 90 institutions, mainly outpatient practices, were documented. The median age of the 843 (39.8%) female and 1,275 (60.2%) male pts was 74.9y (min-max: 26.5 - 94.2). 631 patients were excluded from analysis due to missing IPSS risk. The duration of observation, frequencies of IPSS, Tx at d, and the Charlson comorbidity index (CCI) are given in the table. Increased age and IPSS risk were significantly associated with the risk of death. An additional interaction between age and IPSS risk was significant (p=0.0198, Cox model, lower IPSS risk in increased age). In the subgroup of elderly patients (n=332, 147 died) after variable selection, IPSS, gender and Tx at d (22 missings) were significantly associated with the risk of death. Furthermore, even in the low risk group an elevated risk was estimated (SMR 1.773) compared to the normal population in the same age class. SMRs increase with higher IPSS risk. Analysis of comorbidities using CCI showed no significant association with mortality in the low risk group of the elderly patients (n=121, 44 died). Because of low sample sizes in the CCI subgroups the power is small, but even the survival curves did not show a clear trend (p= 0.497). Conclusion: IPSS risk and age are significantly associated with the risk of death. In elderly pts associated risk factors were IPSS, male gender and transfusion at diagnosis. Even the diagnosis of low risk MDS has a negative impact on life expectancy. Supported by an unrestricted grant from Celgene and Novartis. Table 1 Table 1. Figure Figure. Table 2 Table 2. Disclosures Steinmetz: Vifor: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Celgene: Consultancy, Research Funding, Speakers Bureau. Haastert:X-Med: Honoraria. Tesch:Celgene: 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, Speakers Bureau. Schmitz:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Speakers Bureau.

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Incidence and Risk Factors for Central Nervous System Relapse in Very Elderly Patients over 80 with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Two Lysa Studies

Blood ◽

10.1182/blood.v128.22.927.927 ◽

2016 ◽

Vol 128 (22) ◽

pp. 927-927

Author(s):

Aurelie Cabannes-Hamy ◽

Frederic Peyrade ◽

Fabrice Jardin ◽

Jean-Francois Emile ◽

Sylvie Castaigne ◽

...

Keyword(s):

Risk Factors ◽

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Risk Group ◽

B Cell Lymphoma ◽

Very Elderly ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Cns Relapse

Abstract Background. The prevalence of diffuse large B-cell lymphoma (DLBCL) in patients aged over 80 years is reported to have tripled compared to patients in their sixties. Treating very elderly patients is particularly challenging given the likelihood of comorbidities and concerns over risks of toxicity. One of the most devastating and rapidly fatal complications in DLBCL is central nervous system (CNS) relapse. Most studies reporting incidence and risk factors of CNS relapse concern DLBCL patients under the age of 80 years, and little is known about CNS recurrence in the very elderly, aged over 80 years. CNS prophylaxis is rarely implemented in this population due to the burden of comorbidities, frequent antiplatelet or anticoagulant treatment along with renal failure and hypoalbuminemia, as well as potential prophylaxis toxicity of IV high dose methotrexate and/or the invasiveness of IT therapy. Aim. We retrospectively evaluated the incidence of CNS relapse, risk factors and specific survival in very elderly DLBCL patients aged 80 years Patients and Methods. Data were collected retrospectively from two multicentre, open-label, single arm phase II LYSA trials (LNH 03-7B (NCT01087424) between 2004 and 2007, LNH09-7B (NCT01195714) between 2009 and 2013) evaluating the addition of rituximab or ofatumumab to miniCHOP as front-line therapy. Results. A total of 270 elderly patients were included in the two trials, 150 treated with R-miniCHOP and 120 with O-miniCHOP. Median age was 83 years (range 79-95) and none received CNS prophylaxis. At inclusion, most patients (76%) presented with disseminated disease (Ann Arbor stage III or IV), and 37% had at least two extra-nodal sites. Overall 18% of patients had bone marrow involvement, while renal, adrenal, testis or cavum involvement was rare (4%, 2%, 3%, and 2%, respectively). After a median follow-up of 28.7 months (range 0.1-72.1), 8 (3%) cases of CNS relapse were reported. Median time between inclusion and CNS relapse was 19.2 months (range 3.2 - 32.6). Cumulative 1 and 2-year incidence of CNS relapse was 1.4% (95% CI 3.2-25.4) and 2.5% (95% CI 6.9-9.2), respectively. At inclusion, clinical characteristics of the CNS relapse patients were not significantly different from patients without relapse. At CNS relapse, all patients except one present a performance status ECOG > 2. neurological symptoms were either mild with loss of autonomy, asthenia, hearing impairment, urinary incontinence, or more prominent with delirium, aphasia, intracranial hypertension, or consciousness disorder. Treatment of CNS relapse was a supportive care based- treatment with corticosteroid only in 5 patients, radiation therapy in one patient, and chemotherapy for 2 patients including rituximab-temodal (5 cycles) in one patient and rituximab -aracytine-vepeside (2 cycles) for the other one. Patients survived for a median of 1.5 months after CNS relapse diagnosis (range, 0.4 to 4). The CNS international prognostic index (CNS-IPI) classified 33 (12%) patients in the low-risk group, 164 (62%) in the intermediate-risk group, and 71 (26%) in the high-risk group. The low-risk and intermediate-risk CNS-IPI groups showed 2-year rate of CNS disease of 3%, and the high-risk of 2.8% (p=0.9483). Conclusion. Incidence of CNS relapse in very elderly previously untreated patients is approximately 3% and is associated with a very poor survival. The absence of prophylaxis in this population did not appear to have a strong impact on CNS relapse incidence. Higher number of patients is warranted to identify risk factors for CNS relapse in this population Disclosures Coiffier: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: 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; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salles:Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Thieblemont:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽

10.1182/blood-2020-141890 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Maël Heiblig ◽

Hélène Labussière ◽

Marie Virginie Larcher ◽

Gaelle Fossard ◽

Marie Balsat ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Predictive Value ◽

Scoring System ◽

Research Funding ◽

Risk Group ◽

Advisory Committees ◽

Post Induction ◽

Mutational Status ◽

Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p<0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p<0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P <0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P <0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

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Combining Information Regarding Chromosomal Aberrations t(4;14), Del(17p13) and the Copy Number of 1q21 with the International Staging System Classification Allows Stratification of Myeloma Patients Undergoing Autologous Stem Cell Transplantation: Results From the HOVON-65/GMMG HD4 Trial

Blood ◽

10.1182/blood.v118.21.332.332 ◽

2011 ◽

Vol 118 (21) ◽

pp. 332-332

Author(s):

Kai Neben ◽

Henk M. Lokhorst ◽

Anna Jauch ◽

Uta Bertsch ◽

Thomas Hielscher ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Risk Group ◽

Staging System ◽

Risk Groups ◽

Low Risk ◽

Advisory Committees ◽

International Staging System

Abstract Abstract 332 PURPOSE : In Multiple Myeloma (MM), the combination of serum beta-2-microglobulin level with serum albumin concentration has been proposed as an outcome predictor in the International Staging System (ISS). More recently, subgroups of MM defined by genetic and cytogenetic abnormalities have been associated with unique biologic, clinical, and prognostic features. PATIENTS AND METHODS: We analyzed the prognostic value of 12 chromosomal abnormalities by fluorescent in situ hybridization (FISH) in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Patients with newly diagnosed MM were randomized to receive either three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). All patients underwent autologous stem cell transplantation (ASCT) followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively. In addition, a second cohort of patients was analyzed as a control group (n=462), undergoing ASCT at the University of Heidelberg between September 1994 and December 2010. RESULTS: For the entire group of patients treated within the HOVON-65/GMMG-HD4 trial, we identified 233 patients with 2 copies (67.7%), 95 patients with 3 copies (27.6%) and 16 patients (4.7%) with more than three copies of the chromosomal region 1q21. In addition to del(17p13) and t(4;14), we added +1q21 (>3 copies) to the group of high-risk aberrations, since the outcome of these patients was almost as poor as it was observed for patients with del(17p13). Subsequently, we analyzed whether combining the ISS score with information on the presence of high-risk aberrations could improve the prognostic value with regard to patients' outcome. A combination of the presence or absence of del(17p13), t(4;14), or +1q21 (>3 copies) with the ISS score allowed patients to be stratified into three distinct groups: low-risk [absence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS I], high-risk [presence of del(17p13)/t(4;14)/+1q21 (>3 copies) and ISS II/III], and intermediate-risk (all remaining patients). Most of the patients belonged to the low- (33%) and intermediate-risk (49%) groups, whereas 18% were allocated to the high-risk group. The median PFS times for the low-, intermediate-, and high-risk groups were 41.9 months, 31.1 months (HR=1.7; p=0.0018) and 18.7 months (HR=3.6; p<0.0001), respectively. The 3yr-overall survival (OS) decreased from 94% in the low-risk group to 80% (HR=4.6; p=0.0001) and 43% (HR=12.8; p<0.0001) in the intermediate- and high-risk groups, respectively. These results were confirmed in the independent cohort of patients: From date of first ASCT, the median PFS times for the low-, intermediate-, and high-risk groups were 43.3 months, 23.0 months (HR=1.5; p=0.015) and 13.8 months (HR=2.4; p=0.0003), respectively. The 4yr-OS decreased from 84% in the low-risk group to 71% (HR=2.1; p=0.0043) and 49% (HR=3.84; p<0.0001) in the intermediate- and high-risk groups, respectively. CONCLUSION: In our series, the ISS/FISH-based score/algorithm predicted PFS and OS much better than the ISS alone. Our results with molecular cytogenetic techniques may already have implications for the risk-adapted clinical management of patients with MM particularly in younger patients. Disclosures: van de Velde: Ortho Biotech Oncology Research & Development: Employment. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees.

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Prognostic and Biologic Significance of Long Non-Coding RNA (lncRNA) Profiling in Cytogenetically Abnormal Acute Myeloid Leukemia (CA-AML)

Blood ◽

10.1182/blood-2018-99-114035 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2767-2767

Author(s):

Dimitrios Papaioannou ◽

Deedra Nicolet ◽

Xiaoqing Rong-Mullins ◽

Krzysztof Mrózek ◽

Jessica Kohlschmidt ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Group Status ◽

Advisory Committees ◽

Expression Levels ◽

Pathway Analyses

Abstract Introduction: Aberrant expression levels of lncRNAs have been shown to independently associate with outcome of younger and older patients (pts) with cytogenetically normal AML. However, the prognostic and biologic significance of lncRNA expression in CA-AML pts have not been extensively studied. Methods: We performed whole transcriptome profiling (RNA-seq) in 469 pts with de novo CA-AML. Cytogenetic analyses were performed in institutional laboratories and the results were reviewed centrally. All pts were treated on frontline Cancer and Leukemia Group B (CALGB)/Alliance protocols. Results: To evaluate the prognostic significance of lncRNA expression in CA-AML, we analyzed RNA-seq data of 469 pts by applying a machine learning algorithm-based approach. As CA-AML pts constitute a heterogeneous group, we first determined which other clinical and molecular parameters were prognostic [i.e., associated with event-free survival (EFS)] in our dataset. Among the parameters tested, the European LeukemiaNet (ELN) Risk Group status and age group [i.e., younger than 60 years (y) or aged 60 y and older] significantly associated with clinical outcome of CA-AML pts. Next, we individually identified each lncRNA that associated with EFS while adjusting for ELN Risk Group and age group. We conducted random forest analyses to select the prognostic lncRNAs, whose combined expression levels could generate an effective outcome predictor for CA-AML pts. For each step of the random forest analyses, a bootstrap technique was applied; a simple random sample of pts was drawn which served as the training set and the out-of-sample pts were used as the independent validation set. We identified 55 prognostic lncRNAs and used their expression levels to separate our CA-AML cohort into a lncRNA low-risk (n=161) and a lncRNA high-risk (n=308) group. With regard to clinical characteristics, pts in the lncRNA low-risk group were younger (P<.001) and had lower platelet counts (P<.001) and higher white blood cell counts (P=.01) than pts in the lncRNA high-risk group. Concerning cytogenetic abnormalities, pts in the low-risk group more often had core-binding factor translocations or inversions (P<.001) and less often complex karyotypes (P<.001) than pts in the high-risk group. Pts in the lncRNA low-risk group had higher complete remission (CR) rates than pts in the high-risk group (91% vs 48%, P<.001). LncRNA low-risk group status also associated with longer disease-free survival (DFS; 5-y rates 49% vs 12%, P<.001), overall survival (OS; 5-y rates: 58% vs 14%, P<.001) and EFS (5-y rates: 45% vs 6%, P<.001). With regard to the accuracy of outcome prediction, the lncRNA risk classification had a C-index of 0.73, which compares favorably with other prognostic classifiers of AML pts. In multivariable analyses, lncRNA low-risk status was an independent marker for higher CR rates, as well as for longer DFS, OS and EFS (P<.001 in all comparisons), after adjusting for other covariates. Finally, we examined the prognostic value of the lncRNA risk classification within the Favorable and Intermediate ELN Groups of our dataset, for which lncRNA risk groups had adequate pt numbers. Among pts in ELN Favorable Group, lncRNA low-risk pts (n=128) had higher CR rates (P=.003) and longer DFS (P<.001), OS (P<.001) and EFS (P<.001) than lncRNA high-risk pts (n=32). Similarly, in the ELN Intermediate Group (n=85), lncRNA low-risk group status (n=28) associated with higher CR rates (P=.01), longer OS (P=.01) and EFS (P=.005) and a trend for longer DFS (P=.08). To gain biological insights, we examined the molecular pathways regulated by the 55 prognostic lncRNAs. To minimize the confounding effects of differences in the concurrent cytogenetic abnormalities, we restricted these analyses to the ELN Favorable Group. We identified approximately 900 transcripts that were differentially expressed between lncRNA low- and high-risk pts. DAVID pathway analyses showed enrichment of genes involved in the processes of phosphorylation, acetylation and RNA-binding. Ingenuity pathway analyses of up-stream regulators identified aberrant activity of homeobox genes such as MEIS1, HOXA9 and HOXA10 in the lncRNA low-risk group and other transcription factors such as MYC, FOSB and JUN in the high-risk group. Conclusion: We conclude that lncRNA profiling provides meaningful prognostic and biologic information in CA-AML pts. Disclosures Kolitz: Magellan Health: Consultancy, Honoraria. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Stone:Cornerstone: Consultancy; Astellas: Consultancy; Orsenix: Consultancy; Merck: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Novartis: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Fujifilm: Consultancy; Ono: Consultancy; Jazz: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy; AbbVie: Consultancy; Agios: Consultancy, Research Funding. Uy:Curis: Consultancy; GlycoMimetics: Consultancy. Wang:Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau. Stock:Jazz Pharmaceuticals: Consultancy.

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High CRP-Albumin Ratio Predicts Poor Prognosis in Transplant Ineligible Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2021-144832 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3388-3388

Author(s):

Hajime Senjo ◽

Masahiro Onozawa ◽

Daisuke Hidaka ◽

Shota Yokoyama ◽

Satoshi Yamamoto ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Risk Group ◽

Intermediate Risk ◽

Newly Diagnosed ◽

High Group ◽

Advisory Committees ◽

Intermediate Group

Abstract Introduction. Older patients aged over 65 with acute myeloid leukemia (AML) are often ineligible for hematopoietic stem cell transplantation (HSCT) and generally have a poor prognosis. The personalized strategy for appropriate treatment for these patients has not yet been completely established. While C-reactive-protein (CRP) to albumin ratio (CAR) based on serum level of CRP and albumin (Alb) predicts prognosis of patients with hematological malignancies treated with HSCT (Miyashita E, BBMT. 2019), the prognostic significance of this inflammatory and nutritional assessment in transplant-ineligible elderly patients with AML remains to be clarified. Methods. Hokkaido Leukemia Net (HLN) is prospective cohort study collecting AML samples from hospitals of North Japan Hematology Study Group (NJHSG). In this study, we focused on older (≥65 years) patients with newly diagnosed AML treated without HSCT and investigated cytogenetic and molecular abnormality of leukemic cells including FLT3-ITD, NPM1, CEBPA, and KIT. We stratified the patients into favorable, intermediate, and adverse risk group based on NCCN 2017. Based on the result of blood sample test, we assessed CAR [CRP (mg/dL) / Alb (g/dL)] at diagnosis for each patient. Since the median CAR at diagnosis was 0.52 in this cohort, we defined CAR < 0.52 and ≥ 0.52 as CAR low and CAR high, respectively. We evaluated the impacts of NCCN 2017 and CAR on overall survival (OS) in these patients. The study procedures were in accordance with the Helsinki Declaration and institutional ethical guidelines, conducted under the auspices of the institutional ethics committee, and approved by the institutional review boards. Results. In total, 197 patients with newly diagnosed AML patients aged 65 or older enrolled in HLN between April 2010 and March 2019. Nine patients undergone HSCT were excluded, and 188 patients were reviewed (Age 65-93, median 72; male 119, female 69). In this cohort, classification based on NCCN 2017 successfully divided the prognosis of the patients for 2-year and 5-year OS [2-year OS; favorable group, 58.1%; intermediate group, 29.4%; adverse group, 12.6%, 5-year OS; favorable group, 33.7%, intermediate group, 8.74%; adverse group, 9.44%, P=0.000079, Figure A]. OS in patients with CAR 0.52 or more was significantly lower than the low score group [2-year OS; CAR low group, 43.4%; CAR high group, 21.5%; 5-year OS; CAR low group, 21.0%; CAR high group, 9.96%, P=0.00013, Figure B]. In a univariate analysis, higher age, adverse group in NCCN 2017, high CAR, and not reached complete remission (CR) after first induction chemotherapy were associated with poor 2-year OS. A multivariate analysis demonstrated that adverse group in NCCN 2017 and high CAR were independently associated with poor 2-year OS (adverse group in NCCN 2017; HR, 1.671; 95% CI, 1.157 to 2.421, P=0.007, high CAR; HR, 1.572; 95% CI, 1.093 to 2.276, P=0.01618; log-rank). Combined with NCCN 2017, while there were no significant prognostic impacts of CAR at diagnosis in patients with favorable or adverse risk groups (Figure C, E), we found that in intermediate risk group the patients with high CAR had poorer prognosis than patients with low CAR [2-year OS; CAR low group, 43.7%; CAR high group, 15.9%, P=0.0000658; Figure D]. Altogether, we demonstrated that high CAR predicts poor prognosis in the transplant-ineligible elderly patients with newly diagnosed AML and improves risk stratification of the patients with NCCN 2017 intermediate risk group. Conclusion. CAR is a simple and easily evaluable parameter for predicting outcomes of transplant-ineligible elderly patients with newly diagnosed AML, independently from NCCN disease risk classification. Moreover, CAR can further stratify the prognosis of patients with NCCN 2017 intermediate risk group and improve the predictive risk stratification for elderly AML patients. Figure 1 Figure 1. Disclosures Kondo: SANWA KAGAKU KENKYUSHO CO.,LTD.: Consultancy; Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Teshima: Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Inc.: Honoraria; Fuji pharma CO.,Ltd: Research Funding; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; TEIJIN PHARMA Limited: Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Astellas Pharma Inc.: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Gentium/Jazz Pharmaceuticals: Consultancy; Sanofi S.A.: Research Funding.

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Clinical and Molecular Variables Associated with Atherosclerotic Vascular Disease in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2018-99-110846 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4366-4366

Author(s):

Mark G. Faber ◽

Amanda Przespolewski ◽

Jeffrey Baron ◽

Tara Cronin ◽

Wei Tan ◽

...

Keyword(s):

Vascular Disease ◽

Board Of Directors ◽

Research Funding ◽

Low Risk ◽

Atherosclerotic Vascular Disease ◽

Vascular Events ◽

Advisory Committees ◽

Risk Of Death ◽

Clonal Hematopoiesis ◽

Increased Risk

Abstract BACKGROUND: Healthy adults with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of death from vascular disease. CHIP-associated genetic mutations such as ASXL1, TET2 and DNMT3A have been linked to the pathogenesis of atherosclerosis (Jaiswal et al, 2017). MDS and CHIP share common genetics events; in fact, certain MDS cases are believed to arise from preexisting clonal hematopoiesis. A recent SEER study demonstrated that 60 months from diagnosis, patients (pts) with low-risk MDS are at higher risk of death from cardiovascular causes than from MDS itself (Brunner et al, 2017). As the relationship between vascular disease and clonal hematopoiesis is delineated, management of vascular disease in patients with MDS is becoming increasingly important. Here we performed a retrospective analysis of MDS pts from Roswell Park to evaluate whether MDS-related factors such as morphologic subtype, treatment, cytopenias, iron status, blast percentage and karyotype modify atherosclerosis risk when molecular events are taken into account. METHODS: Over the past decade, 850 pts were diagnosed with MDS were seen and treated at Roswell Park. For the purpose of this study, 192 pts with a confirmed diagnosis of MDS seen between 2012- 2017 were investigated for cardiac events, blood counts, iron or inflammatory status as ferritin, MDS-related morphology, molecular profile and treatment. Cases were comprehensively annotated for the presence of vascular events, (defined as imaging or procedure verified coronary artery disease, cerebrovascular accident, or peripheral vascular disease) by review of the medical record. Conventional karyotype information was present in 98% of the cohort and NGS based multi-gene sequencing results through FoundationOne Heme was evaluated in 30% of the cohort. Numeric variables were summarized using simple descriptive statistics. A logistic regression model was used to investigate the association between vascular events and a set of explanatory variables for multivariate analysis. RESULTS: The median age at diagnosis for this cohort is 69 (range: 21-91) years; 60% were male and 57% had MDS with excess blasts. By IPSS-R, 25% had very low/low risk MDS, 22% had intermediate risk MDS and 46% had high risk MDS. The most common karyotypic abnormalities were normal (42%), complex (17%), trisomy 8 (10%) and del 7/7q (10%). Of the 59 patients with molecular data, the most common recurrent somatic mutations were in ASXL1 (47%), TET2 (30%), SRSF2 (27%), RAS pathway (22%) SF3B1 (22%), RUNX1 (20%) and TP53 (17%). The overall incidence of vascular events in this cohort was 27%. Vascular disease was noted at similar frequencies for pts with low grade and high grade MDS (based on subtype of MDS), 23% vs. 30% (p=0.33) respectively. Women with MDS were significantly less likely to develop to vascular events than were men, 16% vs. 34% (p=0.007) and the mean age of pts with vascular disease was significantly higher, 71 vs. 65 years (p=0.005). Traditional risk factors such as hypertension and hyperlipidemia were more prevalent in MDS pts with vascular disease. Baseline hemoglobin, transfusion requirements and blast % levels were comparable in MDS patients with or without vascular disease. MDS pts with vascular disease had higher median ferritin levels, 432 vs. 301 ng/ml (p=0.093). When stratified by the IPSS-R, pts with very low risk MDS had a non-significant lower incidence of cardiac events, 14% vs. 25% (p=0.30), compared to other groups. Treatment with erythropoietin, lenalidomide or hypomethylating agents was not associated with vascular events. MDS pts with mutations in ASXL1 and SRSF2 had a higher incidence of vascular disease, 43% vs. 13% (p=0.01) and 38% vs 20% (p=0.18) respectively. On multivariable analysis, older age and male gender were most strongly predictive for vascular events. CONCLUSION: Here we retrospectively examined the potential factors associated with cardiovascular events in MDS pts treated at our institute over a 5-year time span. Male gender and older age were positively associated. Treatment regimen (erythropoietin injections or lenalidomide) and IPSS-R were not associated with an increased risk for vascular events. Factors independent of traditional cardiac risk factors, such as somatic mutations in ASXL1, iron overload and/or an inflammatory milieu i.e, ferritin, may contribute to atherosclerotic vascular disease in pts with MDS. Disclosures Baron: Pfizer Pharmaceuticals: Other: Previously served as a consult on the Advisory Boards (May 2017).. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Griffiths:Pfizer, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Alexion Inc.: Honoraria, Research Funding. Thota:Incyte: Speakers Bureau.

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Prognostic Value of the Hevylite Chain in MGUS Patients in a Population Study

Blood ◽

10.1182/blood-2018-99-110329 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4506-4506

Author(s):

Aránzazu García Mateo ◽

Maria-Victoria Mateos ◽

Alberto Orfao ◽

Teresa Contreras Sanfeliciano ◽

Luzalba del Carmen Contreras Sanfeliciano ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Prognostic Value ◽

Plasma Cells ◽

Risk Group ◽

Clonal Expansion ◽

Low Risk ◽

Advisory Committees ◽

Risk Of Progression

Abstract Introduction: Studies have shown that a large monoclonal protein (MP) and immunoparesis in MGUS/SMM have predictive value of progression since they may be indirectly related to the degree of clonal expansion of bone marrow plasma cells (BMPC). A recently available assay, the Hevylite® (HLC), has allowed a more precise determination of MP and the quantification of isotype-matched immunosuppression (i.e. suppression of the monoclonal isotype but of the alternative light chain) which has shown prognostic value in some studies. In this study, we aim to evaluate the association between the alteration of the HLC parameters in MGUS patients with already known prognostic factors, but also, with less studied biomarkers such as circulating clonal plasma cells (cCPC) by Next Generation Flow (NGF) (Flores-Montero et al., Leukemia, 2017). Methods: A total of 175 MGUS patients diagnosed between October 2008 and September 2015 were included in the study. The median follow-up was 64 months (range: 1-100 months). MGUS and MGUS progression were defined according to the International Myeloma Working Group (IMWG) criteria. Clinical records were retrieved for all patients. HLC determinations were carried on a SPA+ turbidimeter analyzer and using specific reagents (Binding Site®, UK). The 6 HLCs pairs (IgGk, IgGl, IgAk, IgAl, IgMk and IgMl) were analyzed in all samples. HLC normal ranges were defined by the laboratory based on normal sera. Statistical analysis was done using IBM-SPSS-22. Results: HLC ratio was altered in 56.3% of the 111 patients with available sera (47.5% for IgG MGUS and 73.9% and 87.5% for IgA and IgM), respectively (p = 0.026). Patients with altered HLC ratio presented an MP significantly higher (Table 1) than those with normal ratio (0.62 g/dL vs 0.33 g/dL, p<0.0001; HR: 53.23 with 95% CI (2.82 / 1005.54), p=0.008); 100% of the patients had MP>1.5 g/dL (p = 0.044)). Interestingly, it also correlated with a greater frequency and a greater amount of cCPC by NGF (68.29%, p=0.001; 0.2864 /mL vs 0.0139 /mL p=0.0001). Regarding BMPC infiltration, there was a correlation between altered HLC ratios and greater percentages of infiltration of BMPC (3.72% vs. 2.43%, p = 0.001) and higher percentage of BMPC measured by multiparameter flow cytometry (MFC) (54.42% vs 24.42%, p <0.001; HR: 1.02 with 95% CI (1.01 / 1.03), p = 0.007). Patients with altered HLC ratio presented MP> 1.5 mg/dL (100%, p = 0.044), non-IgG (78,12%, p = 0.003) and ratio of altered CLL (77,77%, p = 0.011). Patients with normal HLC ratios correlated with other low risk of progression to MM parameters, such as a MP <1 g/dL (100%, p=0.0001) or <0,5 g/dL (87.8%, p=0.0001) or less than 5% of BMPC (91.3%, p=0.007).Considering the IMWG risk stratification model, 100% of the patients classified as intermediate risk (p = 0.0001) had an altered HLC ratio, while in the low risk group, ratios were evenly distributed. When considering the Spanish (GEM) model, 92% of the patients in the low risk group had normal HLC ratios (p = 0.010). Uninvolved HLC suppression >25% was observed in 15.2% of the patients. These patients presented significantly higher MP (0.91 g/dL vs 0.42 g/dL, p<0.0001; HR: 7.22 with 95% CI (1.11 / 46.83), p=0.038), greater infiltration of BMPC by MFC (70.54% vs 35.52%, p<0.0001; HR: 1.02 with 95% CI (1 / 1.04), p=0.040) and a greater amount of cCPC (0.8905 /mL vs 0.0256 /mL, p=0.030) compared to those without HLC suppression. Patients with moderate (<25%) or no suppression correlated with less aggressive parameters, such as the lower MP, <1 g/dL (95.8%, p = 0.0001) or < 0.5 g/dL (70.5%, p = 0.005). However, no significant correlation was found between the IMWG or the Spanish risk stratification models, and the frequency of HLC suppression. Conclusions: HLC abnormalities have been associated with negative prognostic factors previously established, reinforcing the idea that the HLC parameters are directly related to a greater propensity of clonal expansion, or a greater tumor load. However, the short follow-up time did not allow the confirmation of the prognostic value of HLC alterations regarding greater risk of progression to MM. A re-evaluation of the results at 10 years is foreseen. We expect to be able to access whether an evolving pattern exists for the HLC parameters mainly to investigate if the immune suppression by HLC progressively intensifies in patients closest to progressing to MM. Disclosures García Mateo: Celgene: Honoraria; Amgen: Honoraria; Binding Site: Research Funding. Mateos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Puig:Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Queizan:Janssen: Consultancy. Olivier:Celgene: Honoraria; Jassen: Honoraria.

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Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽

10.1182/blood.v130.suppl_1.901.901 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 901-901

Author(s):

Sara Bringhen ◽

Massimo Offidani ◽

Pellegrino Musto ◽

Anna Marina Liberati ◽

Giulia Benevolo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Cell Transplant ◽

Newly Diagnosed ◽

Community Based ◽

Advisory Committees ◽

Risk Of Death ◽

Grade 3 ◽

To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in >75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p<0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

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Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽

10.1182/blood.v128.22.3306.3306 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3306-3306

Author(s):

Yi L. Hwa ◽

Qian Shi ◽

Shaji Kumar ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Research Funding ◽

Beta Blockers ◽

Multivariable Analysis ◽

Advisory Committees ◽

Risk Of Death ◽

Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset

Blood ◽

10.1182/blood.v124.21.3339.3339 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3339-3339 ◽

Cited By ~ 4

Author(s):

Ciara Louise Freeman ◽

Mark Dixon ◽

Richard Houghton ◽

Kathryn Humphrey ◽

Gunter Fingerle-Rowson ◽

...

Keyword(s):

Risk Factors ◽

Monoclonal Antibodies ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukaemia ◽

Signs And Symptoms ◽

Leukemic Cells ◽

Tumour Burden ◽

Advisory Committees ◽

Anti Cd20

Abstract Background: The administration of anti-CD20 monoclonal antibodies (mAb) in patients with B-cell lympho-proliferative disorders is frequently accompanied by a constellation of signs and symptoms that have been labelled as infusion-related reactions (IRR). The pathophysiology of IRR remains poorly understood as do predictors of risk, which may relate to the mechanism of action of the anti-CD20, disease-related factors such as tumour burden or host factors such as polymorphisms of Fc gamma receptor 3A (FcγRIIIA). In the CLL11 trial (NCT01010061), patients with previously untreated chronic lymphocytic leukaemia and comorbidities were randomised to receive either rituximab (type I anti-CD20 mAb) or obinutuzumab (type II and glycoengineered anti-CD20 mAb) in combination with chlorambucil for six cycles. Obinutuzumab led to faster depletion of B cells and achieved an improvement in outcome parameters such as response and progression-free survival compared with the rituximab arm, but was also associated with a higher rate and increased severity of IRR. To better understand the profile of risk for IRR in patients with CLL, we performed an exploratory analysis on data obtained from patients treated with either one of the two antibodies given in combination with chlorambucil. Methods: Patients from the prospective, randomized Phase III CLL11 study who received a first infusion of obinutuzumab (N=331) or rituximab (N=326) were included. Baseline pre-treatment risk factors thought to play a possible role in the development of IRR were identified a priori and included patient demographics, concurrent conditions and premedications, parameters of disease burden, prognostic factors, laboratory variables and FcγR genotype. Baseline values for mean fluorescence intensity (MFI) of CD20, gated on the circulating CLL clone, and MFI of CD16, gated on the natural killer (NK) cell population (CD56+16+) in peripheral blood were also available for N=510 patients. The primary outcome, development of an IRR with the first infusion, was defined as the occurrence of related signs and symptoms during or within 24 hours of administration of antibody. Due to the short-term nature of the initial IRR a multivariate logistical regression analysis was performed rather than a time to event analysis. Internal validation of this model, derived from a single dataset, was conducted using the established resampling technique of bootstrapping. This assessed the proportion of times each variable retained significance at α=0.10 when the model was fitted to bootstrapped samples of the dataset. Results: Patients that appeared to be at greater risk of developing any grade of IRR with the first infusion of rituximab or obinutuzumab were those treated with obinutuzumab, those with higher surface expression CD20 on CLL cells (MFI CD20) and greater FcγRIIIA (MFI CD16) on NK cells in peripheral blood, those with higher affinity FcγRIIIA genotype (VV), more pronounced neutropenia and splenomegaly at baseline (Table 1). Higher baseline absolute lymphocyte count and the presence of respiratory comorbidity also appeared to increase risk. All variables significant for inclusion in the model are shown in Table 1. Looking at those patients treated with obinutuzumab only, the most important determinant of risk was MFI CD20 (OR 3.6 95% CI 1.6-7.9). The impact of glucocorticoid premedication in reducing risk in obinutuzumab treated patients was not sufficient to reach significance, however, patients were not randomised to this intervention. Conclusion: This work identifies novel disease- and patient-specific biological variables that appear to play a role in the development of IRR in patients with CLL treated with anti-CD20 mAb, although the treatment received (obinutuzumab >rituximab) confers greatest risk. In addition to parameters of tumour burden, target antigen expression and gene polymorphisms of FcγR also appear to contribute to the risk of developing an IRR. Our results support the hypothesis that higher rates of IRR seen with the administration of obinutuzumab may result from stronger activation upon binding to CD20 on leukemic cells and subsequent enhanced cross-linking between CD20 expressing leukemic cells and FcγRIIIA bearing effector cells. Further studies involving obinutuzumab in this patient population will be needed to externally validate the results of this exploratory analysis. Disclosures Freeman: Roche Pharmaceuticals: clinical research fellowship supported by Roche Pharmaceuticals (secondment from Bart's) Other. Dixon:Roche Pharmaceuticals: Employment. Houghton:Roche Pharmaceuticals: Employment. Humphrey:Roche: Employment. Fingerle-Rowson:Roche Pharmaceuticals: Employment. Kreuzer:Roche Pharmaceuticals: Research Funding. Engelke:Roche: Travel grants Other. Hallek:Roche Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Goede:Bristol Myers Squibb: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

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