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In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1794-1794

Abstract: BACKGROUND: The INTERIM study (ClinicalTrials.gov NCT 00858806) showed that in elderly ( 〉 65 years) Ph+ CML patients selected for a stable complete cytogenetic response (CCgR) lasting 〉 2 years, the policy of intermittent imatinib treatment (one month on/one month off) may affect the markers of residual disease (CCgR and major molecular response, MMR or MR3.0), but not the clinical outcomes (overall survival and progression-free survival) (Russo D et al, Blood 2013; 121(26):5138-44). AIMS: To update the results of the INTERIM Study, with a follow up ≥ 5 years. METHODS: After 4 years of follow up, patients continouing INTERIM treatment were monitored with peripheral blood RT-Q-PCR every 3 months according to the ELN-2013 guidelines. RESULTS: At 48thmonth, out of 76 patients enrolled in the INTERIM study, 13 (17%) had lost CCgR and MMR, 14 (18%) had lost MMR only and 50 patients (75%) continued INTERIM. The patients who had lost CCgR and/or MMR resumed imatinib continuously and all of them regained the CCgR and the MMR, within 3 to 12 months. No patient progressed to accelerated or blastic phase, or developed clonal chromosomal abnormalities in Ph+ cells, or BCR-ABL mutations. No patient complained of new or more severe side effects during the months “on”. After a follow up ≥ 5 years, 45/76 (59%) enrolled patients are on INTERIM, with a probability of maintaining intermittent administration of 59% (95% CI: 46-69). No patient lost the CCgR and only 9 additional patients lost the MMR while on intermittent treatment. All these patients resumed continuous imatinib treatment and regained the MMR. Thus, at ≥ 5 years, the probability of maintaing CCgR is 80% (95% CI 68-87) and the probability of maintaining the MMR is 61% (95% CI: 48-71). From start of INTERIM, 6 patients died but no deaths were related to CML progression (3 cases of other non haematological neoplasms, 1 stroke, 1 myocardial infarction, 1 chronic obstructive pulmonary disease).The PFS at ≥ 5 years is 94% (95% CI: 89-100) CONCLUSIONS: In summary, with a follow up ≥ 5 years, intermittent imatinib administration (INTERIM) confirmed to be safe, to produce a reversible increase of residual molecular disease in about one third of patients, but not to affect the long-term outcome. Aknowledgments: This work was supported in part by EuropeanLeukemiaNet (contract LSHC-CT-2004-503216) through the European Treatment and Outcome Study (EUTOS), supported by Novartis Oncology Europe, and COFIN 2009 Disclosures Russo: Celgene: Research Funding; Gilead: Research Funding; Novartis: Consultancy. Martinelli:Novartis: Speakers Bureau; Bristol-Meyers and Squibb: Speakers Bureau; Pfizer: Speakers Bureau. Soverini:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Speakers Bureau. Turri:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Meyers Squibb: Consultancy, Honoraria. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Tiribelli:Novartis: Consultancy, Honoraria; Bristol-Meyers and Squibb: Consultancy, Honoraria. Rosti:Consultant: Consultancy, Speakers Bureau; Bristol-Meiers Squibb: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.1794.1794

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1023-1023

Abstract: Abstract 1023 Background: The annual incidence rate of myelodysplastic syndromes (MDS) in the general population is estimated at around 3–5/100,000. Because of a lack of specific therapies, until recently small attention has been devoted to costs of treatment of MDS. A specific Diagnosis-Related Group is still missing. In the US the mean annual cost for MDS patients ranges from $19,811 to $51,066. Aims: To assess the annual cost of illness (COI) and quality of life (QoL) of patients with MDS in Italy. Methods: The Costo Sociale delle Sindromi Mielodisplastiche e Qualità della vita in Italia (CoSMIQ) is an observational, cross-sectional, retrospective, prevalence-based, multicenter study based on an International Prognostic Scoring System (IPSS)-stratified sample of patients with MDS ≥18 years of age seen in standard clinical practice at 7 hematologic institutions across Italy (3 in the North; 2 in the Center; and 2 in the South). Demographics, clinical history, health care and non-healthcare resource consumption, and patients' and caregivers' productivity losses were collected by physicians using clinical records and information provided by patients. COI (in Euro (€) 2010) was determined utilizing a societal perspective. QoL was assessed via EORTC QLQ-C30 and QOL-E v.2 questionnaires, the latter being a new specific tool for the assessment of health-related QoL in patients with MDS. Kendall's tau rank correlation, chi-squared test, multivariate analysis of variance (ANOVA; MANOVA) and multiple linear regressions were performed when appropriate. Results: In all, 225 of 234 patients who met the inclusion criteria were analyzed (IPSS low risk: 124 patients; intermediate-1 (Int-1) risk: 75 patients; Int-2 and high risk: 26 patients) (Table). The total COI reached €27,980.4 ± 28,322.2 (mean ± standard deviation) (Figure). Cost-drivers of COI were antianemics (lower-risk) and antineoplastics (higher-risk). The Italian National Health Service (INHS) funded the greatest share of COI (from 97.4% to 99.5%). In general, CoSMIQ patients perform worse than the general population in all EORTC QLQ-C30 domains; the total global health status (QL) domain reached 65.1 ± 22.2 (low risk: 64.2 ± 22.3; Int-1 risk: 67.4 ± 22.1; higher-risk: 62.5 ± 22.3). QL was negatively correlated with COI (p=0.049) and patients' age (p=0.089), and positively correlated with disease duration (p=0.203). Keeping the other predictors constant, RBC transfusion dependence predicts increased COI (p=0.006) and lower QL (p=0.009). Regarding the QOL-E questionnaire, the QOL-E MDS-specific domain (MDSS) was positively correlated with total COI (p=0.0002), and patients' age (p=0.348) and negatively correlated with disease duration (p=0.013). The total QOL MDSS was 27.5 ± 19.8 (low risk: 25.3 ± 19.4; Int-1 risk: 29.6 ± 19.3; higher-risk: 31.6 ± 22.2). The total treatment-outcome index domain (QOL TOI) was 49.4 ± 14.4 (low risk: 49.1 ± 14.7; Int-1 risk: 48.3 ± 14.7; higher-risk: 53.9 ± 11.7). QOL TOI was negatively correlated with total COI (p=0.379), and patients' age (p=0.0003) and positively correlated with disease duration (p=0.162). Differences by IPSS group were not statistically significant for COI (p=0.191) or for any domain of the EORTC QLQ-C30 or QOL-E questionnaires (p=0.124; p=0.467). Conclusion: MDS dramatically increases INHS budgets while negatively impacting patients' QoL. The results of the CoSMIQ study highlight the strong correlation between RBC transfusion dependence and both COI and QL. Disclosures: Lazzaro: Celgene Srl: Research Funding. Martelli:Celgene Srl: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.1023.1023

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4389-4389

Abstract: Different CSF3R mutations (CSF3RMT) result in aberrant G-CSF signaling pathways and are linked to a wide range of myeloid disorders. Loss-of-function mutations in its extracellular domain cause severe congenital neutropenia (SCN). Activating mutations in the juxtamembrane region have been associated with a variety of myeloid malignancies. Truncating mutations in the cytoplasmic domain are associated with SCN cases that progress to MDS or AML. In this study, we evaluate the extent to which different CSF3RMT associate with disease onset, progression to leukemia and neutrophil counts in patients (pts) diagnosed with myeloid malignancies. We identified CSF3RMT cases in a cohort of 1400 pts [median age 71 years (yrs)]. We analyzed somatic and germline mutational patterns, and cross-sectional correlation with other gene mutations in CSF3RMT. A stringent algorithm based on conserved amino acid residues and alterations of protein features was used to predict the pathogenic significance of CSF3RMT. We identified 44 CSF3RMT: 33 germline (CSF3RGL) and 11 somatic (CSF3RS) variants. Most CSF3RGL were found in pts (median age 63 yrs) with MDS or related conditions (87% of all mutant cases), conversely these mutations were present in 5% (n= 22/424) of MDS, 3% (n= 7/244) MDS/MPN and 〈 1% (n= 3/392) of AML and in 1 out of 3 pts with aCML tested. Mutations were mostly missense and located between the cytoplasmic (58%: M696T, R698C (isoform III), D732N, P733T, S744F, Y752*, E808K), and extracellular (42%: C131Y, E149Q, A208V, Q216H, D320N, E405K, S413L, Y562H) domains. No mutations were detected in the juxtamembrane domain. Variants were grouped in Tier-1 (61%: C131Y, E149Q, A208V, Q216H, D320N, E405K, S413L, Y562H Y752*, E808K) and Tier-2 (variants with uncertain significance, 39%: S413L, M696T, R689C, D732N, P733T, S744F). E808K and R698C were the most common amino acid changes in Tier-1 (53%) and Tier-2 (44%), respectively. A total of 4/7 pts with E808K progressed to AML (but none with R698C), supporting previous observations that E808K (or E785K) represents a pathogenic variant predisposing to leukemia. A total of 46% (n=14) of pts with CSF3RGL had neutropenia [median 0.9x109/L (0.02-1.22x109/L)] at the time of sampling. Two pts diagnosed with a prior cancer manifested sustained neutropenia before the diagnosis of MDS and MDS/MPN. G-CSF was administered in 21% of pts. Alterations in -7/7q- were common (21%). Some pts also harbored other somatic mutations in NF1 (15%), DNMT3A (12%), SETBP1 (12%), or U2AF1 (12%). Of note, 1 patient carried mutations in WAS and GATA2 and another carried a mutation in VPS45, which have been previously associated with SCN/MDS. The patient with aCML harbored also a CSF3RS (T615A). Overall combined allelic burden in pts cohort was 2% vs. 1.6% expected allelic burden in control populations for the same variants (P=.02). CSF3R S were found in 11 pts (median age 71 yrs) with AML or MDS related conditions (73% of all mutant cases), conversely these mutations were present in 1.4% (n= 6/424) of AML, 〈 1% in MDS (n= 2/244) and MDS/MPN (n= 1/392) and in 2/3 pts with aCML tested. Mutations were missense in 63% of pts, T618I being most recurrent (n=5/11; 45%). Frameshifts accounted for 36% of the mutations and were localized in the cytoplasmic domain (Q741*, Q749*, Y752*, Q768*). All mutations were heterozygous. At the time of sampling 3/11 pts had leukocytosis and 3/11 had neutropenia. Mutations were distributed between the juxtamembrane domain (55%) and the cytoplasmic domain (45%). Mutations in the extracellular domain were not detected. Pts with sAML mostly carried mutations in the juxtamembrane domain (67%), those with MDS carried only in cytoplasmic domain, and those with MDS/MPN or aCML carried mutations in both the juxtamembrane and extracellular domains. There was one somatic and one RUNX1GL mutation. The cytogenetic abnormalities -7/7q- were detected in 18% (2/11) of cases. Interestingly, T618I was found solely in pts with sAML. Focusing on associations between CSF3RMT and mutations in the class III receptor tyrosine kinases CSF1R, FLT3, and KIT we identified only FLT3 to be co-mutated with CSF3RMT. All 3 pts (2 CSF3RGL and 1 CSF3RS) with such co-mutations evolved to AML. In sum, we found that CSF3RGL do not commonly co-occur with CSF3RS, suggesting that the neutropenia observed at the sampling time most likely is causative of undetected GL variants and/or is representative of a long unrecognized disease. Disclosures Nazha: MEI: Consultancy. Carraway:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau; FibroGen: Consultancy. Santini:Otsuka: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-116554

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2363-2363

Abstract: INTRODUCTION: Patients with myelodysplastic syndromes (MDS) are at continuous risk of complications and must face the reality of a relatively low survival while still mainly depending on supportive care. The chronic nature of MDS, the risk of progressive evolution, advanced age, anemia and the rapid changes in physical status make the MDS patient unique within the cancer population. Quality of Life (QoL) in MDS is undoubtedly compromised by functional, psychological, and disease-specific components. Treatment options are still scarce in this elderly population and hematologists must select candidates for experimental therapy. Patients’ preferences are requisites for therapeutic choice so that it is essential that clinicians understand patients’ perceptions. STUDY DESIGN: We designed a multicenter Italian 18-month prospective observational study in 150 MDS patients from diagnosis to evaluate the correlation between QoL changes and changes in Hb and other MDS-related variables. Comparison between the patients’ and the physicians’ perception of QoL, QoL changes related to adaptation, progression and treatment response, and feasibility, consistency and validity of the QoL instruments were evaluated. Selection criteria included adult age, MDS at diagnosis with IPSS score & lt; 2, at least 1 cytopenia, ability to complete the QoL questionnaires and ECOG PS & lt; 3. METHODS: The QoL instruments (QOL-E v.2, LASA scale, and EQ-5D) were completed by patients and physicians (both blind to each other’s responses) at baseline, months 1, 3, 6, 12, and 18. Clinical and laboratory data were collected throughout the study. RESULTS: Median age was 74 (IQ range 67–79); 85 were males (57%). Patients were classified according to WHO: 48 RA (32%), 30 RCMD (20%), 21 RAEB-1 (14%), 7 RAEB-2 (5%), 6 5q-syndrome (4%), 4 RARS (3%), 3 CMML (2%), 1 RCMD/RS (1%), 30 MDS-U (20%). Fifty-six patients (37%) had IPSS low risk, 62 (41%) Int-1 and 14 (9%) Int-2. In 18 (12%) patients IPSS was not evaluable due to karyotype. Thirty-nine patients (26%) were transfusion-dependent (TD) and 28 (72%) had at least 1 additional cytopenia. In the transfusion-free (TF) patients, median Hb was 10.5 g/dL (IQ range 9.2–12.6); 77 patients (69%) were anemic (Hb & lt; 12.0 g/dL) and 48 (43%) had at least 1 additional cytopenia. ECOG PS was significantly better in TF patients (p=0.0061). Charlson’s comorbidity index was 0 in 78 patients (52%), 1 in 38 patients (25%), 2 in 20 patients (13%) and ≥ 3 in 14 patients (9%). Median serum epo was 50.4 U/L (N=94). Of the 29 QOL-E items, 25 items had a response rate & gt; 90%. Though 26 of the 29 QOL-E items showed significant correlations between patients’ and physicians’ scores, there were significant score differences in 9 (31%) of the items with a general trend of physicians to overestimate patients’ problems. Several QoL scores correlated with Hb levels and were significantly lower in TD patients than in TF patients (Table). Table. Patient QoL scores in transfusion-dependent (TD) and transfusion-free (TF) patients and correlations with Hb values. QOL domain Whole group Correlation with Hb r (p) TD patients (n = 39) TF patients (n = 111) p QOL-E, scores Q1 33 (33–67) 0.186 (0.023) 33 (0–33) 33 (33–67) 0.036 Q2 67 (67–100) −0.032 (0.70) 67 (33–100) 67 (67–67) 0.11 Physical 63 (38–75) 0.286 (0.0004) 50 (38–63) 63 (50–75) 0.0072 Social 50 (25–63) 0.197 (0.017) 44 (17–63) 50 (38–63) 0.064 Sexual 100 (50–100) 0.250 (0.011) 50 (0–100) 100 (75–100) 0.0011 Fatigue 81 (71–86) 0.236 (0.0038) 78 (67–86) 81 (71–90) 0.14 MDS-specific 81 (71–90) 0.287 (0.0005) 74 (63–83) 83 (74–93) 0.0005 LASA, scores Energy 48 ± 25 0.285 (0.0004) 42 ± 25 50 ± 25 0.081 Activity 54 ± 27 0.226 (0.0055) 50 ± 29 56 ± 26 0.24 General 53 ± 27 0.304 (0.0002) 44 ± 25 57 ± 27 0.0093 EQ-5D, scores Mobility 50 (50–100) 0.119 (0.15) 50 (50–100) 75 (50–100) 0.45 Self-Care 100 (100–100) 0.148 (0.074) 100 (100–100) 100 (100–100) 0.14 Usual Activity 100 (50–100) 0.129 (0.12) 50 (50–100) 100 (50–100) 0.0050 Pain/Discomfort 50 (50–100) −0.027 (0.75) 100 (50–100) 50 (50–100) 0.48 Anxiety/Depression 50 (50–100) 0.010 (0.90) 50 (50–100) 50 (50–100) 0.88 VAS Health State 60 ± 20 0.212 (0.010) 52 ± 19 63 ± 19 0.0020 Data are reported as mean ± standard deviation or median and interquartile range as appropriate. CONCLUSIONS: QoL is compromised in MDS and is associated with Hb values and transfusion-dependence. Patient preferences must be evaluated when considering treatment options since hematologists seem to overestimate patients’ perception of healthrelated problems. The disease-specific questionnaire, QOL-E, and the LASA scale are valid tools for the evaluation of QoL in MDS patients.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.2363.2363

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

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In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 6971-6973

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157487

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9785-9788

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-162397

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 4079-4081

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157489

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 1-2

Abstract: Introduction: Anemia is the predominant cytopenia observed in patients with myelodysplastic syndromes (MDS), with many patients requiring regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) remain a standard of care among patients with lower-risk MDS (LR-MDS), defined by International Prognostic Scoring System-Revised (IPSS-R) as Very Low-, Low-, or Intermediate-risk MDS, and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L. Recent studies of epoetin alfa and darbepoetin alfa have demonstrated efficacy among patients with LR-MDS, but the patient population in whom a clinically significant effect is seen may be limited (Fenaux P, et al. Leukemia 2018;32:2648-2658; Platzbecker U, et al. Leukemia 2017;31:1944-1950). A novel therapeutic option that increases the frequency of response and the duration of RBC transfusion independence (TI) in patients with LR-MDS would provide an important clinical benefit in this patient population. Luspatercept is a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs (Suragani RNVS, et al. Nat Med 2014;20:408-414). It is now approved in both the US and EU for patients with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs on the basis of results from a phase 3 study (Fenaux P, Platzbecker U, et al. N Engl J Med 2020;382:140-151). Luspatercept may also be beneficial in treating anemia in patients with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic patients with LR-MDS, 63% of patients receiving luspatercept (0.75-1.75 mg/kg) achieved a modified hematologic improvement - erythroid (mHI-E) response (Platzbecker U, et al. Lancet Oncol 2017;18:1338-1347); when analyzed by RS status, 69% of patients with ≥ 15% RS and 43% of patients with & lt; 15% RS achieved mHI-E response. Study Design and Methods: The COMMANDS trial is a phase 3, open-label randomized study to compare the efficacy and safety of luspatercept versus epoetin alfa in anemic patients with IPSS-R defined LR-MDS, either with or without ≥ 15% RS, who are ESA naive, and who require regular RBC transfusions. Eligible patients must be aged ≥ 18 years at time of consent, have a documented diagnosis of IPSS-R defined LR-MDS with & lt; 5% blasts in the bone marrow, have sEPO levels & lt; 500 U/L, and require RBC transfusions (defined as an average transfusion requirement of 2-6 RBC units/8 weeks for ≥ 8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤ 2 doses of prior epoetin alfa permitted if ≥ 8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for the treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. A total of approximately 350 eligible patients will be randomized in a 1:1 ratio to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) SC once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, may be used in combination with study treatment in both arms. Randomization will be stratified by baseline RBC transfusion burden ( & lt; 4 vs ≥ 4 RBC units per 8 weeks), RS status (with RS+ defined as RS ≥ 15%, or ≥ 5% [but & lt; 15%] if SF3B1 mutation is present), and baseline sEPO level (≤ 200 U/L versus & gt; 200 U/L). In addition, ≥ 40% and ≤ 60% of randomized patients will be RS+, and ≥ 25% will have sEPO & gt; 200 U/L. The primary endpoint is the proportion of patients who achieve RBC-TI for 12 weeks within the first 24 weeks on study, with a concurrent mean hemoglobin (Hb) increase of ≥ 1.5 g/dL compared with baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E response per International Working Group (IWG) 2006 criteria, and safety. The COMMANDS trial is registered at ClinicalTrials.gov (NCT03682536) and EudraCT (number 2017-003190-34). Disclosures Platzbecker: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria. Santini:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding. Komrokji:Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-140284

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 23-24

Abstract: Introduction Sex represents a major source of diversity among patients in terms of pathophysiology, clinical presentation, prognosis and response to therapy, and therefore sex (gender)-informed medicine is becoming a new paradigm to refine clinical decision making process in different human diseases. Myelodysplastic syndromes (MDS) are heterogeneous disease characterized by ineffective hematopoiesis and risk of leukemic evolution. We aimed to study clinical effect of sex in MDS as a basis to improve patient prognostication and personalized treatment. Material and Methods We analysed three MDS populations from disease-specific registries (Italian registry n=3015, Dusseldorf registry, n=1185 and Spanish registry, n=7678). Results We first analysed the association of sex with clinical and biological disease-specific features. These analyses were conducted on Italian MDS cohort. Considering WHO categories, female patients showed higher prevalence of single lineage dysplasia and MDS with del(5q), while males were characterized by higher frequency of multilineage dysplasia and excess blasts (P & lt;.001). Considering cytogenetic abnormalities, an increased frequency of del(5q) in female patients was observed (P & lt;.001). We analysed mutations in 47 MDS-associated genes. Males presented higher prevalence of mutations with respect to females (82.2% vs. 76.2%, P & lt;.001), with higher prevalence of co-mutations. Considering specific gene pathways, splicing factors mutations were reported more frequently in males vs. females (66% vs. 56%, P & lt;.001). Focusing on MDS with ring sideroblasts (MDS-RS), we noticed a significant different distribution of splicing factor mutations according to sex: SF3B1 was mutated in large majority of female patients (95% of mutated cases), while SRSF2 and ZRSR2 mutations accounts for a significant proportion (26%) of mutated cases in males. In addition, males showed higher prevalence of mutations in DNA methylation genes (P & lt;.001), while tumor suppressor genes (TP53) were more frequently mutated in female patients. Clustering analysis showed specific co-mutation patterns in splicing and DNA methylation genes according to sex. Overall survival was significantly worse for male vs. female patients (P & lt;.001). In a multivariable analysis including age, neutrophils, hemoglobin and platelet counts, percentage of marrow blasts and cytogenetics as covariate, sex showed an independent effect on probability of survival (HR for female vs. male patients 0.56, P=.012). The prognostic effect of sex was observed in very-low, low and intermediate risk category according to IPSS-R (Table 1). The independent prognostic effect of sex was confirmed in two independent populations (Dusseldorf and Spanish registries). Competitive risk analysis showed higher prevalence of non-leukemic vs. leukemic deaths (P & lt;.001) in patients with early disease stage. In these patients, we observed a higher prevalence of cardiac comorbidity/deaths in males vs. females (P & lt;.001 and P=.005, respectively). Moreover, the risk of non-leukemic death was higher in males vs. females especially when hemoglobin levels were & lt;10 g/dl. These results suggest that in MDS patients, sex may capture prognostic information on the detrimental interactions between anemia and cardiac comorbidity. As a final step we aimed to integrate the prognostic value of sex into currently available prognostic systems (IPSS-R). We used random effects Cox proportional-hazards multistate modelling for developing an innovative personalized prognostic model ("Sex and age-adjusted IPSS-R", IPSS-RAS). All the three study populations were included (n=11.878). The predicted and observed outcomes correlate well in internal cross-validation. IPSS-RAS substantially improved predictive accuracy of original IPSS-R (concordance 0.68 vs. 0.62), especially in patients with early disease stage. Interestingly, demographic factors (age and sex) accounted for & gt;30% of whole prognostic power. Conclusion In MDS, sex captures additional prognostic information at individual patient level, possibly reflecting a different molecular background and, most importantly, a sex-specific interaction between disease-related factors and comorbidity. Our results strengthen the rationale to include sex in personalized prognostic assessment in these diseases. Table 1 Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Passamonti:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; BMS: Speakers Bureau. Santoro:Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD: Speakers Bureau; Arqule, Sanofi: Consultancy; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy, Speakers Bureau; Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule: Consultancy; Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, MSD: Membership on an entity's Board of Directors or advisory committees. Santini:Menarini: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Acceleron: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Johnson & Johnson: Honoraria. Sanz:Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees; LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Celgene BMS: 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; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-138775

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 9828-9830

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-166802

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7