scholarly journals Severe Anemia Is Associated with a Risk of Infection in Patients with Myelodysplastic Syndromes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4668-4668
Author(s):  
Annika Kasprzak ◽  
Julia Andresen ◽  
Barbara Hildebrandt ◽  
Kathrin Nachtkamp ◽  
Andrea Kündgen ◽  
...  
Keyword(s):  
Risk Factor ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Infectious Complication ◽  
Infectious Complications ◽  
Morbidity And Mortality ◽  
Severe Thrombocytopenia ◽  
Infectious Episode ◽  
The Difference

Abstract Introduction: Infections are a well-recognized complication in patients (pts) with myelodysplastic syndromes (MDS) that contribute substantially to the morbidity and mortality particularly in pts suffering from neutropenia. Neutropenia and other immune defects including impaired neutrophil function have been reported to be predisposing factors for severe infections. Furthermore, some of the therapies may worsen neutropenia and lead to an additional risk factor to develop infectious episodes. Since infectious complications are no primary endpoint in clinical trials epidemiological data on infections in large cohorts of MDS pts is sparse. Methods: We performed a retrospective analysis of 3.787 MDS-patients from the Duesseldorf MDS Registry who were diagnosed between 1980 and 2018. Infectious complications were defined as clinical symptoms of infection associated with the need for antibiotic and/or antifungal therapy, and/or the isolation of a pathogen and/or an identifiable site of infection by physical examination. Infectious episodes were categorized as fever of unknown origin, microbiologically or clinically documented infection. Results: Amongst our study cohort, 42% of the pts suffered from at least one infectious complication of any type during the course of their disease. Most infectious diseases were of bacterial origin (34.7%) and in 17% a pathogen was isolated. Pneumonia was the most common site of infection (64%). Pts who experienced at least one infectious episode had a significant poorer overall survival (OS) than pts without such events (21 vs 37 months, p<0.001). Pts with a higher risk disease according to the IPSS-R had fewer infections during the course of the disease than pts with a lower-risk MDS (487 total infections vs 1481, p<0.001). Nevertheless, the presence of any infectious episode lead to an inferior OS in lower-risk (40 vs 29 months, p<0.001) as well as in higher-risk disease (38 vs 24 months, p=0.006). In univariate analyses comparing pts who had no infections versus those who had one or more, pts with older age (>65 years) tended to have a higher incidence of infectious episodes (p<0.001). In addition, patients older than 65 suffering from infections had a shorter OS than patients who did not experience an infectious complication. The difference in OS was highly significant with 16 months for pts suffering from infectious complications compared to 24 months (p<0.001). Likewise, an excruciating higher incidence of infections was noted in MDS pts compared to infections incidence in a non-MDS population in Germany. The risk of a 65-year-old or older MDS pt to suffer from pneumonia was 6.9 times higher compared to a non-MDS pt of the same age. We found a highly significant negative correlation between the depth of cytopenia in all three myeloid lineages and the presence of infections (p<0.001), suggesting that patients with severe cytopenia suffer from infectious episodes more frequently. However, pts with an isolated neutropenia having an absolute neutrophil count below a threshold of 0.8 × 10 9/L and suffering from infectious episodes had no inferior OS than neutropenic pts without any infection (25 vs 32 months, p=0.583). Pts with isolated severe thrombocytopenia with a platelet count <50 × 10 9/L had a similar OS of 26 months for pts with infectious complications. The difference in OS between pts with and without infections was even more pronounced in this group (26 vs 48 months, p=0.002). Still, a low hemoglobin (Hb) level <9g/dl appeared to be the most significant risk factor for pts with infections, resulting in the poorest OAS of only 17 months in pts with isolated anemia suffering from infections. In multivariate analyses, we found that Hb <9g/dl, followed by ANC <0.8 × 10 9/L, were independently associated with the risk to suffer from an infection during the disease. In addition, a Hb <9g/dl was the most important blood count parameter with regard to OS when compared to platelets <50 × 10 9/L, and ANC <0.8 × 10 9/L. Conclusion: The incidence of infections significantly increases in pts with advanced age. MDS-pts in general are more vulnerable for infection-related morbidity and mortality than non-MDS-pts. Low hemoglobin and platelet counts were both found to be associated with a worse prognosis compared to low neutrophil counts. The appearance of at least one infectious episode leads to an inferior Disclosures Nachtkamp: Jazz: Speakers Bureau; bsh medical: Speakers Bureau; Celgene: Other: Travel Support. Kobbe: Celgene: Research Funding. Gattermann: Celgene: Honoraria; Takeda: Research Funding; Novartis: Honoraria. Germing: Novartis: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Janssen: Honoraria.

Lenalidomide Treatment For Lower Risk Non-Deletion 5q Myelodysplastic Syndromes Patients Yields Higher Response Rates When Used Prior To Azanucleosides

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1507-1507
Author(s):  
Rami S Komrokji ◽  
Maria G. Corrales-Yepez ◽  
Najla H Al Ali ◽  
Eric Padron ◽  
Jeffrey E Lancet ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Response Rates ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy

Abstract Introduction Lenalidomide (LEN) is the standard of care for treatment of transfusion dependent lower risk myelodysplastic syndromes (MDS) with chromosome 5q deletion (del 5q). In the MDS-002 study, 26% of lower risk transfusion dependent MDS patients became red blood cell transfusion independent after LEN treatment. National Comprehensive Cancer Network (NCCN) clinical guidelines list LEN as a second line treatment alternative for transfusion dependent anemia in lower risk non-del 5q MDS after azanucleosides failure. The response rate to LEN after azanucleosides failure, however, is not known given that the MDS-002 study preceded FDA approval of azanucleosides. To address the best sequence of LEN to optimize response potential in lower risk MDS, we examined the response rates to LEN in non-del 5q lower risk MDS when offered as first line after (erythroid stimulating agents) ESA's or after azacitidine failure. Methods This was a retrospective study conducted using the Moffitt Cancer Center (MCC) MDS database. We identified patients with lower risk MDS who received both LEN and azacitidine as first or second line therapy after erythroid stimulating agents. Lower risk MDS was defined according to the international prognostic scoring system (IPSS) Low or intermediate-1 (int-1) risk groups. The primary endpoint was to compare rates of erythroid hematological improvement (HI-E) between the group of patients who received LEN as first line therapy followed by azacitidine as second line (LEN 1st line group) and those who received LEN as second line therapy after azacitidine (LEN 2nd line group). HI was defined according to international working group criteria (IWG 2006). Chi- square test was used for categorical variables, T-test was used for continuous variables, and Kaplan Meier estimates for overall survival. All analyses were conducted using SPSS statistical software (IBM version 21) Results We identified 63 patients who received both azacitidine and LEN as first and second line where 37 patients were in group 1 (LEN 1st line) and 26 patients were in group 2 (LEN 2nd line). Baseline characteristics between the two groups are summarized in Table-1. There were no statistically significant differences between the 2 groups in terms of mean age at diagnosis, gender, WHO subtype, revised IPSS, or mean blood counts. The majority of patients had refractory cytopenia with multilineage dysplasia (RCMD) and had low risk revised IPSS . The rate of HI-E was 38% (n=14) among LEN 1st line group compared to 12% (n=3) in LEN 2nd line group. (p=0.04). There was no difference in overall survival (OS) among the two groups with a median OS of 104 months and 87 months, respectively, p=0.55. There was no difference in AML transformation rate, 5.4% (n=2) and 11% (n=3) among the two groups, respectively, p=0.33. There were no differences in response rates to azacitidine among the two groups. Among the Len 1st line group response to 2nd line azacitidine was 38% (n=14) compared to 35% (n=9) among those who received azacitidine as first line followed by LEN as 2nd line. (p=0.69). Conclusion LEN yields a higher rate of HI-E in non-del 5q lower risk MDS when used as first line therapy. If validated in a larger cohort, LEN should be considered for 1st line therapy after ESAs rather than after azacitidine failure. Responses to azacitidine were similar among the two groups, indicating no adverse effect of LEN on azacitidine response. Disclosures: Komrokji: Celgene: Research Funding, Speakers Bureau. Off Label Use: use of lenalidomide in non del 5q. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

Activity Of Single Agent Temsirolimus and Associated Impact On Bone Marrow Vascularization and T-Cell Composition In Patients With Myelodysplastic Syndromes – Result Of The Prospective Temds Trial Of The German MDS-SG

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2808-2808
Author(s):  
Martin Wermke ◽  
Claudia Schuster ◽  
Claudia Schönefeldt ◽  
Christiane Jakob ◽  
Malte von Bonin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Single Agent ◽  
Infectious Complications ◽  
T Cell Subsets ◽  
Concentration Data ◽  
Cell Composition

Abstract Introduction Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

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

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

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

scholarly journals Mutation Profiles Identify Distinct Clusters of Lower Risk Myelodysplastic Syndromes with Unique Clinical and Biological Features and Clinical Endpoints

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Luca Malcovati ◽  
Simon Crouch ◽  
Aniek O. De Graaf ◽  
Sarah Sandmann ◽  
Magnus Tobiasson ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Disease Progression ◽  
Board Of Directors ◽  
Clinical Features ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Information Criterion ◽  
Advisory Committees ◽  
The Right

Background. The severity of hematopoietic impairment and the kinetics of disease progression in lower risk myelodysplastic syndromes (LR-MDS) are extremely variable. Genomic profiling has the potential to inform the clinical management of these disorders, including improved classification, risk assessment and therapeutic choice. In the present study, based on a comprehensive mutation analysis in a large and clinically well-characterized cohort of LR-MDS patients, either recruited into the European MDS Registry or referred to European excellence centers involved in the MDS-RIGHT project, we adopted unsupervised hierarchical clustering analyses to identify relevant genetically defined disease subtypes within early stage MDS. Methods. The dataset comprised 856 cases identified as LR-MDS based on IPSS risk low or intermediate-1. Median age was 73 years (range 36-98); IPSS-R risk was very low in 30.1% of patients, low in 50.4%, intermediate in 19.5%. We investigated possible sub-structure amongst patients according to their mutational profiles, and correlated this sub-structure with relevant endpoints. For this analysis, unsupervised clustering was used, based on a mixture model of multivariate Bernoulli distributions. The optimal number of clusters was chosen using the Bayes Information Criterion (BIC), with secondary structure identified with the Akaike Information Criterion (AIC). Results. This analysis identified three distinct clusters within LR-MDS. Cluster 1 comprised exclusively patients with SF3B1 mutation, either isolated or associated with other mutations (SF3B1-mutant cluster) (37% of patients). Cluster 2 was characterized by excess mutations associated with higher risk disease (high-risk (HR) cluster) (27% of patients), including a significantly higher prevalence of ASXL1, IDH1/IDH2, SRSF2, RUNX1, CBL and EZH2 mutations (P&lt;.001). This cluster also showed a significantly higher number of mutations per patient compared to other groups (P&lt;.001), suggesting a subtending clonal progression resulting in the accumulation of sub-clonal mutations. Finally, cluster 3 was characterized by mutation profiles as observed in Clonal Hematopoiesis of Indeterminate Potential (CHIP) (CHIP-like cluster) (36% of patients), mainly including isolated DNMT3A, TET2 or ASXL1 mutations, pointing toward the contribution of extra-clonal factors to disease expressivity. In addition, this cluster showed enrichment in TP53 mutations, as recently reported in community-dwelling elderly individuals with unexplained anemia (Blood 2020;135:1161-70). The three recognized clusters showed distinct clinical features and outcome measures. Patients within HR cluster were significantly older (P=.008) and showed significant enrichment in WHO categories with multi-lineage dysplasia and excess blasts (P&lt;.001) and IPSS-R intermediate risk scores (P&lt;.001), as well as significantly lower platelet count (P=.001). Conversely, patients within the CHIP-like cluster showed significantly higher hemoglobin values compared with the other two clusters (P=.001). As expected, the SF3B1-mutant cluster was significantly enriched for MDS with ring sideroblasts (MDS-RS) and showed significantly lower hemoglobin values (P=.001) and increased values of serum ferritin and transferrin saturation compared to other clusters (P=.001 and P=.002, respectively). HR-cluster showed significantly lower overall survival (OS) compared to CHIP-like and SF3B1-mutant clusters (median 2.6 vs 6.8 or 6.4 years; P&lt;.001), and higher risk of progression into higher-risk MDS or acute myeloid leukemia (AML) (median 4.2 vs 12.7 years or not reached; P&lt;.001). No significant difference in either OS or risk of disease progression was noticed between SF3B1-mutant and CHIP-like clusters. However, a significantly shorter time-to-treatment with erythropoiesis stimulating agents was noticed in the SF3B1-mutant cluster (P=.007), suggesting a more rapid erythropoietic impairment that did not translate into a worse outcome. Conclusion. Mutation profiling identifies meaningful clusters of lower risk MDS with distinct molecular pathways, clinical features and endpoints. These results represent a robust basis to inform genetic ontogeny-based classification and individual risk assessment, as well as to inspire biology-driven clinical trials in lower risk MDS. Disclosures Symeonidis: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi/Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; WinMedica: Research Funding; Celgene: Honoraria, Research Funding; Astellas: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stauder:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Van Marrewijk:EUMDS and MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Other: Project manager of the EUMDS Registry.

scholarly journals Potential Barriers to Clinical Trials of New Therapeutics for Myelodysplastic Syndromes: Wide Variation in Risk Definitions and Trial Enrollment Criteria

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4378-4378
Author(s):  
Andrew M. Brunner ◽  
Jacqueline S. Garcia ◽  
R. Coleman Lindsley ◽  
Gregory A. Abel ◽  
Donna S Neuberg ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Phase 1 ◽  
Phase Iii ◽  
Pharmacological Intervention ◽  
Exclusion Criteria ◽  
Very High

Abstract Introduction: Myelodysplastic syndromes (MDS) are neoplasms characterized by cytopenias, high risk of leukemic progression, and poor overall survival. Chemotherapy for MDS is not curative, and no new drugs have been approved for the treatment of MDS in over a decade. Clinical trials should be considered at any time during the management of patients with MDS, but enrollment criteria may be barriers that limit accrual. In this study, we extracted MDS clinical trial data from clinicaltrials.gov, and compared study indications and characteristics, including inclusion and exclusion criteria. Methods: We identified MDS clinical trials via clinicaltrials.gov (accessed: April 16, 2018). Studies were included if they allowed "MDS," "Myelodysplastic syndromes," "Preleukemia," and/or "Myelodysplasia," based on the pre-defined 'related terms' criteria in the database. We included interventional studies open in the United States that were listed as recruiting or not yet recruiting, for adults (age 18-64) and older adults (age 65+). We excluded studies that were observational in nature, involved a transplant-based intervention, or did not use a pharmacological intervention. We coded inclusion and exclusion criteria based on those provided by study authors in the database. Results: 83 interventional clinical trials enrolling patients with MDS were identified. Studies started enrollment between 4/1/2013 and 3/27/2018, and anticipated reaching the primary objective between 5/1/2017 and 6/1/2025. The median planned study duration was 38 mo (range 10-95). In total, studies sought to enroll 8866 patients over 273 study-years; the median study enrollment estimate was 1.7 patients/month, or across all trials 247 patients/month. Clinical trials could be exclusive to MDS patients (n=28), include MDS patients and other myeloid malignancies e.g. AML (n=44), or include MDS patients and other cancers including solid tumors (n=11). For clinical trials exclusive to MDS, the total enrollment goal was 1966 patients over 96 study-years, with a median rate of 1.4 patients/month (range 0.3-13.2) or total of 63 patients/month across all studies. 33 trials were phase 1 studies, 17 were phase 1/2, 26 were phase II, 1 trial was phase 2/3, and 6 were phase III studies. The primary endpoint was typically MTD (n=50) or ORR (n=22), while 5 studies had an OS endpoint. Most trials specified "higher risk" MDS (n=44); 8 specified "lower risk" MDS and 31 allowed all MDS risk or did not specify risk (Figure 1). Lower risk MDS studies were all exclusive to MDS patients. Inclusion criteria related to MDS risk varied significantly according to whether a study was MDS-specific or not (p=0.021): 82% of MDS-specific trials had risk exclusions, compared to 72% of myeloid trials, and only 36% of trials open across cancers. Of 52 trials specifying MDS risk, 20 included IPSS criteria, 24 included IPSS-R criteria, and 27 had blast count criteria. Lower risk MDS criteria was variably defined as IPSS low or INT-1 disease (n=3), IPSS-R very low or low risk (n=1), IPSS-R VL, L, or intermediate risk (n=4), or blast counts < 5% (n=1), < 10% (n=2), or <20% (n=2). There were variations in the criteria for transfusion dependence, including 2 transfusion units in 8 weeks (n=3), 4 in 8 weeks (n=2), 2 in 4 weeks (n=2), 1 in 6 weeks (n=1), and 2 in 16 weeks (n=1). For higher risk MDS, criteria included IPSS INT-1, INT-2, or High risk (n=7), IPSS INT-2 or High risk (n=12), IPSS-R intermediate, high, or very high risk (n=12), or IPSS-R high or very high (n=9); blast counts were set at >5% (n=12) or >10% blasts (n=12). Most studies specified exclusion of CNS disease, even though CNS involvement is exceptionally rare in MDS. 43 trials excluded concurrent cardiovascular disease; most often (n=18) requiring 6mo since a cardiovascular event. 46 trials had language excluding concurrent cancers, including 4 that did not allow any prior cancer, and 17 required ³24mo disease free. Exclusions for prior cancers did not vary according to primary outcome (MTD or PK, vs ORR/OS, p=0.16). 20 of 56 studies with MTD or early outcomes (e.g. PK) required cancer-free intervals of ³1y, while 7 allowed concurrent cancers if not on active therapy. Discussion: Currently enrolling MDS clinical trials show significant variation in their inclusion and exclusion criteria. Heterogeneous definitions of basic entry criteria, such as the definition of higher- and lower-risk MDS, may cause barriers to enrollment. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Garcia:Celgene: Consultancy.

scholarly journals PARAMETERS OF HAEMOSTASIS SYSTEM, CAPILLAROTROPHIC DISORDERS, COMPLICATION AND THEIR CORRECTION IN PATIENTS WITH ACUTE LEUKEMIA

2019 ◽  
Vol 6 (1) ◽  
pp. 16-23
Author(s):  
N. I. Makieieva ◽  
S.O. Gubar ◽  
V.A. Koval ◽  
T.S. Zharkova
Keyword(s):  
Acute Leukemia ◽  
Replacement Therapy ◽  
Therapy Group ◽  
Infectious Complications ◽  
Severe Thrombocytopenia ◽  
Leading Role ◽  
Treatment And Prevention ◽  
The Difference ◽  
Group 2

DISORDERS OF HAEMOSTASIS, COMPLICATIONS AND THEIR CORRECTION IN CHILDREN WITH ACUTE LEUKEMIAMakieieva N. I., Gubar S.O., Koval V. A., Zharkova T. S.Purpose. To study the significance of capillarotrophic disorders in the development of complications of chemotherapy in children with acute leukemia and the effectiveness of the treatment and prevention of these complications. Patients and methods. Parameters of haemostasis system (plasma, platelet and vascular chains) have been studied in 86 children aged 1 - 17 years with acute leukemia in the dynamics of the disease, before the start and on the background of chemotherapy during the development of infectious and non-infectious complications. The patients received standard therapy according to the BFM protocols were divided into two groups according to the difference in the substitution therapy: group 1 - patients did not receive platelet replacement therapy, group 2 - ones received replacement therapy, including preventive platelet transfusion. The effectiveness of therapy was accessed by comparing the number of complications in patients of both groups.  Results. In 100% of patients, severe myelosuppression was observed. A decrease in the number of platelets in the blood lower than 20*109/l was found to be in 43% of patients, agranulocytosis was found in 35%. Patients of the 1st group had bleeding  in 33% of cases, anemia of II-III stage of severity  in 76%, gastroenterologic inflammation  in 21%, respiratory distress syndrome in 33% , pneumonia  in 47% , sepsis  in 14%, other localization of infection in 13%. In patients of the 2nd group the incidence of complications of chemotherapy and their severity decreased in 2–6 times. The concept of the leading role of thrombocytopenia in the development of stages of capillarotrophic disorders is presented. Conclusions. The results indicate the important role of severe thrombocytopenia and capillarotrophic disorders in the occurrence of infectious and non-infectious complications of chemotherapy in patients with acute leukemia. Adequate replacement therapy with donor platelets reduces the number and severity of complications, increases the effectiveness of treatment.Key words:  acute leukemia, children,  complications, correction, haemostasis Порушення гемостазу,  ускладненнята їх корекція у хворихна гостру лейкемію дітей.Макєєва Н.І., Губар С.О., Коваль В.А., Жаркова Т.С.Мета: вивчити значимість капілляротрофічних порушень в розвитку ускладнень хіміотерапії у дітей хворих на гостру лейкеміюй ефективність лікування і профілактики цих ускладнень. Пацієнти і методи. У 86 дітей у віці 1 - 17 років хворих на гостру лейкемію вивчені показники системи гемостазу (плазмового, тромбоцитарного та судинної ланок) в динаміці захворювання, до початку і на тлі застосування хіміотерапії при розвитку інфекційних і не інфекційних ускладнень. Хворі отримували стандартну терапію за протоколами BFM були розділені на дві групи за відмінностями в терапії супроводу: 1 група - хворі не отримували замісну терапію тромбоконцентратом, 2 група - отримувала замісну терапію, в тому числі, і превентивну трансфузию тромбоцитів. Ефективність терапії оцінювали порівняням числа ускладнень у пацієнтів обох груп. Результати. У 100% хворих виявлена тяжка мієлосупресія зі зниженням числа тромбоцитів у крові нижче 20 * '10 9 / л у 43%, агранулоцитоз - у 35%. У хворих 1 групи реєстрували кровотечу - у 33%, анемію II-III ступеня тяжкості - у 76%, стоматоезофагоентероколіт - у 21%, респіраторний дистрес-синдром - у 33%, пневмонію - в 47%, сепсис - у 14%, інші локалізації інфекції – у 13% випадків. У хворих 2 групи в 2 - 6 разів зменшилася частота розвитку ускладнень хіміотерапії та їх тяжкість. Представлена концепція провідної ролі тромбоцитопенії в розвитку стадій капілляротрофічних порушень. Висновки. Отримані результати свідчать про важливу роль важкої тромбоцитопенії і капілляротрофічних порушень у виникненні інфекційних і неінфекційних ускладнень хіміотерапії у хворих на гостру лейкемію. Адекватна замісна терапія донорським тромбоконцентратом знижує число і тяжкість ускладнень, підвищує ефективність лікування.Ключові слова: гемостаз, гостра лейкемія, діти, корекція, ускладнення Нарушения гемостаза, осложнения и их коррекция у детей сострым лейкозом.Макеева Н.И., Губарь С.О., Коваль В.А., Жаркова Т.С. Цель: изучить значимость капилляротрофических нарушений в развитии осложнений химиотерапии у детей больных острым лейкозом  и эффективность лечения  и профилактики этих осложнений. Пациенты и методы. У 86 детей в возрасте 1 – 17 лет больных острым лейкозом изучены показатели системы гемостаза (плазменного, тромбоцитарного и сосудистого звеньев) в динамике заболевания, до начала  и на фоне применения химиотерапии при развитии инфекционных и не инфекционных осложнений. Больные получали стандартную терапию по протоколам BFM были разделены на две группы по различию в проводимой терапии сопровождения: 1 группа – больные не получали заместительную терапию тромбоконцентратом, 2 группа -  получала заместительную терапию, в том числе, и превентивную трансфузию тромбоцитов. Эффективность терапии оценивали сравнением числа осложнений у пациентов обеих групп.Результаты. У 100% больных выявлена тяжелая миелосупрессия со снижением числа тромбоцитов в крови ниже 20*10 9/л у 43%, агранулоцитоз – у 35%. У больных І группы регистрировали кровотечение - в 33%, анемия II-III степени тяжести - в 76%, стоматоэзофагоентероколит - в 21%,  респираторный дистресс-синдром – в 33%, пневмония – в 47%, сепсис – в 14%, иные локализации инфекции – 13% случаев.  У больных II группы  в 2 – 6 раз уменьшилась частота развития осложнений химиотерапии и их тяжесть. Представлена концепция ведущей роли тромбоцитопении в развитии стадий капилляротрофических нарушений. Выводы. Полученные результаты свидетельствуют о важной роли тяжелой тромбоцитопении и капилляротрофических нарушений в возникновении инфекционных и неинфекционных осложнений химиотерапии у больных острым лейкозом. Адекватная заместительная терапия донорским тромбоконцентратом снижает число и тяжесть осложнений, повышает эффективность лечения.Ключевые слова:  гемостаз, дети,коррекция, осложнения, острый лейкоз  

Randomized Open-Label Phase II Study of Decitabine in Patients with Low- or Intermediate-1 Risk Myelodysplastic Syndromes,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3812-3812
Author(s):  
Guillermo Garcia-Manero ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
De Novo ◽  
Phase Ii Study ◽  
Refractory Anemia ◽  
Metabolic Inhibitor ◽  
Open Label ◽  
Improvement Rate

Abstract Abstract 3812 Background: Decitabine (DAC) is a hypomethylating agent indicated for the treatment of myelodysplastic syndromes (MDS). We hypothesized that low-dose subcutaneous (SC) schedules of DAC may be active and safe in patients with lower risk MDS. Methods: This randomized, open-label, multicenter phase II study evaluated 2 DAC regimens in patients with low- or intermediate-1 risk MDS: 20 mg/m2/day SC for 3 consecutive days every 28 days (Arm A) or 20 mg/m2/day SC every 7 days (on days 1, 8, and 15) for 21 days, followed by 7 days without DAC (Arm B). The aim was to determine clinical activity, safety, and tolerability of the 2 regimens. The primary objective was overall improvement rate (OIR), defined as complete remission (CR), partial remission (PR), marrow CR (mCR), or hematologic improvement (HI), measured at the end of each cycle using patient's best response according to International Working Group (IWG) 2006 criteria. Secondary objectives included safety, HI, transfusion independence, cytogenetic response, and overall survival (OS). The tertiary objective was change in DNA methylation. Treatment on study was for ≤1 year, but patients who had clinical benefit could continue DAC off protocol. Target enrollment was 80 patients. Categorical and continuous variables were compared using Fisher's exact test and 1-way ANOVA, respectively; survival was analyzed with Kaplan-Meier, Cox regression, and log-rank methods. Results: Sixty-seven patients were randomized at 5 sites when the trial terminated early after achievement of protocol-defined superiority. On Oct 12, 2009, the posterior probability of at least 95% was met that OIR to Arm A was superior to Arm B. Thus enrollment in Arm B was terminated on Oct 16, 2009. Arm A was terminated on Dec 2, 2009, based on sponsor review and confirmation of achievement of protocol-defined superiority. The mITT population comprised 65 patients (Arm A, n=43; Arm B, n=22). Overall mean age (SD) was 68 y (13), 69% men; 89% had de novo MDS, and median time since diagnosis was 3.6 months (range, 0, 118). 94% had ECOG performance status (PS) 0–1, 29% had IPSS low-risk classification, and 69% had normal baseline cytogenetics. Arms were balanced apart from having more men in Arm B (P =.01). Patients received a median 7.0 (range, 1, 13) cycles of therapy in Arm A and 5.5 (2, 16) in Arm B. At study end, OIR was 10/43 (23%; 7 CR, 3 HI) and 5/22 (23%; 1 mCR, 1 PR, 3 HI) for Arms A and B, respectively (95% CI of difference: -21.1, 22.1). For transfusion status, of patients who were RBC dependent at baseline, 6/17 (35%) in Arm A and 4/8 (50%) in Arm B became independent on study. Corresponding data for platelets were 3/4 (75%) and 1/4 (25%), respectively. Approximately 40% of patients in each arm who were RBC/platelet dependent at baseline became independent on study. Of patients who were RBC independent at baseline, 24/26 (92%) in Arm A and 11/14 (79%) in Arm B remained independent on study. Corresponding data for platelets were 34/39 (87%) and 17/18 (94%), respectively, and for patients who were RBC/platelet independent, 22/25 (88%) and 9/12 (75%), respectively. IPSS, age, time from MDS diagnosis, type of MDS, prior MDS therapy, baseline cytogenetics, and ECOG PS were similar and did not affect OIR, HI, or transfusion status. There were no cytogenetic responses. At 500 days follow-up, median OS had not been reached (Figure); there were 8 deaths (19%) in Arm A and 6 (27%) in Arm B (hazard ratio 1.5; 95% CI: 0.5, 4.5). Induction of hypomethylation was seen in patients in both arms. All patients experienced ≥1 treatment-emergent AE. The most frequent at least possibly drug-related AEs for Arms A and B, respectively, were neutropenia (28% vs 36%), anemia (23% vs 18%), thrombocytopenia (16% vs 32%), fatigue (19% vs 9%), and leukopenia (9% vs 27%). Drug-related AEs of grade ≥3 were mainly hematologic and reported in 17 patients (40%) in Arm A and 10 patients (46%) in Arm B. There were no deaths within the first 8 weeks on study. One patient (neutropenic sepsis) in Arm A and 2 patients (1 each of anemia and MDS) in Arm B died as a result of an AE; none were reported to be drug related. Conclusions: DAC 20 mg/m2/day SC is active and well tolerated in lower-risk MDS. The OIR was similar in both arms, but a 3-day regimen appears more favorable than a 3x per week regimen based on all efficacy and safety results and the statistical decision to terminate the study early based on Arm A superiority. Further studies with these regimens are warranted. Disclosures: Off Label Use: Dacogen is a nucleoside metabolic inhibitor indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. Borthakur:Eisai: Research Funding. Faderl:Eisai: Research Funding. Stein:Eisai: Employment. Noble:Eisai: Employment. Kassalow:Eisai: Employment. Kantarjian:Eisai: Research Funding.

Increased Number of Driver Mutations Is a Predictor of Response to Hypomethylating Agents in Patients with Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 51-51
Author(s):  
Guillermo Montalban-Bravo ◽  
Ana Alfonso Pierola ◽  
Feng Wang ◽  
Song Xingzhi ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Advisory Board ◽  
Response To Therapy ◽  
Driver Mutations ◽  
Hypomethylating Agents ◽  
Risk Patients ◽  
Clinical Records ◽  
The Impact

Abstract INTRODUCTION: Hypomethylating agents (HMA) such as azacitidine and decitabine remain the standard of care for the treatment of myelodysplastic syndromes (MDS). Although responses are seen in 40-60% patients, median response duration is 12-14 months. Eventual loss of response is associated with poor outcomes. Multiple studies have tried do identify biomarkers of response. Presence of TET2 mutations has been associated to increased response in several studies. Clear identification of predictors of response is still required. METHODS: We evaluated a total of 180 previously untreated patients with MDS or CMML that received HMA therapy at The University of Texas MD Anderson Cancer Center. Next generation sequencing (NGS), analyzing a panel of 28 genes (ABL1, ASXL1, BRAF, DNMT3A, EGFR, EZH2, FLT3, GATA1, GATA2, HRAS, IDH1, IDH2, IKZF2, JAK2, KIT, KRAS, MDM2, MLL, MPL, MYD88, NOTCH1, NPM1, NRAS, PTPN11, RUNX1, TET2, TP53 and WT1) was performed prior to therapy with HMA. Clinical and demographic data was obtained from clinical records. Generalized linear models were used to study association of response rates (ORR=overall and CR=complete) and risk factors. Response was defined following 2006 IWG criteria. The Kaplan-Meier produce limit methods were used to estimate the median overall survival (OS) and leukemia-free survival (LFS). RESULTS: Patient characteristics are shown in Table 1. Median age at diagnosis was 67 years (range 20-88). A total of 108 patients (60%) had lower-risk MDS based on IPSS and 72 (40%) had higher-risk MDS. A total of 143 patients (79%) had MDS and 37 (21%) had CMML. Eighty-seven (49%) patients had normal karyotype with 36 (20%) having complex karyotype. Therapy consisted in azacitidine monotherapy in 60 (33%) patients, decitabine monotherapy in 55 (31%) and guadecitabine or combinations in 65 (36%). The ORR was 58% (105/180) with 66 (37%) patients achieving CR. A total of 123 (68%) patients had at least one detectable mutation. Median number of mutations was 1 (range 0-5). The most frequently detected mutations included TET2 (23%), TP53 (16%) and RUNX1 (12%) which were all present in >10% cases. Frequency of detected mutations is shown in Figure 1A. Presence of ASXL1 mutation was associated with decreased likelihood of achieving CR (OR 0.30, 95% CI 0.10-0.93, p=0.037). No differences in ORR were observed based on presence of any individual mutation or any other clinical characteristic. Presence of TET2 mutation was not significantly associated with an increased likelihood of response (OR 1.32, 95% CI 0.64-2.70, p=0.453) or CR (OR 1.30, 95% CI 0.64-2.65, p=0.469). We subsequently analyzed the impact of number of detected mutations on response to therapy. Presence of three or more detectable mutations was associated with lower ORR (OR 0.29, 95% CI 0.10-0.88, p=0.028) and a trend to lower likelihood of achieving a CR (OR 0.22, 95% CI 0.05-1.01, p=0.052). Mutations in ASXL1 (p=0.003), BRAF (p=0.021), DNMT3A (p=0.018), EZH2 (p=0.01), GATA2 (p=0.021), MLL (p<0.001), NRAS (p<0.001), PTPN11 (p=0.002), RUNX1 (p=0.015), TET2 (p=0.001) and WT1 (p=0.04) tended to appear in patients with three or more mutations. Presence of TET2 mutations did not predict for ORR (OR 1.83, 95% CI 0.78-4.25, p=0.163) or CR (OR 1.75, 95% CI 0.80-3.81, p=0.159) within cases with less than three mutations. The median follow up of the cohort was 14.5 months (range 2.4-101.3 months). Patients who did not achieve a response had significantly shorter OS (median OS NR vs 21.3 months, HR 1.68, 95% CI 1.03-2.73, p=0.037) (Figure 1B) and LFS (median LFS NR vs 34.3 months, HR 2.13, 95% CI 1.00-4.50, p=0.049) (Figure 1C). Achievement of a CR predicted for improved OS in patients with higher-risk MDS (median OS NR vs 14.6 months, p=0.046) but not in lower-risk patients (NR vs 27.3 months, p=0.239). No significant differences in LFS were observed based on achievement of CR in both higher (p=0.238) and lower risk patients (p=0.453). CONCLUSION: The number of driver mutations may be a new biomarker to predict response to therapy with HMA in patients with MDS and CMML. Presence of ASXL1 mutations may be associated with a decreased risk of achieving a CR. As previously reported, response to therapy with HMA impacts the OS and LFS of patients with MDS. Incorporating sequencing data at diagnosis may help predict response to therapy and patient outcomes. Table 1. Table 1. Figure 1. Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Celgene: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Agios: Other: advisory board, Research Funding. Daver:Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; BMS: Research Funding; Karyopharm: Honoraria, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding.

scholarly journals Gender Disparities in Myelodysplastic Syndromes: Phenotype, Genotype, and Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1984-1984
Author(s):  
Sara Marie Tinsley-Vance ◽  
Najla Al Ali ◽  
Somedeb Ball ◽  
Luis E. E. Aguirre ◽  
Akriti G Jain ◽  
...  
Keyword(s):  
Gender Differences ◽  
Overall Survival ◽  
Data Base ◽  
Board Of Directors ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Research Funding ◽  
Cancer Center ◽  
Advisory Committees ◽  
Men And Women

Abstract BACKGROUND: Over the past 25 years research has shifted from predominantly focused on men to research that includes both men and women. In addition, myelodysplastic syndromes (MDS) have only been included in the SEER registry since 2001 and are largely understudied. This has resulted in a knowledge gap in the difference in clinical phenotype, genotype, and outcomes between men and women diagnosed with MDS. The aim of this abstract is to identify those gender-based differences. METHODS: This was a retrospective study using a large MDS database at Moffitt Cancer Center. We compared baseline clinical and molecular characteristics and outcomes based on gender. Chi-square tests were used for comparing categorical variables and t-test for continuous variables. Kaplan-Meier method was used to compare survival. RESULTS: The Moffitt Cancer Center MDS data base includes 4413 patients among whom 2922 (66%) were men and 1658 (34%) were women. Table-1 summarizes baseline characteristics based on gender. Women were slightly younger (mean age at diagnosis 66.5 versus 69 years for men, p &lt; 0.001). There were more Hispanic/black women than men (9% versus 5%, p =&lt;0.001). Women had slightly lower hemoglobin (mean Hgb 9.4 versus 9.8 g/dl for men, p=0.032) and higher platelet count (mean platelets count 171 versus 136, p &lt; 0.001). More women had del 5/monosomy abnormalities compared to men (p=&lt;0.001), with 353 women (25%) affected. Therapy-related MDS also occurred more often in women (p=&lt;0.001) 413 (25%). More women had isolated del5 q by WHO 2016. (6% vs 2%, p=&lt;0.001). There was no difference in disease risk based on R-IPSS. There were gender differences in molecular profile. (Table-2). SRSF2 mutation, U2AF1 mutation, ZRSR2 mutation, ASXL1 mutation, and RUNX1 mutations were observed more frequently in men. ZRSR2 was expected. The median overall Survival (mOS) was longer for women in lower-risk MDS, but not in higher-risk MDS. (Figure- 1 and 2) The overall mOS was 37.5 months (mo) for females compared to 35 mo for males, p=0.002). The mOS for very/low R-IPSS was 81 and 62 mo, for intermediate risk R-IPSS 35 mo vs 33 mo, and for high/very high-risk R-IPSS 16.7 versus 17.4 mo respectively for females and males (p&lt; 0.001). The rate of AML transformation was not different (32% and 34%, respectively for women and men, p =0.16). Women were more likely response to ATG/CSA than men (38% versus 19%, p= 0.04) There were no differences in response to erythroid stimulating agents, hypomethylating agents, lenalidomide treatment or rate of allogeneic hematopoietic stem cell transplant (AHSCT). CONCLUSION: This retrospective review of a large data base of MDS patients highlights important gender differences in clinical and molecular MDS disease features. We identified differences in rates of selected somatic mutations. Men had more splicing machinery mutations, ASXL-1, and RUNX-1 mutations. Women had better overall survival mainly in lower risk MDS and higher responses to immunosuppressive therapy. Acknowledgement of Funding: NINR Grant # 1K23NR018488-01A Figure 1 Figure 1. Disclosures Tinsley-Vance: Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Taiho: Consultancy; Fresenius Kabi: Consultancy; Abbvie: Honoraria; Astellas: Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Padron: Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria; BMS: Research Funding; Taiho: Honoraria; Incyte: Research Funding. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: Daiichi Sankyo: Consultancy; Agios: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Celgene/BMS: Consultancy; Jazz: Consultancy. Kuykendall: BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sallman: Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Komrokji: Geron: Consultancy; Acceleron: Consultancy; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Demonstration of the Safety of Post Induction Infusion of Ex-Vivo Expanded Cord Blood Progenitor Cells in Pediatric Patients with Relapsed/Refractory Acute Myelogenous Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2614-2614 ◽  
Author(s):  
Ann Dahlberg ◽  
Muna Qayed ◽  
Katherine Tarlock ◽  
Jessica A. Pollard ◽  
Filippo Milano ◽  
...  
Keyword(s):  
Pilot Study ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Research Funding ◽  
Pediatric Patients ◽  
Ex Vivo ◽  
Infectious Complications ◽  
Morbidity And Mortality ◽  
Treatment Related Mortality ◽  
Related Mortality

Introduction AML therapy requires intensive and highly immunosuppressive cytotoxic therapy leading to prolonged neutropenia. Prolonged neutropenia leads to highly invasive bacterial and fungal infections causing high rates of infection related morbidity and mortality. Even with improved antimicrobial and antifungal therapy, infectious complications remain a common cause of treatment related morbidity and mortality. There is a large need for strategies to reduce the toxicity of AML therapy and infectious complications in particular. We proposed that post induction infusion of non HLA-matched, off-the-shelf (OTS) ex-vivo expanded cord blood progenitor cells may provide rapid, short term bridging hematopoiesis and truncated period of neutropenia. Here we describe results of a pilot study assessing the safety of infusing this OTS product following FLAG chemotherapy in pediatric patients. Methods Between March 2013 and July 2016, 7 pediatric patients with relapsed/refractory AML or acute leukemia of ambiguous lineage (ALAL) were enrolled in this pilot study to evaluate the use of the OTS product as supportive care following FLAG chemotherapy (n=4 at Fred Hutchinson Cancer Research Center/Seattle Children's Hospital and n=3 at Children's Healthcare of Atlanta). All patients received 1 round of FLAG chemotherapy: total dose of 35 mcg/kg of G-CSF, 150 mg/m2 of Fludarabine, and 10 g/m2 of Cytarabine (Ara-C). OTS products were infused no sooner than 24 hours after last dose of Ara-C. The primary study endpoint was safety of infusing a single OTS product as measured by a. infusion toxicity (> grade 3), b. allo-immune platelet refractoriness, c. treatment related mortality, d. delayed marrow recovery beyond day 42, and e. transfusion related GVHD. Chimerism studies were done on cycle days 15 and 22 (+/- 1 day). To monitor for alloimmunization, pre- and post-treatment panel reactive antibody (PRA) tests were conducted. Bone marrow evaluations were performed at the end of the chemotherapy cycle. Absolute neutrophil count (ANC) of both 100 and 500 were used to assess myeloid recovery. Infectious complications were collected. Results Table 1 shows demographics, disease characteristics and disease status at the time of study enrollment. There were no infusional toxicities reported. No alloimmunization, treatment related mortality, delayed marrow recovery, or transfusion related GVHD occurred in any patient. No adverse events were attributed to the OTS product. Chimerism results showed lack of persistence of OTS products after cycle day 15 (7 days post-infusion of OTS product). The median TNC dose infused was 7.66x107 (range 4.8-9.84 x107), and the median CD34+ cell dose was 9.58x106 (range 8.89-17.6 x106) (Table I). Six of the 7 patients demonstrated an ANC > 100. One patient relapsed prior to count recovery with 33% blasts in the marrow. The median time to reach an ANC > 100 was cycle day 30 (range 25-35). Five patients recovered an ANC > 500. The patient who did not reach this point relapsed on cycle day 33 with 80% blasts in the marrow. For these 5 patients, the median time to reach an ANC > 500 was cycle day 38 (range 28-42) (Fig 1). Of the 7 patients enrolled on the study, 3 achieved complete remission (CR), 3 had persistent disease after initial response, and 1 had treatment failure. Infectious complications occurred in 4 patients and included 3 bacteremias in 3 patients (Strep viridans, E. coli, and Staph aureus), one RSV URI (in patient with concurrent Strep viridans bacteremia) and a single case of C. difficile colitis. There were no induction deaths with all patients completing induction therapy and all but one receiving further treatment. Overall, all study patients met pre-specified safety criteria. Conclusion These preliminary data demonstrate safety of the use of OTS products in the setting of intensive chemotherapy in pediatric patients with relapsed/refractory high-risk AML. More comprehensive randomized studies will enable evaluation of efficacy of OTS products in decreasing infection related morbidity and mortality. Given demonstrated safety of this product, its use in newly diagnosed AML should be considered to eliminate the substantial infection related toxicities. Disclosures Qayed: Bristol-Myers Squibb: Honoraria. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Delaney:Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees.

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