scholarly journals TP53 Status As Well As Cytogenetic Complexity Significantly Impact on Prognosis in Myelodysplastic Syndromes with Complex (≥3 anomalies) Aberrant Karyotypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3007-3007
Author(s):  
Christina Ganster ◽  
Roxana Schaab ◽  
Katayoon Shirneshan ◽  
Lea Naomi Eder ◽  
Anna Mies ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Genetic Profile ◽  
Fish Analysis ◽  
Advisory Committees ◽  
Clone Size ◽  
Increased Risk ◽  
Travel Grant ◽  
The Impact ◽  
Tp53 Status

Introduction: Complex aberrant karyotypes (CK, ≥3 cytogenetic aberrations, CA) are associated with an unfavorable prognosis and an increased AML transformation rate in MDS. However, even MDS with CK (CK-MDS) are heterogeneous in terms of genetic profile and prognosis. Recently, we demonstrated that a high number of CA as well as mutations in TP53 (TP53mut) are associated with increased risk in CK-MDS (Haase et al, 2019). However, as there is a strong association between CK-MDS and TP53mut, it is still a matter of debate whether the karyotype and TP53mut are prognostically independent genetic markers. Furthermore, loss of heterozygosity (LOH) of 17p13 (TP53LOH), due to loss of genetic material or to copy number neutral LOH (CN-LOH), is also associated with a poor prognosis. We here aimed to characterize TP53mut andTP53LOH in CK-MDS and to elucidate the impact of cytogenetics, TP53mut and TP53LOH on the outcome of CK-MDS. Methods: We included 178 pts with MDS (N=138), CMML (N=5) and secondary AML after MDS (AML with myelodysplasia-related changes, N=35), all with CK. The median precentage of bone marrow (bm) blasts was 11% (range: 0-90%). The median age was 72 yrs (range: 30-95 yrs). The male:female ratio was 1.23:1. The number of CA was determined by banding analysis in all cases. The karyotype was confirmed by multicolor FISH in 134 cases. TP53LOH was verified by FISH analysis of the TP53 locus in 17p13 (146 analyses) and/or molecular karyotyping (MK, 41 analyses). In 144 cases further FISH probes in addition to TP53 were used. TP53mut was identified by NGS (54 cases) or Sanger sequencing (124 cases). Follow-up data for survival analyses were available for 127 pts with MDS and oligoblastic AML with less than 30% bm blasts. Results: The median number of CA was 7 (range: 3-46), 98/178 pts (55%) showed a TP53mut (median VAF: 34%, range: 8-93%) and 64/178 (36%) a TP53LOH (median FISH clone size: 65%, range: 6-99%), including 9 pts with a CN-LOH in 17p13. The CN-LOH was either identified by MK (5/41 pts (12%) where MK was available showed a CN-LOH, 4/5 with TP53mut) or by NGS (4/54 pts (7%) where NGS was available showed a VAF >70% and normal TP53-FISH). In total, a TP53mut and/or a TP53LOH was identified in 116/178 pts (65%). Overall survival (OS) did not significantly differ between CK-MDS with TP53mut only, TP53LOH only, and TP53mut+TP53LOH (Fig.1). Therefore, we merged TP53mut and TP53LOH to TP53altered in all further analyses. Regarding the cytogenetic characterization of pts with TP53altered, the number of CA was significantly higher in pts with TP53altered than in pts with normal TP53 (median 9 CA (range: 3-46) vs 5 CA (range: 3-24), P<0.001). Also notable was that the founder clone of pts with TP53altered included significantly more cases with del(5q) (determined by FISH, 69/92 cases, 75%) compared to pts with normal TP53 (22/52 cases, 42%, P<0.001). The number of CA as well as the TP53 status contributed significantly to OS (Fig.2). The presence of anemia (Hb <10 g/dl) at first diagnosis of the CK had the greatest impact on OS (HR: 3.95) in the multivariate model (Cox regression), followed by an altered TP53 gene (TP53mut and/or TP53LOH; HR: 3.53) and the presence of ≥5 CA (HR: 2.33). Based on these three parameters with the greatest impact on OS, we created a simple provisional prognostic system. One scoring point each was assigned to anemia (Hb <10 g/dl), TP53altered, and ≥5 CA. Regarding OS, the resulting four risk groups separated very well (Fig.4). Conclusions: The presence of ≥5 CA is associated with reduced OS in CK-MDS. A TP53mut as well as a TP53LOH both further segregate outcome. The impact of the clone size of TP53mut and TP53LOH on survival is currently being evaluated. Our data imply that the TP53 status (TP53mut and/or TP53LOH) and the complexity of the karyotype are independent prognostic markers. Based on the presence of anemia, the TP53 status (TP53mut and/or TP53LOH), and the number of CA, the individual risk of CK-MDS can be estimated more accurately. This will allow to better tailor treatment decisions for individual pts with CA. Funding (FS): 2017 SGR 288-GRC Disclosures Germing: Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Kröger:Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding. Hertenstein:RS Media: Research Funding. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Bug:Hexal: Membership on an entity's Board of Directors or advisory committees; Celgene Neovii: Other: travel grant; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Sanofi: Other: travel grants; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Nickelsen:Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Platzbecker:Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

scholarly journals The Impact of Fractures on Survival in Multiple Myeloma: Results from a Population-Based Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4490-4490
Author(s):  
Sigrun Thorsteinsdottir ◽  
Ingigerdur S Sverrisdottir ◽  
Gauti Gislason ◽  
Ola Landgren ◽  
Ingemar Turesson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Population Based ◽  
Advisory Committees ◽  
Population Based Study ◽  
Risk Of Death ◽  
Increased Risk ◽  
The Impact

Abstract Introduction Multiple myeloma (MM) causes lytic bone lesions, osteopenia, and fractures, which increase the morbidity of MM patients. Results from small previous studies have indicated that fractures in MM have a negative effect on survival. Aims The aim of the study was to evaluate the impact of fractures on survival in MM patients diagnosed in Sweden in the years 1990-2013. Furthermore, to analyze the effect of bone fractures at MM diagnosis on subsequent survival. Methods Patients diagnosed with MM in 1990-2013 were identified from the Swedish Cancer Registry. Information on date of birth, diagnosis, and death were collected from the Registry of Total Population. Information on all fractures were retrieved from the Swedish Patient Registry. Cox regression model was used with fractures as time-dependent variables. The effect of fractures on survival was assessed for any fracture or a subtype of fracture (a specific bone fracture or ICD-coded pathologic fracture). Either first fracture or the first subtype of fracture was used in the analysis. The effect of a fracture at MM diagnosis (within 30 days before or 30 days after MM diagnosis) on survival was also estimated using a Cox regression model. All models were adjusted for age, sex, time of diagnosis, and previous fractures. Results A total of 14,008 patients were diagnosed with MM in the study period. A total of 4,141 (29.6%) patients developed a fracture including fractures that occurred within a year before MM diagnosis and thereafter. Hereof 2,893 (20.7%) patients developed a fracture after MM diagnosis. The risk of death was significantly increased for patients that developed a fracture after the time of MM diagnosis with a hazard ratio (HR) of 2.00 (95% confidence interval (CI) 1.91-2.10) for all fractures combined. The risk of death was significantly increased for patients that developed all subtypes of fractures after MM diagnosis except ankle fractures. The risk of death was significantly increased for patients that developed pathologic fractures (HR=2.17; 95% CI 2.03-2.32), vertebral fractures (HR=1.73; 95% CI 1.61-1.87), hip fractures (HR=1.99; 95% CI 1.82-2.18), femoral fractures (HR=2.62; 95% CI 2.32-2.98), humerus fractures (HR=2.57; 95% CI 2.32-2.86), forearm fractures (HR=1.24; 95% CI 1.05-1.46), and rib fractures (HR=1.52; 95% CI 1.31-1.77), but not for ankle fractures (HR 1.07; 95% CI 0.79-1.44). A total of 942 (6.7%) of all MM patients were diagnosed with a fracture within 30 days before or 30 days after MM diagnosis. The patients with a fracture at diagnosis were at a significantly increased risk of death compared to those without (HR 1.31; 95% CI 1.21-1.41; Figure) Conclusions Our large population-based study, including over 14,000 patients diagnosed with MM in Sweden in the years 1990-2013, showed that MM patients that developed a fracture after the time of diagnosis were at twofold increased risk of dying compared to MM patients without a fracture. Furthermore, MM patients with a fracture at diagnosis had a 30% higher risk of dying compared to patients without a fracture. Our results indicate that fractures in MM reflect a more advanced disease at diagnosis and stress the importance of managing MM bone disease in all MM patients. Figure. Figure. Disclosures Landgren: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

scholarly journals Systemic Mastocytosis: Management and Outcome. Data Analysis from the Greek Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5463-5463
Author(s):  
Ioannis Tsonis ◽  
Nikolaos Kanellias ◽  
Vasileios Lazaris ◽  
Panayiotis Panayiotidis ◽  
Damianos Sotiropoulos ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Systemic Mastocytosis ◽  
Cell Leukaemia ◽  
Line Treatment ◽  
Advisory Committees ◽  
Increased Risk ◽  
Travel Grant

Abstract Background and Methods: Systemic Mastocytosis (SM) is a rare haematologic malignancy characterized by the abnormal growth and accumulation of neoplastic mast cells in one or more organs. The cKIT D816V mutation is a common genetic finding in most cases. A subset of patients appears to be at increased risk for mediator release related symptoms as well as organ dysfunction, including skeletal problems such as osteoporosis, osteolytic lesions and fractures. The diversity of clinical manifestations results in both delayed diagnosis and therapeutic dilemmas. SM cases diagnosed in Greece, between 1987 and 2018, are presented. This project is included in the current activities of Myeloproliferative Neoplasm Working Party of Hellenic Society of Haematology for registry and research development. The medical files of the patients were retrospectively evaluated for disease characteristics, treatment and outcome. Results: Overall 59 patients, median age 52.0 years, with SM were included in the study. Median time of symptoms onset to diagnosis was two years. Twenty-one patients were categorized as indolent SM (ISM), 19 as SM with an associated haematological neoplasm (SM-AHN), 18 as aggressive SM (ASM) and one with mast cell leukaemia (MCL). The main characteristics of the disease are shown in Table 1. Several haematologic neoplasms were associated with SM. Although myeloid malignancies were the most common, including MDS or MDS/MPN (n=9), CMML (n=2), AML (n=1), CML (n=1) and ET (n=1), lymphoid malignancies were also reported and included NHL (n=3), HL (n=1) and B-ALL (n=1). SM and the AHN were diagnosed simultaneously in 12 cases. AHN diagnosis preceded the diagnosis of SM in 4 cases (median time: 22 months), while the opposite occurred in three cases (median time: 7.0 months). Most of the patients with ISM (16/21) did not receive any specific treatment. As far as the remaining five are concerned, one was treated with imatinib, one with hydroxyurea and the rest three received corticosteroids to control the mediators' related symptoms. One of the latter had diarrhoea without infiltration of the gastrointestinal tract and received consecutively Interferon alpha (IFNα), imatinib and corticosteroids without resolution of the syndrome. Eight patients with SM-AHN received treatment for both the SM and the co-existing haematological neoplasm, six only for the AHN, three only for SM, while three did not require treatment yet. The most common treatment for SM was IFNα (n=6), followed by imatinib (n=4), cladribine (2-CdA) (n=3) and dasatinib (n=1). Patients with ASM received either IFNα (n=8) or 2-CdA (n=5) as first line treatment. Second line treatment included imatinib (n=2), 2-CdA due to IFNα intolerance (n=1) and corticosteroids (n=2). Two patients with vertebrae fractures required surgical intervention. All patients with skeletal involvement received additionally biphosphonates. The patient with MCL received consecutively 2-CdA, chemotherapy (FLAG-Ida) and dasatinib achieving partial response and proceeded to allogeneic stem cell transplantation. He died 6 months later due to complications related to graft versus host disease. With a median follow-up of 31 months the median overall survival in the entire cohort is not reached. The median follow-up for patients with ISM and ASM is 33.5 and 18.5 months respectively, and all of them are alive with adequate disease control. Seven deaths were reported only in the group of patients with SM-AHN. Six patients died due to acute leukaemia and one due to infection, indicating that the aggressiveness of the underlying haematological malignancy is the strongest factor that affects survival in this group. Conclusion: Systemic Mastocytosis is a rare disease with variable manifestations and outcome. Nowadays, several therapeutic modalities are available for effective disease management over time. Novel targeted therapies seem to be promising to further improve the outcome, but still early and accurate diagnosis, in accordance to WHO classification, remains important. Table 1. Table 1. Disclosures Gavriilaki: European Hematology Association: Research Funding. Terpos:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria.

Genetic Response to Lenalidomide in the Circulating Progenitor Cell Compartment of MDS Cohort. Preliminary Results of the Multicenter German LE-MON-5 Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1721-1721
Author(s):  
Katayoon Shirneshan ◽  
Ulrich Germing ◽  
Friederike Braulke ◽  
Julie Schanz ◽  
Uwe Platzbecker ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Response To Therapy ◽  
Fish Analysis ◽  
Trisomy 8 ◽  
Advisory Committees ◽  
Clone Size ◽  
Observation Period

Abstract Abstract 1721 Introduction: LE-MON-5 is a multicenter German phase-II study to verify the safety of monotherapy with lenalidomide (LEN) in MDS patients (pts) with IPSS low or Int-1 and isolated del(5q). We report our cytogenetic results after a monitoring period of sixteen months since start of the trial. Methods: For sequential and frequent survey of LEN-treated pts we applied FISH on enriched CD34+ stem cells from peripheral blood (CD34+ pb) every 2–3 months using a panel of 8 to 13 probes. Karyotyping and FISH on bone marrow aspirates was performed at initial screening and every six months. The median number of analyzed metaphases was 25 (4–30) and FISH analyzing was based on 200 interphase nuclei. Results: We have already screened 94 pts and could confirm isolated del(5q) in 76 (81%). Due to our cytogenetic results demonstrating additional changes in 18/94 (19%) pts, these were registered as screening failures and thus excluded from the study. Until now cytogenetic follow-up data for 40 pts is available. After a median follow-up of 9 months (2–16 months) we have observed a significant impact of LEN on the reduction of the clone size (p < 0.05) by FISH-monitoring. Based on cytogenetic remission, we have separated the cohort into three groups: Fast responders (14/40 (35%) pts) showed a very rapid cytogenetic response to therapy with >50% reduction of 5q- clone size within two months. In the second group, the slow responders, we observed >50% reduction of clone size in 9/40 (22.5%) after > two months. However, two pts showed an increase of 5q- clone after 12 and 13 months respectively after initial response in the sense of a relapse. In the third group, the non responders, (11/34 (27.5%)) we could not observe any cytogenetic response during the as yet limited observation period. In six cases (15%) we detected a reduction of the 5q- clone during follow-up, but the emergence of additional aberrations were also observed such as: 1. trisomy 8 in 6.7% of metaphases after 8 months and is reduced to 3.6% after 12 months, 2. trisomy 4 in 6.7% of metaphases after 6 months and is disappeared after 12 months, followed by emergence of trisomy 8 in 8% of interphase cells, 3. finally, two cases showed loss of Y-chromosome after 4 months in 6% and 19% of CD34+ pb cells, respectively. In CD34+ pb cells of another case, trisomy 8 was detectable after two months in 3.5% of cells. All these new secondary abnormalities occurred in cells with normal chromosomes 5 and were slightly above or below our laboratory thresholds (3 times standard variation). In only one case, a new abnormality emerged in the 5q- clone: In this case additional del(20q) occurred after 2 months in 46% of CD34+ pb cells. In this case no reduction of 5q- cells after 4 months of treatment was observed. However, FISH analysis after 6 months of treatment showed a 14% reduction for both aberrations. To date we could not identify any pts who acquired complex anomalies while treated with LEN. Conclusion: FISH analysis of CD34+ pb cells allows a reliable frequent and relevant genetic monitoring of treatment response to LEN. Our results confirm the positive and rapid effects of LEN on clones with del(5q): Thus, already after 2 months, we could observe up to 90% reduction in the 5q- clone size in 35% of pts. In general, remission rates increased with duration of therapy. We suspect that trisomy 4, 8 and Y-loss are fluctuant “mini clones” without any clinical relevance. Inclusion of additional pts and prolonged observation period will help us to better evaluate the clinical response to LEN. Disclosures: Off Label Use: lenalidomide for MDS del(5q) provided by Celgene for this clinical study. Germing:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Braulke:Celgene: Honoraria, Research Funding. Schanz:Celgene: Honoraria, Research Funding. Giagounidis:Celgene: Honoraria. Götze:Celgene: Honoraria. Haase:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Risk Factors for Thrombotic Events in Patients with PNH: A Nested Case-Control Study in the International PNH Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-8
Author(s):  
Britta Hoechsmann ◽  
Regis Peffault De Latour ◽  
Anita Hill ◽  
Alexander Röth ◽  
Timothy Devos ◽  
...  
Keyword(s):  
Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Index Date ◽  
Case Control Study ◽  
Advisory Committees ◽  
Clone Size ◽  
Increased Risk ◽  
History Of ◽  
Control Study

INTRODUCTION Although thrombotic events (TEs) are the leading cause of paroxysmal nocturnal hemoglobinuria (PNH)-related mortality, the risk factors predictive of TEs are not well established. Several small or previous studies reported that the proportion of PNH cells, elevated lactate dehydrogenase (LDH), age, thrombosis at diagnosis, and treatment may impact TE risk.1-5 The International PNH Registry (NCT01374360) is an observational cohort study containing the largest database of safety, quality-of-life, and outcome data from patients with PNH. Here, we analyzed patient data from the Registry to identify risk factors for TEs. METHODS Data from Registry patients who were untreated at enrollment, had an incident TE after enrollment, non-zero follow-up time, and with documented birthdate, sex, enrollment date, treatment status, and country, were included in this analysis. The first TEs experienced by eligible patients after enrollment were identified as TE cases; the date of the index TE event was defined as the Index Date. Up to five controls were selected from the risk set for each TE case matched on age (±5 years at Index Date), gender, country, and history of bone marrow disease (BMD). Cases that could not be matched with at least one control were excluded from the study. For covariates included in the analysis, conflicting or absent values were marked as "missing." Univariate conditional logistic regression was used to estimate odds ratios (ORs) with 95% Wald confidence intervals (CIs) of TE associated with candidate risk factors: glycophosphatidylinositol (GPI)-deficient granulocytes, GPI-deficient erythrocytes, LDH ratio, recent high-disease activity (HDA; defined as within six months prior to the Index Date, LDH ratio ≥1.5xULN, and hemoglobin &lt;10 g/dL or at least one of the following symptoms: abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria, and/or male erectile dysfunction), LDH ratio and number of HDA symptoms, history of TE, history of major adverse vascular event (MAVE), and recent prophylactic anticoagulant (PA) use. RESULTS Due to the strict eligibility criteria, 57 TE cases and 189 non-TE controls met the conditions and were matched for the case-control study. The mean age at Index Date was 46.8 years for TE cases and 47.1 years for non-TE control (Table A). Cases were more likely to have a clone size of ≥ 50% GPI-deficient granulocytes, an LDH ratio ≥ 1.5xULN, recent HDA, and a history of TE or MAVE, compared with controls. From univariate analyses, the following factors were found to be associated with statistically significantly increased risk of TE: recent HDA (OR, 2.65; 95% CI, 1.10-6.61), LDH ≥1.5xULN and 2-3 HDA symptoms (OR, 8.61; 95% CI, 1.46-96.96), LDH ≥1.5xULN and ≥4 HDA symptoms (OR, 14.50; 95% CI, 1.70-209.25), and a history of TE (OR, 3.60; 95% CI, 1.41-9.24) or MAVE (OR, 2.17; 95% CI, 0.96-4.80), and recent PA use (OR, 4.35; 95% CI, 1.57-13.13) (Figure A). The strengths of this analysis include a robust study design for evaluation of a rare outcome and multiple risk factors, increased generalizability with an international patient population, and the ability to evaluate both medical history and recent clinical characteristics relevant to PNH and TE; however, not all patients had available data for each parameter assessed and the number of TE cases identified were relatively small. Despite these limitations, factors that were statistically significantly associated with increased TE risk were identified from the analysis. CONCLUSIONS Based on this observational PNH Registry analysis, we identified several clinical features of PNH that were associated with an elevated risk of TE, including ≥50% GPI-deficient granulocyte clone size, LDH ratios ≥1.5xULN, recent HDA, LDH ≥1.5xULN plus HDA symptoms, a history of TE or MAVE, and recent PA use compared with non-TE controls; for recent PA use, these patients were most likely at increased risk of TE, which may explain why they received treatment. Our data add to the findings of previously published studies1,4 by expanding the results to a broader patient population. These results highlight the importance and urgency of identifying and monitoring risk factors for TE in patients with PNH to inform treatment decisions. Disclosures Hoechsmann: Roche: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Research Funding. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hill:Alexion Pharmaceuticals, Inc.: Current Employment. Röth:Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Devos:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin:Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:Alexion Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zu:Alexion Pharmaceuticals, Inc.: Ended employment in the past 24 months; Merck & Co.: Current Employment. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Pre-CAR Blinatumomab Is Associated with Increased Post-CD19 CAR Relapse and Decreased Event Free Survival

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Agne Taraseviciute ◽  
Seth M. Steinberg ◽  
Regina M. Myers ◽  
Lia Gore ◽  
Adam J. Lamble ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Committees ◽  
Car T Cell ◽  
Increased Risk ◽  
Car T ◽  
The Impact ◽  
Cd19 Expression

Introduction: Both CD19 CAR T-cells (CD19 CAR) and blinatumomab (blina) effectively induce remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r ALL). However, blina use prior to CD19 CAR has raised concerns for increased relapse risk and/or CAR non-response due to selective pressure on CD19. The tisagenlecleucel registration trial in pediatric ALL excluded patients who had received prior blina. Thus, there is limited data regarding the impact of blina on long-term outcomes in patients receiving subsequent CD19 CAR. Methods: This retrospective, multicenter study was performed to evaluate the impact of pre-CAR blina on subsequent CD19 CAR outcomes in pediatric and young adult patients with r/r ALL &lt; 25 years at diagnosis. The primary objective was to evaluate relapse (RFS) and event free survival (EFS) at 6 months following CD19 CAR stratified by blina use. Secondary objectives included: evaluation of RFS at 12 months and response to CD19 CAR. All patients had their first CAR T-cell infusion between the years 2012-2019 and had at least 30 days of follow-up (or an event prior to 30 days). Descriptive statistics were used for baseline demographics and comparison between cohorts. Kaplan-Meier estimates were used to evaluate survival. Results: A total of 420 patients from 7 centers received 1 of 3 CD19 CAR T-cell constructs. (Table 1) The median age at diagnosis and at CAR infusion was 7.1 years and 12.4 years, respectively (range, 0.6-30 years). Amongst 412 patients evaluable for response, a total of 375 (91.0%) patients achieved a complete remission (CR); 363 (96.8%) of whom were minimal residual disease (MRD) negative (by flow cytometry). Thirty-seven (9.0%) of evaluable patients were CD19 CAR non-responders. With a median potential follow-up of 2.3 years (IQR, 1.6-3.3 years), 164 (43.7%) patients experienced relapse. Seventy-five (17.8%) patients received blina prior to CD19 CAR. The median time from last blina use to CD19 CAR was 129 days (IQR, 79-304 days). Blina was associated with an increased risk of CAR non-response; 13/71 (18.3%) blina patients versus 24/341 (7.0%) non-blina patients were non-responders (p=0.0052). Ten of 71 (14.1%) were non-responders to both CD19 CAR and blina; 19 of 29 (66%) blina non-responders achieved remission with subsequent CD19 CAR. Baseline disease status did not differ between blina and non-blina patients at CAR T-cell infusion, although a higher fraction of blina patients harbored KMT2Ar cytogenetics (11/75 (14.7%) versus 22/345 (6.4%), p=0.03). Pre-CAR blina was associated with worse EFS and RFS, but not overall survival (OS). The 6-month RFS for blina and non-blina patients was 63.4% (95% CI, 49.6-74.4%) and 81.1% (95% CI, 76.3-85.0%), respectively (Figure 1A). The 6-month EFS for blina and non-blina patients was 49.7% (95% CI, 37.8-60.5%) and 72.1% (95% CI, 67.1-76.6%), respectively (Figure 1B). Analysis excluding KMT2Ar patients to evaluate for the possibility that these patients represented a higher-risk subgroup and could skew the data, revealed similar EFS and RFS. Amongst 408 patients with pre-CAR CD19 analysis, 6/69 (13.0%) of blina patients versus 21/339 (6.2%) of non-blina patients had CD19 dim/partial/negative disease (p=0.07). Serial CD19 evaluation pre/post blina revealed that 6/52 (11.5%) had CD19 evolution to dim expression. Conclusions: This large, multicenter analysis demonstrate an association with blina use and 1) increased risk of CAR non-response; 2) worse RFS and EFS and 3) a trend towards a higher incidence of pre-CAR CD19 dim disease. While blina non-response did not preclude CD19 CAR response, blina non-responders had lower remission rates to CD19 CAR and a cohort of patients were refractory to both, potentially suggesting resistance to immunotherapeutic CD19 targeting. Additionally, we found that blina may impact CD19 expression, which could subsequently affect response and relapse. Mechanisms of resistance to CD19 CAR include antigen escape or an inherent resistance to T-cell mediated killing. Our data suggest that 1) patients relapsing after or refractory to blina who proceed to CD19 CAR may have an inherent resistance and 2) blina may impact CD19 expression. Ongoing analysis includes detailed analysis of low/dim/partial CD19 expression to delineate the potential impact of blina exposure on leukemic blasts and evaluation of the role of HSCT. Disclosures Gore: Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Brown:Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Laetsch:Bayer: Consultancy, Research Funding; Cellectis: Consultancy; Pfizer: Research Funding; Novartis: Consultancy, Research Funding. Gardner:Novartis: Honoraria. Rheingold:Pfizer: Research Funding. Pulsipher:Mesoblast: Honoraria; Novartis: Honoraria; Adaptive: Research Funding; Miltenyi: Honoraria, Research Funding; Bellicum: Honoraria; Jasper: Honoraria.

scholarly journals Relative Clone Size By FISH of Both Del(13q) and Del(17p) Independently Impact Overall Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4444-4444
Author(s):  
Soluman Culver ◽  
Nita Williams ◽  
Nidhi Sharma ◽  
Yvonne A Efebera ◽  
Ashley E Rosko ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Staging System ◽  
Maximal Effect ◽  
Advisory Committees ◽  
Clone Size ◽  
Interphase Fish ◽  
The Impact

Abstract Introduction: Interphase FISH is used in the risk stratification of newly diagnosed multiple myeloma. The presence of high-risk cytogenetics is a key component of the Revised International Staging System (R-ISS), despite the fact that precise cutoffs for positivity have yet to be standardized and usage differs between institutions and reference labs. For deletion 17p, Avet-Loiseau et al (2007) used a 60% cutoff and An et al (2015) used 50% as a positive cutoff. For del(13q), Avet-Loiseau used del(13q14) 74% and An et al used 10%. Methods: Since 2011, consecutive patients in Ohio State University's myeloma clinic were consented to participate in the Ohio Myeloma Initiative (NCT01408225), an observational registry. We identified patients with multiple myeloma who had a bone marrow biopsy performed within six months of diagnosis. All FISH was performed after CD138 magnetic separation. We assessed the impact of del17p (P53) and del13q (RB1) on overall survival (OS). Results: 1,029 myeloma patient were identified, 767 patients with a FISH study within 6 months of diagnosis with an age range of 26-91. 39% of patients had an ISS 1, 34% had ISS 2, and 27% had ISS 3 disease. The median duration of follow-up for these patients was 3.17 years. 82.7% of patients had data regarding del13q, 82.5% had data regarding del17p, and 78.4% had data regarding both del13q and 17p. Using iterative survival analysis we calculated a maximal effect of del17p on OS occurring at 50% positivity on interphase FISH. Additionally, our data suggests that positivity for del13q is maximal at 40% positivity and a predictor of moderately decreased overall survival independent of 17p status. Moreover, our data suggests that intermediate FISH positivity for 17p does have a dose-dependent effect on OS with the presence of even non-dominant del17p clones exerting a measurable influence similar in effect size to del13q. Analyzing those patients with del13q >40% that were negative for del(17p) and t(4;14) (n=27), these patients suffered an inferior overall survival when compared to patients that were negative for del13q, del17p, and t(4;14) (n=116), p=0.0042. Conclusions: These findings suggest that specific cutoffs for both the del(13q) and del(17p) clones at diagnosis independently have statistically significant effects on overall survival. At the meeting, additional analyses will demonstrate the percentages of del(13q) that impact similarly on overall survival to those patients with del(17p) alone. A scoring system will be created to estimate hazard ratios for relative clone size % of del(13q) and del(17p) separately and when combined. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Hofmeister: Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Incidence and Risk Factors for Venous Thrombosis in Human Immunodeficiency Virus (HIV) Infection, Data from the Dutch Athena Cohort Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 271-271
Author(s):  
James Francis Borjas-Howard ◽  
Casper Rokx ◽  
Colette Smit ◽  
Ferdinand Wit ◽  
Elise Pieterman ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
General Population ◽  
Board Of Directors ◽  
Research Funding ◽  
Cd4 T Cell ◽  
Advisory Committees ◽  
Cell Counts ◽  
Increased Risk ◽  
Travel Grant

Abstract Introduction HIV-infected patients have an increased risk of venous thrombosis (VT), but the most recently published data are from before 2007 (Rasmussen et al. HIV Med2011). However, since 2008, recommended CD4+ T-cell thresholds for starting combination anti-retroviral therapy (cART) have steadily increased from 200 to the current (2015) recommendation to start cART irrespective of CD4+ count. As the increased risk of VT is predominantly the result of the HIV-associated pro-inflammatory state, we hypothesize that initiation of cART at higher CD4+ T-cell counts might have attenuated the risk of VT over the last decade. However, in contrast and more controversial is the possible prothrombotic effect of certain antiretroviral agents, namely abacavir (ABC) and HIV protease inhibitors (PI). To elucidate this, we assessed the relationship of CD4+ T-cell counts and cART regimens with the risk of VT, using data from the Dutch ATHENA cohort. Methods ATHENA is the Dutch National HIV cohort study, prospectively collecting data of all HIV-infected patients in the Netherlands. As VT is not routinely registered, we developed a strategy of targeted VT case finding through the registered use of anticoagulants (recorded since January 2003). Any anticoagulant use registered in ATHENA led to a review of a patients medical records looking for a VT diagnosis (either confirmed by radiological examination or by clinicians correspondence/ resumes). We confirmed the sensitivity (100% sensitivity) of our search strategy in a pilot study in one participating center and used it to collect VT cases in twelve HIV treatment centers (>70% of all HIV-infected patients in care in the Netherlands). Main outcome was occurrence of a first VT: deep vein thrombosis of the lower/upper extremity (no more distal than popliteal/subclavian vein), pulmonary embolism, splanchnic and/or cerebral VT. Data were analyzed using Cox regression. Covariates of interest were HIV-specific events (coded as CDC-C events), CD4+ & CD8+ T-cell counts, HIV-RNA viral load, use of antiretroviral medication (by class), history of intra-venous drug use and classic VT risk factors (pregnancy, malignancy and hospitalization). Covariates remaining significant after correction for classic VT risk factors (table 1, adjusted), were forced into two fully adjusted models; one excluding (Model 1) and one including hospitalization as a covariate (Model 2). This enabled separation of effects for variables that are not confounded by hospitalization (i.e. in most cases, hospitalization is a consequence- not the cause- of infection/inflammation) and variables potentially confounded by hospitalization (i.e. starting cART during a hospitalization). Results 14,386 eligible patients were included. Median age at inclusion was 40 years, 79% was male. There were 229 VTs during 97,556 years of follow up (2.3 VT per 1000 person years [py]). All classic risk factors introduced were independently associated with VT. HIV specific markers except CD4+/CD8+ T-cell ratio were independently associated with VT, with CD4+ T-cell count category showing a consistent decrease in hazard for VT for each category. The absolute VT risk in patients with CD4+ count >500 was close to that of the general population (1.3 [95%CI 1.0-1.6] versus 1.2 VTs per 1000 py [Silverstein et al, Arch Int Med, 1998]). We did not observe an association between VT and PIs or ABC, but we did for the use of integrase inhibitors (INIs). The effect lost statistical significance after adjustment for hospitalization. Conclusions Overall, HIV-infected patients have a twofold increased risk of VT compared with the general population. This risk declined progressively with increasing CD4+ T-cell counts, from 7.1 to 1.3 VTs per 1000 py for CD4+ T-cell counts >500, thereby approaching the incidence of the general population. Markers for more advanced HIV-disease (higher viral load, AIDS-defining illness) were also associated with an elevated risk of VT. INIs (at that time only raltegravir) were the only antiretroviral agents associated with increased VT risk, with a borderline significance in a fully adjusted model. This association might be due to confounding by indication, as at the time, INIs were mostly used in patients with prior therapy failure or comorbidities. Overall, our findings suggest that the elevated risk in the HIV-infected population is explained by uncontrolled HIV infection and provoking factors. Disclosures Rokx: Virology Education: Honoraria; Janssen-Cilag: Honoraria; Boehringer-Ingelheim: Honoraria; Gilead: Honoraria, Other: travel grants; ViiV Healthcare: Honoraria, Other: travel grant; Merck & Co: Research Funding; MSD: Other: travel grant. Wit:Abbvie: Other: travel grant; Janssen-Cilag: Other: travel grant; ViiV Healthcare: Other: travel grant; MSD: Other: travel grant; Bristol-Myers Squibb: Other: travel grant; Gilead Sciences: Honoraria, Other: travel grant; Boeringer Ingelheim: Other: travel grant. Meijer:Baxter: Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bristol-Myers Squibb: Honoraria. Rijnders:AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; EUR trust fund: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; ViiV Healthcare: Other: Travel grants; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; Great Lakes Pharmaceuticals, inc.: Honoraria; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding. Bierman:Janssen-Cilag: Other: unrestricted symposium support grant, Research Funding. Tichelaar:Bayer: Other: travel grant; Baxter: Other: travel grant.

scholarly journals BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-15
Author(s):  
Austin Kulasekararaj ◽  
Jacques Le Roux Malherbe ◽  
Andrew McDonald ◽  
Melanie Cornpropst ◽  
Phil Collis ◽  
...  
Keyword(s):  
South Africa ◽  
Board Of Directors ◽  
Research Funding ◽  
Total Bilirubin ◽  
Proof Of Concept ◽  
Advisory Committees ◽  
Clone Size ◽  
The Past ◽  
History Of ◽  
Pre Treatment

INTRODUCTION: PNH, a rare, chronic, life-threatening disease, is characterized by hemolytic anemia due to uncontrolled activity of the complement alternative pathway (AP), bone marrow failure, and thrombosis. Inhibition of C5 by intravenously administered eculizumab and ravulizumab reduces intravascular hemolysis, but PNH red blood cells (RBCs) become opsonized and susceptible to extravascular hemolysis (Risitano et al, Blood 2009). Only approximately half of PNH patients become transfusion independent with eculizumab treatment (Hillmen et al, NEJM 2006). BCX9930 is a potent, selective, orally administered inhibitor of complement factor D. Inhibition of factor D may prevent both intravascular and extravascular hemolysis in PNH. In healthy subjects, BCX9930 showed linear pharmacokinetics and dose-related AP suppression, and was safe and generally well-tolerated over a wide dose range. Here we describe safety and laboratory data establishing proof-of-concept for BCX9930 monotherapy in PNH patients in Study BCX9930-101 (NCT04330534). METHODS: Ongoing Study BCX9930-101 includes an open-label, dose-ranging evaluation of BCX9930 in PNH subjects who may either be naïve to C5 inhibitors (and receive BCX9930 as monotherapy) or have an incomplete treatment response to eculizumab or ravulizumab (with BCX9930 added to existing treatment). Up to 4 sequential cohorts each use a forced titration design for the first 28 days (Figure 1). Subjects enrolled in South Africa can participate in an individualized 48-week extension if they derive benefit at Day 28. Clinical benefit from BCX9930 is evaluated using laboratory monitoring and symptom assessment. Safety and tolerability are evaluated via clinical and laboratory monitoring, causality of adverse events is assessed by investigators, and the study is overseen by an independent Data Monitoring Committee. Data from Cohort 1 through 28 days is reported; data from the extension and subsequent cohorts will be subsequently summarized as available. RESULTS: To date, four C5 inhibitor naïve PNH subjects in South Africa have enrolled in Cohort 1. These subjects had PNH for a median of 4.5 years; 2 subjects had a history of transfusions in the past year; 1 subject each had a history of aplastic anemia or major thrombosis. Pre-treatment lactate dehydrogenase (LDH), total bilirubin, hemoglobin (Hb), reticulocyte count, and RBC PNH Type III clone size ranged from 3.7-11.1 × ULN, 0.61-3.3 mg/dL, 6.1-11.6 g/dL, 0.13-0.29 × 106/µL, and 41.4%-88.6% respectively. Treatment over 28 days with 50 mg twice daily (BID; Days 1-14) and 100 mg BID (Days 15-28) of BCX9930 produced dose-dependent, clinically meaningful improvements across hemolysis biomarkers (Figure 2). Decreases were observed in LDH (4/4), reticulocytes (4/4), and total bilirubin (2/2 subjects with elevated pre-treatment values). Increases were observed in Hb (3/4) and PNH RBC clone size (4/4). One subject showed an initial response to BCX9930 50 mg BID, followed by worsening indicators of hemolysis temporally associated with an upper respiratory tract infection (URTI; onset on Day 7). With an increase in dose to 100 mg BID and resolution of the URTI, LDH and reticulocytes fell and Hb rose. All four subjects reported one or more PNH-associated symptoms, including hemoglobinuria, jaundice, fatigue, erectile dysfunction, headache and abdominal pain, prior to enrollment. With the exception of one subject with persistent hemoglobinuria, all symptoms resolved by Day 28 on BCX9930. Three subjects experienced moderate headache that resolved in &lt; 3 days after initiating BCX9930. One subject developed a rash during treatment with amoxicillin for an URTI; the rash resolved while continuing BCX9930 dosing. One subject on concomitant chronic corticosteroids and azathioprine had an unrelated fatal serious adverse event of disseminated varicella during the study extension. Based on review of safety data, Cohort 2 opened at doses of 200 mg BID and 400 mg BID and, in the 3 subjects who continued into the extension, the dose was titrated to ≥ 200 mg BID. CONCLUSIONS: Oral BCX9930 elicited rapid changes in laboratory parameters indicative of reduced hemolysis and clinical benefit and was safe and generally well-tolerated over a 28-day dosing interval. These interim results establish proof of concept for monotherapy with BCX9930 in the treatment of C5-inhibitor naïve PNH patients and support evaluation of higher doses. Disclosures Kulasekararaj: Alexion:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Ra Pharma:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;BioCryst Pharmaceuticals, Inc.:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Apellis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.Malherbe:Key Oncologics:Honoraria, Other: Conference sponsor;Novartis:Other: Conference sponsor;Astellas:Honoraria, Other: Conference sponsor;Takeda:Consultancy;Acino:Honoraria;Shire:Other: Conference sponsor;BioCryst Pharmaceuticals, Inc.:Consultancy;Janssen:Consultancy, Honoraria, Other: Conference sponsor;Roche:Honoraria, Other: Conference sponsor.McDonald:venetoclax advisory board in South Africa (in CLL context):Consultancy;Alberts Cellular Therapy:Current Employment.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Collis:BioCryst Pharmaceuticals, Inc.:Current Employment.Davidson:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Tower:BioCryst Pharmaceuticals, Inc.:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Risitano:Alexion:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Alnylam:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;Achillion:Membership on an entity's Board of Directors or advisory committees;Apellis:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Biocryst:Membership on an entity's Board of Directors or advisory committees;RA pharma:Research Funding;Amyndas:Consultancy;Samsung:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;Jazz:Speakers Bureau.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

scholarly journals Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Liliana Preiss ◽  
Mitchell Knisely ◽  
Eleanor Stevenson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Transfusion Requirement ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Maternal Outcomes ◽  
Maternal Complications ◽  
Advisory Committees ◽  
Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

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