scholarly journals Survival Outcomes of Patients with Therapy-Related Acute Myeloid Leukemia in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2298-2298
Author(s):  
Raffi Tchekmedyian ◽  
Tomas Radivoyevitch ◽  
Aaron T. Gerds ◽  
Aziz Nazha ◽  
Hetty E. Carraway ◽  
...  
Keyword(s):  
Board Of Directors ◽  
De Novo ◽  
Population Based ◽  
Cancer Type ◽  
Cancer Therapies ◽  
Primary Cancer ◽  
Primary Malignancy ◽  
Advisory Committees ◽  
Lung Cancers ◽  
Survival Probabilities

Abstract Background The development of therapy-related AML (t-AML) is a rare but fatal complication of cancer therapies, with varying leukemogenicity associated with individual chemotherapies and radiation modalities. In recent years, there is an increase in t-AML incidence explained by increased use of cancer therapies and increased cancer survivorship. We investigated changes in t-AML outcomes over time among cancer patients (pts) treated with chemotherapy and radiation using data from population-based cancer registries in the Surveillance, Epidemiology and End Results (SEER) Program of the US. Methods A previously validated R package (SEERaBomb) was used to query all 18 SEER registries to identify adult pts (≥15 years) with multiple types of primary malignancies who were treated with chemotherapy and radiation, and subsequently developed AML. Pts were observed from the date of first diagnosis of a primary malignancy until occurrence of AML as a second cancer, death, loss to follow-up or end of the study period, whichever occurred earlier. Cases of AML that developed at least 1 year following diagnosis and treatment of a primary malignancy were classified as t-AML. Primary cancers associated with at least 100 t-AML cases were included. Survival probabilities were compared for pts with: (1) primary cancers which did and did not subsequently develop AML, (2) primary (de novo) AML, and t-AML. Multivariate Cox regression analysis was performed to identify factors associated with overall survival (OS) in the t-AML cohort, including the following covariates: age group [adolescents and young adults (AYA) (15-39 years); middle-aged (40-59); and older adults (≥60)], sex, year of diagnosis, race, primary cancer type, and whether or not treatment was received for t-AML. Tests of significance were based on two-sided hypothesis at the .05 level. Results A total of 1,425,840 adult cancer pts diagnosed between the years 1973-2015 were assembled from all 18 SEER registries which included 1,392,784 primary cancers, 31,112 primary AML cases and 1,944 t-AML cases [breast (781), lung (205), lymphoma (612), and prostate (346)]. Median survival of t-AML in months (m) with (range) by primary site was as follows: breast: 5.5m (0.5-263); lymphoma: 4.5m (0.5-255.5); lung: 1.5m (0.5-178.5); and prostate: 3.5m (0.5-196.5); combined: 3.5m (0.5-263). Median latency periods in years (y) with (range) to develop t-AML were as follows: breast: 3y (1-38); lymphoma: 4y (1-30); lung: 2y (1-22); and prostate: 4y (1-18); combined: 4y (1-39) . Figure 1 shows comparison of survival probabilities of primary malignancies with and without subsequent development of t-AML over three time periods (1973-1990, 1991-2005 and 2006-2015) organized by year of diagnosis and primary cancer type. Development of t-AML was significantly associated with worse survival for all the four primaries that contribute to the bulk of t-AML cases. Figure 2 shows survival probabilities of primary (de novo) AML versus t-AML (all pooled cases). In multivariate analyses, the hazard ratio (HR) of death was significantly higher in older adults [vsAYA, 1.39 (95% CI 1.11-1.75)] but not middle-aged adults [vsAYA, 0.931 (95% CI 0.738-1.175)], lower in other races [vsCaucasian, 0.81 (95% CI 0.66-0.988)] but not in African Americans [vsCaucasian, 1.078 (95% CI 0.917-1.267)] and lower in those diagnosed between the years 2006-2015 [vs1973-1990, 0.69 (95% CI 0.58-0.82)]. Pts treated for their t-AML had a HR of death significantly lower than those who did not receive treatment [0.426 (95% CI 0.38-0.47)]. There was no significant difference in HR between male and female patients [0.971 (95% CI 0.839-1.123)]. When analyzed by treatment periods, there was no difference noted between the time periods 1973-1990 and 1991-2005 [0.878 (95% CI 0.737-1.045)]. Among primary cancer type, only those t-AML cases preceded by lung cancers had a significantly higher HR of death {[lung vsbreast, 1.56 (95% CI 1.27-1.92)]; [lymphoma vs breast, 1.006 (95% CI 0.847-1.194)]; [prostate vsbreast, 0.861 (95% CI 0.679-1.093)]. Conclusions In our population based analysis, we show that although the OS of t-AML is significantly worse than primary AML, those t-AML diagnosed and treated in recent years (2006-2015) had significantly better survival compared to earlier treatment periods. Among all primaries, outcomes of t-AML particularly following lung cancers are dismal compared to other primaries. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Nazha:MEI: Consultancy. Carraway:FibroGen: Consultancy; Jazz: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Survival Outcomes of Patients with Therapy-Related Myelodysplastic Syndromes in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 371-371
Author(s):  
Raffi Tchekmedyian ◽  
Tomas Radivoyevitch ◽  
Aaron T. Gerds ◽  
Aziz Nazha ◽  
Hetty E. Carraway ◽  
...  
Keyword(s):  
Older Adults ◽  
Board Of Directors ◽  
De Novo ◽  
Population Based ◽  
Cancer Type ◽  
Primary Cancer ◽  
Primary Malignancy ◽  
Advisory Committees ◽  
Factors Associated ◽  
Survival Probabilities

Abstract Background: The development of therapy-related MDS (t-MDS) is a rare but highly fatal complication of cancer therapies, with varying leukemogenicity associated with individual chemotherapeutic agents and radiation modalities. In recent years, an increase in t-MDS incidence explained by increased use of cancer treatment combined with an increasing number of cancer survivors has been reported. We investigated changes in t-MDS outcomes over time among cancer patients (pts) treated with chemotherapy and radiation using data from population-based cancer registries in the Surveillance, Epidemiology and End Results (SEER) Program of the US. Methods: A previously validated R package (SEERaBomb) was used to query all 18 SEER registries to identify adult pts (≥15 years of age) with multiple types of primary malignancies who were treated with chemotherapy and radiation as part of their initial cancer treatment, and subsequently developed MDS. Pts were observed from the date of first diagnosis of a primary malignancy until occurrence of MDS as second cancer, death, loss to follow-up, or end of the study period, whichever occurred earlier. Cases of MDS that developed at least 1 year (yr) following diagnosis and treatment of a primary malignancy were classified as t-MDS according to the World Health Organization classification. Primary cancers associated with at least 100 t-MDS cases were included in the analysis. Survival probabilities were compared for pts with: (1) primary cancers who did and did not subsequently develop MDS, (2) primary (de novo) MDS, and (3) t-MDS. Multivariate Cox regression analysis was performed to identify factors associated with overall survival (OS) in the t-MDS cohort, including the following covariates: age group [adolescents and young adults (AYA) (15-39 yrs); middle-aged (40-59 yrs); and older adults (≥60 yrs)], sex, year of diagnosis, race, and primary cancer type. Tests of significance were based on two-sided hypothesis at the .05 level. Results: A total of 933,789 adult cancer pts diagnosed between the years 2001-2015 were assembled from all 18 SEER registries which included 926,552 primary cancers, 5,478 primary MDS cases, and 1,759 t-MDS cases [breast (528), lung (207), lymphoma (663) and prostate (361)]. Median survival of t-MDS in months (m) with (range) by primary site was as follows: breast: 17.5m (0.5-172.5); lymphoma: 10.5m (0.5-168.5); lung: 5.5m (0.5-88.5); prostate: 21.5m (0.5-170.5); and combined: 13.5m (0.5-172.5). Median latency periods in yrs with (range) to develop t-MDS were as follows: breast: 5 yrs (1-40); lymphoma: 5 yrs (1-38); lung: 2 yrs (1-21); prostate: 5 yrs (1-25); combined: 5 yrs (1-40). Figure 1 shows comparison of survival probabilities of primary malignancies with and without subsequent development of t-MDS over two treatment eras (2001-2006 and 2007-2015), organized by yr of diagnosis and primary cancer type. As expected, development of t-MDS was significantly associated with worse survival for all four primaries that contribute to the bulk of t-MDS cases. Figure 2 shows survival probabilities of primary (de novo) MDS versus t-MDS. In multivariate analyses of factors associated with survival in the t-MDS cohort, the hazard ratio (HR) of death was significantly higher in middle aged adults [vs AYA, 2.20 (95% CI 1.34-3.62)] and older adults (vs AYA, 2.39 (95% CI 1.47-3.90)], in lung cancer [vs breast, 2.98 (95% CI 2.31-3.84)] and in lymphomas [vs breast, 1.467 (95% CI 1.18-1.83)], but was not influenced by sex [female vs male, 0.94 (95% CI 0.819-1.079)], race {[white vs black, 1.0 (95% CI 0.839-1.195)], [white vs other, 0.957 (95% CI 0.795-1.151)]}, or year of diagnosis of t-MDS [2001-2006 vs 2007-2015, 1.025 (95% CI 0.923-1.139)]. Conclusions: In population-based analyses, the survival of t-MDS remains dismal with outcomes particularly worse with advancing age and following primary cancer sites that are typically managed with combined modality regimens including chemotherapy and radiation. Findings from the real-world population level data such as this should be used as outcome benchmarks in clinical trials to assess therapeutic effectiveness of experimental treatments. Disclosures Gerds: Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Nazha:MEI: Consultancy. Carraway:Jazz: Speakers Bureau; FibroGen: Consultancy; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy, Speakers Bureau. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Long-Term Experience with Large Granular Lymphocytic Leukemia Evolving after Solid Organ and Hematopoietic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1226-1226
Author(s):  
Hassan Awada ◽  
Reda Z. Mahfouz ◽  
Jibran Durrani ◽  
Ashwin Kishtagari ◽  
Deepa Jagadeesh ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Viral Infections ◽  
De Novo ◽  
Post Transplantation ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Stat3 Mutations

T-cell large granular lymphocyte leukemia (T-LGLL) is a clonal proliferation of cytotoxic T lymphocytes (CTL). T-LGLL mainly manifest in elderly and is associated with autoimmune diseases including rheumatoid arthritis (RA), B cell dyscrasias, non-hematologic cancers and immunodeficiency (e.g., hypogammaglobulinemia). LGL manifestations often resemble reactive immune processes leading to the dilemmas that LGLs act like CTL expansion during viral infections (for example EBV associated infectious mononucleosis). While studying a cohort of 246 adult patients with T-LGLL seen at Cleveland Clinic over the past 10 years, we encountered 15 cases of overt T-LGLL following transplantation of solid organs (SOT; n=8) and hematopoietic stem cell transplantation (HSCT; n=7). Although early studies reported on the occurrence of LGL post-transplant, these studies focused on the analysis of oligoclonality skewed reactive CTL responses rather than frank T-LGLL. We aimed to characterize post-transplantation T-LGLL in SOT and HSCT simultaneously and compare them to a control group of 231 de novo T-LGLL (cases with no history of SOT or HSCT). To characterize an unambiguous "WHO-defined T-LGLL" we applied stringent and uniform criteria. All cases were diagnosed if 3 out of 4 criteria were fulfilled, including: 1) LGL count >500/µL in blood for more than 6 months; 2) abnormal CTLs expressing CD3, CD8 and CD57 by flow cytometry; 3) preferential usage of a TCR Vβ family by flow cytometry; 4) TCR gene rearrangement by PCR. In addition, targeted deep sequencing for STAT3 mutations was performed and charts of bone marrow biopsies were reviewed to exclude other possible conditions. Diagnosis was made 0.2-27 yrs post-transplantation (median: 4 yrs). At the time of T-LGLL diagnosis, relative lymphocytosis (15-91%), T lymphocytosis (49-99%) and elevated absolute LGL counts (>500 /µL; 93%) were also seen. Post-transplantation T-LGLL were significantly younger than de novo T-LGLL, (median age: 48 vs. 61 yr; P<.0001). Sixty% of post-transplantation T-LGLL patients were males. Fifteen% of patients had more cytogenetic abnormalities compared to de novo T-LGLL, had a lower absolute LGL count (median: 4.5 vs. 8.5 k/µL) and had less frequent neutropenia, thrombocytopenia and anemia (27 vs. 43%, 33 vs. 35% and 20% vs. 55%; P=.01). TCR Vb analysis identified clonal expansion of ≥1 of the Vb proteins in 60% (n=9) of the patients; the remaining 40% (n=6) of the cases had either a clonal process involving a Vb protein not tested in the panel (20%; n=3) or no clear expansion (20%; n=3). Signs of rejection were observed in 20% (n=3/15) and GvHD in 13% (n=2/15) of the patients. Post-transplantation, 27% of cases presented with neutropenia (absolute neutrophil count <1.5 x109/L; n=4), 33% with thrombocytopenia (platelet count <150 x109/L; n=5) and 25% with anemia (hemoglobin <10 g/dL; n=3). T-LGLL evolved in 10 patients (67%; 10/15) despite IST including cyclosporine (n=5), tacrolimus (n=4), mycophenolate mofetil (n=5), cyclophosphamide (n=1), anti-thymocyte globulin (n=1), and corticosteroids (n=6). Lymphadenopathy and splenomegaly were seen in 13% (n=2) and 33% (n=5) of the patients. Other conditions observed were MGUS (20%; n=3) and RA (7%; n=1). Conventional cytogenetic showed normal karyotype in 89% (n=11, tested individuals 13/15). Somatic STAT3 mutations were identified in 2 patients. Sixty% of cases (n=9) were seropositive for EBV when tested at different time points after transplant. Similarly, 53% (n=8) were seropositive for CMV, of which, 5 were positive post-transplantation and 3 pre-/post-transplantation. The complexity of T-LGLL expansion post-transplantation might be due to several mechanisms including active viral infections, latent oncogenic viral reactivation and graft allo-antigenic stimulation. However, in our cohort graft rejection or GvHD was encountered in a few patients (2 allo-HSCT recipients). Autoimmune conditions were present in 50% of SOT recipients (n=4/ 8, including RA, ulcerative colitis, systemic lupus erythematosus). Some of our patients also had low immunoglobulin levels. Overt EBV (post-transplant lymphoproliferative disorder) and CMV reactivation was diagnosed in only 27% (4/15) of the patients. In sum we report the long term follow up of a cohort of T-LGLL and emphasize the expansion of T-LGLL post-transplant highlighting the difficulty in assigning one unique origin of LGLL. Disclosures Hill: Genentech: Consultancy, Research Funding; Takeda: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria; Amgen: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria. Majhail:Atara Bio: Consultancy; Mallinckrodt: Honoraria; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Incyte: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

scholarly journals Prospective Population-Based Analysis of Characteristics and Therapy Options in AML: The Case of Catalonia (PERIS Project)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Montserrat Hoyos ◽  
Ana Garrido ◽  
Montserrat Arnan ◽  
Marina Diaz-Beyá ◽  
Olga Salamero ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Board Of Directors ◽  
Hematopoietic Cell Transplantation ◽  
Clinical Laboratory ◽  
Laboratory Data ◽  
Population Based ◽  
Advanced Age ◽  
Age Group ◽  
Advisory Committees ◽  
Low Intensity

Introduction:Acute myeloid leukemia (AML) real-world incidence has been investigated in a limited number of European countries such as Sweden, Denmark and a few others. These prospective population-based analyses give a more precise idea of AML as a health problem than registry data from cooperative groups or other sources, that usually include selected cases as part of research studies and/or therapy trials. In October 2016, the Autonomous Government of Catalonia funded a project (PERIS SLT002/16/00433) to prospectively collect all AML cases from our territory. Objective:To investigate the incidence, characteristics and treatment decisions in all consecutive AML patients diagnosed in Catalonia between January 2017 and December 2019. Methods:Inclusion criteria were diagnosis of AML according the WHO 2016 criteria, both primary and secondary (APL excluded) with an age &gt;18 years. The project was disseminated to all hospitals from Catalonia regardless of their size, having at least one hematologist. A specific informatics tool was implemented for remote reporting of the cases. All data were anonymized. In parallel, a circuit for centralized bio banking of patients' samples was designed. The database included the main clinical, laboratory data as well as the initial therapeutic approach. Cases included in our CETLAM group cooperative studies were automatically linked to the trial database for collecting detailed information. Statistical analyses were performed with R packages. Results:Assuming an incidence of AML of 4 cases per 100,000 inhabitants (based on previous reported data from others), we expected 912 cases during three years in the 7,6 million population of Catalonia. Our prospective registry included 750 consecutive AML patients, 82% of the expected cases. The remaining 18% could be explained by the exclusion of APL, age below 18 years, or underreporting. Seventy percent of patients (n=527) were diagnosed and treated in the 5 large University Hospitals from Barcelona and the two adjacent cities (Badalona and Hospitalet). Table 1 shows the main characteristics of the patients. Among the 390 patients up to 70 years, 272 (70%) were enrolled in the CETLAM AML-12 protocol that included intensive chemotherapy (ICT) and risk adapted hematopoietic cell transplantation (HCT). Forty-one additional patients (11%) in this age group received other ICT in different clinical trials. A remaining 73 patients (20%) were treated with other intensive or non-intensive approaches outside trials. In the group of 360 patients older than 70 years only a 33% (n= 119) were treated under the risk-adapted CETLAM AML-16 protocol for elderly AML patients. This trial included ICT as in the CETLAM-12 in case of favorable genetic features; this was received by 13 of the 119 patients (11%) enrolled. The remaining patients of CETLAM-16 were treated with low-intensity chemotherapy (oral fludarabine, subcutaneous (SC) cytarabine and G-CSF or azacytidine) and 97 additional elderly patients were included in other clinical trials mostly with targeted and hypomethylating agents (27%). Other active therapies outside trials (usually low-intensity) were administered in 50 additional patients (14%) whereas the remaining 94 patients (26%) only received supportive measures (transfusions, hydroxyurea, antibiotics, palliation, or no treatment), because of one or more of the following: advanced age, poor AML features or severe clinical condition. Overall survival (OS) of the whole series at 2 years was 31±2% (CI: 27-35). Patients younger than 70 years had a 2-year OS of 47±3% (CI: 41-53) compared to 11±3% (CI: 7-17) for those above 70 years (p&lt;0.001) (Image 1). Conclusions:This prospective study is highly representative of the diagnosis and treatment of AML in Catalonia. The median age at diagnosis was 70 years. Of note, 81% of patients up to 70 years were enrolled in ICT trials. The proportion of patients in trials in the elderly group was lower although still remarkable (60%). In this advanced age group, a 26% of patients were treated with supportive measures only. Despite the high inclusion rate in clinical trials, only one third of newly diagnosed AML patients have the probability to survive at 2 years, with a dismal outcome in those above 70 years. Therefore, the investigation of novel and more effective treatments remains mandatory. This series will be detailed and updated during the meeting. Disclosures Salamero: Pfizer:Consultancy;Jazz Pharmaceuticals:Consultancy, Honoraria;Daichii Sankyo:Honoraria;Novartis:Consultancy, Honoraria;Celgene:Consultancy, Honoraria.Olivera:BAYER:Consultancy;Pfizer:Consultancy, Speakers Bureau;Daiichi Sankyo:Consultancy, Speakers Bureau;Boehringer Ingelheim:Consultancy, Speakers Bureau.Sureda Balari:Celgene:Consultancy, Honoraria;Merck Sharpe and Dohme:Consultancy, Honoraria, Speakers Bureau;Sanofi:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;Gilead/Kite:Consultancy, Honoraria;Janssen:Consultancy, Honoraria;Incyte:Consultancy;Roche:Honoraria;BMS:Speakers Bureau;Celgene/Bristol-Myers Squibb:Consultancy, Honoraria;Takeda:Consultancy, Honoraria, Speakers Bureau.Ribera:Pfizer, Amgen:Research Funding;Pfizer, Amgen, Ariad, Novartis:Consultancy, Speakers Bureau.Sierra:Jazz Pharmaceuticals:Research Funding;Pfizer:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Daiichi Sankyo:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: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, Speakers Bureau;Astellas:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead-Kite:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Clinically Suspected Cast Nephropathy: A Retrospective, Multi-Center, Real-World Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5553-5553
Author(s):  
Agoston Gyula Szabo ◽  
Jonathan Thorsen ◽  
Charlotte Toftmann Hansen ◽  
Maja Ølholm Vase ◽  
Manuela Teodorescu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Serum Creatinine ◽  
Board Of Directors ◽  
Kidney Biopsy ◽  
Population Based ◽  
First Line ◽  
Advisory Committees ◽  
Cast Nephropathy ◽  
Initiation Of Therapy

INTRODUCTION Myeloma cast nephropathy (CN) is the most common form of monoclonal immunoglobulin-mediated kidney disease, resulting from the precipitation of excessive amounts of monoclonal serum free light chains (sFLC) and causing around 70% of the cases of dialysis-dependent renal failure in multiple myeloma (MM)(Heher et al. 2013; Nasr et al. 2012; Sanders et al. 1991). In patients with acute renal failure, the finding of a high sFLC concentration with an abnormal sFLC ratio raises the clinical suspicion of CN (Hutchison et al. 2011). Although the histopathologic diagnosis of CN is established by renal biopsy, in routine clinical practice, the diagnostic yield of this procedure is often outweighed by the urgent need of anti-myeloma treatment and the risk of procedure-related complications. Recruitment of patients with CN into clinical trials is challenging and therefore real-world data on clinically suspected CN are necessary to understand the clinical characteristics, treatment and prognosis of these patients (Bridoux et al. 2017; Hutchison et al. 2019). METHODS We searched the population-based Danish Multiple Myeloma Registry for patients diagnosed with MM according to the International Myeloma Working Group criteria between 1st of January 2013 and 31st of December 2017 with a serum creatinine concentration of 200 µg/L or higher and a sFLC concentration of 1000 mg/L or higher at diagnosis. We conducted a retrospective patient chart review in eight Danish centers and assessed baseline characteristics, biopsy results, and overall survival. Anti-myeloma treatment, sFLC levels and renal function were registered during the first 12 months after MM diagnosis. RESULTS We identified 181 patients (176 with accessible clinical records). The median age was 72 years, the median serum creatinine was 384 µg/L, the median involved sFLC concentration was 5960 mg/L and dialysis dependent renal failure was present in 35%. Pre-myeloma estimated glomerular filtration rate (eGFR) was available in 80%, the median eGFR was 66 ml/min/1.73 m2. A kidney biopsy was carried out in 21% of patients and showed CN in 70% of cases. The median time from first sFLC measurement to initiation of therapy was 4 days. The number of lines of therapy ranged between zero and six. 173 patients received one, 35 patients received two and 14 patients received three lines of therapy during the first 12 months from diagnosis. High-dose melphalan with autologous stem cell transplantation (HDT-ASCT) was carried out in 45 (26%) patients. Bortezomib was administered as part of the first-line regimen in 163 (94%) patients. The most common first-line regimens were bortezomib-dexamethasone (n=67) and cyclophosphamide-bortezomib-dexamethasone (n=46). The first line of therapy resulted in very good partial response or better in 50% (Figure 1A), but was discontinued due to death, toxicity or progressive disease in 38% of patients. Dialysis dependency, eGFR and involved sFLC concentration were assessed at the end of the first cycle, at three months, six months and 12 months after initiation of therapy. At all these time points, achievement of renal recovery was associated with the magnitude of reduction of involved sFLC (Figure 1B). The median overall survival was 3.3 years (Figure 1C). At 12 months after diagnosis, 68% of patients were alive and 15% were dialysis dependent. Reduction of the initial involved sFLC concentration to ≤ 10% at three months was strongly associated with longer OS in a multivariate cox regression analysis adjusted for age and HDT-ASCT; hazard ratio 0.42, p=0.003. CONCLUSION In conclusion, we assessed a population-based cohort of newly diagnosed MM patients presenting with a serum creatinine of 200 µg/L or higher together with a sFLC of 1000 mg/L or higher. Although CN could have been clinically suspected in these cases, a kidney biopsy was only performed in one fifth of the population. Bortezomib-based therapy was initiated quickly and resulted in deep responses in most patients. Approximately one third of patients died within a year from MM diagnosis. Achievement of early and deep reduction in involved sFLC resulted in longer OS. Figure 1 Disclosures Szabo: Janssen: Consultancy. Vangsted:Takeda: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Celgene: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Plesner:Celgene: Consultancy; AbbVie: Consultancy; Genmab: Consultancy; Oncopeptides: Consultancy; Takeda: Consultancy; Janssen: Consultancy, Research Funding.

scholarly journals 10-Year Mortality in Patients with Sickle Cell Disease from a Large Population-Based Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 56-56
Author(s):  
Kristina Lai ◽  
Marianne McPherson Yee ◽  
Beatrice Gee ◽  
Maa-Ohui Quarmyne ◽  
Ross M. Fasano ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Bacterial Infections ◽  
Mortality Rates ◽  
Population Based ◽  
Cell Disease ◽  
Adult Care ◽  
Advisory Committees ◽  
Hb S

Background Mortality rates and causes of death in children with sickle cell disease (SCD) have changed significantly over the past several decades. With ongoing improvements in standards of care, modern mortality estimates must be updated. Children's Healthcare of Atlanta (CHOA) houses one of the largest pediatric SCD programs in the country. This analysis reviews mortality in children with SCD who were treated at CHOA between June 2010-June 2020. Methods We reviewed the CHOA's Sickle Cell Clinical Database (SCCD) for deceased patients. Demographics, SCD genotype, date and age at death, healthcare utilization, hydroxyurea (HU) use, chronic transfusion therapy (CTT), and bone marrow transplant (BMT) were obtained from the SCCD. Cause of death and history of significant comorbidities were abstracted from the medical record. Mortality rates were calculated using person-time for all CHOA SCD patients and population-based mortality was obtained from CDC WONDER Online Database. Results A total of 3,698 patients with SCD were seen at CHOA from June 2010-June 2020 and accounted for 19,998 person-years. Of the 46 patients who died during that time, all but 1 patient had been seen in the CHOA Sickle Cell Outpatient Clinic at least once. That patient received SCD care at a different institution, died from complications of a non-SCD related disease following transfer to CHOA, and was excluded from analysis. Of the 45 remaining patients (178 person-years), the majority were sickle cell anemia genotypes (n=37, 82%; Hb SS or Hb S β0 thalassemia), followed by Hb SC (n=5, 11.1%) and Hb S β+ thalassemia (n=3, 6.7%); 53% (n=24) were female. The average age at death was 12.8 years (1.0-22.8 years). Twenty-one (46.7%) patients had ever been treated with HU and 11 (24.4%) were currently on HU at the time of last contact (either death or last CHOA encounter). Eleven (24.4%) patients had ever been treated with CTT, and 3 (8.9%) were being treated with CTT at time of last contact. In comparison, during the same time period an average of 58% and 12% of the overall CHOA SCD population were being treated with HU and CTT, respectively. Forty-one patients had at least 1 SCD-related encounter at CHOA within 12 months prior to death. For the 4 patients who had not been seen at CHOA within 12 months, the average time since last contact was 1.72 years (1.03 - 2.7 years). Eighty percent (n=8) of the 10 patients who died at age &gt;19 had either recently transitioned to adult care or had documentation of a transition plan. During this 10-year period, the crude death rate was 2.3 per 1,000 person-years. The majority of deaths (62%, n=28) were attributable SCD-related causes and corresponded to a cause-specific mortality rate of 1.40 per 1,000 person-years. The remaining 38% (n=17) of deaths were caused by complex non-SCD comorbidities or accidental trauma and corresponded to a non-SCD related mortality rate of 0.85 per 1,000 person-years. In comparison, the mortality rate for African American persons age &lt;22 in Georgia from 2009-2018 was 0.9 per 1,000 person-years. Of the 28 patients who died due to an SCD-related cause: 12 (27%) experienced an acute illness related to SCD, 4 (9%) succumbed to acute bacterial infections, 3 (7%) died from complications of SCD treatment (1 procedure-related, 2 drug-induced hemolytic anemia), and 1 (2%) died from complications of BMT. Nine (20%) had either recently transitioned to adult care or were lost to follow-up and had no significant non-SCD comorbidities, therefore cause of death was unknown. Of the 17 non-SCD related deaths, 16 (36%) were due to complex non-SCD comorbidities (including cancers, autoimmune disorders, and congenital heart disease) and 1 (2%) from an accidental trauma. Conclusions To our knowledge, this is the largest and most recent study of mortality in patients with SCD from a single institution. Overall, the demographics of deceased patients were similar to those of the CHOA SCD population as a whole. This cohort indicates that trends in mortality of children with SCD have largely shifted away from bacterial infections to other complications of SCD, subsequent treatments, or comorbidities. Our data confirm that patients nearing transition to adult care are at high risk of mortality. This study is limited to deaths that are known to the CHOA system, so future analyses will expand this cohort to include data from death certificates and CDC's National Death Index. Disclosures Lane: FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5444-5444
Author(s):  
Sæmundur Rögnvaldsson ◽  
Ingemar Turesson ◽  
Magnus Björkholm ◽  
Ola Landgren ◽  
Sigurður Yngvi Kristinsson
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Large Population ◽  
Diagnostic Delay ◽  
Population Based ◽  
Lymphoproliferative Disorders ◽  
First Year ◽  
Advisory Committees ◽  
Population Based Study ◽  
Increased Risk

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: 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; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

The Population-Based ‘real world’ of Low Risk Myelodysplastic Syndromes; Second Interim Analysis of the European LeukemiaNet MDS Registry at 800 Registered New Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1867-1867
Author(s):  
David Bowen ◽  
Alex Smith ◽  
Jackie Droste ◽  
Pierre Fenaux ◽  
Argyris Symeonidis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Creatinine Clearance ◽  
Board Of Directors ◽  
Neutrophil Count ◽  
Real World ◽  
Research Funding ◽  
Population Based ◽  
Low Risk ◽  
Advisory Committees

Abstract Abstract 1867 Background: The European LeukemiaNet MDS Registry programme is the largest and most comprehensive prospective population-based registry of ‘low-risk’ MDS patients followed from diagnosis. Objective: The primary objective of this study is to describe the demographics and the disease-management of newly diagnosed MDS patients within IPSS low and intermediate-1 categories. Methods: The project recruits patients from 107 sites in 11 countries, ranging from 2–25 sites per country and including a high proportion of non-University centres in small cities. Consecutive eligible adult patients are registered within 3 months of diagnosis. Local diagnosis is accepted and a large dataset is collected including laboratory data, clinical information (including co-morbidity and concomitant medication) plus health utility (EQ-5D). Data are entered via a web portal and are source verified by study monitoring visits to sites. Results: As of July 2010, 828 patients are registered; data are presented for the first 800 patients. Recruitment is highest from France (n=237) then UK (104), Greece (99), Spain (92), and Sweden (73). Median age is 74.2 yrs (range 18.7–95.3) and from the four largest recruiting countries is 74.6–77.1 yrs. Sixty one percent of patients are male. Twenty patients are non-Caucasian (n=763). Body mass index is overweight (WHO definition) in 43.4% pts and obese in 18.3%, comparable to WHO data for the general adult population (http://apps.who.int/bmi/index.jsp). RCMD is the largest WHO subgroup (34%), followed by RARS (19%), RA (18.4%), RAEB-1 (12.5%), del5q (5.4%), MDS-U (3.5%) and RAEB-2 (0.5%). All WHO subgroups have male predominance except del5q with a striking female excess (79%). IPSS score (n=743) is 0 (52.3%), 0.5 (33.2%), and 1 (14.4%). 84.5% patients have IPSS ‘good’ cytogenetics. 19% patients have 0 cytopenias, 53% 1 cytopenia, 20% 2 cytopenias and 8% 3 cytopenias. WPSS category (with transfusion dependence assessed at time of registration, n=727) is Very Low (35.5%), Low (39.5%), Intermediate (21%), High (4%). Bone marrow features: mean no. of dysplastic lineages = 1.9, bone marrow ring sideroblasts percent = 0 (60% pts), <15 (11.5%), ≥15<50 (19.2%), ≥50 (9.6%). Median haemoglobin (Hb) concentration at presentation is 10.1 g/dl; 36% values were < 10 g/dl and 10% < 8 g/dl. Hb decreased with age (categorical variable Hb. <13>11.5, <11.5>10, <10; Χ2 test, P<.0001). Mean neutrophil count was 2.8 × 109/l with 27% values <1.5 × 109/l, 16% < 1 × 109/l, and 5% < 0.5 × 109/l. Median platelet count was 184 × 109/l; 5% patients had values < 50 × 109/l and 3% < 20 × 109/l. Platelet count and neutrophil count did not change with age. Median serum erythropoietin (EPO) concentration (n=418) was 49 IU/l, 81% values were <200 IU/l and 7% > 500 IU/l. Mean creatinine clearance was 71 mls/min with a marked reduction with age (P<.0001). Baseline serum EPO correlated with Hb. (r=.37, P<.0001), creatinine clearance (r=.22, P<.0001) and age (r=.1, P<.0001). The relationship between creatinine clearance, baseline EPO and response to EPO therapy will be explored. Discussion: This registry records data from the ‘real world’, namely what the hematopathologists in 100 sites diagnose locally as low-risk MDS and will as such be managed as MDS. Median age is consistent with other population-based data (US Medicare, Yorkshire Haematological Malignancy Research Network [www.hmrn.org]). In comparison with registries from specialist MDS centres, median age is higher and a lower proportion have del(5q) WHO subtype. Conclusion: The ELN registry clearly maps the diagnosis and management of low-risk MDS in routine clinical practice in hospitals large and small, specialist and non-specialist and is a unique resource. Acknowledgments: The Steering Committee (SC) acknowledges the commitment and enthusiasm from all 107 sites contributing high quality data to the project. The SC is also grateful for the funding commitment of Novartis Oncology Europe through the University of Nijmegen. Disclosures: Bowen: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Honoraria; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Hellstrom-Lindberg:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Impact Of The Early Intensification Of Induction Chemotherapy On Complete Remission and Survival Rates For De Novo Adult Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3402-3402
Author(s):  
Seung-Ah Yahng ◽  
Jae-Ho Yoon ◽  
Sung-Eun Lee ◽  
Seung-Hwan Shin ◽  
Byung-Sik Cho ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Remission Induction ◽  
Advisory Committees ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Background The successful induction chemotherapy of acute myeloid leukemia (AML) depends on the ability to achieve complete remission (CR) and to maintain remission status as long as possible. Approach to improve the rate of CR includes the intensification of induction chemotherapy for AML. The primary goal of this study was to evaluate and compare the long-term outcomes between remission induction therapy with and without early intensification added to the standard 3+7 remission induction regimen. Methods A retrospective analysis was performed on de novo AML patients diagnosed and treated at Catholic Blood and Marrow Transplantation Center between January 2001 and December 2010. Six hundred forty-one adults of ages between 16 and 60 were included, all of whom received induction chemotherapy starting with 3 days of idarubicin and 7 days of cytarabine or behenoyl cytarabine (BHAC). Cases with t(9;22) and t(15;17) were excluded. Bone marrow (BM) aspiration study was assessed on day 7 of induction in all patients. Factors which were considered for early intensification of induction were the presence of ≥ 5% BM blasts, patient performance, and other high risk clinical characteristics, such as karyotype. Groups according to early intensification on days 8 to 10 of induction were as followings: no intensification (3+7), n=156; cytarabine or BHAC for 3 days (3+10), n=233; addition of idarubicin for 2 days to 3+10 regimen (5+10), n=252. After a median duration of 5.5 months (3.3-19.0) from diagnosis, 479 patients underwent stem cell transplantation (autologous [auto-SCT], n=144; allogeneic [allo-SCT], n=335). Conditioning regimen for auto-SCT consisted of fractionated total body irradiation (TBI), melphalan, and cytarabine, whereas 83% (n=278) of patients with allo-SCT received myeloablative conditioning, of which was mostly TBI-based regimen (92%). Donors were matched sibling (n=213), matched unrelated (n=63), mismatched unrelated (n=39), and haploidentical related (n=20). Results The median age at diagnosis was 39 years (16-60). Mean values of BM blast % on day 7 of induction was 3.5 in 3+7 group, 7.9 in 3+10, and 33.6 in 5+10 (p=<0.0001), while no significant difference in the proportion of adverse karyotype was shown (11.7% vs. 12.8%, p=0.804). After first induction (3+7, n=165; 3+10/5+10, n=465), the CR/CRi rate was significantly higher in 3+10/5+10 versus 3+7 (78.1% vs. 69.2%, p=0.023), while the rate for death in aplasia was lower (4.3% vs. 9.6%, p=0.013). After re-induction with various regimens, the CR/CRi rate was still significantly higher in intensified group (p=0.012). The relapse rates between the groups in 536 patients achieving CR (83.6%), however, was not significantly different (8.9% vs. 9.9%, p=0.737). SCT was performed at CR1 (n=459), CR2 (n=10), or relapsed/refractory status (n=10). Patients with auto-SCT mostly had better/intermediate cytogenetic risk (96%) at diagnosis, while 12% of allo-SCT had poor karyotype. After the median follow-up duration of 60.2 months (2.2-143.5), the median overall survival (OS) in all patients (n=641) was 65.6 months. The 5-year disease-free survival (DFS) of patients with auto- and allo-SCT was 58.4±4.2 and 64.9±2.7, respectively. Of 334 patients receiving allo-SCT, the 5-year DFS was significantly higher in patients achieving CR1 (n=299) after first induction therapy (p<0.0001), in whom 75% of them had early intensification. Other factors with significant impact on DFS after allo-SCT (n=334) were karyotype at diagnosis (p=0.032) and donor type (HLA-matched vs. HLA-mismatched sibling or unrelated, 58.1%±3.8 vs. 45.1±8.0, p=0.016). The significances were confirmed in multivariate analysis, which demonstrated that achieving CR1 after first induction regimen and its maintenance until SCT was the most powerful predictor for DFS after allo-SCT (67.1±2.9 vs. 34.6±7.8, p=<0.0001). When all patients were analyzed, according to induction intensification, a statistically significant benefit in 10-year OS was observed in 5+10 intensified group (44.8% vs. 52.9%, p=0.032). Conclusion Our results suggest possible benefit of examining day 7 BM aspiration for the strategy of early intensification of induction chemotherapy for adult AML patients and our intensification doses can be safely added with high efficacy in the achievement of CR1 compared to 3+7 standard regimen, and may have affected for better DFS after allo-SCT. Disclosures: Kim: BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Myelodysplastic Syndrome (MDS)-Determining Clonal Events at Presentation of Aplastic Anemia (AA)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1652-1652
Author(s):  
Eiju Negoro ◽  
Naoko Hosono ◽  
Wenyi Shen ◽  
Tetsuichi Yoshizato ◽  
Bhumika J. Patel ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Board Of Directors ◽  
Somatic Mutations ◽  
De Novo ◽  
Initial Presentation ◽  
Progression Rate ◽  
Advisory Committees ◽  
Increased Risk ◽  
Slow Expansion ◽  
Secondary Mds

Abstract Historically, the evolution rate of aplastic anemia (AA) to MDS approaches 15% in 10 yrs; thus, AA can be considered a major predisposition factor for secondary MDS (sMDS). The likely etiology includes expansion of a preexisting clone or truly late clonogenic events. In both instances, progression can be a result of a clonal escape, but confirmation of the presence of mutant cells at presentation would indicate that initial autoimmune processes may represent a tumor surveillance reaction. We studied 326 patients with AA and 47 patients with paroxysmal nocturnal hemoglobinuria (PNH) and identified 36 cases (progression rate: 11% in median follow up of 6 years) that evolved to MDS or AML (median time to progression: 3.2 yrs.; transplanted patients were not censored). Cytogenetic analysis upon progression showed abnormal karyotype in 83% of cases; 7% had complex karyotype and -7/del(7q) was present in 62% of cases. The presence of a PNH clone was detected in 17% of cases that transformed to sMDS vs. 35% in non-progressors (P=.1). For comparison, we have also analyzed primary de novo cases of MDS (pMDS) with (N=94) and without (N=557) -7/del(7q). In contrast to sMDS, -7/del(7q) was present in 14.4% of cases in pMDS. Because sMDS following AA or PNH included a high proportion of patients with -7/del(7q), we compared sMDS with -7/del(7q) to pMDS with -7/del(7q) for coexisting mutational events. Mutations in RUNX1, CBL, SETBP1 and ASXL1 appeared to be more frequent in sMDS vs. pMDS (28.6% vs. 2.1%, 21.4% vs. 2.1%, 21.4% vs. 5.3%, 21.4% vs. 10.6%, P=.003, P=.02, P=.07, P=.37, respectively). In contrast, TP53 and DMT3A were more common in pMDS (7.1% for sMDS vs. 17%, 0% for sMDS vs. 8.5%, P=.69, P=.59). Similarly, there were several other distinctive differences between all sMDS and pMDS irrespective of the cytogenetics: mutations in SF3B1, SRSF2, NPM1, DNMT3A were common in primary AML but entirely absent from cases after AA; mutations in RUNX1 and SETBP1 appeared to be more frequent in sMDS vs. pMDS (26.3% vs. 8.3%, 21.1% vs. 3.2%, 15.8% vs. 3.9%, P=.03, P=.005, respectively). Whole exome NGS was performed after progression, with confirmed somatic mutations subsequently tracked back by targeted deep NGS applied to serial samples starting at initial presentation. Confirmed mutational events and chromosomal aberrations were found in 19/36 patients with sMDS; 17/19 cases of sMDS had at least 1 confirmed somatic mutation. Remarkably, in retrospective analysis in 6/7 cases studied serially, at least one of the identified mutations was detectable at presentation when deep targeted sequencing (depth 5,000~20,000 reads) was performed. In 5 of these cases the alterations appeared to be ancestral events for sMDS evolution. When anadditional 77 AA or PNH cases were studied by deep sequencing, somatic mutations were present in 48% of AA patients at presentation. Detection of clonal events at presentation was associated with an increased risk of subsequent MDS evolution (14/37 mutant cases vs. 3/40 nonclonal cases evolved, P=.002). Mutations found at both initial presentation and upon evolution were suggestive of a slow expansion of previously cryptic clones (ASXL1, CUX1, TET2, CBL, RUNX1, and SETBP1). Patients with these genes (n=18) had worseoverall survival compared to patients without these mutations (P=.03). To assess the potential impact of immunosuppressive therapies (IST), we also investigated a subset (out of 77) of 53 patients (39 responders and 14 refractory cases) following IST. Clonal somatic events were identified in 27 of them, but there was no association between the response to IST and somatic mutations at presentation. Our results demonstrate that while subclonal mutations indicative of oligoclonal hematopoiesis are frequent in AA, the presence of permissive ancestral somatic events at the outset of AA predisposes patients to sMDS, a feature that had diagnostic and prognostic implications. Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees.

Efficacy of Single-Agent Decitabine in Relapsed and Primary Refractory (rel/ref) Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2518-2518
Author(s):  
Andrew Hantel ◽  
Niloufer Khan ◽  
Richard A. Larson ◽  
Lucy A. Godley ◽  
Michael J. Thirman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Genetic Risk ◽  
Research Funding ◽  
De Novo ◽  
Median Number ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Induction Regimen ◽  
De Novo Aml ◽  
Wbc Count

Abstract Introduction Improving therapy for rel/ref AML remains a challenge. Decitabine, a DNA methyl-transferase inhibitor, initially showed promise in AML as a 5-day, first-line induction regimen and more recently as a 10-day regimen in older and unfit patients (1). However, little is known about the activity of decitabine in the rel/ref patient population despite increased use. Therefore, we sought to analyze the outcomes of these pts treated at our institution. Methods To obtain data regarding decitabine efficacy in rel/ref AML, we performed a retrospective analysis of outcomes following decitabine treatment in 34 adult pts treated at The University of Chicago from January 2009 to June 2014. Permission to access patient charts was granted by the medical centerÕs Institutional Review Board. AML was defined by WHO criteria, genetic risk grouping and complete remission (CR) was according to ELN classification; PR was defined as >50% decrease in bone marrow blasts and normalization of blood counts. Rel/ref AML was defined as either having had a prior CR with recurrence of disease or having received a prior induction regimen (1-2 cycles) without CR. Results Median pt age was 62 yrs (range, 18-81) and 60% were male. Median Charlson comorbidity index (CCI) was 5 (range, 0-8); 29% had ECOG performance status 0-1 and 71% had >2. 21 pts (62%) had de novo AML (7 with myelodysplasia-related changes), 3 (9%) had therapy-related myeloid neoplasm (t-MN), and 10 (29%) had secondary AML after myelodysplastic syndrome. 6% were in the ELN favorable genetic group, 3% intermediate-I, 18% intermediate-II, and 67% adverse; 2 cases were unevaluable. The median number of prior treatment regimens was three. 9% had received prior azacitidine, 85% had received prior HiDAC, and 38% had a prior allogeneic stem cell transplant (SCT). 34 pts received a total of 71 cycles of decitabine, 20 mg/m2 daily, in 5 or 10-day cycles every 28 days. All patients received 10-day courses, 91% had an initial 10-day course, and 74% had only 10-day courses. The median number of cycles per pt was 2; 59% received >1 cycle. 7 (21%) achieved CR and 4 (12%) had a partial response (PR), for an overall response rate (OR) of 33%. Responses occurred in 24% of pts with de novo AML, 66% with t-MN, and 50% with secondary AML. Intermediate and adverse group pts had OR of 14% and 39%, respectively. All pts achieving CR did so after 1 cycle; PR required a median of 3 cycles. Pts who achieved CR or PR had a significantly lower pretreatment WBC count (median, 9.5 vs 49.5 x 103/µL in non-responders; p=0.015) and blast percentage (44 vs 59.4; p=0.035) than those who did not. Pts with secondary AML or t-MN had a higher probability of OR compared to those with de novo AML (54 vs 23%; p=0.042). Median overall survival (OS) of all pts was 256 days; prior SCT was associated with reduced OS (p=0.017). When comparing de novo to secondary AML & t-MN, 1-year OS was not significantly different (Figure 1). Responders had a significantly longer OS (median, 622 days vs 278 days for non-responders; p=0.012). Age, race, CCI, ECOG PS, genetic risk group, prior HiDAC, dysplasia, azacitidine, and number of prior treatments did not impact OR or OS. 16 (47%) pts proceeded to SCT. During treatment, 70% had a grade 3-4 non-hematologic toxicity (based on NCI CTACE v4.0); the most common was fatigue. The median number of hospitalizations for complications per patient was 2 (range, 0-7). Causes of hospitalization were febrile neutropenia (40%), infection (22%), cytopenias (18%), rash (6%), acute kidney injury (6%), and 8% were for other causes. Conclusion Decitabine treatment of 34 adults with rel/ref AML resulted in an OR of 33% (21% CR) and allowed nearly one-half of these pts to proceed to SCT. All pts achieving CR did so after 1 cycle. Responding pts had improved OS over those without response (p=0.012). Interestingly, secondary AML or t-MN were 7.8 times more likely to achieve a response compared to de novo AML (p=0.046); lower WBC count and marrow blast percentage also correlated with higher OR. Further delineation of molecular subsets associated with response to decitabine should be evaluated in a larger prospective trial in this high-risk AML population. Citation 1. Blum KA, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J of Haem. Jul 2010;150(2):189-195. Figure 1. Figure 1. Disclosures Off Label Use: Decitabine is indicated for treatment of MDS but is often used to treat newly diagnosed or relapsed/refractory AML. In this study we analyzed results of patients with AML who were treated with decitabine in the relapsed/refractory setting.. Thirman:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; Merck: Research Funding. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy; Astra Zeneca/Medimmune: Consultancy; Pfizer: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees.

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