scholarly journals Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin (FLAG-GO) Regimen Results in Better Molecular Response and Relapse-Free Survival in Core Binding Factor Acute Myeloid Leukemia Than FLAG and Idarubicin (FLAG-Ida)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 290-290 ◽  
Author(s):  
Gautam M. Borthakur ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
Guillermo Garcia-Manero ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Fusion Transcript ◽  
Gemtuzumab Ozogamicin ◽  
Newly Diagnosed ◽  
Relapse Free Survival ◽  
Core Binding Factor ◽  
Advisory Committees ◽  
Free Survival ◽  
Binding Factor

Background: A regimen comprising of fludarabine, cytarabine, G-CSF (FLAG) has been our frontline treatment for patients with core binding factor acute myelogenous leukemia (CBF-AML) since 2007, initially in combination with gemtuzumab ozogamicin (FLAG-GO) (at 3 mg/m2 on day 1 in induction and and in 2 of the planned 6 post-remission cycles) and after withdrawal of GO from US market in combination with idarubicin at 6 mg/m2 on days 3 and 4 in induction and in one post remission cycle during cycles 3-6 (FLAG-Ida). Fusion transcripts, RUNX1-RUNX1T1 or CBFB-MYH11, were assessed at base line and monitored every 2-3 months by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) during consolidation therapy. Results: Between April 2007 and January 2018, 162 patients (Inv 16 =84, 8;21= 78) with newly diagnosed CBF-AML have been treated, median age 49 years (range, 19-78 years, 15% older than 65 years). Fifty-seven (35%) patients were treated with FLAG-GO. Amongst all patients, 95% (N=154) achieved complete remission (CR), 6 (4%) achieved CR with incomplete platelet recovery (CRp) and 2 patients died within first 4 weeks. Of the planned total of 7 cycles of therapy, median number of cycles of therapy delivered is 5 (range 1-7); prolonged cytopenias being the limiting factor in delivery of all planned cycles. With median follow up of 6.5 years, the 5 year overall survival (OS) is 71% and relapse free survival (RFS) is 75%. Patients treated with FLAG-GO and FLAG-Ida were comparable in age, cytogenetic subgroups and presence of kinase (KIT, FLT3, RAS) mutations. OS was not significantly different (p=.7) among treatment regimens but RFS was significantly better among patients treated with FLAG-GO (p=.02) (Fig.1). RFS at 5 years was 87% with FLAG-GO regimen while the same was 68% for FLAG-Ida regimen. Presence of KIT (p=.6) or any kinase mutation (KIT,RAS or FLT3) (p=.8) did not impact RFS. Reduction of fusion transcript ratio by 3 log at end of induction (p=.01) (Fig.2), by 4 log at end of cycle 3-4 (p=.03) and end of all cycles (p=.001), resulted in better RFS. FLAG-GO regimen but not cytogenetic subgroups was associated with better reduction in fusion transcript. Seventy-six percent of patients treated with FLAG-GO achieved reduction of fusion transcript to <0.01 by mid-consolidation while the same was 42% for patients treated with FLAG-Ida (p=0.002). Conclusion: FLAG-GO or FLAG-Ida regimen results in high remission rates among patients with newly diagnosed patients with CBF-AML with low induction mortalities. Induction consolidation with FLAG-GO results in better RFS and quantitative reduction in fusion transcript ratio, compared to FLAG-Ida. Serial quantitative monitoring of fusion transcript identifies patients with better chances of sustained remission. Disclosures Borthakur: PTC Therapeutics: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Polaris: Research Funding; Cantargia AB: Research Funding; GSK: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Tetralogic Pharmaceuticals: Research Funding; Oncoceutics, Inc.: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; NKarta: Consultancy; Strategia Therapeutics: Research Funding. Cortes:Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Merus: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Ravandi:Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding. Garcia-Manero:Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Daver:BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Karyopharm: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Servier: Research Funding; Celgene: Consultancy; Astellas: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Glycomimetics: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Cyclacel: Research Funding.

scholarly journals Addition of Gemtuzumab Ozogamicin (GO) to Fludarabine, Cytarabine and G-CSF (FLAG) Based Induction Regimen Results in Better Early Molecular Response and Relapse Free Survival Compared to Idarubicin (FLAG-Ida) in Newly Diagnosed Core Binding Factor Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3993-3993 ◽  
Author(s):  
Gautam Borthakur ◽  
Jorge E. Cortes ◽  
Guillermo Garcia-Manero ◽  
Keyur Patel ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Relapse Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Acute Myelogenous

Abstract Background: Fludarabine, cytarabine and G-CSF (FLAG) based regimens have resulted in marked improvement in newly diagnosed core binding factor (CBF) acute myelogenous leukemia (AML)(1-3). Addition of gemtuzumab ozogamicin (GO) to chemotherapy has also improved survival outcomes in CBF-AML(4). In 2007 we initiated a frontline study of FLAG-GO in newly diagnosed CBF-AML but after withdrawal of GO from US market, GO was replaced with idarubicin (FLAG-Ida). We report on mature data including early molecular response in patients treated in these sequential protocols. Methods: One hundred and forty five patients [Median age, 48 years (range, 19-78 years) were treated in these sequential protocols (FLAG=GO=50, FLAG-Ida= 95 patients). The treatment groups were comparable for age and distribution of cytogenetic (T8;21 or Inv16) subgroups (p≥0.5). FLAG regimen has been published before(2), GO was administered at 3 mg/m2 on day 1 in induction and in 2 consolidations out of planned 6 and idarubicin was administered at 6 mg/m2 on days 3 and 4 in induction and on day 2 in one of the consolidation cycles out of planned 6. Serial assessment of fusion transcript product relevant to the cytogenetic abnormality was performed in bone marrow samples at baseline, end of induction and every 2-3 cycles thereafter. Results: All except 3 patients (2 induction deaths) achieved remission (98%). After median follow up of 5 years, 5 year overall survival (OS) and relapse free survival (RFS) for the entire cohort is 77% and 72% respectively. There were no differences in OS among FLAG-GO vs FLAG-Ida (p=0.3) and Inv16 vs T(8;21) (p=0.6). While RFS was similar among Inv 16 and T(8;21) subgroups, it was significantly better among the cohort treated with FLAG-GO compared to FLAG-Ida (p=0.04)(Fig 1). We confirmed our earlier report of higher than 3 log reduction of fusion transcript ratio at end of induction(5) being most indicative of sustained RFS (p=0.006) (Fig 2) and this end point was more frequently achieved in the FLAG-GO cohort (57%) compared to FLAG-Ida cohort (29%) (p=0.002). On the other hand, within each regimen there was no difference in RFS between Inv 16 andf T(8;21) subgroups (p=0.3) (Fig. 3). SAEs were mostly related to cytopenias and associated infectious complications for both regimens and no hepatic veno-occlusive disease (VOD) was encountered. Presence of KIT, RAS, FLT3 mutations individually or in combination did not have any impact on outcomes. Conclusion: Compared to idarubicin, GO when added to FLAG based frontline induction/consolidation regimen results in better early molecular responses and improved relapse free survival in CBF AML. Our current frontline protocol is exploring safety and efficacy of addition of both GO and Ida to FLAG based regimen. ReferencesBorthakur G, Cortes JE, Estey EE, Jabbour E, Faderl S, O'Brien S, et al. Gemtuzumab ozogamicin with fludarabine, cytarabine, and granulocyte colony stimulating factor (FLAG-GO) as front-line regimen in patients with core binding factor acute myelogenous leukemia. Am J Hematol. 2014;89(10):964-8.Borthakur G, Kantarjian H, Wang X, Plunkett WK, Jr., Gandhi VV, Faderl S, et al. Treatment of core-binding-factor in acute myelogenous leukemia with fludarabine, cytarabine, and granulocyte colony-stimulating factor results in improved event-free survival. Cancer. 2008;113(11):3181-5.Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, et al. Optimization of Chemotherapy for Younger Patients With Acute Myeloid Leukemia: Results of the Medical Research Council AML15 Trial. Journal of Clinical Oncology. 2013;31(27):3360-8.Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. The Lancet Oncology. 2014;15(9):986-96.Boddu P, Gurguis C, Sanford D, Cortes J, Akosile M, Ravandi F, et al. Response kinetics and factors predicting survival in core-binding factor leukemia. 2018. Disclosures Cortes: novartis: Research Funding. Ravandi:Jazz: Honoraria; Sunesis: Honoraria; Jazz: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Xencor: Research Funding; Orsenix: Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Orsenix: Honoraria. Kadia:Novartis: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy. Pemmaraju:SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Daver:ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; Alexion: Consultancy; Otsuka: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; BMS: Research Funding; Karyopharm: Research Funding; Pfizer: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; Sunesis: Research Funding; Novartis: Consultancy; Novartis: Research Funding; Incyte: Research Funding; ImmunoGen: Consultancy.

Effect of fludarabine, cytarabine, filgrastim, and gemtuzumab ozogamicin (FLAG-GO) on relapse-free survival in patients with newly diagnosed core-binding factor acute myelogenous leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6528-6528
Author(s):  
Gautam Borthakur ◽  
Jorge E. Cortes ◽  
Susan Mary O'Brien ◽  
Tapan M. Kadia ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Relapse Free Survival ◽  
Core Binding Factor ◽  
Platelet Recovery ◽  
Free Survival ◽  
Binding Factor ◽  
Acute Myelogenous

6528 Background: Prior modulation with fludarabine increases cytarabine-triphosphate (ara-CTP) accumulation and granulocyte-colony-stimulating factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in leukemic blasts. Our front-line regimen of fludarabine, cytarabine and filgrastim (FLAG) based on this rationale showed improved event-free survival compared to anthracycline and cytarabine based regimens in patients (pts) with core-binding factor acute myelogenous leukemia (CBF-AML). Medical Research Council AML 15 trial reported survival benefit from addition of gemtuzumab ozogamicin (GO) to chemotherapy regimens in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed CBF-AML, pts received GO on day 1 of induction and of post-remission cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in induction and 3-4 days in post-remission cycles) with filgrastim started on day-1 and continued till neutrophil recovery. Pts who received one non-FLAG-GO induction could enroll irrespective of their remission status. Results: Fifty pts [30 with t(8;21) and 20 with Inv16] have been enrolled [5 of 50 (10%) were in remission at enrollment from prior induction]. Median age is 48 years (range, 19-76), median WBC count 12.3 x106/L (range, 1.3-97.2); 12 patients (24%) were >60 years of age and frequency of kit mutation is 8%. Complete remission with or without platelet recovery (CR/CRp) was achieved in 43/45 (96%) pts with 2 deaths in induction. With 6 planned consolidations, the median number of consolidation treatments received is 5 (range, 0-6). Two-thirds of pts needed dose reduction during post-remission cycles. Seven (14%) pts [t(8;21)= 5, Inv 16=2] relapsed and with a median follow-up of 34 months (range, 15-54 months) the relapse-free survival rate is 83%. Conclusions: FLAG-GO is a highly effective regimen and has resulted in high rate of relapse-free survival in pts with newly diagnosed CBF AML.

scholarly journals Clonal Hematopoiesis Is Frequent and Associated with Inferior Survival Irrespective of Transplantation Strategy in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1127-1127
Author(s):  
Adam S. Sperling ◽  
Robert Redd ◽  
Christopher J. Gibson ◽  
Peter G. Miller ◽  
Jill Corre ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Board Of Directors ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Newly Diagnosed ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Clonal Hematopoiesis

Abstract Background: The acquisition of somatic clonal mutations in the blood of healthy individuals is referred to as clonal hematopoiesis (CH) and is associated with increased age, risk of hematologic malignancy, and non-malignant inflammatory outcomes. The presence of CH in patients with non-Hodgkin lymphoma (NHL) has been associated with adverse outcomes and decreased overall survival (OS) especially in the setting of autologous transplantation. In multiple myeloma (MM), the presence of CH at the time of stem cell collection was associated with decreased OS only in those patients who did not receive thalidomide analog maintenance. However, the clinical significance of CH in patients with newly diagnosed MM undergoing autologous transplant has not been assessed. We sought to determine the frequency and clinical outcome of CH in patients with newly diagnosed MM. The IFM 2009 study randomized 700 newly diagnosed patients with MM to lenalidomide, bortezomib and dexamethasone (RVd) versus RVd plus high-dose therapy (HDT). This patient cohort provides a unique opportunity to examine the prevalence of CH in newly diagnosed MM patients and assess its influence on clinical outcomes, including early transplantation, in a homogeneously treated population of MM patients. Methods: We performed targeted error-corrected next generation sequencing of 100 genes recurrently mutated in hematologic malignancies in 377 patients with newly diagnosed MM who were part of the IFM 2009 study (additional patient samples are pending analysis). CH was defined as the presence of any pathogenic mutation with a variant allele fraction (VAF) ≥ 0.005. Sample DNA was collected from peripheral blood of subjects at the time of screening/diagnosis. The median age at sample collection was 59 years. Median follow-up was 7.8 years. Results: We identified CH in 188 (48%) patients with VAF ≥ 0.005, in 119 (32%) patients with VAF ≥ 0.01 and in 59 (16%) patients with VAF ≥ 0.02. Because prior studies have primarily assessed clinical significance of VAF ≥ 0.02, further analysis was restricted to this threshold. Consistent with prior reports DNMT3A (30 patients), TET2 (11 patients) and ASXL1 (3 patients) were the most commonly mutated genes. The presence of CH was associated with increased median age (61 vs 59 years, p = 0.003), ISS stage III (p = 0.007) and increased LDH (p = 0.006), but not with sex, monoclonal protein isotype, b2-microglobulin level, or assignment to RVd or HDT arms. As previously reported, randomization to the early transplant arm was associated with increased relapse free survival but not with improved OS. Across the entire cohort, the presence of CH was associated with inferior OS (p = 0.003), but had no association with relapse-free survival or time to relapse. The decrement in OS was seen equally in both the RVd and HDT arms of the study. The presence of mutant clones smaller than a VAF < 0.02 was not associated with adverse clinical outcomes. Fourteen patients developed a second primary malignancy (SPM), only two of which were hematologic neoplasms. There was no difference in the frequency of SPM development in those patients with or without CH. Conclusions: In patients with newly diagnosed multiple myeloma, the presence of CH at a VAF ≥ 0.02 is frequently observed and is associated with decreased overall survival regardless of transplantation strategy. The presence of CH did not affect the risk of developing an SPM. Taken together, these data suggest that while CH is associated with decreased survival the presence of CH should not alter eligibility of patients for autologous transplantation. Figure 1 Figure 1. Disclosures Sperling: Adaptive: Consultancy. Miller: Foundation Medicine: Consultancy. Moreau: Amgen: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. Ebert: Celgene: Research Funding; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Deerfield: Research Funding. Munshi: Amgen: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Pfizer: Consultancy; Adaptive Biotechnology: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Legend: Consultancy; Bristol-Myers Squibb: Consultancy.

scholarly journals Routine Use of Gemtuzumab Ozogamicin in 7+3-Based Inductions for All "Non-Adverse" Risk AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Gavin Hui ◽  
Abdullah Ladha ◽  
Edna Cheung ◽  
Caroline Berube ◽  
Steven Coutre ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Myeloablative Conditioning ◽  
Advisory Committees ◽  
Monosomy 7

Introduction: The addition of gemtuzumab ozogamicin (GO) to 7+3 chemotherapy for newly diagnosed acute myeloid leukemia (AML) has been shown to significantly improve event-free survival (EFS) for cytogenetically favorable-risk AML, with marginal benefit for intermediate-risk AML, and no benefit for cytogenetically adverse-risk AML. Of note, with the exception of mutated FLT3-ITD, little is known about the impact of GO in ELN 2017-defined genotypically adverse-risk AML, and a recent randomized trial found no EFS benefit for 7+3+GO in patients (pts) with genotypically favorable-risk, NPM1-mutated AML. Since 2017, our institution incorporated GO into 7+3-based inductions for all "non-adverse" risk AML pts, as defined by wild-type FLT3 and no abnormalities on rapid FISH analysis for del(5q)/monosomy 5, del(7q)/monosomy 7, and del(20q). We report our experience treating all pts with "non-adverse" risk AML-as defined by this algorithm-with 7+3+GO. Methods: An institutional database was queried in order to identify all pts ≥18 years old who received 7+3-based chemotherapy for newly diagnosed AML between 2017 and 2020; pts who received the FDA-approved fractionated dose of GO were included in the analysis. Data collection included demographic variables, karyotype/FISH, targeted PCR analyses, and multigene NGS panels for AML-related mutations including, but not limited to, mutations in FLT3, NPM1, CEBPA, TP53, RUNX1, and ASXL1. Outcome data included response to induction, relapse, and death, as well as hematopoietic cell transplant (HCT) rates, conditioning regimens, and post-transplant complications. Results: Between January 2017 and July 2020, 96 pts received 7+3-based induction at our institution. Of these, 29 (30%) received 7+3 in combination with GO. Median age at diagnosis was 46 years (range 23-66), with 17 (59%) males. Sixteen (55%) pts had ELN favorable-risk AML (5 [31%] by cytogenetics and 11 [69%] by genotype), 6 (21%) pts had ELN intermediate-risk AML, and 7 (24%) pts had ELN adverse-risk AML (4 [57%] by cytogenetics and 3 [43%] by genotype). Median time from diagnosis to start of induction was 4 days (range 0-43). For cytogenetically adverse-risk pts, median time from diagnostic bone marrow biopsy to receipt of adverse karyotype results was 8 days (7-14). Median time from start of induction to receipt of multigene NGS results for all pts was 15 days (3-32). Overall, 22 (76%) pts achieved remission. All genotypically adverse-risk pts (1 with mutated TP53 and 2 with mutated RUNX1) were refractory to induction, while 3 of 4 (75%) cytogenetically adverse-risk pts (1 with t(6;9), 1 with monosomy 7, and 2 with 11q23 abnormalities) achieved remission. Eight of the 29 (28%) pts proceeded to HCT, including 4 adverse-risk pts. Of the adverse-risk pts, all received myeloablative conditioning prior to HCT and 3 (75%) developed veno-occlusive disease (VOD), with 2 (50%) requiring defibrotide therapy. In favorable/intermediate-risk pts, 4 (18%) proceeded to HCT (2 intermediate-risk pts in first remission and 2 favorable-risk pts in second remission). Of these, 2 (50%) received myeloablative conditioning and 1 (25%) developed VOD. At last follow-up, 23 of 29 pts (79%) remained alive, with a median overall survival not reached (range 1-29 months) and a median EFS of 20 months (9-31). The percentage of ELN favorable-, intermediate-, and adverse-risk pts who remained event-free at last follow-up was 75%, 33%, and 43%, respectively. Discussion: This single-center, retrospective cohort describes the outcomes of pts with "non-adverse" risk AML who received induction chemotherapy with 7+3+GO according to a pre-defined algorithm. Using this algorithm, 30% of all pts receiving 7+3-based inductions received GO. Of these, nearly 25% were ultimately found to have adverse-risk AML as defined by ELN 2017 criteria, largely driven by long turn-around times for karyotyping and NGS multigene panel results. No patient with genotypically adverse-risk AML by ELN criteria responded to induction chemotherapy, and 75% of cytogenetically adverse-risk pts who proceeded to HCT developed VOD. Routine use of 7+3+GO induction outside of the context of cytogenetically favorable-risk AML remains controversial, and further study is needed to define the role of GO, particularly for pts with ELN genotypically adverse-risk AML. Table Disclosures Gotlib: Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair of the Response Adjudication Committee and Research Funding, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: co-chair of the Study Steering Committee and Research Funding. Liedtke:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Adaptive: Research Funding; Amgen: Consultancy; Servier: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding.

ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 207-207 ◽  
Author(s):  
Timothy P. Hughes ◽  
Andreas Hochhaus ◽  
Giuseppe Saglio ◽  
Dong-Wook Kim ◽  
Saengsuree Jootar ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Superior Efficacy ◽  
Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

scholarly journals Single UM171 Expanded Cord Blood Permits Transplantation of Better HLA Matched Cords with Excellent Gvhd Relapse Free Survival

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4658-4658 ◽  
Author(s):  
Sandra Cohen ◽  
Jean Roy ◽  
Silvy Lachance ◽  
Anne Marinier ◽  
Jean-Sébastien Delisle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Culture System ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Cell Dose ◽  
Equity Ownership

Abstract Cord blood (CB) transplants have fallen into disfavor in large part due to low cell dose leading to prolonged hospitalizations and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities of lower risk of chronic GVHD and relapse to prevail. In addition, UM171 could permit transplantation of smaller, better HLA matched cords, associated with lower TRM. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). Our goal was to design a clinically viable eCB transplant with a TRM as low or lower than other HSC sources all the while maintaining CB's low relapse rate. Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 7/16-6/18, 21 adult pts (median age 44 years) were transplanted with an eCB. Median final culture volume and net viable CD34 fold expansion were 670 mL and 35, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with our pts receiving peripheral blood (PB) or marrow (BM) and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment (defined as 500 neutrophils). Pts' median last day of fever prior to 500 neutrophils was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained early, provide significant defense against infection, ii) the graft contains a significant proportion of dendritic cell precursors (30-40%) which offer mucosal protection during severe neutropenia. Duration of hospitalization was shorter by 12 days and longer by 2 days compared to our non eCB and PB-BM transplants, respectively. In addition, because cell dose requirements were lower, 12/21 pts received a better HLA matched CB, thus >80% of patients were transplanted with a ≥6/8 HLA matched eCB. As a result of lower minimal cell dose criteria, we can now use ∼half the CBs in the banks instead of only 5% for a 70 kg patient. Platelet engraftment occurred at a median of 42 days. With a median follow up of 14 months, there has been no CMV disease, no PTLD, 2 adenovirus cystitis, 2 (10%) grade 3-4 acute GVHD, no moderate/severe chronic GVHD and 1 TRM (5%) despite a median comorbidity index of 2 (0-5). Full donor chimerism was achieved in all cell subsets. Immune recovery was faster than seen in our unrelated donor transplants who routinely receive ATG prophylaxis with 196, 300 and 413 CD4+/µL at 3, 6 and 12 months, respectively. Interestingly, transcriptome analysis of UM171-eCB cells shows an enhanced lymphoid progenitor-associated gene signature when compared to DMSO exposed cells. Animals transplanted with UM171-eCB cells showed a 20 to 35-fold increase in thymic cellularity at 8 weeks post-transplant. Despite some very high risk pts in our trial, only 3 relapsed. Overall, progression free, and GVHD/relapse free survival (GRFS) are excellent at 95, 77 and 67%, respectively, at 12 months. A 7 day UM171 single eCB protocol is feasible and provides clinical benefits beyond faster engraftment with fewer infectious complications, better HLA matching and very low TRM, all the while saving production and hospitalization costs. Nevertheless, longer follow up will be required to better assess relapse howbeit encouraging preliminary results. Furthermore, patients' quality of life is paramount and best evaluated by GRFS which is excellent thanks to a very low rate of significant chronic GVHD all the while maintaining a low risk of relapse. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-eCB as a promising HSC source which could compete with the current standard of care. Figure. Figure. Disclosures Cohen: ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent; Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Caudrelier:ExCellThera: Employment. Zandstra:ExCellThera: Equity Ownership. Sauvageau:ExCellThera: Employment, Equity Ownership.

scholarly journals Poor Outcomes with Hyper CVAD Induction for T-Cell Lymphoblastic Leukemia/Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3762-3762 ◽  
Author(s):  
Vamsi K Kota ◽  
Amanda Redden Hathaway ◽  
Bijal D. Shah ◽  
Deniz Peker ◽  
Ling Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Cancer Center ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Genetics Research

Abstract Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) in adults is an aggressive bone marrow malignancy that historically has a poor prognosis. Hyper-CVAD/methotrexate-cytarabine (hyper CVAD) regimen is a commonly used induction regimen following the protocol developed at MD Anderson Cancer center. Recent reports from Swedish Cancer Registry showed that relapse rates were much higher than expected with this regimen. We report our retrospective experiences across three different centers, Winship Cancer Institute of Emory University (Atlanta), University of Alabama Cancer Center (Birmingham) and Moffitt Cancer Center, (Tampa), with the use of this regimen for management of T-ALL/LBL. Methods: We conducted a retrospective chart review of all adult T-ALL/T-LBL cases at three large cancer centers between the years 2005-2015, treated at the physician's discretion. Data collected included patient demographics, tumor characteristics (white count at diagnosis, flow cytometry, FISH, cytogenetics, bone marrow involvement), treatment regimens and patient outcomes. Since hyper CVAD is a commonly used regimen outside of clinical trials, we focused our analysis on outcomes with this regimen. This regimen consisted of 4 courses of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone; the odd courses 1, 3, 5, 7); and 4 courses of MTX-Ara-C (methotrexate-cytarabine; the even courses 2, 4, 6, 8). CNS prophylaxis was given to all patients as per standard of care recommendations. All patients eligible for maintenance received 2 years of POMP (6 mercaptopurine, methotrexate, vincristine and prednisone) maintenance. Relapse-free survival (RFS) and overall survival (OS) were examined looking at medians and interquartile ranges of times to events. Kaplan Meier curves provided a graphical representation of the survival probability. Results: The final analysis included 95 adult patients with 64/95 (67%) patients receiving hyper-CVAD induction. Among the hyper-CVAD patients the median age at diagnosis was 30 (range 17-74). 71% of patients were male. Median white cell count (WBC) was 13.6/mm3 (1.7-500). Cytogenetic analysis revealed diploid in 36, complex (1 or more abnormalities in 16) and was not available in 12. WBC count was > 100,000/mm3 in 9 patients. 14 patients had mediastinal disease while 7 had CNS disease at diagnosis. Hyper-CVAD was the primary induction regimen in 56/64. Other patients either started on non-hyper CVAD induction prior to switching (n=3) or had asparaginase added to induction (n=5). The median number of cycles given as 7 (range 2-10) with 27(45%) patients receiving the planned 8 cycles. 37 patients did not complete 8 cycles due to stem cell transplant in remission (n=12), progressive disease (n=10) and unclear reasons (n=15). After induction therapy, remission status was unknown in 3 patients while 43/61 patients (70%) achieved remission. Maintenance with POMP was started in 21 patients that were in remission while 12 patients were taken to transplant without starting on maintenance. At the time of analysis, 23/64 (35%) patients are alive. The median relapse free survival was 387 days (12.9 months) and the median overall survival was 536 days (17.6 months). Excluding one patient lost to follow up, 44/63 (69.8%) relapsed. There was no difference in relapse versus non relapse patients in terms of median age (30 vs 33 years), median WBC at diagnosis (13.2 vs 13.6 mm3). Relapse rate was lower in patients with diploid karyotype (22/36, 61%) as compared to those with complex karyotype (14/16). Median survival in patients post relapse was 150 days. Only 9 patients were able to go for transplant after relapse with post transplant survival also being low (6 deaths). For the entire group, the two year survival was 35%. Conclusion: Our multi-institutional retrospective review shows that outcomes are poor across various centers in patients outside of clinical trials. This is the largest reported series of patients with adult T-ALL/T-LBL treated with hyper-CVAD outside of clinical trials. This data warrants investigation with newer agents to improve outcomes in this disease. Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Figure 1. Relapse free survival and overall survival in patients treated with hyper-CVAD (n=64) Disclosures Kota: Leukemia Lymphoma Society: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hathaway:OnQ Health: Research Funding. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acetylon: Membership on an entity's Board of Directors or advisory committees; PLexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria; Rosetta Genomics: Research Funding; Seattle Genetics: Research Funding. Jillella:Seattle Genetics, Inc.: Research Funding. Borate:Genoptix: Consultancy; Seattle Genetics: Research Funding; Gilead: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau.

scholarly journals African American Race Is Associated with Decreased Relapse-Free Survival in Immune Thrombotic Thrombocytopenic Purpura

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1066-1066
Author(s):  
Angela Liu ◽  
Marshall Mazepa ◽  
Elizabeth Davis ◽  
Andrew Johnson ◽  
Ana G Antun ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
First Episode ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Count Recovery ◽  
White Patients

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ impairment. The incidence of iTTP is higher among African-Americans (AA), however, differences in presentation and outcomes have not been fully investigated. In a multi-center cohort of patients with iTTP from the United States Thrombotic Microangiopathy (USTMA) Consortium, we tested the hypothesis that AA race is an independent predictor of poor outcomes including iTTP related mortality and relapse. Methods: We queried data from the USTMA iTTP registry, which currently includes data from 785 individual patients from 15 institutions across the United States. Data from at least one iTTP episode are available for 734 patients. The cohort is 35.1% (N = 272) White, 58.7% (N = 455) African American, 0.4% (N=3) Asian, 1.8% (N=14) Hispanic, and 4.0 % (N=31) other/unknown race. We restricted our analyses to AA and White participants because of small numbers in the other groups. We compared presenting features and treatments using the chi-squared test and t-test for categorical and continuous variables, respectively. A relapse was defined as a recurrent iTTP episode occurring at least 30 days after last therapeutic plasma exchange. To evaluate relapse-free survival, we included only patients enrolled in the registry at their first TTP episode (144 White and 246 AA) since patients presenting with a relapse as their index episode are already confirmed to have relapsing iTTP. Kaplan Meier analysis was used to compare relapse-free survival in White and AA patients, and a Cox regression model was developed to evaluate the independent effect of race on relapse, adjusting for potential confounders including age, sex, and the use of rituximab. Results: Demographics and presenting features of 390 individuals (144 White and 246 AA) presenting with a first episode of iTTP are shown in Table 1. Presenting symptoms including fever, confusion, seizure, memory deficits, stupor, headache, stroke, chest pain, abdominal pain, fatigue, and dark urine were similar between Whites and AA except for petechiae, which were more frequently documented in Whites (28.8% vs 17.7%, p=0.011). Presenting laboratory studies were also comparable though AA had a higher rate of elevated serum troponin (50.6% vs 32.5%, p=0.003), lower hemoglobin level (8.27 ± 0.13 vs 8.81 ± 0.19, p=0.0176) and platelet count (20.3 ± 1.2 vs 26.2 ± 3.2, p=0.0432). In addition to therapeutic plasma exchange and corticosteroids, rituximab was administered to 23.7% of White patients and 22.7% of AA during their first iTTP episode (P=0.815). Median time to platelet count recovery (days of daily plasma exchange until normal platelet count for two consecutive days) was shorter in AA compared with White patients [5 (IQR 4, 10) vs. 8 (IQR 5, 14), log rank P = 0.004]. AA race remained a significant predictor of the shorter time to platelet count recovery [HR 1.44 (95% CI 1.12, 1.85), P=0.004] after adjusting for rituximab therapy [HR 0.60 (95% CI 0.0.46, 0.80), P<0.001], female sex [HR 0.95 (95% CI 0.73, 1.22), P=0.669], age [HR 0.99 (95% CI 0.99, 1.01), P=0.682], platelet count [HR 1.00 (95% CI 0.99, 1.04), P=0.820] and LDH at presentation [HR 1.00 (95% CI 1.00, 1.00), P=0.525]. Death during the first episode occurred in 8.9% of White patients and 5.5% of AA patients (P=0.206). Relapse-free survival after the first episode of iTTP was lower in AA than White patients (Figure 1). AA race was associated with the reduced relapse free survival [HR 1.79 (95% CI 1.08, 2.98), P=0.024] in a Cox regression model adjusted for age [HR 1.00 (95% CI 0.98, 1.01), P=0.683], sex [HR 0.96 (95% CI 0.60, 1.54), P=0.867], and rituximab therapy [HR 0.93 (95% CI 0.55, 1.59), P=0.806]. Conclusion: African Americans with iTTP have a higher relapse rate and shorter relapse free survival after the first episode of the disease compared with Caucasian patients, which is independent of age, sex and rituximab therapy. Contrary to our hypothesis, acute outcomes of iTTP (time to platelet count recovery and mortality) were not worse in AA patients. The factors contributing to the higher relapse rate in AA with iTTP need to be further investigated. Our findings suggest that AA patients may also benefit from closer follow up. Disclosures Farland: Sanofi: Membership on an entity's Board of Directors or advisory committees. Metjian:Sanofi: Membership on an entity's Board of Directors or advisory committees. Raval:Bayer, Inc: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Liles:Shire: Other: PI on clinical trial Sickle cell ; Imara: Other: PI on Clinical trial- Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell . Baumann Kreuziger:CSL Behring: Consultancy; Vaccine Injury Compensation Program: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Zheng:Alexion: Speakers Bureau; Ablynx/Sanofi: Consultancy, Speakers Bureau; Clotsolution: Other: Co-Founder; Shire/Takeda: Research Funding. Cataland:Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Chaturvedi:Shire/Takeda: Research Funding; Sanofi: Consultancy; Alexion: Consultancy.

Trends In Outcomes In Core Binding Factor Acute Myeloid Leukemia: A SEER Database Analysis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3880-3880 ◽  
Author(s):  
Andrew M. Brunner ◽  
Traci Blonquist ◽  
Hossein Sadrzadeh ◽  
Yi-Bin Chen ◽  
Donna S. Neuberg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Seer Database ◽  
Core Binding Factor ◽  
Advisory Committees ◽  
Patients Âgés ◽  
Binding Factor ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with chromosomal alterations impacting the core binding factor transcription complex (CBF-AML), specifically t(8;21) and inv(16), are associated with a greater responsiveness to cytarabine-based chemotherapies and a more favorable prognosis. The latter has been primarily gleaned from outcomes of large clinical trials of AML. However, to date, there is limited population-based outcomes data on CBF-AML. We therefore performed an epidemiologic retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to assess survival trends for CBF-AML at the population level between 2000 and 2010. Patients and Methods Patients with a diagnosis of CBF-AML between 2000 and 2010 were identified using the SEER 18 registries database. We included patients with a diagnosis code of inv(16)/t(16;16) AML (Code 9871) or t(8;21) AML (Code 9896) diagnosed between January 2000 and December 2010. Patients were divided into cohorts based on age at diagnosis: 15-44 years old, 45-64 years old, 65-74 years old, and 75-84 years old. Disease incidence was calculated, as were early mortality rates, defined as death within 1 month. Overall survival (OS) was estimated using the method of Kaplan and Meier. Cox regression was performed to estimate predictors of survival by specific CBF-AML type, age cohorts, race/ethnicity, gender, year of diagnosis, number of primary malignancies, and residence. Results We identified 777 patients with a new diagnosis of CBF-AML between 2000 and 2010. The incidence of CBF-AML increased with advancing age (ages 15-44, 0.06 per 100,000 people; ages 45-64, 0.13; ages 65-74, 0.25; ages 75-84, 0.28). Median OS for all patients was 22 months, and the combined 3-year OS was 44.3% (Fig. 1). Median OS increased from 16 months during the period encompassing 2000 and 2002 to 25 months during the period from 2006 to 2008 (p=0.002) (Fig. 2). The rate of early death was 13%, which increased with age (15-44 5%, 45-64 10%, 65-74 20%, 75-84 33%; P<0.0001). OS also worsened with advancing age; patients ages 75-84 had a 3 year OS of 9.3% and an increased HR for mortality compared to patients ages 15-44, who had a 3 year OS of 68.7% (HR 5.61, P<0.0001) (Fig. 3). Of note, worsening OS with advancing age was observed even among the subset of patients alive at 1 month. Black race was associated with an increased HR for mortality compared to white non-Hispanic patients (HR 1.50, P=0.03). Patients with inv(16) disease had an improved OS compared to patients with t(8;21) disease (HR for mortality 0.65, P<0.0001). The 3 year OS for patients with inv(16) disease was 57.3%, while for those with t(8;21) disease it was only 35.5% (Fig. 1). Conclusion In spite of historically favorable prognoses associated with CBF-AML in clinical trials, we found poorer survival in the general population. Unlike inv(16) disease, patients with t(8;21) CBF-AML did not appear to have a favorable OS. Survival was significantly worse among African Americans and the elderly. The reason for these differences is unknown, and merits further evaluation. Disclosures: Chen: Otsuka Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bayer / Onyx: Research Funding. Fathi:Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity’s Board of Directors or advisory committees; Agios: Membership on an entity’s Board of Directors or advisory committees; Millenium: Research Funding.

scholarly journals Delayed Hematologic Recovery in AML Patients after Induction Chemotherapy Is Associated with Inferior Relapse-Free Survival and Persistence of Preleukemic Mutations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 992-992
Author(s):  
Tracy Murphy ◽  
Jinfeng Zou ◽  
Georgina S Daher-Reyes ◽  
Vikas Gupta ◽  
Caroline J McNamara ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Risk Patients ◽  
Delayed Recovery ◽  
Duplex Sequencing ◽  
Count Recovery

Abstract Introduction:Induction chemotherapy debulks the leukemic burden in AML patients. Blood count recovery usually occurs during the fourth week of starting chemotherapy in patients who achieve a morphologic remission in bone marrow. However, a subset of patients experience significantly delayed recovery. The relevance of delayed recovery on long-term clinical outcomes and its contributing factors have not been well studied. Specifically, the association between recurrent mutations in AML and hematologic recovery is unknown. Methods:We studied a total of 262 newly diagnosed adult AML patients treated between September 2014 and December 2017 at Princess Margaret Cancer Centre who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) after one cycle of induction chemotherapy. The regimens consisted of 3+7 (N=194) and FLAG-IDA (N=68). We collected information on disease characteristics and blood count results at baseline and during chemotherapy. Mutation profiling of diagnostic samples was performed using a 54-gene next generation sequencing panel (TruSight Myeloid Sequencing Panel, Illumina). Detection of persistent mutations in remission samples was performed using a custom 37-gene duplex sequencing platform with a lower detection limit of ~0.05% variant allele frequency (VAF). Results:Of the cohort of 262 patients, 256 patients (97.7%) achieved neutrophil recovery (defined as > 1x109/L), with time to recovery ranging from 17 to 84 days. Two hundred forty-four (93.1%) patients achieved platelet recovery (defined as > 100x109/L); time to recovery ranged from 17 to 117 days. The percentage of patients who achieved neutrophil and platelet count recovery before day 35 was 82.4% and 84.0% respectively (Fig. 1). To evaluate the prognostic significance of delayed recovery, we categorized patients who achieved CR into two groups, "normal" or "delayed" recovery, according to whether they achieved recovery before or after day 35, respectively. Relapse-free survival (RFS) of patients with delayed recovery was significantly worse than those with normal recovery and only marginally better than those with CRi (P=0.02; Fig. 2). Analysis restricted to 3+7 treated patients showed the same trend (P=0.02), excluding the possibility that the inferior outcome was due to treatment of higher risk patients with more intensive regimens. To study the factors associated with delayed recovery, we performed multivariable Cox regression analysis that included clinical factors and mutations identified at the time of diagnosis as covariates. Four factors were found to be independently correlated with delayed recovery: treatment with FLAG-IDA, truncating ASXL1mutations, SRSF2mutations, and DNMT3AR882 mutations (Table 1). Because FLAG-IDA is the preferred frontline regimen for higher risk patients at our institution, we performed a secondary analysis restricted to patients treated with 3+7 to exclude chemotherapy regimen as a potential confounding variable. This analysis identified six independent factors: AML with myelodysplasia-related changes, lower hemoglobin levels at presentation, truncating ASXL1mutations, TET2mutations, CEBPAmutations, and DNMT3AR882 mutations (Table 1). Somatic mutations in DNMT3A, TET2, ASXL1, and SRSF2(DTAS) mutations are associated with preleukemic conditions, such as myelodysplastic syndrome and age-related clonal hematopoiesis, and frequently persist in remission. These mutations are acquired in hematopoietic stem cells resulting in their propagation to progenitors and terminally differentiated blood cells. We hypothesized that the persistence of DTAS mutations in progenitors might compromise their capacity for reconstitution of normal hematopoiesis resulting in delayed recovery. To test this hypothesis, we performed duplex sequencing on peripheral blood DNA samples collected from a random subset of 43 patients during remission. The detection of DTAS mutations in remission above a VAF of 2% was strongly associated with delayed recovery (P=0.0004; Fig. 3). Conclusion:Delayed hematologic recovery in AML patients after induction chemotherapy is associated with inferior RFS and persistence of preleukemic mutations (i.e., DTAS mutations). Our results support a model in which progenitors harboring DTAS mutations have reduced repopulation capacity leading to delayed hematologic recovery after induction chemotherapy. Disclosures Gupta: Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schimmer:Otsuka Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medivir AB: Research Funding. Yee:Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding; Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees. Maze:Novartis: Consultancy, Honoraria. Bratman:Roche: Other: SVB is a co-inventor on a patent describing methods for circulating tumor DNA analysis, which has been licensed to Roche Molecular Diagnostics.. Schuh:Shire: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Teva: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Amgen Inc.: Consultancy.

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