Mutational Profiling Predicts Clinical Outcomes to Azacytidine and Low Dose Cytarabine Plus Fludarabine (FLUGA) in Elderly Acute Myeloid Leukemia Patients Enrolled in the Pethema Phase III Flugaza Trial

BACKGROUND: Older patients with acute myeloid leukaemia (AML) who are unsuitable for standard induction therapy have limited treatment options. While DNMT3A, TET2, IDH1/2 and TP53 mutations have been previously associated to better response to hypomethylating agents, there are no molecular biomarkers for low-dose cytarabine (LDAC)-based regimens. AIMS: To predict outcome in AML older patients at diagnosis based on mutation status in the context of FLUGAZA trial. FLUGAZA trial was focus on >65 years AML de novo patients comparing azacytidine vs. fludarabine and LDAC (FLUGA Scheme). METHODS: We analyzed bone marrow (BM) samples at diagnosis from 209 out of 285 AML patients treated according Flugaza trial (NCT02319135), azacytidine-arm (n=97) and FLUGA-arm (n=112). In this trial, patients were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5-azacytidine (AZA) followed by 6 consolidation cycles with AZA. Median age at diagnosis was 75 years (65-90). Both treatment groups were balanced for age, leucocytes count, baseline BM blasts, karyotype risk (ELN), and FLT3-internal tandem duplication and NPM1 gene mutations. Mutational profile analysis was carried out by NGS targeted gene sequencing (Ion Torrent S5XL System-Thermo Fisher Scientific) using a 43 genes custom panel implicated in leukemia prognosis. RESULTS: We detected 893 variants, 247 Indels and 646 SNVs. 206 (23.1%) of them were included as pathogenic or like-pathogenic by clinvar database. Ninety-five percent of patients (n=203) had at least one detectable mutation, and the median number of mutations was 4 (range = 0-8 mutations). The most common gene mutations were TET2 (N=55), FLT3 (n=52), SRSF2 (n=49), TP53 (n=45), DNMT3A (n=45), ASXL1 (n=45), RUNX1 (n=43), IDH2 (n=36), IDH1 (n=34), NPM1, (n=33) and NRAS (n=23). This mutational landscape is different to previous published in younger patients (Grimwade, Blood 2016), with higher number of patients with mutations in TP53 (21.5 vs 8%), SRSF2 (23.9 vs 2%), IDH1 (16.3 vs 7%) and IDH2 (17.2 vs 9%) and lower number of patients with mutation in NMP1 (15.8 vs 33%). The median OS of global series was 6 months (range 0-40). Multivariate Cox regression in the global series showed that NRAS and TP53 mutations predict reduced OS (Table 1). Distribution of mutations between both arms was not homogeneous (Figure 1) and NRAS (p=0.012) was more frequent among patients randomized to the FLUGA-arm. However, TP53 mutation frequency distribution was homogeneous: 23.7% in AZA-arm and 19.6% in FLUGA-arm (p=NS). In the AZA-arm, patient´s age was the only variable associated with not achieving composite complete remission (CR plus CR with incomplete recovery) and TET2 and EZH2 mutations were predictors to achieve composite CR. In the FLUGA-arm, TP53 and NRAS mutations were associated with not reaching composite CR (table 2). In the AZA-arm, cytogenetic was the only variable associated with risk of early death. In the FLUGA-arm, leucocyte count, TP53 and NRAS mutations were associated with risk of early death (table 3). In the AZA-arm, BCORL1 mutations (4.1%) were the only variable associated with high risk of relapse. In the FLUGA-arm, BCOR (7.1%) and TP53 (19.6%) mutations were associated with high risk of relapse (table 4). CONCLUSION The mutational profile of AML in elderly patients is different from the previously published in young patients. We have confirmed that a molecular pattern can identify patients with poor prognosis in elderly AML patients. NRAS and TP53 mutations confer a poor prognosis in LDAC (FLUGA-arm) patients, but this effect disappeared in the AZA-arm. BCOR and BCORL1 mutations were associated to a reduced DFS. These results confirm that azacytidine could be more efficacious than LDAC treatment for older patients with AML and mutations in TP53, NRAS, TET2 and EZH2. The percentage of patients who presented mutations in these genes amounted to 77% in this AML series. The study is registered at www.ClinicalTrials.gov as NCT02319135. This study was supported by the Subdirección General de Investigación Sanitaria (ISCIII, Spain) grants PI13/02387 and PI16/01530. Disclosures Salamero: Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Daichii Sankyo: Honoraria. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fernandez:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Progressive Hyperleukocytosis during Initial Therapy Is a Predictive Marker for Differentiation Syndrome and Early Mortality in Adult Patients with Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood.v128.22.4009.4009 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4009-4009

Author(s):

Jae-Ho Yoon ◽

Heeje Kim ◽

Sung-Soo Park ◽

Young-Woo Jeon ◽

Sung-Eun Lee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Risk Group ◽

Early Death ◽

Initial Therapy ◽

High Risk Group ◽

Advisory Committees ◽

Leukocyte Counts ◽

Low Dose Cytarabine

Abstract Background: Acute promyelocytic leukemia (APL) is classified into a favorable-risk group and long-term overall survival (OS) is estimated at around 80%. Relapse rate of APL is lower than another acute myeloid leukemia (AML) subtypes, but we confront higher incidence of early deaths caused by fatal complications including bleeding events and differentiation syndromes (DS) during initial therapy. Recently, although arsenic trioxide (ATO) is introduced with a better survival outcome, the results were from data of low to intermediate-risk group. Thus, patients in high-risk group still show poor survival outcome with high probability of early complications and deaths. We calculated the incidence of DS and early deaths, and tried to find out affecting factors for those early events. Methods: In this single center retrospective study, 259 APL patients (median 42 years old (16-72), follow-up was 65.4 months (11.1 - 170.5) from 2002 to 2014 were analyzed. APL was diagnosed by RT-PCR method for detection of PML-RARa and all patients were available with cytogenetic results. All except 5 patients with normal karyotype was identified with t(15;17)(q22;q21) and 77 showed combination of additional karyotypes. All patients were supported with sufficient transfusion and received ATRA. Our treatment protocol was based on the modified AIDA protocol using ATRA and idarubicin monotherapy (Sanz et al. Blood. 1999; 94: 3015-21) but some patients with comorbidity were treated with ATO, low-dose cytarabine, and ATRA alone for remission induction. For hyperleukocytosis, we conducted leukapheresis when leukocyte counts exceeded 50 (x109/L) and some were treated with hydroxyurea, cytarabine and prophylactic dexamethasone. High-risk group was determined according to the Sanz criteria which presented leukocyte count > 10 (x109/L) at diagnosis. For leukocyte count, we checked diagnostic level (WBCdx) and the maximal level (WBCmax) during initial therapy and identified a group which showed a meaningful increment of WBCmax compared to WBCdx. Results: ATRA was applied in 258 patients and 217 (84.1%) were treated with idarubicin, 13 (5.0%) were with ATO, 3 (1.2%) were with low-dose cytarabine. Eight-week cumulative incidence of early death and DS was 13.5% and 17.8%, and hematological CR was identified in 222 (86.0%) patients. Five-year OS and EFS was 76.8% and 69.8%, and CIR rate was 15.7%. Six patients showed clonal evolution to therapy-related AML and 3 patients died in CR. FLT3-TKD and FLT3-ITD mutation was identified in 12 (7.3%) and 34 (20.7%) patients, and PML-RARa BCR3 and BCR1 subtype was identified in 70 (36.8%) and 120 (63.2%) patients, respectively. For leukocyte counts, except for WBCdx higher than 43 (x109/L), which showed significantly higher rate of early death and DS, patient groups with WBCdx <10 (x109/L) vs. 10 to 43 (x109/L) showed no differences regarding early death or DS. We identified that the significance of WBCdx has been changed with increment during initial therapy which revealed WBCmax was more influential. Among the patients with WBCdx <43 (x109/L), WBCmax increased higher than 43 (x109/L) was related with higher incidence of early death (35.5%) and DS (30.6%), while more DS (40%) was identified in patients with higher increment ratio from WBDdx <10 (x109/L). Multivariate analysis revealed WBCmax > 43 (x109/L) and low antithrombin III were significant for DS, while old age, WBCmax, and high D-dimer were associated with early death. In our data, dexamethasone prophylaxis did not show a preventive effect for DS or early death, while leukapheresis in patients with WBCmax >43 (x109/L) showed marginally decreased early death rate `resulting superior OS without significant bleeding complications. Conclusion: Our data revealed WBCmax with higher increment ratio was a significant predictive factor for early death and DS compared to WBCdx even in the low Sanz-risk group. The role of dexamethasone, transfusion support including antithrombin III, leukapheresis or cytoreduction should be evaluated in the specific patient subset for reducing early events in APL. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Impact of Gene Mutations on Overall Survival in Older Patients with Acute Myeloid Leukemia (AML) Treated with Azacitidine (AZA) or Conventional Care Regimens (CCR)

Blood ◽

10.1182/blood.v128.22.2859.2859 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2859-2859 ◽

Cited By ~ 4

Author(s):

Lin Tang ◽

Anna Dolnik ◽

Kyle J. MacBeth ◽

Hervé Dombret ◽

John F. Seymour ◽

...

Keyword(s):

Dna Methylation ◽

Overall Survival ◽

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Gene Mutations ◽

Molecular Heterogeneity ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: AML is characterized by molecular heterogeneity and specific mutations are prognostically important (Papaemmanuil, Gerstung et al, NEJM,2016). Mutational analysis of NPM1, CEBPA, and FLT3 is included in the 2010 European LeukemiaNet recommendations for AML (Döhner et al, Blood, 2010). Additional recurrently mutated genes have since been identified with potential value for prognosis and prediction of treatment (Tx) response. The phase 3 AZA-AML-001 study showed AZA prolonged median overall survival (OS) vs CCR (10.4 vs 6.5 months [mos]; P=0.101) and improved 1-year survival (46.5% vs 34.2%) in older patients (pts) with AML (Dombret et al, Blood, 2015). Aim: To investigate relationships between gene mutations and OS in the subpopulation of AZA-AML-001 pts with available baseline bone marrow (BM) for molecular analyses ("biomarker" cohort). Methods: Eligible pts were age ≥65 years with newly diagnosed AML (>30% BM blasts), ECOG performance status (PS) score 0-2, WBC count ≤15x109/L, and NCCN-defined intermediate- or poor-risk cytogenetics. Pts received AZA (75 mg/m2/day [d] x 7d/28d cycle) or a preselected CCR: intensive chemotherapy (7 + 3 regimen), low-dose ara-C, or best supportive care only. DNA was isolated from BM mononuclear cells and targeted sequencing of 39 genes was performed with Haloplex target enrichment (Agilent) on Illumina HiSeq 2500 using 2x100bp read lengths. FLT3 tyrosine kinase domain (TKD) mutations were determined by next-generation sequencing (NGS) and internal tandem duplications (ITD) were determined by capillary electrophoresis sizing of PCR amplicons. Target regions varied by gene from all exons to hot-spots. Log-rank test, stratified by ECOG PS score (0-1 vs 2) and cytogenetic risk (intermediate vs poor) at baseline, was used to assess OS of pts with mutations (mut) in genes detected in ≥5 pts vs OS in pts with wild-type (wt) genes within the AZA and CCR arms. Median OS was estimated using Kaplan-Meier methods. Results: The biomarker cohort comprised 156 of all 488 pts in AZA-AML-001 (32%; AZA n=83, CCR n=73). Baseline characteristics and hematologic response rates were well-matched between biomarker and non-biomarker pts. Mutations were detected in 33 of 39 sequenced genes. The most frequently mutated genes were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140 15%, R172 8%]), TP53 (21%), RUNX1 (18%), NPM1 (16%), NRAS (12%), FLT3 (12% [-ITD 10%, -TKD 5%]), ASXL1 (11%), and STAG2 (10%). Stratified log-rank tests showed that median OS was significantly reduced for CCR pts with TP53mut (2.4 vs 12.5 mos with TP53wt; P=0.026) and with NRASmut (4.3 vs 10.3 mos with NRASwt; P=0.020). In the AZA arm, median OS was not significantly different between pts with TP53mutor TP53wt (7.2 vs 12 mos; P=0.40) or between pts with NRASmut or NRASwt (11.8 vs 8.9 mos; P=0.95), but was reduced in pts with FLT3mut (5.4 vs 12.0 mos with FLT3wt; P=0.017). Compared with similar pts treated with CCR, pts with TP53mut and/or NRASmut treated with AZA had nominally better median OS (7.2 vs 2.4 mos for TP53mut; 11.8 vs 4.3 mos for NRASmut), and pts with FLT3mut had nominally worse OS (5.4 vs 6.4 mos) (Table). Median OS was similar for pts with or without mutations in each of the genes known to influence DNA methylation (DNMT3A, IDH1, IDH2, and TET2); however, there was a statistical difference in OS within the AZA arm for pts with TET2mut (P=0.005) despite similar median OS for pts with TET2mut vs TET2wt (9.6 vs 9.5 mos) that was not observed within the CCR arm (P=0.45). Median OS for pts with a mutation in any 1 of the DNA methylation genes listed above was similar in the AZA and CCR arms (Table). Conclusion: These exploratory analyses suggest older AML pts with TP53 or NRAS mutations have a better prognosis when treated with AZA than with CCR. Mutations in genes that regulate DNA methylation did not impact median OS with AZA Tx, although the potential negative effects of TET2mut and FLT3mut warrant further evaluation. Prognostic implications of isolated gene mutations can vary due to co-mutations; larger pt cohorts are needed to establish the influence of recurring co-mutational patterns in AZA-treated pts. Disclosures Tang: Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties, Research Funding. Dombret:Agios: Honoraria; Sunesis: Honoraria; Ambit (Daiichi Sankyo): Honoraria; Karyopharm: Honoraria; Kite Pharma.: Honoraria, Research Funding; Menarini: Honoraria; Menarini: Honoraria; Astellas: Honoraria; Janssen: Honoraria; Servier: Honoraria; Seattle Genetics: Honoraria; Roche/Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Ariad: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria; Jazz Pharma: Honoraria, Research Funding. Seymour:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stone:Pfizer: Consultancy; Sunesis Pharmaceuticals: Consultancy; Karyopharm: Consultancy; ONO: Consultancy; Jansen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celator: Consultancy; Roche: Consultancy; Agios: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy. Beach:Celgene Corporation: Employment, Equity Ownership.

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Lintuzumab and Low-Dose Cytarabine Compared to Placebo and Low-Dose Cytarabine in Patients with Untreated Acute Myeloid Leukemia (AML) 60 Years and Older: Results of a Randomized, Double-Blinded Phase 2b Study,

Blood ◽

10.1182/blood.v118.21.3613.3613 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3613-3613 ◽

Cited By ~ 4

Author(s):

Jeffrey E. Lancet ◽

Mikkael A. Sekeres ◽

Brent L. Wood ◽

Laurie E. Grove ◽

Larissa Sandalic ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

P Value ◽

Advisory Committees ◽

History Of ◽

Equity Ownership ◽

Double Blinded ◽

Low Dose Cytarabine

Abstract Abstract 3613 Background: Older adults with AML who decline intensive induction chemotherapy lack effective therapeutic options, as evidenced by a median overall survival (OS) of ∼5 months with low-dose cytarabine treatment (Burnett 2007). Leukemic blast cells express CD33 in most patients with AML. While antitumor activity has been previously demonstrated by CD33-directed agents, none of these are currently available. Lintuzumab (SGN-33) is a humanized antibody directed to CD33 that was studied in patients with myeloid malignancies and demonstrated tolerability with modest monotherapy activity. To determine if the addition of lintuzumab to low-dose cytarabine could prolong survival in older patients with untreated AML, a randomized, placebo-controlled, double-blinded phase 2b study was conducted (ClinicalTrials.gov #NCT00528333). Methods: The study was conducted at 72 international sites between November 2007 and August 2010. Patients were >60 years of age with centrally confirmed, previously untreated AML; the minimum blast percentage required was 20% with ≥50% CD33 expression. Maximum allowed WBC at baseline was 30,000/μL. All patients declined treatment with intensive induction chemotherapy. Cytarabine 20 mg was administered SC twice daily on Days 1–10 of each 28-day cycle (12 cycles maximum). Patients were randomized to additionally receive either lintuzumab 600 mg or placebo IV: in Cycle 1 on Days 1, 8, 15, and 22, and on Days 1 and 15 of subsequent cycles. Patients were stratified according to age, ECOG performance status (PS), and history of antecedent hematologic disorder (AHD). Cytogenetic risk was determined at baseline according to Fröling 2006. The primary endpoint of the study was OS, determined using an unstratified log rank test. Secondary endpoints included peripheral blood count recovery, transfusion requirements, infection rates, and quality of life. As patients choosing less-intensive therapy often incorporate quality of life into their treatment decision, follow-up bone marrow biopsies were not required in the study. Results: 211 patients were randomized in the study (107 lintuzumab arm, 104 placebo arm). The study arms appeared balanced; overall, the median patient age was 70 years (range 60–90), 53% were female, and baseline ECOG PS was 0/1 (55%) or 2 (45%). Baseline blast percentages were ≥30% in 74% of patients and 23% had a history of AHD. A median of 95% CD33 expression was documented at baseline in either bone marrow or peripheral blood. Median number of treatment cycles was 4 in the lintuzumab arm and 3 in the placebo arm. At the time of the analysis, 24 patients were alive and the maximum follow-up was 32 months. The estimated median OS for the lintuzumab + low-dose cytarabine arm was 4.7 months compared with 5.1 months for the placebo + low-dose cytarabine arm with a hazard ratio (lintuzumab to placebo) of 0.96, indicating that lintuzumab was not associated with a treatment effect (P value 0.76, 95% CI [0.72, 1.28]). Rates of infections or fevers of unknown origin requiring hospitalization or IV antibiotics did not differ between the study arms. Overall, 28% of patients were observed to have no peripheral blasts, ANC >1.0 x109/L, platelets >100 × 109/L, and no transfusions for at least 1 week. The median OS among all patients was 5.0 months, which was significantly impacted by cytogenetic risk (8.7 months for standard-risk compared with 4.5 months for high-risk; P value 0.0024). The incidence of adverse events (AEs) was comparable between the treatment groups, with the exception of infusion-related reactions which occurred more frequently in the lintuzumab arm. The most common ≥ Grade 3 non-hematologic AEs in the study were pneumonia (12%) and sepsis (8%). Conclusions: In this randomized, placebo-controlled, double-blinded phase 2b trial, the combination of lintuzumab and low-dose cytarabine did not improve OS compared with placebo and low-dose cytarabine. While lintuzumab was not effective, CD33 remains a compelling target for AML because it is widely expressed by malignant cells and appears to be absent from pluripotent hematopoietic stem cells. This was the largest study to date of patients treated with low-dose cytarabine; the median OS across both treatment arms was 5 months. A similar outcome was observed in the subgroup of patients with high-risk cytogenetics, confirming that low-dose cytarabine remains a valid comparator in trials of older patients with AML. Disclosures: Lancet: Seattle Genetics, Inc.: Research Funding. Off Label Use: Lintuzumab is an investigational monoclonal antibody directed against CD33. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp.: Honoraria; Seattle Genetics, Inc.: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Wood:Seattle Genetics, Inc.: Research Funding. Grove:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sandalic:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics: Employment, Equity Ownership. Jurcic:Seattle Genetics, Inc.: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Research Funding.

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A Randomised Evaluation of Low-Dose Cytarabine Arabinoside Plus Lenalidomide Versus Single-Agent Low-Dose Cytarabine Arabinoside in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial

Blood ◽

10.1182/blood-2021-147802 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1266-1266

Author(s):

Mhairi Copland ◽

Cono Ariti ◽

Ian Thomas ◽

Laura Upton ◽

Mia Sydenham ◽

...

Keyword(s):

Elderly Patients ◽

Supportive Care ◽

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Advisory Committees ◽

Grade 3 ◽

Care Requirements ◽

Low Dose Cytarabine ◽

Acute Myeloid

Abstract Background: Many patients with Acute Myeloid Leukemia (AML) diagnosed after 60 years of age are not considered suitable for intensive remission induction chemotherapy, either due to co-morbidities or frailty associated with advanced age. Despite treatment with either a hypomethylating agent or low-dose cytarabine arabinoside (LDAC), survival is usually poor, with 1-year survival after LDAC of 24-37% in NCRI AML16 and historical arms of LI-1. Combination therapy with additional agents represents an attractive option, and has the potential to improve patient outcomes without substantially increasing toxicity. Lenalidomide (Revlimid TM) is an immunomodulatory drug, used to treat myeloma, and some cases of myelodysplastic syndrome, and has potent antineoplastic, anti-angiogenic, anti-inflammatory and pro-erythropoietic properties. Early-phase trials of lenalidomide in AML have demonstrated clinical activity with acceptable toxicity. Aim: To assess the efficacy and tolerability of LDAC+lenalidomide versus LDAC alone in patients aged 60+ unsuitable for intensive therapy. The aim was to double 2-year survival from 11% to 22% (HR 0.69). Methods: LI-1 was an international multicentre, multi-arm, randomised phase II trial developed to study the efficacy and tolerability of novel non-intensive therapies in AML using a "pick a winner" design. LDAC was given at 20mg BD SC on days 1-10 of each course. Lenalidomide was administered orally once daily in a flat 10mg dose for 21 days, where day 1 is day 1 of LDAC with courses occurring at 5-week intervals for courses 1-4. Patients considered to be benefitting after 4 courses, i.e. in remission or stable disease, could continue to receive treatment until disease progression, either with LDAC+lenalidomide at 6-week intervals, or lenalidomide only at 4-week intervals if patient had experienced significant toxicity. Toxicities were recorded using CTCAEv3. Primary objectives included overall survival (OS), complete remission (CR + CRi) achievement, reasons for failure, duration of response (CR/CRi), relapse rates and deaths in first CR. Secondary objectives included toxicity, supportive care requirements, and Quality of Life assessments (measured using EORTC QLQ-30, EQ5D and HADS tools). Results: Between Jan-17 and Jun-19, 202 patients from Denmark (8%), New Zealand (16%) and the UK (76%) were randomised. Median age was 78 years (range 62-89). Overall, 58% were male; 76% de novo AML, 20% secondary AML, and 4% high risk MDS; 1% favourable, 66% intermediate, 19% adverse and 14% unknown cytogenetics; WHO performance status 0 for 15%, 1 for 58%, 2 for 22% and 3 for 5%. Median of 2 courses (range 0-24; mean 3.28) was delivered in LDAC arm and 1 course in LDAC+lenalidomide arm (range 0-25; mean 3.48). Overall response (CR/CRi) was achieved in 40/202 patients (20%), (LDAC+lenalidomide 25%, LDAC 14%, OR 0.45 (0.22, 0.93), P=0.031). 30-day mortality was not significantly increased (19% in both arms); and 2-year OS showed no significant difference (14% vs 11.5%, HR 0.94 (0.69, 1.29, P=0.719). Median OS was 3.5 vs 4.6 months; HR 0.96 (0.71, 1.30), P=0.80. 1-year OS for patients that didn't enter CR/CRi was 6.8% for LDAC+lenalidomide vs 16.9% for LDAC (P=0.028). Cause of death for the majority of patients was resistant/recurrent disease: 45(53%) vs 47(58%). Most adverse events (AEs) were grade 1/2 in both arms. During cycle 1, there were 78 vs 51 grade 3/4 AEs in the LDAC+lenalidomide and LDAC arms, respectively (P=0.02). This included 5 thrombotic events in the LDAC+lenalidomide arm (4 grade 3 and 1 grade 4) and none in the LDAC arm. In course 1, supportive care requirements were higher in terms of both days of antibiotics (7 vs 3; p=0.001) and hospitalisation days (11 vs 6.5; p=0.005) for the LDAC+lenalidomide arm. There was no difference in transfusion requirements. Conclusions: Despite improving the CR/CRi rate, the combination of lenalidomide+LDAC did not improve OS, relapse-free survival or time in remission in elderly patients with AML. The addition of lenalidomide to LDAC resulted in increased toxicity, including episodes of thrombosis, as well as increased supportive care requirements. Alternative strategies to improve survival for elderly patients with AML remain a significant clinical need. Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Celgene for providing drug and additional support for this IIS. Fig 1: OS All patients Figure 1 Figure 1. Disclosures Copland: Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau. OffLabel Disclosure: Off label use of lenalidomide in combination with low dose cytarabine will be discussed in the setting of elderly unfit AML.

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A Single-Arm PHASE 2A Study of NM-IL-12 (rHu-IL12) in Patients with Mycosis Fungoides-Type CTCL (MF) Undergoing Low-Dose TOTAL Skin Electron BEAM Therapy (LD-TSEBT)

Blood ◽

10.1182/blood.v128.22.4165.4165 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4165-4165

Author(s):

Youn H Kim ◽

Richard T. Hoppe ◽

Alain H Rook ◽

Amit Maity ◽

Larisa J Geskin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Response Rate ◽

Topical Steroid ◽

Response Duration ◽

Treatment Modalities ◽

Interleukin 12 ◽

Advisory Committees ◽

Number Of Patients

Abstract Multiple treatment modalities are available for MF, but most result in inevitable relapse. Therefore, new treatment strategies that improve response rate and prolong response duration are greatly needed. TSEBT is a highly effective therapy in MF. LD-TSEBT (12 Gy) is much more tolerable than the conventional 36+ Gy dose, thereby allowing for re-treatment; however, LD-TSEBT has a less favorable complete response rate and response duration. Combining LD-TSEBT with immunostimulatory modalities in MF has a strong biological rationale, since radiation-induced exposure of cancer-specific antigens should be synergistic with concomitant stimulation of anti-cancer immune responses. Interleukin-12 is a robust candidate for radioimmunotherapy, as IL-12 has significant anti-MF activity as monotherapy, is very well tolerated without overlapping toxicity with TSEBT, and is a potent stimulator of innate and adaptive immunity. We report on a single-arm open-label phase 2a trial of combination of LD-TSEBT and NM-IL-12. Ten patients are planned for enrollment. Eligibility includes MF-type CTCL stages IB-IIIB and patients must be eligible for LD-TSEBT. TSEBT is started on study day 1 (fractionated 4 Gy/week, up to 12 Gy). NM-IL-12 is administered subcutaneously at 150 ng/kg on days 2 and 15, followed by 6 maintenance doses q4w at 100 ng/kg. The primary endpoint is safety with secondary endpoints being response rate and PFS. Currently, 6 patients are enrolled, 5 evaluable for response; 4 male; median age 55; three have stage IB, one IIB and one IIIB. Median number of previous therapies is 2 (0-6). The treatment was well-tolerated with only grade 1 or 2 AEs; most common AEs include grade 1 headache and chills. One patient achieved CR, 2 PR, and 2 SD. Median follow-up is so far 15 weeks and 5 patients remain on study. One patient has been withdrawn from the study due to development of a suspected PLC (pityriasis lichenoides chronica)-like skin reaction requiring topical steroid therapy. PK and PD analysis was completed in the first 4 patients. It demonstrated measurable drug levels in all patients studied, Cmax being 10.8-56.1 pg/ml achieved at 5-24 hours post injection. Interferon-γ and IP-10 (hallmark PD markers of IL-12 activity) were measurable after the first and the second injections in all patients. Levels of the inhibitory cytokine IL-10 were generally measurable after NM-IL-12 injections, but were very low (<1 pg/ml up to 12 pg/ml) - much lower than previously reported in IL-12 studies, thus unlikely to be associated with negative immunosuppressive feedback. There was no clear correlation between PK and PD measurements and either efficacy or toxicity, but the number of patients fully evaluated is small. Total RNA was extracted from patient blood samples and subjected to qRT-PCR. Gene specific primers were used to analyse intracellular expression of the IL-12 receptor and immune cell markers. Ongoing work investigates an activated cellular phenotype at week 15 of LD-TSEBT and NM-IL-12 treatment compared with the respective baseline samples. Overall these early results demonstrate that NM-IL-12 can be safely administered together with LD-TSEBT in CTCL patients. Encouraging clinical activity is observed including a CR. Enrollment is currently ongoing and planned PD and correlative biomarker studies are in progress. A phase 2B randomized trial of NM-IL-12 and low dose TSEBT compared against low-dose TSEBT alone in patients with MF is being developed based on the apparent benign AE profile as compared to approved systemic therapies. Disclosures Kim: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Neumedicine: Research Funding; Merck: Research Funding; Kyowa Kirin Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; miRagen: Research Funding; Innate: Research Funding; Horizon Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding. Ma:Neumedicines: Employment. Kha:Neumedicines: Employment. Lawrence:Neumedicines: Employment, Patents & Royalties. Vainstein:Neumedicines: Employment. Basile:Neumedicines: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

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Lenalidomide Plus Low-Dose Dexamethasone (Ld): Superior One and Two Year Survival Regardless of Age Compared to Lenalidomide Plus High-Dose Dexamethasone (LD)

Blood ◽

10.1182/blood.v116.21.308.308 ◽

2010 ◽

Vol 116 (21) ◽

pp. 308-308 ◽

Cited By ~ 2

Author(s):

David H. Vesole ◽

Susanna Jacobus ◽

S. Vincent Rajkumar ◽

Rafat Abonour ◽

Natalie Scott Callander ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

Early Death ◽

Standard Of Care ◽

Age Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Landmark Analysis ◽

Intent To Treat

Abstract Abstract 308 Introduction: The Eastern Cooperative Oncology Group (ECOG) has previously reported the superior 1 and 2 year survival of Ld versus LD as initial therapy in newly diagnosed symptomatic multiple myeloma (MM) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). The 1 year and 2 year OS for Ld vs LD were 96% and 85% vs 88% and 78%, (p < 0.01), respectively. This despite higher ORR in LD vs Ld (79% vs 68%; p = 0.008). The difference in OS was predominantly due to early death in the LD group (5% vs 0.5%; p = 0.003). As a result of this analysis, Ld is now considered the standard of care. However, it should be noted that the majority of these deaths occurred in pts > 65. In this analysis, we evaluated the impact of age on dexamethasone dose intensity and OS. Methods: 445 pts were randomly assigned: 223 to LD and 222 to Ld. Pts were analyzed on an intent-to-treat basis for OS. The pts were analyzed by age in 2 groups: < 65 and > 65 (the age corresponding to transplant eligibility outside the US). The pts > 65 were then further subdivided into >70 and > 75 yrs. Results are expressed as OS probability at 1 and 2 years post randomization. In addition, to eliminate the early death ‘penalty’ in the LD group in the original analysis, a landmark analysis was performed at 4 months. Results: Overall Survival Probability: Intent-to Treat Analysis Overall Survival Probability: 4 month Landmark Analysis Conclusions: As previously reported, OS in the trial at 1 and 2 years was superior with Ld. OS was not superior with LD compared with Ld in any age group despite a higher response rate. This was true even when using a landmark analysis to eliminate the 5% early deaths seen in the first 4 months of treatment. We conclude the following: 1) LD is not definitively superior to Ld in any age group; 2) Given the higher toxicity in the absence of a clear survival benefit with LD, Ld remains the best choice for all ages. This analysis confirms the original opinion that low-dose dexamethasone is the standard of care for all newly diagnosed MM pts, regardless of age. Disclosures: Vesole: Millennium Pharmaceuticals: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centorcor-Ortho-Biotech: Speakers Bureau. Off Label Use: Lenalidomide for front-line therapy in multiple myeloma. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy; Intellikine: Consultancy. Siegel:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees.

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Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia (AML): Princess Margaret Cancer Centre Experience

Blood ◽

10.1182/blood-2019-125449 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2609-2609

Author(s):

Muhned Alhumaid ◽

Georgina S Daher-Reyes ◽

Wilson Lam ◽

Arjun Law ◽

Tracy Murphy ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Treatment Strategies ◽

Patient Characteristics ◽

Cancer Center ◽

Advisory Committees ◽

Disease Behavior

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

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Efficacy and Safety of Ravulizumab in Older Patients Aged >65 Years with Paroxysmal Nocturnal Hemoglobinuria in the 301 and 302 Phase 3 Extension Studies

Blood ◽

10.1182/blood-2020-140777 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-43

Author(s):

Regis Peffault De Latour ◽

Jeffrey Szer ◽

Austin Kulasekararaj ◽

Jin Seok Kim ◽

Caroline I. Piatek ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Complement Inhibitor ◽

Efficacy And Safety ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Naïve ◽

Secondary Endpoints

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Treatment in Dual Expressor Diffuse Large B-Cell and Double/Triple Hit Lymphomas: TP53 Mutations Influence on Clinical Outcome

Blood ◽

10.1182/blood-2019-124350 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4116-4116

Author(s):

Anna Dodero ◽

Anna Guidetti ◽

Fabrizio Marino ◽

Cristiana Carniti ◽

Stefania Banfi ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Poor Prognosis ◽

Tp53 Mutation ◽

Advisory Committees ◽

Tp53 Mutations ◽

Travel Costs ◽

Large B Cell

Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

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