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

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

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

Blood ◽

10.1182/blood-2021-149894 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1984-1984

Author(s):

Sara Marie Tinsley-Vance ◽

Najla Al Ali ◽

Somedeb Ball ◽

Luis E. E. Aguirre ◽

Akriti G Jain ◽

...

Keyword(s):

Gender Differences ◽

Overall Survival ◽

Data Base ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Lower Risk ◽

Research Funding ◽

Cancer Center ◽

Advisory Committees ◽

Men And Women

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

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Integrative Network Analysis of Newly Diagnosed Multiple Myeloma Identifies a Novel RNA-Seq Based High Riskgene Signature

Blood ◽

10.1182/blood.v128.22.3285.3285 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3285-3285

Author(s):

Alessandro Lagana ◽

Deepak Perumal ◽

David Melnekoff ◽

Ben Readhead ◽

Brian Kidd ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Kaplan Meier ◽

Risk Patients ◽

Equity Ownership

Abstract High-risk Multiple Myeloma (MM) is characterized by unresponsiveness to multiple therapies, rapid disease progression and short overall survival, and may be significantly different from relapsed MM, where aggressiveness is usually a result of drug-resistance associated to clonal selection. Several gene expression-based signatures have been proposed in the past years, however the identification of high-risk patients at diagnosis still represents a challenge. Next generation high-throughput sequencing technologies have enabled a deeper insight into cancer genomes and transcriptomes at an unprecedented level of detail. MMRF CoMMpass is a longitudinal, prospective observational study, started in 2011, that aims to collect and analyze sequencing and clinical data from >1,000 MM patients at initial diagnosis and at relapse. CoMMpass is a real world observational study and, as such, reflects the therapeutic heterogeneity seen across patient populations and provides a unique opportunity to correlate molecular profiles, genomic alterations and clinical characteristics of MM with treatment outcome. Here we present a network approach to identify high-risk myeloma patients developed using next generation sequencing data from 450 patients in the IA7 release of CoMMpass. We generated MMNet, an integrated network model of newly diagnosed myeloma based on RNA-seq, Whole-Exome (WXS) and Whole-Genome (WGS) data correlated with clinical outcomes. MMNet consisted of 37 modules of coexpressed genes, that were further characterized by functional enrichment analysis and correlation with clinical traits and genomic alterations, i.e. somatic mutations and copy number alterations inferred from WGS and WXS data. A total of 89 progression/death events have been reported for the cohort within the second year since the beginning of the study. Cox regression analysis identified a module of co-expressed genes whose over-expression was significantly correlated with early relapse (<2yr) (HR 1.75, 95%CI = 1.169-2.614, p=0.005). The module was also associated to stage III R-ISS, high clonality (>4 clones) and high mutational burden, as well as higher percentage of plasma cells in both bone marrow and peripheral blood, which are traits associated with high-risk disease. Module expression was also up regulated in patients with mutations in TP53 and MAX, 13q deletion and 1q amplification. We further narrowed down the signature to 286 genes (the MMNet-286 signature) strongly correlated with time to Event Free Survival (EFS) (r = -0.81, p = 0). This gene-set was significantly enriched for several pathways including Cell Cycle, DNA repair and Homologous Recombination (q < 0.01). Cox regression analysis showed that the two clusters induced by MMNet-286 discriminated between lower and higher risk patients with respect to EFS (HR = 2.22, 95% CI = 1.505-3.295, p = 4.007e-5) (Fig. 1). The prognostic value of MMNet-286 was confirmed on two independent datasets: Broyl-2010 (HR = 1.76, 95% CI = 1.182-2.642, p = 0.005) and Shaughnessy-2006 (HR = 2.65, 95% CI = 1.746-4.031, p = 2.03e-6) (Fig. 2 and 3). The Broyl-2010 dataset consisted of 275 samples from newly diagnosed myeloma patients included in the HOVON65/GMMG-HD4 trial (GSE19784). The Shaughnessy-2006 dataset consisted of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658). Comparison of MMNet-286 with previous high risk signatures and disease classes revealed an overlap of five genes with the UAMS-70 signature, twelve genes with the EMC-92 signature and fifteen genes with the set of up-regulated genes in the UAMS PR class, for which the coexpression module was enriched. In Conclusion, our results demonstrate the advantages of employing integrated network models to identify prognostic features based on next generation sequencing data from large cohort of patients. Applications of the MMNet-286 signature include the generation of a prognostic assay (i.e. NanoString) for the identification of high-risk patients. Future work will aim at validation of the signature in larger cohorts from CoMMpass and other studies. Figure 1 Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 1. Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 2 Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 2. Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Disclosures Chari: Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Dudley:GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Ayasdi, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ontomics, Inc.: Equity Ownership; AstraZeneca: Speakers Bureau; NuMedii, Inc.: Patents & Royalties; Personalis: Patents & Royalties.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Overall Survival and Subgroup Analysis from a Randomized Phase III Study of Intravenous Rigosertib Versus Best Supportive Care (BSC) in Patients (pts) with Higher-Risk Myelodysplastic Syndrome (HR-MDS) after Failure of Hypomethylating Agents (HMAs)

Blood ◽

10.1182/blood.v124.21.163.163 ◽

2014 ◽

Vol 124 (21) ◽

pp. 163-163 ◽

Cited By ~ 9

Author(s):

Guillermo Garcia-Manero ◽

Pierre Fenaux ◽

Aref Al-Kali ◽

Maria R. Baer ◽

Mikkael A. Sekeres ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Primary Endpoint ◽

Research Funding ◽

Phase Iii ◽

Controlled Study ◽

Advisory Committees ◽

Phase Iii Study ◽

Very High

Abstract Background: No approved treatment options are available to HR-MDS pts after HMA therapy. Study 04-21 (“ONTIME” trial) was a Phase III, randomized, controlled study of the efficacy and safety of rigosertib, a novel small molecule inhibitor of PI3-kinase and PLK pathways, in a heterogeneous population of MDS pts who had relapsed after, failed to respond to, or progressed during administration of HMAs. The study was conducted at 87 sites in the United States and 5 European countries. Methods:From Dec 2010 to Aug 2013, 299 HR-MDS pts [<30% bone marrow blasts (BMBL)] who had progressed on (37% of total enrollment), failed to respond to (25%), or relapsed after (38%) HMA treatment were stratified on BMBL count and randomized 2:1 to receive rigosertib (199 pts) or BSC (100 pts). Rigosertib was administered at 1800 mg/24 hr for 72-hr as a continuous intravenous (CIV) ambulatory infusion, every 2 weeks for the first 16 weeks, and then every 4 weeks. The primary endpoint was overall survival (OS), analyzed on an intention-to-treat (ITT) basis using the Kaplan-Meier method stratified on BMBL (5% to 19% vs. 20% to 30%). The trial had a 95% power to detect a 13-wk increase in median OS from 17 wks on BSC, with a 2-sided alpha = 0.05. The following results are based on 242 deaths: 161 in the rigosertib arm and 81 in the BSC arm. Results : Overall, the 2 arms were balanced in terms of baseline characteristics, with the majority of pts being male (66%), and White (82%). Age ranged from 50-90 yrs in the rigosertib arm and 55-86 years in the BSC arm (median, 74 yrs). The majority of pts (85%) had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. The median duration of the last HMA therapy was 8.8 months (mo) in the rigosertib arm and 10.3 mo in the BSC arm; 127 (64%) of rigosertib pts and 57% of BSC pts were classified as “primary HMA failure” (ie, they failed to respond to or progressed during HMA therapy, as defined by Prebet et al, J Clin Oncol, 2011). A 2.3-mo improvement in median OS was found in the overall (ITT) population (8.2 mo rigosertib vs. 5.9 mo BSC) (Figure 1). The ITT survival for rigosertib was similar to that noted in Phase I/II studies (35 weeks). The stratified log-rank p-value was 0.33. The stratified hazard ratio was 0.87, which was quite different from the ratio of medians (5.9/8.2 = 0.72), due to the fact that the 2 survival curves converged at 15 mo. Notably, among the 184 patients with primary HMA failure, the median OS was 8.6 mo in the rigosertib arm (N = 127) vs. 5.3 mo in the BSC arm (N = 57), HR= 0.69, p= 0.040 (Figure 2). Multivariate Cox regression, adjusting for pretreatment prognostic factors, showed little change in the treatment effect. The following subgroups were correlated with better OS: pts with failure of/progression on HMA treatment, pts with duration of HMA treatment ≤ 9 mo, pts < 75 years of age, and pts with very high risk per IPSS-R (Figure 3). Rigosertib was well tolerated, with a median dose intensity of 92%. There were no significant compliance or operations issues related to ambulatory continuous infusion. Protocol-defined dose reductions were reported in 5% of pts, with 24% experiencing dose delays of >7 days, mostly due to unrelated adverse events (AEs). No obvious differences between rigosertib and BSC were found in the incidence of AEs (rigosertib, 99%; BSC, 85%) or of ≥ Grade 3 AEs (rigosertib, 79%; BSC, 68%). In the rigosertib arm, AEs reported by ≥ 20% of pts, irrespective of severity or causality, were nausea (35%), diarrhea (33%), constipation (31%), fatigue (30%), fever (27%), anemia (22%), and peripheral edema (21%). Rigosertib had low myelotoxicity, consistent with previous clinical experience. Conclusions:Although the primary endpoint in this Phase III study of rigosertib vs BSC in pts with HR-MDS did not reach statistical significance in the ITT population, encouraging rigosertib treatment-related improvement in OS was noted in several subgroups of MDS pts, including those with “primary HMA failure and in patients in the IPSS-R Very High Risk category. CIV therapy with rigosertib had a favorable safety profile in this orphan population of elderly pts with MDS. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Roboz:Novartis: Consultancy; Agios: Consultancy; Celgene: Consultancy; Glaxo SmithKline: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Wilhelm:Onconova Therapeutics, Inc: Employment. Azarnia:Onconova Therapeutics, Inc: Employment. Maniar:Onconova Therapeutics, Inc: Employment.

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A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽

10.1182/blood-2018-99-114620 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2872-2872 ◽

Cited By ~ 2

Author(s):

Farheen Mir ◽

Andrew Grigg ◽

Michael Herold ◽

Wolfgang Hiddemann ◽

Robert Marcus ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Prognostic Model ◽

Low Risk ◽

Prognostic Variables ◽

Advisory Committees ◽

High Risk Disease ◽

Risk Patients ◽

Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

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Revised-MALT-IPI: A New Predictive Model That Identifies High-Risk Patients with Extranodal Marginal Zone Lymphoma (EMZL)

Blood ◽

10.1182/blood-2019-125008 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4010-4010

Author(s):

Juan Pablo Alderuccio ◽

Isildinha M Reis ◽

Thomas M. Habermann ◽

Brian K. Link ◽

Catherine Thieblemont ◽

...

Keyword(s):

High Risk ◽

Family Member ◽

Board Of Directors ◽

Risk Score ◽

Research Funding ◽

Stage Iii ◽

Advisory Committees ◽

High Risk Patients ◽

Disease Characteristics ◽

Risk Patients

INTRODUCTION: EMZL is a heterogeneous disease with variable risk for relapse and progression. Based on age ≥70 years, stage III-IV and elevated LDH, Thieblemont et al (Blood. 2017) developed the MALT-IPI to identify high-risk patients. In this index, disease characteristics (stage and LDH) account for 66% while a disease nonspecific characteristic (age) for 33% of the index score. We reported (Am J Hematol. 2019) that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival and increased incidence of higher grade transformation. To better recognize disease-attributable high-risk patients, we developed a new EMZL prognosis score chiefly based on patient's disease characteristics. METHODS: The revised (R)-MALT-IPI was developed using a retrospective data set of 405 EMZL patients treated at the University of Miami (UM) from 1995 to 2017. Cox proportional hazards regression analysis was conducted to evaluate the effect of the potential prognostic variables on progression-free survival (PFS) and overall survival (OS) and to develop the new index R-MALTI-IPI based on PFS. Model validation was performed in two independent cohorts of EMZL patients from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) database (n=297) and the IELSG-19 study (n=400) used for the development of MALT-IPI. Performance of various prognostic indices was compared using AIC statistics, and concordance c-statistics by Harrell (CH) and by Gonen and Heller (CGH). RESULTS: Among the candidate variables tested in univariable analysis, the following were statistically significant predictors of shorter PFS: age >60, age ≥70, anemia (Hb<12g/dL), stage III-IV, ECOG PS ≥2, elevated serum LDH, number of extranodal sites >1, number of nodal sites >4, and presence of MMS at diagnosis, defined as EMZL with ≥2 different extranodal sites excluding spleen and bone marrow. A stepwise Cox regression analysis yielded a multivariable model with four independent predictors of shorter PFS: age >60 (HR=1.53, p=0.010), elevated LDH (HR=1.73, p=0.004), stage III-IV (HR=2.03, p=0.0003) and presence of MMS (HR=2.78, p<0.0001). Based on this, a new index R-MALT-IPI was developed with scores ranging from 0 to 5, calculated as a sum of 1 point for age >60, elevated LDH, stage III-IV, and 2 points for MMS. The R-MALT-IPI defined 4 risk groups: low-risk (score 0 (35%), reference group), low-medium risk (score 1 (39%), HR=1.91, p=0.005), medium-high risk (score 2 (13%), HR=3.77, p<0.0001), and high-risk (score 3+ (13%), HR=8.54, p<0.0001). When compared with MALT-IPI, R-MALT-IPI better stratifies and separates high risk patients (26%) into medium-high risk and high-risk patients with a median PFS of 5.8 years (2.9-9.1) and 1.8 years (1.3-2.6) respectively, compared to 2.6 years (1.8-4.7) in the high-risk MALT-IPI patients (16.8%). The R-MALT-IPI index also distinguished patients with different OS. For validation, we analyzed R-MALT-IPI index performance in independent Iowa/Mayo Clinic MER and IELSG-19 cohorts. Both R-MALT-IPI and MALT-IPI were useful in distinguishing PFS and OS in all the cohorts. In the UM training cohort, the concordance c-statistics' values for the two indices were similar: for PFS, CH=0.6893 and CGH=0.6611 for R-MALT-IPI, and CH=0.6551 and CGH=0.6367 for MALT-IPI; for OS, CH=0.7017 and CGH=0.6813 for R-MALT-IPI, and CH=0.7029 and CGH=0.67715 for MALT-IPI. In the validation cohorts, the concordance c-statistics' values for the two indices were also similar, but slightly lower than in the UM cohort for PFS. When comparing medium-high to high-risk R-MALT-IPI groups, there was a reduction of 4 years in median PFS in the UM cohort, and reduction in median EFS of 5.6 years in the MER cohort, an important difference between these risk groups identified by the R-MALT-IPI index. CONCLUSIONS: R-MALT-IPI is a new index for EMZL centered principally on disease characteristics. Overall, there is a similar prediction of PFS (EFS) by R-MALT-IPI and MALT-IPI indexes; however, R-MALT-IPI better recognizes a high-risk group accounting for 13% of EMZL patients with short median PFS and thus obviates the waiting period needed to recognize patients with shorter EFS24. Collaborative studies addressing best treatment approach for these high-risk EMZL patients are eagerly needed. Disclosures Alderuccio: Agios: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; OncLive: Consultancy; Targeted Oncology: Honoraria; Puma Biotechnology: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member. Thieblemont:Cellectis: Membership on an entity's Board of Directors or advisory committees; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Zucca:Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees.

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Bortezomib, Lenalidomide and Dexamethasone (VRD) Followed By Autologous Stem Cell Transplant for Newly Diagnosed Multiple Myeloma; The Mayo Clinic Experience

Blood ◽

10.1182/blood-2018-99-111147 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2147-2147

Author(s):

M Hasib Sidiqi ◽

Mohammed A Aljama ◽

Angela Dispenzieri ◽

Eli Muchtar ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Advisory Committees ◽

Post Transplant ◽

Standard Risk

Abstract We retrospectively reviewed all patients receiving bortezomib, lenalidomide and dexamethasone induction followed by autologous stem cell transplantation (ASCT) within 12 months of diagnosis for multiple myeloma at the Mayo Clinic. 243 patients treated between January 2010 and April of 2017 were included in the study. Median age was 61 (interquartile range, 55-67) with 62% of patients being male. High risk cytogenetic abnormalities (HRA) were present in 34% of patients. 166 (68%) patients received some form of maintenance/other therapy post transplant (no maintenance (NM, n=77), lenalidomide maintenance (LM, n=108), bortezomib maintenance (BM, n=39) and other therapy (OT, n=19)). Overall response rate was 99% with complete response (CR) rate of 42% and 62% at day 100 and time of best response post transplant respectively. The four cohorts categorized by post transplant therapy were well matched for age, gender and ISS stage. HRA were more common amongst patients receiving bortezomib maintenance or other therapy post transplant (NM 18% vs LM 22% vs BM 68% vs OT 79%, p<0.0001). Two year and five year overall survival rates were 90% and 67% respectively with an estimated median overall survival (OS) and progression free survival (PFS) of 96 months and 28 months respectively for the whole cohort. OS was not significantly different when stratified by post-transplant therapy (Median OS 96 months for NM vs not reached for LM vs 62 months for BM vs not reached for OT, p=0.61), however post-transplant therapy was predictive of PFS (median PFS 23 months for NM vs 34 months for LM vs 28 months for BM vs 76 months for OT, p=0.01). High risk cytogenetics was associated with a worse OS but not PFS when compared to patients with standard risk (median OS: not reached for standard risk vs 60 months for HRA, p=0.0006; median PFS: 27 months for standard risk vs 22 months for HRA, p=0.70). In patients that did not receive maintenance therapy presence of HRA was a strong predictor of OS and PFS (median OS: not reached for standard risk vs 36 months for HRA, p<0.0001; median PFS: 24 months for standard risk vs 7 months for HRA, p<0.0001). Patients receiving maintenance therapy appeared to have a similar PFS and OS irrespective of cytogenetics (median OS: not reached for standard risk vs 62 months for HRA, p=0.14; median PFS: 35 months for standard risk vs 34 months for HRA, p=0.79).On multivariable analysis ISS stage III and achieving CR/stringent CR predicted PFS whilst the only independent predictors of OS were presence of HRA and achieving CR/stringent CR. The combination of bortezomib, lenalidomide and dexamethasone followed by ASCT is a highly effective regimen producing deep and durable responses in many patients. Maintenance therapy in this cohort may overcome the poor prognostic impact of high risk cytogenetic abnormalities. Table Table. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Dingli:Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Kumar:KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gertz:Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; Medscape: Consultancy; celgene: Consultancy; Prothena: Honoraria; spectrum: Consultancy, Honoraria; Amgen: Consultancy; janssen: Consultancy; Ionis: Honoraria; Teva: Consultancy; Alnylam: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy.

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The Combination of Frailty and ISS Scores Identifies a Simple Prognostic Index for Overall Survival in Elderly Patients Treated with Novel Agents-Based Induction Therapy

Blood ◽

10.1182/blood.v124.21.4740.4740 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4740-4740

Author(s):

Alessandra Larocca ◽

Sara Bringhen ◽

Roman Hajek ◽

Maria Teresa Petrucci ◽

Massimo Offidani ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Dose Intensity ◽

Staging System ◽

Advisory Committees ◽

Frail Patients ◽

International Staging System ◽

Frailty Score

Abstract Background: Several biological parameters define patients with multiple myeloma (MM) at high-risk of progression or death. The well-known International Staging System (ISS), as well as age per se, are insufficient to explain differences of overall survival (OS) in patients over 65 years, who are 2/3 of newly diagnosed (ND) MM patients. We have recently showed that a frailty score combining age, functional status (Activity of Daily Living and Instrumental Activity of Daily living scores) and comorbidities (Charlson index) defines 3 categories of patients - fit, intermediate-fitness, frail - with significantly differences in OS and progression-free survival (Larocca A, et al. Blood 2013 122:687). Here we assess the causes of the different mortality in intermediate-fitness and frail groups compared to fit ones and present a final prognostic score based on the combination of ISS and frailty scores. Methods: NDMM patients over 65 years enrolled in 3 clinical trials, receiving either lenalidomide, bortezomib or carfilzomib were included in the analysis. Details on treatment regimens and results of these studies have previously been reported (Palumbo A, et al. Blood 2013 122:536; Larocca A, et al. Blood 2013 122:539, Bringhen S et al. Blood 2014 Jul 3;124(1):63-9). The cumulative incidences of discontinuation and toxicities were calculated using the Fine & Gray model. The frailty score was combined with ISS with the CHi-squared Automatic Interaction Detector method used as an iterative decision tree. Results: 869 patients (median age 74 years) were included in the analysis; 260 (30%) were frail, 269 (31%) intermediated-fitness and 340 (39%) fit. The 3-year OS was 57% in frail, 76% in intermediated-fitness and 84% in fit patients. Overall, 143 patients (16%) died, 70 (27%) frail, 39 (14%) intermediate-fitness and 34 (10%) fit. The causes of death were: disease progression [35 (13%) in frail, 22 (8%) in intermediate-fitness and 18 (5%) in fit patients] and toxicity [21 (8%), 10 (4%) and 11 (3%), respectively]. The higher risk of death for progression was related with the lower dose-intensity due to the higher rate of drug discontinuation and/or dose reduction. The average dose intensity was lower in frail (74%, p=0.0006) and intermediate-fitness patients (80%, p=0.07) compared with fit patients (85%). The cumulative incidence of drug discontinuation for any cause, excluding progression and death, was higher in frail (25%; HR 2.21, p<0.001) and intermediate-fitness (22%; HR: 1.41, p=0.052) patients compared with fit ones (17%). The most frequent reasons for toxicity-related death were cardiac events [11 (4%) in frail patients, 2 (1%) in intermediate-fitness, 3 (1%) in fit] and infections [8 (3%), 2 (1%) and 2 (1%), respectively]. When we combined the frailty score with the ISS, 6 groups of patients and 4 risk categories were identified: fit patients with ISS I at low risk (15%; 3-year OS: 94%), fit patients with ISS stage II or III and intermediate-fitness patients with ISS I, II or III at intermediate risk (55%; 3-year OS: 75-77%.), frail patients with ISS stage I or II at high risk (19%; 3-year OS: 61%) and frail patients with ISS stage III at very-high risk (11%, 3-year OS: 55%) (Figure 1). Conclusion: The inferior survival observed among intermediate-fitness and in frail patients as compared to fit ones, is related to a higher rate of toxic deaths and disease progression, due to a lower dose intensity. The combination of the frailty score, evaluating the patient's status, and the standard ISS, taking into account the biological characteristics of the disease, can predict survival and enhances the single predictive values of the scores, thus representing a valuable tool for treatment-decision in the clinical practice. Figure 1. Overall survival of patients classified into 6 categories according to the recursive partitioning analysis by combining the frailty score and the International Staging System. Figure 1. Overall survival of patients classified into 6 categories according to the recursive partitioning analysis by combining the frailty score and the International Staging System. Disclosures Larocca: Janssen Cilag: Honoraria; Celgene: Honoraria. Off Label Use: Use off-label of lenalidomide (immunomodulatory drug), carfilzomib (proteasome inhibitor), subcutaneous bortezomib (proteasome inhibitor) in terms of schedule used and combination.. Bringhen:Onyx: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Offidani:Celgene: Honoraria; Janssen: Honoraria. Maracci:Mundipharma: Honoraria. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marasca:Janssen: Honoraria; Celgene: Honoraria. Giuliani:Celgene: Research Funding. Musto:Janssen: Honoraria; Celgene: Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Millenium: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Palumbo:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Array BioPharma: Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria.

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Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽

10.1182/blood-2021-150948 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2856-2856

Author(s):

Sumithira Vasu ◽

Meghan Kromer ◽

Qiuhong Zhao ◽

Hannah Choe ◽

Karilyn Larkin ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Transplant ◽

Advisory Committees ◽

High Incidence ◽

Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

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Trial in Progress: A Phase I Trial of BTX-A51 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽

10.1182/blood-2020-142557 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Brian J. Ball ◽

Anthony S. Stein ◽

Gautam Borthakur ◽

Crystal Murray ◽

Karin Kook ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Cancer Center ◽

Phase 1 Study ◽

Advisory Committees ◽

Expansion Phase

Background: For patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), low response rates and poor overall survival remain unmet clinical needs. AML cells evade apoptosis through overexpression of antiapoptotic genes and inactivation of p53. The antiapoptotic gene Mcl1 is overexpressed in AML cell lines resistant to venetoclax. Similarly, the sensitivity of AML patients' samples to venetoclax inversely correlates with the presence of a TP53 mutation or low expression of p53. In AML, p53 inactivation more commonly results from overexpression of its negative regulators, Mdmx and Mdm2. BTX-A51 is a novel, oral, direct inhibitor of Casein kinase 1α (CK1α), cyclin dependent kinase 7 (CDK7), and CDK9. CK1α phosphorylates Mdmx and Mdm2 leading to enhanced binding and degradation of p53. CDK7 and CDK9 phosphorylate RNA polymerase II (Pol II) to enable transcriptional initiation and elongation, particularly at large clusters of transcriptional enhancers termed super-enhancers (SE). Preclinical studies have demonstrated that BTX-A51 robustly increased p53 protein levels via CK1a inhibition and Mdm2 downregulation while preferentially decreasing SE transcription of key oncogenes such as Myc andMcl1, enabling selective apoptosis of leukemia cells. The combination of CK1α, CDK7, and CDK9 inhibition was synergistic and prolonged survival in multiple genetic and patient-derived xenograft AML models. Study Design and Methods: This is an open-label, multi-center, first-in-human Phase 1 study evaluating the safety of BTX-A51 in patients with R/R AML or high-risk MDS. The trial will be performed in two phases, a dose escalation (phase 1a) and dose expansion (phase 1b). Phase 1a utilizes a hybrid accelerated titration with single patient cohorts and a Bayesian optimal interval (BOIN) design to assess 8 potential dosing cohorts. The maximum tolerated dose (MTD) will be the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.3. Up to a maximum of 35 patients will be enrolled in the dose escalation phase of the study at Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and City of Hope Cancer Center. Following determination of the MTD, 15 patients will be enrolled in the dose expansion phase for further evaluation of dose-limiting toxicities (DLTs) and for preliminary evidence of efficacy. BTX-A51 will be dosed 3 weeks on drug, followed by 1 week off drug over a 28-day cycle. For the first cycle, patients will receive tumor lysis syndrome prophylaxis with allopurinol and intravenous fluids and be closely monitored. Key inclusion criteria are age ³ 18 years, R/R AML or R/R high-risk MDS, Eastern Cooperative Oncology Group (ECOG) £ 2 and life expectancy of ³ 6 weeks, and adequate kidney and liver function. Key exclusion criteria are receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug, transplantation within 3 months prior to screening, active graft-versus-host disease requiring systemic immunosuppressive medications, and a white blood cell count > 20 × 109/L. The primary objective for the Phase 1 study is to determine the MTD and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating overall response (complete remission, complete remission with incomplete blood count recovery, and partial remission) according to the European LeukemiaNet (ELN) 2017 criteria (Döhner et al. Blood. 2017), survival (overall survival and event-free survival) and pharmacokinetics. Correlative objectives include determining the changes in SEs and SE-driven expression of antiapoptotic genes by chromatin immunoprecipitation and RNA-sequencing. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT04243785 Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Borthakur:BioLine Rx: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Polaris: Research Funding; PTC Therapeutics: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. Murray:Salamandra: Current Employment. Kook:Salamandra: Current Employment. Chan:BioTheryx: Current Employment. Stein:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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