Targeted Sequencing of 7 Genes Can Help Reduce Pathologic Misclassification of MDS

Introduction: The NHLBI National MDS Study (NCT02775383) is a prospective cohort study conducted at 92 community hospitals and 29 academic centers. It enrolls patients undergoing work up for suspected MDS to understand the genetic, epigenetic, and biological factors associated with the initiation and progression of the disease. Previously untreated, cytopenic participants undergo both local and centralized pathology review and are assigned a diagnosis, including MDS, MDS/MPN, AML with blasts < 30%, and "Other". Emerging data suggests that Next Generation Sequencing (NGS), along with cytogenetics and clinical variables, may improve MDS diagnostic precision. Given that our study relies on central review (with additional tertiary pathology review used to adjudicate disagreements), we examined whether targeted gene sequencing data could be used to increase the agreement between local and central pathologic diagnosis of MDS vs. Other. Methods: Peripheral blood and bone marrow (BM) biopsy specimens from cytopenic patients, along with clinical history, CBC, and other results including karyotyping, FISH and pathology reports from local pathologists were reviewed by central pathologists. The updated 2016 WHO classifications were used to diagnose MDS. Targeted exon sequencing of 96 genes was performed using BM specimens. A subset of 648 individuals that were classified as MDS (n=212) or Other (n=436, including 90 CCUS and 89 individuals with other cancers) by pathology assessments were selected. A mean coverage of 1,317X was achieved and variants had a minimum variant allele frequency (VAF) of 2% (except FLT3). Variants for 596 subjects were manually reviewed to retain likely disease-causing variants to build a binary classifier (MDS vs. Other) using the maximum VAF per gene as input (Figure 1). Subjects diagnosed with MDS or Other by both central and local pathology were used for training, validation, and testing, and were considered "gold standard" (GS) cases (n=546). These subjects were split into 4 random groups with equal proportions of MDS cases. 75% of the GS cases were used to train and validate lasso-regularized logistic regression models using 3-fold cross validation. ROC curve analysis was carried out using the remaining 25% of GS cases (Test Set 1) on the best model to identify an optimal probability cut off point for classifying subjects as MDS. Model performance was then tested on 50 subjects for which the central and local pathology diagnosis disagreed (Test Set 2), as well as on 52 additional subjects irrespective of agreement (Test Set 3). Results : The best performing logistic regression model retained 7 genes as most informative in a discriminating diagnosis of MDS from Other based on their VAFs, in order of impact: TP53, SF3B1, U2AF1, ASXL1, TET2,STAG2, and SRSF2. We used this model to assign probabilities for each of the subjects in Test Set 1 and to estimate the performance using ROC analysis (Figure 1), resulting in a high area under the curve (AUC) of 0.89. We chose a probability cut-off of ≥0.17, being associated with a high percentage of correct classification of MDS with a sensitivity and specificity of 0.90 and 0.81, respectively. Among the cohort of 50 subjects with a discordant local and central pathology diagnosis (Test Set 2), the classifier accurately reassigned 37 subjects (accuracy = 74%) from the local to the central pathology. The blinded tertiary pathology reviewer agreed with central in all Test Set 2 cases. This included 24/34 MDS cases that had been labeled as Other by local pathology (positive predictive value [PPV]=0.89). 3/16 final pathology-classified Other cases were mis-classified as MDS by the local pathologist (negative predictive value [NPV] = 0.57). Next, we assessed the ability of the model to predict MDS vs. Other for 52 additional independent subjects using the third pathologist's diagnosis to break any ties (Test Set 3). The classifier correctly predicted 15/21 MDS cases (PPV=0.83) and misclassified 6/31 Others as MDS (NPV=0.82). The overall accuracy was 83%. Conclusions: We identified that VAFs for 7 genes can correctly re-classify subjects as either MDS or Other in 74% of cases that were misclassified between local and central pathology review. Further assessment on an independent cohort showed an accuracy of 83% of the model. Taken together, these data suggest that complementing pathology reviews with targeted sequencing of 7 genes could improve MDS diagnosis. Disclosures Lindsley: MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy; Takeda Pharmaceuticals: Consultancy. Bejar:Aptose Biosciences: Current Employment; AbbVie/Genentech: Honoraria; Astex/Otsuka: Honoraria; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Forty-Seven/Gilead: Honoraria; Genoptix/NeoGenomics: Honoraria. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Foran:H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Xencor: Research Funding; Agios: Honoraria, Research Funding; Aprea: Research Funding; Actinium: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Komrokji:Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria; Novartis: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Padron:Novartis: Honoraria; BMS: Research Funding; Incyte: Research Funding; Kura: Research Funding. Starczynowski:Captor Therapeutics: Consultancy; Tolero Therapeutics: Research Funding; Kurome Therapeutics: Consultancy, Current equity holder in private company, Research Funding. Sekeres:BMS: Consultancy; Takeda/Millenium: Consultancy; Pfizer: Consultancy.

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Pre-Clinical Efficacy of Co-Treatment with KDM1A (LSD1) Inhibitor and Ruxolitinib or BET Inhibitor Against Post-MPN-sAML Blast Progenitor Cells

Blood ◽

10.1182/blood-2019-130783 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1274-1274

Author(s):

Warren Fiskus ◽

Christopher Peter Mill ◽

Vrajesh Karkhanis ◽

Bernardo H Lara ◽

Prithviraj Bose ◽

...

Keyword(s):

Growth Inhibition ◽

Progenitor Cells ◽

Board Of Directors ◽

Research Funding ◽

Amine Oxidase ◽

Genetic Alterations ◽

Advisory Committees ◽

Bet Inhibitor ◽

Oncology Research ◽

Differentiation Block

LSD1 (KDM1A) is an FAD-dependent amine-oxidase that demethylates mono and dimethyl histone H3 lysine 4 (H3K4Me1 and H3K4Me2), which regulates active enhancers and transcription in AML stem/progenitor cells (LSCs). LSD1 is part of the repressor complexes involving HDACs, CoREST or GFI1, mediating transcriptional repression and differentiation block in LSCs that persist in the minimal residual disease (MRD) following attainment of clinical complete remission, leading to relapse and poor outcome in AML. In AML LSCs, genetic alterations and epigenetic dysregulation of enhancers affect levels of myeloid transcriptional regulators, including c-Myc, PU.1, GATA 2 and CEBPα, and their target genes, which are involved in differentiation block in LSCs. Our present studies demonstrate that CRISPR/Cas9-mediated knockout of LSD1 in the AML OCI-AML5 cells significantly increased the permissive H3K4Me2/3-marked chromatin, reduced H3K27Ac occupancy at super-enhancers and enhancers (SEs/Es) (by ChIP-Seq), especially of c-Myc and CDK6, as well as repressed CoREST, c-Myc, CDK6, and c-KIT, while inducing p21, CD11b, and CD86 levels (log2 -fold change by RNA-Seq, and protein expression by Western analyses). This led to significant growth inhibition, differentiation and loss of viability of OCI-AML5 and patient-derived AML blasts (p < 0.01). Similar effects were observed following exposure of OCI-AML5 (96 hours) to tet-inducible shRNA to LSD1. Knock-down of GFI1 by shRNA (by 90%) also inhibited growth and induced differentiation, associated with upregulation of PU.1, p21 and CD11b levels. Treatment with irreversible (INCB059872, 0.25 to 1.0 µM) or reversible (SP2577, 1.0 to 2.0 µM) LSD1 inhibitor (LSD1i) inhibited binding of LSD1 to CoREST, and significantly induced growth inhibition, differentiation and loss of viability (over 96 hours) of the OCI-AML5, post-myeloproliferative neoplasm (post-MPN) sAML SET2 and HEL92.1.7 cells, as well as patient-derived AML and post-MPN sAML blasts (p < 0.01). Co-treatment with INCB059872 and ruxolitinib synergistically induced apoptosis of the post-MPN sAML SET2 and HEL92.1.7 cells and patient-derived CD34+ post-MPN sAML blasts (combination indices < 1.0). Notably, pre-treatment with the LSD1i for 48 hours significantly re-sensitized ruxolitinib-persister/resistant SET2 and HEL92.1.7 cells to ruxolitinib (p < 0.001). We previously reported that treatment with the BET inhibitor (BETi) JQ1 or OTX015 represses SE/E-driven AML-relevant oncogenes including MYC, RUNX1, CDK6, PIM1, and Bcl-xL, while inducing p21 and p27 levels in post-MPN sAML blasts (Leukemia 2017;31:678-687). This was associated with inhibition of colony growth and loss of viability of AML and post-MPN sAML blasts (p < 0.01). Here, we determined that INCB059872 treatment induced similar levels of lethality in BETi-sensitive or BETi-persister/resistant AML and post-MPN sAML cells. Since BETi treatment also depleted LSD1 protein levels, co-treatment with the BETi OTX015 and LSD1i INCB059872 or SP2577 induced synergistic lethality in AML and post-MPN sAML blasts (combination indices < 1.0). Co-treatment with INCB059872 (1.5 mg/kg) and OTX015 (50 mg/kg) both orally for 21 days, compared to each agent alone or vehicle control, significantly reduced the sAML burden and improved survival of immune-depleted mice engrafted with HEL92.1.7 or HEL92.1.7/OTX015-resistant-GFP/Luc sAML xenografts (p < 0.01). Collectively, these findings strongly support further in vivo testing and pre-clinical development of LSD1i-based combinations with ruxolitinib against post-MPN sAML and with BETi against AML or post-MPN sAML cells. Disclosures Bose: CTI BioPharma: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Constellation: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Pfizer: Research Funding. Kadia:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Bioline RX: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Bhalla:Beta Cat Pharmaceuticals: Consultancy. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Verstovsek:Ital Pharma: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Incyte: Research Funding; CTI BioPharma Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Sierra Oncology: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding.

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

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

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

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Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽

10.1182/blood-2020-141890 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Maël Heiblig ◽

Hélène Labussière ◽

Marie Virginie Larcher ◽

Gaelle Fossard ◽

Marie Balsat ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Predictive Value ◽

Scoring System ◽

Research Funding ◽

Risk Group ◽

Advisory Committees ◽

Post Induction ◽

Mutational Status ◽

Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p<0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p<0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P <0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P <0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

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Therapeutic Response to Azacitidine (AZA) In Patients with Secondary Myelodysplastic Syndromes (sMDS) Enrolled In the AVIDA Registry

Blood ◽

10.1182/blood.v116.21.2931.2931 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2931-2931 ◽

Cited By ~ 2

Author(s):

Mikkael A. Sekeres ◽

Mohit Narang ◽

Rami S. Komrokji ◽

Jaroslaw P Maciejewski ◽

Alan F. List ◽

...

Keyword(s):

Logistic Regression ◽

Board Of Directors ◽

Research Funding ◽

Platelet Transfusion ◽

Statistical Tests ◽

Risk Scores ◽

Refractory Anemia ◽

Type I ◽

Odds Ratios ◽

Advisory Committees

Abstract Abstract 2931 Background: The incidence of sMDS is increasing due to improved survival of patients (pts) treated with chemotherapy (CT) or radiotherapy (RT) for other cancers. While studies have demonstrated hematologic improvement (HI) and survival benefits of AZA in pts with primary MDS (pMDS) (Lancet Oncol 2009;10:223), the effects of AZA in sMDS, considered rarer (5-10% of MDS diagnoses) (J Natl Cancer Inst 2008;100:1542) and more difficult to treat, are unknown. AVIDA, a longitudinal, US, multicenter, prospective registry of pts in community-based clinics receiving AZA, is the largest database of AZA-treated pts in the world and includes a large cohort of sMDS pts. We compared the tolerability of and response rates to AZA in sMDS vs pMDS pts in the AVIDA database. Methods: MDS pt data were collected at registry entry (baseline), and then quarterly using electronic data capture, between October, 2006 and July, 2010. Treating physicians determined AZA dose, dosing schedule, and treatment duration. Baseline characteristics of sMDS and pMDS pts were evaluated but formal statistical tests comparing cohorts were intentionally not performed to avoid Type I errors. Rates of IWG-2000-defined HI or possibly better responses (HI+) were assessed centrally and compared between sMDS and pMDS cohorts (each assessment included only pts eligible for improvement). RBC and platelet transfusion independence (TI) were also evaluated between groups using logistic regression analyses with patients stratified by International Prognostic Scoring System (IPSS) scores (higher [score >1] vs lower [score ≤1]) and transfusion status at baseline, with age and months since diagnosis included as covariates. Odds ratios (sMDS to pMDS) and 95% confidence intervals (CI) were reported from these models. Results: At data cut-off in July 2010, 37/417 pts (8.9%) in the registry had sMDS associated with exposure to RT, CT, or radioiodine (n=33), benzene (n=2), or radiation (n=2). Median times since diagnosis for pts with sMDS and pMDS were 1 month (range 0 – 69) and 3 months (0 – 207), and median ages were 71 years (range 41 – 86) and 75 years (29 – 91), respectively. At baseline, for pts with available IPSS scores, a larger proportion of pts with sMDS than pts with pMDS had IPSS higher-risk scores (55% vs 30%) and IPSS poor cytogenetics (59% vs 17%). Additionally, a higher proportion of sMDS vs pMDS pts had chromosome 7 abnormalities (47% vs 11%), 2–3 cytopenias (76% vs 62%), and infections requiring IV antibiotics (41% vs 16%); but similar proportions had >10% blasts (18% of both cohorts) and were dependent on RBC (57% vs 52%) and platelet (22% vs 13%) transfusions at baseline. Median follow-up was 5.9 months (range 0.2 – 24) in the sMDS and 6.7 months (0.1 – 37) in the pMDS cohorts, and median numbers of AZA treatment cycles were 4 (range 1 – 21) and 5 (1 – 26), respectively. In both the sMDS and pMDS groups, the most common treatment dose and schedules were 75 mg/m2 AZA (91% and 83%, respectively) for 5 consecutive days (46% and 55%) in ≤28-day cycles (45% and 54%). Pts with sMDS had a high rate of HI+, which was comparable to that in pts with pMDS (Table). Rates of RBC TI in baseline RBC transfusion-dependent pts with sMDS vs pMDS were 57% vs 61%, and of platelet TI for baseline platelet transfusion-dependent sMDS vs pMDS pts were 50% vs 64% (Table). Odds ratios from the logistic regression models were 1.4 (95%CI: 0.6, 3.5; p=0.47) and 0.6 (95%CI: 0.2, 1.4; p=0.23) for RBC TI and platelet TI, respectively, after adjusting for the other covariates in the model. Grade 3 or 4 adverse events were similar in the 2 groups, with the exception of higher frequencies of thrombocytopenia (27% vs 11%) and infections (24% vs. 12%) in sMDS vs pMDS pts, respectively. Conclusion: Pts with sMDS treated with AZA had rates of HI or better responses comparable to those of pMDS patients, despite worse pretreatment disease characteristics. AZA was well tolerated by pts with sMDS and pMDS. A diagnosis of sMDS alone should not preclude treatment with the disease-modifying drug, azacitidine. Disclosures: Sekeres: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Azacitidine is approved in the US for treatment of patients with the FAB myelodysplastic syndrome (MDS) subtypes: Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML); and is approved in the EU for IPSS Int-2 and High risk MDS, CMML with 10–29 percent marrow blasts without myeloproliferative disorder, and AML with 20–30% blasts and multi-lineage dysplasia, according to WHO classification. This abstract describes azacitidine use in secondary MDS. Komrokji:Celgene: Research Funding, Speakers Bureau. Maciejewski:Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. List:Celgene: Research Funding. Street:Celgene: Employment. Swern:Celgene Corporation: Employment. Sullivan:Celgene: Employment, Equity Ownership. Grinblatt:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Preliminary Results of a Phase 2 Study of PD 0332991 in Combination with Bortezomib and Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2940.2940 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2940-2940

Author(s):

Ruben Niesvizky ◽

Luciano J Costa ◽

Nisreen A. Haideri ◽

Georg Hess ◽

Seema Singhal ◽

...

Keyword(s):

Cell Cycle ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Phase 2 ◽

Advisory Committees ◽

Oncology Research ◽

Equity Ownership ◽

D 20 ◽

Ecog Ps

Abstract Abstract 2940 Background: PD 0332991 is an orally bioavailable selective inhibitor of cyclin-dependent kinase (CDK) 4/6. Inhibition of CDK4/6 phosphorylation of retinoblastoma (Rb) induces prolonged early G1 cell cycle arrest (pG1) and synchronous progression to S phase (pG1-S) upon withdrawal, which sensitizes human multiple myeloma (MM) cells to killing by bortezomib (B) or dexamethasone (D) in vitro and in animal models. Based on these observations, a phase 1/2 study in combination with B plus D in patients (pts) with relapsed and/or refractory MM was initiated. The phase 1 part of the study (completed) determined the recommended phase 2 dose and schedule to be PD 0332991 100 mg QD 12 days on followed by 9 days off treatment in a 21-day cycle with intravenous B 1.0 mg/m2 plus oral D 20 mg administered on Days 8 and 11 in pG1 and 15 and 18 in pG1-S (Niesvizky et al. ASH 2010). We present preliminary data from the phase 2 part of the study. Methods: Pts with Rb protein-positive, measurable (as defined by International Myeloma Working Group [IMWG]) progressive, relapsed or refractory MM after ≥1 prior treatment were eligible. Prior B was allowed only if there was a response and disease progression occurred off therapy. Pts received oral PD 0332991 once daily on Days 1–12 in a 21-day cycle in combination with intravenous B 1.0 mg/m2 plus oral D 20 mg administered on Days 8, 11, 15, and 18. The primary endpoint is overall response rate (ORR); secondary endpoints include time to progression (TTP), progression-free survival (PFS), overall survival, duration of response, and safety. PD 0332991-mediated inhibition of CDK4/6-specific phosphorylation of Rb (pSRb) and Ki67 in bone marrow MM cells were also assessed. The phase 2 part of the study is a Simon Two-Stage Minimax design; 25 response evaluable patients were to be enrolled into the first stage. Results: 39 pts have been tested for Rb and 36 pts (92%) were positive. Of the 36 pts, 30 pts have been enrolled to date including 2 pts who did not receive the study treatment, and 23 pts are considered response evaluable as of the data cut-off. 56% of pts had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 and 8% had ECOG PS of 2. At baseline, median β2 microglobulin was 3.1 (range 1.6–26.2), median hemoglobin was 11.2 (7.2–13.6), median calcium was 9.4 (8.7–11.9). The median number of prior therapies was 2 (range 1–8); 55% had received prior B. Sixteen pts have discontinued (9 due to progressive disease, 3 due to AE, 2 consent withdrawal, and 2 not treated). The most common treatment-related AEs were thrombocytopenia (44%), nausea (20%), anemia, constipation, fatigue, and neutropenia (all 16%); 32% of pts reported grade ≥3 thrombocytopenia. IHC data showed on-treatment reduction in pSRb and Ki67 in MM cells from bone marrow of 3/3 patients with available samples. To date, 1 pt achieved a complete response (CR), 1 achieved a very good partial response (VGPR), 1 partial response (PR), 1 minor response (MR), and 5 stable disease (SD); 6 pts are too early for assessment. Conclusions: To date, the combination of PD 0332991 and B plus D has shown response in 4 pts with relapsed/refractory MM. The most commonly reported AEs were cytopenias, consistent with the known safety profiles of PD 0332991 and B. PD 0332991 inhibited phosphorylation of Rb and cell cycle progression in MM cells. The accrual to stage 1 is ongoing. Updated efficacy and safety data will be presented. Disclosures: Niesvizky: Millennium Pharmaceuticals: Consultancy; Millennium Pharmaceuticals: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Hess:Pfizer Oncology: Consultancy; Pfizer Oncology: Research Funding; Pfizer Oncology: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen-Cilag: Consultancy; Celgene: Consultancy; Celgene: Research Funding; Janssen-Cilag: Honoraria; Celgene: Honoraria; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jakubczak:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Kim:Pfizer Oncology: Equity Ownership; Pfizer Oncology: Employment. Randolph:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Chen-Kiang:Pfizer Oncology: Research Funding.

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Efficacy of Ruxolitinib By Baseline Spleen Volume in Patients with Polycythemia Vera Resistant to or Intolerant of Hydroxyurea

Blood ◽

10.1182/blood.v124.21.1840.1840 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1840-1840 ◽

Cited By ~ 1

Author(s):

Alessandro M. Vannucchi ◽

Srdan Verstovsek ◽

Mark M Jones ◽

Shui He ◽

Jingjin Li ◽

...

Keyword(s):

Logistic Regression ◽

Linear Regression ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Response Trial

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm defined by erythrocytosis; patients may also have increased platelets and white blood cells as well as splenomegaly and disease-related symptoms. JAK/STAT activation is the primary driver of PV pathogenesis, in most cases resulting from the JAK2V617F mutation. The RESPONSE trial compared ruxolitinib (RUX) and best available therapy (BAT) in patients with PV and splenomegaly who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNet criteria. At the time of the primary analysis, RUX demonstrated superior improvements in hematocrit (HCT) control, symptom burden, and spleen volume compared with BAT. This post hoc analysis of RESPONSE was conducted to determine if treatment outcomes were influenced by baseline spleen volume. Methods : Patients with PV ≥18 years of age who were resistant to or intolerant of HU with palpable spleen (confirmed by MRI/CT to be ≥450 cm3) and phlebotomy requirement were randomized 1:1 to receive open-label RUX 10 mg BID or BAT. The primary endpoint was a composite that required a ≥35% reduction in spleen volume at Week 32 and hematocrit (HCT) control. HCT control was defined as lack of phlebotomy eligibility (based on HCT values) between Weeks 8–32 with no more than 1 phlebotomy eligibility between randomization and Week 8. A linear regression was conducted to determine the effect of baseline spleen volume on the percent change in spleen volume at Week 32. A logistic regression was conducted to determine the effect of baseline spleen volume on HCT control through Week 32. Spleen volume was measured by MRI at screening and Weeks 16 and 32. Hematocrit was assessed at screening, prerandomization, and every 2 weeks from Day 1 to Week 12, followed by every 4 weeks until Week 32. Results :The RESPONSE trial enrolled 222 patients (RUX, 110; BAT, 112). Median (range) spleen volume at baseline was 1195 cm3 (396–4631 cm3) in the RUX arm and 1322 cm3 (254–5147 cm3) in the BAT arm. Baseline median (range) spleen length by palpation was 7.0 cm (0.0–24.0 cm) in the RUX arm and 7.0 cm (0.0–25.0 cm) in the BAT arm. In the 24 weeks prior to screening, most patients in both arms had ≥2 phlebotomy procedures (RUX, 87%; BAT, 80%). There was no correlation between the percentage change in spleen volume at Week 32 and baseline spleen volume; linear regression showed no significant effect of baseline spleen volume on the percentage change in spleen volume at Week 32 (P=0.40). No significant effect of baseline spleen volume on HCT control through Week 32 was identified based on logistic regression analysis (P=0.37). Conclusion : In PV patients with inadequate response to or intolerant of HU, the degree of splenomegaly at baseline did not influence achievement of HCT control or reduction in spleen volume with RUX therapy. Disclosures Vannucchi: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Verstovsek:Incyte Corporation: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Determinants of "Fitness" for Intensive Therapy Among Acute Myeloid Leukemia (AML) Patients

Blood ◽

10.1182/blood-2019-128853 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3836-3836

Author(s):

Abby Statler ◽

Brian P. Hobbs ◽

Tomas Radivoyevitch ◽

Caitlin Siebenaller ◽

Sudipto Mukherjee ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

De Novo ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Advisory Committees ◽

Cart Analysis ◽

Cardiac Abnormalities ◽

Oncology Research ◽

Baseline Characteristics

Background: Determining which AML patients (pts) are "fit" for intensive chemotherapy (IC), both in real-world scenarios and for clinical trial eligibility (particularly as it relates to regulatory indications) is challenging. While age, AML etiology, and cardiac function have been invoked, these oversimplify the clinical assessment and recommendation for IC vs. Non-IC (NIC). We compared baseline characteristics among pts receiving IC and NIC, and evaluated associations between treatment receipt and pt characteristics. Adjusting for treatment received, pts' attributes were further evaluated for association with overall survival (OS). Methods: Adult (≥18 years) AML pts who received IC or NIC at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic and renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariate logistic and Cox regression were used to identify significant prognostic factors for treatment receipt and OS, respectively. The Kaplan-Meier method estimated distributions of OS, which were compared among pt cohorts using the log-rank test. Classification and regression tree (CART) analysis was performed to characterize the best decision process used to select pts for NIC. Results: Of 1,082 AML pts analyzed, 901 (83.2%) were treated with intensive, cytarabine-based chemotherapy, and 181 (16.8%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. As expected, baseline characteristics were significantly imbalanced between groups; pts receiving NIC were more likely to be older (P<.001), have ≥3 comorbidities (P<.001), another cancer (P=.02), myocardial (P<.001), renal (P=.006) conditions, abnormal renal (creatinine (P=.004), creatinine clearance by Cockcroft-Gault (CrCl, P<.001)), and abnormal liver function (bilirubin (P=.03)). And less likely to have de novo disease (P<.001), favorable ELN risk (P=.008), private insurance (P<.001), and mild cardiac abnormalities (QTc 450-480ms (P<.001), LVEF 50-40% (P<.001)) (Tables 1 & 2). Multivariable stepwise regression revealed independent associations with the following attributes (favoring NIC over IC): older age (OR=1.10, P<.001), etiology (prior MDS vs. de novo; OR=2.52 , P<.001), liver (bilirubin >1.5xULN vs. normal; OR=3.04, P=.02), renal (CrCl <60 ml/min vs. normal; OR=3.17, P=.002), myocardial conditions (atrial fibrillation/congestive heart failure/coronary artery disease vs. normal); OR=2.33, P=.001) and mild cardiac abnormalities (QTc 450-480ms vs. normal: OR=0.46, P=.01; LVEF 50-40% vs. normal: OR=0.33, P=.03). Clinically, in making decisions about NIC, the first step is age, followed by comorbidity. CART analyses revealed that when a comorbidity is identified, age is then re-assessed; depending upon the type of comorbidity present, various age thresholds determined NIC vs. IC. With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). OS was significantly different between groups (median OS, NIC vs. IC: 4.9 vs. 20.4 months, P<.001). In multivariate analyses controlling for treatment (IC vs. NIC), age, sex, insurance, number of comorbidities, AML etiology, and ELN risk, having another cancer (HR= 0.97, P=.78), renal (HR=1.10, P=.56) or myocardial comorbidity (HR= 0.94, P=.60) were not significantly associated with OS. Liver (bilirubin >1.5xULN: HR=1.70, P=.01), renal (creatinine >1.5xULN: HR=1.55, P=.001; CrCl<60ml/min: HR=1.37, P=.01), and cardiac dysfunction (QTc >480-500ms: HR=1.36, P=.04; LVEF 50-40%: HR=1.38, P=.04) were, however, associated with worse survival. Conclusions: Age, comorbidities, and organ dysfunction are associated with AML treatment determination. Pts who presented with cancer/renal/myocardial comorbidities and renal/liver dysfunction were more likely to receive NIC, despite the comorbid conditions not having an impact on OS. Further research needs to elucidate the extent to which NIC is the optimal treatment decision for pts exhibiting varying severities of cancer/renal/myocardial comorbidities. Disclosures Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:McGraw Hill Hematology Oncology Board Review: Other: Editor; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Advani:Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Gerds:Sierra Oncology: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Abbvie: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees.

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Differential Prognostic Impact of IDH1 and IDH2 Mutations in Chronic Myelomonocytic Leukemia

Blood ◽

10.1182/blood-2021-150786 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3684-3684

Author(s):

Connor M. Walsh ◽

Anthony Hunter ◽

Terra Lasho ◽

Christy Finke ◽

Rami S. Komrokji ◽

...

Keyword(s):

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Prognostic Impact ◽

Wild Type ◽

Advisory Committees ◽

Durable Response ◽

Oncology Research ◽

Idh Mutations ◽

Idh1 Mutations

Abstract Introduction: Mutations involving isocitrate dehydrogenase 1/2 (IDH) are known oncogenic drivers in hematological malignancies, conferring neomorphic enzymatic activity to IDH 1/2, resulting in the oncometabolite, 2-hydroxyglutarae (2-HG). 2-HG in turn suppresses TET activity, making IDH and TET2 mutations synthetically lethal and almost mutually exclusive. The frequency of IDH mutations in CMML is <10% and their prognostic impact remains unclear. We carried out this study in a large database of molecularly annotated CMML patients to better define the clinical profile and prognostic impact of these mutations. Methods: After IRB approval, CMML patients from the Mayo Clinic, Minnesota and the Moffitt Cancer Center (MCC), Tampa, Florida, were included in the study. All patients had bone marrow (BM) biopsies with cytogenetics and molecular genetics done either at diagnosis, or at first referral. Clinical and mutational data were abstracted and retrospectively analyzed. Overall survival (OS) was calculated from date of CMML diagnosis to date of death/last follow, while AML-free survival (AML-FS) was calculated from date of CMML diagnosis to date of leukemic transformation (LT). Patients that had undergone allogeneic HCT were excluded from the study (n=3). Statistical analysis was carried out using the Blue Sky software. Results: Six hundred and forty four patients were included in the study (Mayo Clinic-357, MCC- 287), median age 71 years (range, 20-95 years), 67.8% being male. Forty-three (6.7%) patients had IDH mutations, 35 (82%) IDH2 and 8 (18%) IDH1; of which, 34 (97%) involved the IDH2R140 hotspot and 5 (62.5%) involved the IDH1R132 hotspot, respectively. The median variant allele fractions (VAF) for IDH1 mutations was 41% (range, 8-46%) and for IDH2 mutations was 46% (range, 7-70%). There were no significant demographic or clinical differences between IDH mutant and wild type CMML patients, with the exception that IDH mutant CMML patients were less likely to be thrombocytopenic (p=0.006), were less likely to have TET2 co-mutations (14% vs 53.2%; p<0.001) and were more likely to have SRSF2 co-mutations (69.8% VS 40.3%; p<0.001). Importantly there were no differences in proliferative or dysplastic subtypes (p=0.3), cytogenetic (p=0.12) and molecular risk stratifications (p=045). There were also no significant demographic or clinical differences between IDH1 vs IDH2 mutant CMML patients. Six (14%) IDH mutant CMML patients had TET2 co-mutations; 5 (83%) with IDH2R140Q (median VAF-28%;all male) and 1 (17%) with IDH1R132H (VAF-44%;female) (Figure 1). Five (11%) IDH2 mutant patients were treated with enasidenib (IDH2 inhibitor), none with a durable response, while none of the IDH1 mutant patients received targeted therapy. At last follow up (median 18 months), 337 (52%) deaths and 119 (18.5%) LT have been documented, with IDH mutant patients having a higher LT rate (30.2% vs 17.6%, p=0.04) compared to wildtype patients. The median OS of the entire cohort was 35 months, with no difference in OS between IDH mutant and wild type patients (34.5 vs 35 months, p=0.12), with IDH1 mutant patients having a shorter OS in comparison to IDH2 mutant patients (31 vs 37 months; p=0.005- Figure 1). IDH mutant CMML patients also had a shorter AML-FS in comparison to wild type patients (36.6 vs 210 months, p=0.005), with there being no differential impact on AML-FS of IDH1 vs IDH2 mutations (p=0.26, Figure 1). Conclusions: IDH mutations are infrequent in CMML (7%), with IDH2 mutations being more common than IDH1 mutations (80 vs 20%). IDH mutations co-occur very infrequently with TET2 mutations (14%), with IDH mutant patients being less likely to have thrombocytopenia and more likely to have SRSF2 co-mutations. IDH mutations negatively impacting AML-FS without a significant impact on OS. Prospective clinical trials testing the safety and efficacy of IDH1/2 inhibitors in CMML are much needed. Figure 1 Figure 1. Disclosures Komrokji: AbbVie: Consultancy; 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; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Acceleron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Consultancy. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Padron: BMS: Research Funding; Stemline: Honoraria; Taiho: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding.

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Preliminary Study of Ruxolitinib and Venetoclax for Treatment of Patients with T-Cell Prolymphocytic Leukemia Refractory to, or Ineligible for Alemtuzumab

Blood ◽

10.1182/blood-2021-149228 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1201-1201

Author(s):

Charles Herbaux ◽

Stéphanie Poulain ◽

Damien Roos-Weil ◽

Jacques-Olivier Bay ◽

Yann Guillermin ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Advisory Committees ◽

Prolymphocytic Leukemia ◽

Oncology Research ◽

Grade 3 ◽

Stat Pathway

Abstract Background: Ruxolitinib (RUX), a JAK1/JAK2 inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are 2 drug candidates recently identified as promising candidate for the treatment of T-Cell prolymphocytic leukemia (T-PLL). We recently reported that JAK/STAT pathway inhibition with RUX enhances BCL-2 dependence, thereby sensitizing T-PLL cells to VEN (Herbaux et al., Blood, 2021). We also showed that JAK/STAT pathway mutational status could impact RUX activity. Here, we report results on the 15 first patients who were treated with RUX and VEN oral combination for T-PLL. All patients were refractory to, or ineligible for alemtuzumab, the principal therapeutic option to date. Methods: In this multicenter retrospective study from the French Innovative Leukemia Organization, 15 patients with T-PLL (according to consensus criteria) were included. All patients were informed about the off-label use of this combination and provided informed consent. Patients received a maximum dose of RUX 15 mg twice daily, and VEN 800 mg daily. VEN was started with daily ramp-up from 20 mg to 800 mg over 6 days, with TLS prophylaxis (rasburicase and IV hydration). Responses were assessed by consensus criteria. Next generation sequencing (NGS) was performed using a custom-designed panel of 33 genes, including among others: ATM, TP53, IL2R, JAK1, JAK3, and STAT5B. CytoScan HD microarray (Affymetrix) were used to study copy number variation and or uniparental disomy. In vivo dynamic BH3 profiling (DBP) was performed on samples obtained from two patients on treatment. Results: All 15 patients were refractory or relapsing after chemotherapy (mostly bendamustine and pentostatin), except one. They were either refractory to (n=10) or ineligible (n=5) for alemtuzumab (ineligibility was decided by the treating physician based on age and comorbidities). The median age was 70 years (48-88). Within a week of starting RUX, a transient increase of the absolute lymphocyte count was observed in 66.6% of the patients. Based on the molecular status of the JAK/STAT pathway, we established 2 groups of patients. One with samples where no mutations were found (WT, n=3), and one with at least one mutation in the JAK/STAT pathway (MUT, n=12). The overall response rate (ORR) was 73.3%, with only partial responses. Five patients nearly fulfilled CR criteria except that they had persistent lymphocytosis (over 4 x 10 9/L), all of them were in the MUT group. ORR was 83.3% in the MUT group, and only one patient of the WT group obtained a PR. With a median follow-up of 73 days (22 to 368), the median progression free survival was significantly shorter in the WT group in comparison to the MUT group (1.8 months versus 5.6 months, p=0.04, Figure). Of note, four patients were treated with VEN monotherapy before the start of the combination with RUX. With that treatment, 3 of these patients achieved stable disease followed by progression within 2 to 3 months, while 1 was primary refractory to VEN monotherapy. The most frequent reported adverse events (AEs) of the RUX plus VEN combination were cytopenias, with 46.6% grade 3 or 4 thrombocytopenia and 40% grade 3 or 4 neutropenia. DBP showed that overall priming and BCL2 dependence increased in vivo (n=2) during the treatment with RUX and VEN. Finally, SNP arrays identified clonal evolution in the 3 patients evaluated sequentially (before treatment versus at progression). In one case, emergence of EZH2 and JAK1 mutation was also observed at progression using NGS. Conclusions: These preliminary results suggest promising activity of RUX plus VEN in T-PLL, and justify the development of a prospective clinical trial of this combination. Our data seem to show that this combination may be especially active for patients with JAK/STAT pathway activating mutations and that disease progression is associated with clonal evolution. Updated results will be presented at the meeting. Figure 1 Figure 1. Disclosures Herbaux: Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Lemonnier: Gilead: Other: travel grant; Institut Roche: Research Funding. Laribi: Jansen: Research Funding; AstraZeneca: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; BeiGene: Other: Personal Fees. Moreaux: Diag2Tec: Consultancy. Morschhauser: Janssen: Honoraria; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Davids: Ascentage Pharma: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Eli Lilly and Company: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Research to Practice: Consultancy; BeiGene: Consultancy; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Takeda: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding. OffLabel Disclosure: Ruxolitinib and venetoclax are used offlabel for patients refractory to current therapeutic options, based on preclinical data.

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External Validation and Revision of Thrombosis Lymphoma /Throly/ Score

Blood ◽

10.1182/blood-2018-99-115568 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 140-140 ◽

Cited By ~ 1

Author(s):

Darko Antic ◽

Natasa Milic ◽

Biljana Mihaljevic ◽

Bruce Cheson ◽

Mayur Narkhede ◽

...

Keyword(s):

At Risk ◽

Board Of Directors ◽

Predictive Value ◽

Research Funding ◽

Validation Cohort ◽

External Validation ◽

Advisory Committees ◽

Final Model ◽

Risk Patients ◽

Reduced Mobility

Abstract Introduction Lymphoma patients are at increased risk of thromboembolic events (TE), however, thromboprophylaxis in these patients is largely under utilized. Actual guidelines recommend different models for thromboembolic risk estimation in cancer patients. Proposed models are of limited use in lymphoma patients as their development is not based on specific characteristics for this patient population. Previously, we developed and internally validated a simple model, based on individual clinical and laboratory patient characteristics that would classify lymphoma patients at risk for a TE. The variables independently associated with the risk for thromboembolism were: previous venous and/or arterial events, mediastinal involvement, BMI>30 kg/m2, reduced mobility, extranodal localization, development of neutropenia and hemoglobin level < 100g/L. For patients classified at risk in derivation cohort (n=1236), the model revealed positive predictive value of 25.1%, negative predictive value of 98.5%, sensitivity of 75.4%, and specificity of 87.5%. The diagnostic performance measures retained similar values in the internal validation cohort (n=584). The aim of this study was to perform external validation of the previously developed thrombosis lymphoma (Throly) score. Methods The study population included patients with a confirmed diagnosis of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) from 8 lymphoma centers from USA, France, Spain, Croatia, Austria, Switzerland, Macedonia, and Jordan. During 2015 to 2016, data were prospectively collected for venous TE events from time of diagnosis to 3 months after the last cycle of therapy for newly diagnosed and relapsed patients who had completed a minimum of one chemotherapy cycle. The score development and validation were done according to TRIPOD suggested guidelines. Sensitivity analyses were carried out to test the model robustness to possible different settings, according to in/out patient settings and according to different countries included. Results External validation cohort included 1723 patients, similar to the developed group and consisted of 467 indolent NHL, 647 aggressive NHL, 235 CLL/SLL and 366 HL patients, out of which 121 (7%) patients developed venous thromboembolic events. For patients classified at risk in external validation cohort, the model resulted in positive and negative predictive values of 17% and 93%, respectively. Based on new available information from this large prospective cohort study this model was revised to include the following variables: diagnosis/clinical stage, previous VTE, reduced mobility, hemoglobin level < 100g/L and presence of vascular devices. In the new score we divided patients in two groups: low risk patients, score value ≤ 2; and high risk patients, score value > 2. For patients classified at risk by the revised model, the model produced positive predictive value of 22%, negative predictive value of 96%, sensitivity of 51%, and specificity of 72%. In sensitivity analysis, the final model proved its robustness in different settings of major importance for lymphoma patients. The final model presented good discrimination and calibration performance. Concordance C statistics was 0.794 (95% CI 0.750-0.837). Conclusions Revised Thrombosis Lymphoma - ThroLy score is more specific for lymphoma patients than any other available score targeting thrombosis risk in solid cancer patients. We included biological characteristic of lymphoma, indolent vs aggressive, as well as data about dissemination of disease, localized vs advanced stage, reflecting specificity of lymphomas comparing to other types of cancer. Also, we pointed out significance of central vascular devices as risk factor having considered the role of vascular damage during insertion as a potential trigger for activation of the clotting cascade. This score is user friendly for daily clinical practice and provides a very good predictive power to identify patients who are candidates for pharmacological thromboprophylaxis. Disclosures Cheson: AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jaeger:Gilead: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees.

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