NFE2 Mutations Impact AML Transformation and Overall Survival in Patients with Myeloproliferative Neoplasms (MPN)

Introduction: MPN are a heterogeneous group of chronic hematological malignancies often resulting from a combination of a driver gene mutation (JAK2, MPL or CALR) and a variety of somatic mutations harboring diverse prognosis values. A subset of MPN patients carry somatic mutations in the hematopoietic transcription factor NFE2 (nuclear factor erythroid 2) resulting in a functionally enhanced truncated form of NFE2 (Jutzi JS et al., JEM, 2013). Moreover, epigenetically induced overexpression of NFE2 has recently been reported in the majority of MPN patients (Peeken JC et al., Blood, 2018). In transgenic murine models, NFE2 overexpression results in an MPN phenotype (thrombocytosis, leukocytosis, EPO-independent colony formation, characteristic bone marrow histology and expansion of stem and progenitor compartments) and has recently been shown to predispose to the acquisition of additional genetic abnormalities and subsequent leukemic transformation (Kaufmann KB et al., JEM, 2012) (Jutzi JS et al., Blood, 2019). However, clinical impact of NFE2 mutations in MPN patients remains unknown. The aim of this study was to evaluate the phenotypic characteristics and prognostic impact of NFE2 somatic mutations in a large mono-centric cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and May 2020. This study included 707 of them in whom a next-generation sequencing (NGS) molecular analysis targeting 36 myeloid genes was performed at diagnosis and/or during follow-up. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Statistical analyses were performed using the STATA software (STATA 15.0 Corporation, College Station, TX). Results: In our cohort, 411 patients presented with polycythemia vera (PV), 577 with essential thrombocythemia (ET), 184 with primary or pre-fibrotic myelofibrosis (PMF), 59 with unclassified MPN and 12 with MDS/MPN. Median age at diagnosis was 51 years [40-63]. 73.1% patients had a JAK2V617F mutation, 14.1% a CALR mutation and 3.3% a MPL mutation. Overall, 64 (9.05%) patients harbored a NFE2 mutation with a variant allelic frequency (VAF) ≥ 0.5% and 36 had a VAF ≥ 5%, the latest were considered as NFE2 mutated for the rest of the study as VAF <5% may refer to a minor clone without clinical relevance. NFE2 mutations were present in 7.3%, 5.3% and 3.6% of PV, PMF and ET patients respectively. No significant association between the presence of NFE2 mutation and clinical/molecular MPN characteristics (driver mutation, constitutional symptoms, splenomegaly, blood counts, cytogenetic and other molecular features) was observed using a logistic regression association model. Median follow-up was 103.8 months, IQR [47.2; 175.6]. In terms of response to therapy, 52.8% of patients achieved complete response, complete hematological response or clinical improvement in NFE2 mutated vs 61.7% in non-mutated patients (p= 0.026). Interestingly, presence of a NFE2 mutation (HR 9.92, 95%CI[3.21; 30.64], p< 0.001), age at diagnosis (HR 1.09, 95%CI[1.05; 1.12], p< 0.001), PMF subtype (HR 6.92, 95%CI[2.81; 17.06], p < 0.001) and high-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2 and U2AF1) (HR 2.45, 95%CI[1.14; 5.28], p=0.021) were independently associated with AML/MDS transformation free survival (TFS) in a COX regression multivariate analysis (Figure A). Presence of a NFE2 mutation was also independently associated with overall survival (OS) (HR 9.37, 95%CI [4.18; 21.03], p<0.001) (Figure B). Median TFS were 216.1 months and not reached, while median OS were 144.2 months and not reached for NFE2 mutated and non-mutated patients, respectively. No difference was observed in terms of thrombo-hemorrhagic events (HR 0.73; 95%CI [0.10; 5.21], p=0.752) and secondary myelofibrosis free survivals (HR 0.67; 95%CI [0.09; 4.87], p=0.693). Conclusion: In this retrospective study we show that presence of NFE2 mutations with a VAF ≥5% is independently associated with an increased risk of leukemic transformation and shorter overall survival. These findings are in line with recently reported animal models and suggest that NFE2 mutations screening should be routinely performed in MPN patients. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

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Impact of Non-JAK2 Molecular Mutations and Cryptic SNP Lesions in Myelofibrosis Patients Treated with Ruxolitinib

Blood ◽

10.1182/blood.v124.21.3194.3194 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3194-3194

Author(s):

Jing Ai ◽

Valeria Visconte ◽

Ali Tabarroki ◽

Ahmad Zarzour ◽

Christopher Gerace ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Somatic Mutations ◽

Similar Response ◽

Prognostic Impact ◽

Severe Thrombocytopenia ◽

Spleen Size ◽

Advisory Committees ◽

Myeloid Neoplasm

Abstract The identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPN) paved the way for the pivotal studies that led to the FDA approval of a JAK1/2 inhibitor, ruxolitinib (rux) in patients (pts) with myelofibrosis (MF). Improvement in splenomegaly and debilitating disease-related symptoms were the primary clinical responses observed with rux. Although JAK2 mutational status did not impact response/survival in MF pts, cytogenetics had an impact on prognosis. In a related myeloid neoplasm specifically myelodysplastic syndromes, molecular mutations (TET2/DNMT3A) predict for better therapeutic response to DNA methyltransferase inhibitors. We hypothesized that somatic mutations and single nucleotide polymorphism array (SNP-A) lesions are frequent in MF pts treated with rux and may affect their clinical outcomes. To further investigate the predictive and prognostic impact of SNP-A lesions and somatic mutations in MF pts in the rux era, we studied 54 MF pts who received at least 12 weeks of rux therapy (tx) using a modified dose escalation approach (Tabarroki A et al. 55th ASH; Abstract 1586). Clinical (total symptom score [TSS], spleen size), cytogenetic (metaphase cytogenetics [MC], SNP-A), hematologic and survival data were collected before and 12-weeks post rux tx. Categorical data were analyzed using X2 test. A p-value of <.05 was considered statistically significant. Sanger sequencing for genes relevant to myeloid neoplasm pathophysiology like TET2, CBL, LNK, DNMT3A, TP53, SF3B1, U2AF1, SRSF2, ASXL1, EZH2, JAK2, CALR, and IDH1/2 was performed. The median age of the cohort was 66 yrs (41-89); male/female: 28/26. The median follow-up time after initiation of tx was 17 months. The median overall follow-up of the cohort from the time of diagnosis was 35 months. Using DIPSS-plus, pts were stratified as high (24, 44%), int-2 (22, 41%) and int-1 (8, 15%) risk groups. Baseline median WBC=9.4k/μL, Hgb=10.2g/dL, PLT=212k/μl, TSS=20, and median palpable spleen size=13cm. Post-tx median WBC=9.9k/μL, Hgb=10.1g/dL, PLT=150k/μL, TSS=4, and spleen size=6cm. MC identified cytogenetic abnormalities in 24/54 (44.4%) pts. The most frequent chromosomal defects included del(20), +8, and +9. Serial MC was available for 20 pts and no cytogenetic evolution was identified. SNP-A data were available for 29 pts, of which 28 pts had SNP-A lesions. The most commonly involved chromosomes were 9 (15.1%), 20 (14.1%), and 14 (8.5%). Compared to MC analysis, additional SNP-A lesions were found in 66% of pts. Of note 39% of the pts had normal karyotypes but with pathologic SNP-A lesions; another 27% had pathologic SNP-A lesions besides the abnormal MC. Serial SNP-A analysis was available in 10 pts who while on rux tx did not develop any additional/new SNP-A lesion. There was no difference in spleen response rates or TSS between those who carried SNP-A lesions versus those who did not. Molecular analysis was possible for 34 pts. The most frequent somatic mutations observed involved JAK2 (70.6%), ASXL1 (24%), CALR (24%), SRSF2 (15%), and U2AF1 (9%). Pts with int-2 and high DIPSS plus scores were more likely to carry at least 1 mutation in any gene compared to pts with int-1 scores (int-2 vs int-1, p=.05; high vs int-1, p=.06). After a median follow-up of 35 months from diagnosis, 95% of the pts were still alive. 3 pts died from disease progression: 1 had a sole SRSF2 mutation, 1 had an SRSF2 plus CALR mutation, and 1 had a TET2 plus TP53 mutation. SRSF2 mutant pts had more severe thrombocytopenia pre-rux tx (91 vs. 203k/μL; p=.04). ASXL1 mutant pts had increased spleen sizes pre-rux (21 vs. 15cm, p=.06), but had similar response post-rux (10 vs. 8cm, p=0.6) compared to the wild-type. SRSR2 mutant pts had higher DIPSS-plus score (4.4 vs. 3; p=.05). Our study showed that MF pts treated with a rux modified dose escalation approach resulted in meaningful clinical and splenic responses regardless of molecular mutation status. Frequently found cryptic SNP-A lesions in MF pts may explain their poorer outcomes compared to pts with other MPNs. The fact that pts did not acquire additional/new SNP-A lesions during rux tx may be one of the mechanisms of improved survival in these pts. ASXL1, CALR, SRSF2 and U2AF1 were the most frequent non-JAK molecular mutations in MF pts treated with rux and were more frequent in high risk pts. Further studies are necessary to elucidate the clinical/ biological effects of these mutations in MF pts treated with rux. Disclosures Tiu: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees.

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TET 2 Alterations in Myeloid Malignancies, Impact on Clinical Characteristics, Outcome, and Disease Predisposition

Blood ◽

10.1182/blood.v126.23.1645.1645 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1645-1645 ◽

Cited By ~ 1

Author(s):

Aziz Nazha ◽

Manja Meggendorfer ◽

Niroshan Nadarajah ◽

Kassy E Kneen ◽

Tomas Radivoyevitch ◽

...

Keyword(s):

Board Of Directors ◽

Somatic Mutations ◽

Catalytic Domain ◽

Germ Line ◽

Hot Spot ◽

Prognostic Impact ◽

Nucleotide Polymorphisms ◽

Advisory Committees ◽

Myeloid Neoplasms ◽

Increased Risk

Abstract TET2 mutations are the most common somatic genetic lesions in myeloid neoplasms. TET2 mutant clones have been found also in healthy individuals, increase with age, and convey an increased risk for myeloid clonal diseases. The TET2 gene is very polymorphic, with hundreds of single nucleotide polymorphisms (SNPs) of unknown clinical impact, but with some variants that may be pathogenically important. Similarly, somatic mutations affect all portions of the gene, and can be missense or truncating, homo-, hemi- and heterozygous. While the majority of TET2 mutations are ancestral, they can also be subclonal, implicating the clonal architecture in the consequences of TET2 lesions. This diversity may be hampering establishment of the clear prognostic impact of TET2 mutations. Taking advantage of a large cohort of patients (pts, N=4985 including 1616 MDS, 871 MDS/MPN, 1782 pAML, 304 sAML, 333 MPN, and 79 therapy-related MDS/AML/MDS-MPN) analyzed by targeted deep sequencing for TET2 and other common myeloid lesions, we examined the distribution and impact of TET2 mutations. DNA sequencing of all coding exons of TET2 and 61 other genes representing the most common somatic mutations in myeloid neoplasms. Nonsynonymous alterations not present in SNP database (dbSNP) were annotated as somatic mutations or SNPs if present in myeloid and T cells whenever available. Nonsynonymous alterations not in dbSNP or ExAC databases and not confirmed to be somatic were excluded. Overall, TET2 somatic mutations (TET2mut) were present in 920 pts (18%); 38% of MDS/MPN, 19% pAML, 16% MPN, 16% sAML, 12% MDS, and 13% of therapy related MDS/AML/MDS-MPN. Mutations included 16% missense, 33% frameshift deletions, 18% frameshift insertions, and 33% nonsense. TET2mut pts were older than those with TET2 wild type (TET2wt, 72 vs. 67 yrs, p<.001), had a higher presenting WBC (6 vs. 4 x103 /uL, p <.001), and lower blast % (3 vs. 7%, p =.03). Similar findings were observed in each myeloid subtype. Overall, median OS for TET2mut pts was similar to TET2wt (12 vs. 17 mo, p =.20). Median OS was similar in TET2mut pts compared to TET2wt in pts with MDS (23 vs. 23 mo, p =.77), MDS/MPN (15 vs. 21 mo, p=.1), pAML (9 vs. 14 mo, p =.77), sAML (6 vs. 9 mo, p =.07), and MPN (30 vs. 35 mo, p =.66). Neither the type of mutation (mis-, nonsense vs. truncating) nor location (catalytic domain vs. other) impacted the OS. Using variant allelic frequencies (VAF), we established a clonal hierarchy in individual cases; 24% of TET2 mutations were ancestral, 17% subclonal, and 59% codominant. TET2 mutations were ancestral in 23% of MDS samples, 29% of MDS/MPN, 25% of pAML, and 19% of sAML. Whether the mutation was ancestral or subclonal did not impact OS. The presence of TET2mut was associated with different mutations in each myeloid subtype. In MDS, TET2mut were associated with APC (p<.001), ASXL1 (p<.001), BCOR (p<.001), BCORL1 (p<.001), ETV6 (p<.04), SUZ12 (p<.001), RAD21 (p<.02), NF1 (p<.001), KDM6A (p<.001), ZRSR2 (p<.001), and U2AF1 (p=.02), in MDS/MPD correlated with ASXL1 (p<.04), NRAS (p<.02), and SRSF2 (p<.05), in pAML with JAK2 (p<.001), RUNX1 (p =.05), and CBL (p=.05), and in sAML with RUNX1 (p<.001), ASXL1 (p<.001), BCORL1 (p=.01), SUZ12 (p=.02), STAG2 (p=.05), and JAK2 (p<.001). When we next focused on germ line variants, we identified 2518 SNPs of TET2. All recurring SNPs were ranked according to the difference in their frequencies between pts and healthy controls. A large number of these SNPs were more common in our pts compared to controls, among them we identified 2 SNPs (both located in the dioxygenase domain) with a significantly higher frequency: SNP1 (OR 10.6, p<.0001), and SNP2 (OR 6.7, p=.02). We further investigated whether these SNPs were mutually exclusive or increased the risk for acquisition of somatic TET2 mutations; 91% of cases with SNP1 and 67% with SNP2 also acquired somatic mutations in TET2. In silico and crystallographic analyses showed that SNP1 is adjacent to the iron binding site (7th beta stand in the jelly roll motif) and is predicted to change the orientation of a-KG binding and thereby to be hypomorphic. SNP2 is located in a hot spot area known to be targeted by 3 recurrent somatic mutations. In conclusion, both somatic mutations as well as germ line variants affect TET2 in myeloid neoplasia. The interaction between clonal mutations and germ line lesions may lead to gain of function and thus a growth advantage. These mechanisms are currently being explored. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

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Clinical Outcomes for Patients with Myeloid Malignancies Harboring IDH1/2mutations after Intensive Chemotherapy

Blood ◽

10.1182/blood-2018-99-119306 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1389-1389 ◽

Cited By ~ 1

Author(s):

Swapna Thota ◽

Bhumika J. Patel ◽

Hetty E. Carraway ◽

Elizabeth A. Griffiths ◽

Amanda Przespolewski ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Response Rate ◽

Intensive Therapy ◽

Response To Therapy ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

The Impact

Abstract Background: AML and MDS are heterogeneous myeloid neoplasias (MN) characterized by varied pathogenic mechanisms and associated with mixed clinical outcome. Five-year overall survival rates for younger AML patients (pts) are between 40-50% and for elderly pts, a dismal 10%. Until recently, molecular information has informed risk stratification for MN patients, but targeted therapies were limited (i.e ckit, flt3 inhibitors). Clinical characterization of IDH1/2mutant MN is of particular interest since the recent availability of specific IDH1/2inhibitors (i.e., enasidenib and ivosidenib). Datasets describing the outcome for patients with MN harboring IDH1/2mutations are critical to inform the potential utility of these novel IDH inhibitors as single agents or in combination with standard of care. Ongoing clinical trials are investigating the addition of IDH inhibition for upfront AML therapy. In this retrospective study, we combined cohorts from three institutions to enable reporting of the largest cohort (N=425) of IDH mutated MN pts in order to establish a baseline for therapeutic outcomes in an era which pre-dates the availability/addition of IDH inhibitors. Methods:We identified 425 patients from three large academic centers with a confirmed diagnosis of IDH1/2mutant AML (n=387), MDS (n=29) or MPN (n=9). Blood and bone marrow samples were analyzed for the presence of recurrent somatic mutations using NGS based multi-gene targeted sequencing panels. Demographic and disease related variables were annotated for initial treatment, response to therapy (IWG criteria) and subsequent survival details (overall survival, progression free survival). Time to first relapse and duration of remission was collected for 107 patients to date. Comprehensive response assessment details were available for 234 patients. Results: Of the 425 patients, 165 had a mutation inIDH1and 264 had a mutation in IDH2(82% IDH2R140, 18% R172K). Four cases had co-occurring mutations in IDH1 & IDH2. IDH1mutant cases were younger than IDH2mutant cases (62 vs. 65 years, p=0.05), predominantly male (50% vs.38%, p=0.01) and more likely to have intermediate risk AML (68% of IDH1/IDH2mutant cases had normal karyotype). A majority of these patients were treated with cytarabine-based intensive chemotherapy (n=362). Hypomethylating agents (n=29) or other less intensive therapies (n= 27) were also used. The overall response rate (ORR) to initial therapy was 65%. Response rates were similar for patients with both IDH1and IDH2mutation (i.e, 66% to any therapy). Response to intensive chemotherapy was 68% and 64% in IDH1and IDH2mutant cases respectively. As expected IDH1/2 mutant younger pts (<60 years) had a higher response rate to intensive chemotherapy (81% and 80 % respectively). The ORR for HMA therapy was 73% (64% IDH1, 80% IDH2mutants). 34% of IDH1mutants and 30%IDH2mutant patients underwent allogeneic stem cell transplantation. We have analyzed the impact of co-occurring somatic mutations on response to intensive chemotherapy. Non-responders to intensive therapy were enriched for RUNX1(26% vs.7%, p=0.002), SRSF2(34% vs.19%, p=0.045), and ASXL1 (18% vs.9%, p=0.11) mutations and were less likely to have NPM1 (24% vs. 51%, p=0.001) mutation. The median overall survival for IDH1 and IDH2 mutant MN caseswas 16.6 and 19.1 months, respectively. Conclusions: IDH1/2 mutated young AML patients appear to have chemo-sensitive disease. Despite excellent initial responses to intensive and non-intensive chemotherapy, the overall survival for IDH mutated pts was poor with shorter than expected remissions. Co-occurring mutations in RUNX1 and SRSF2 appeared to confer therapeutic resistance. Ongoing combination and maintenance strategies with targeted IDH1/2 inhibitors in conjunction with traditional therapies offer the potential to improve upon these outcomes in IDH1/2mutant MN. Future studies exploring the impact of early transplantation on overall survival for IDH1/2mutated MN are needed Disclosures Thota: Incyte: Speakers Bureau. Carraway:Novartis: Speakers Bureau; Jazz: Speakers Bureau; Agios: Consultancy, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; FibroGen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Griffiths:Pfizer, Inc.: Research Funding; Novartis, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Alexion Inc.: Honoraria, Research Funding. Nazha:MEI: Consultancy. Gerds:CTI Biopharma: Consultancy; Apexx Oncology: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Wang:Amgen: Consultancy; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Amgen: Consultancy; Pfizer: 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. Maciejewski:Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Somatic Mutations in MDS Patients Are Associated with Clinical Features and Predict Prognosis Independent of the IPSS-R: Analysis of Combined Datasets from the International Working Group for Prognosis in MDS-Molecular Committee

Blood ◽

10.1182/blood.v126.23.907.907 ◽

2015 ◽

Vol 126 (23) ◽

pp. 907-907 ◽

Cited By ~ 57

Author(s):

Rafael Bejar ◽

Elli Papaemmanuil ◽

Torsten Haferlach ◽

Guillermo Garcia-Manero ◽

Jaroslaw P. Maciejewski ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Prognostic Significance ◽

Risk Groups ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background Somatic mutations identified in patients with myelodysplastic syndromes (MDS) are associated with disease features and carry prognostic information independent of the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). Risk models that include mutation information have been proposed, but not widely adopted. In practice, there is no consensus on how to best combine clinical information with tumor sequencing data to predict prognosis. To accomplish this, we must define the relevant genes to consider and accurately measure their prognostic impact. Here we examine the relationship between mutations in MDS-associated genes and clinically relevant measures, including overall survival, in a large, multi-center analysis of MDS patient cohorts collected around the globe. Methods Data on 3392 MDS patients gathered by members of the International Working Group for Prognosis in MDS-Molecular Committee were combined under the aegis of the MDS Foundation. Patients gave informed consent for collection of their data and tumor samples at their respective institutions in accordance with the Declaration of Helsinki. Samples were examined for somatic mutations primarily by next generation sequencing. Categorical variables were compared using a chi-squared test, while continuous variables were compared using a Wilcoxon rank-sum test. Overall survival (OS) was calculated from the date of the sequenced sample to the date of death and was censored at transplant or the last known follow-up time. P-values are two-sided and considered significant at the <0.001 level to adjust for multiple comparisons. Results Survival data were available for 3200 patients with a median follow up of 3.7 years and included 1671 deaths. Median survival of the cohort was 2.88 years. The 27 genes sequenced in at least half of the cohort and mutated in > 1.5% of samples were included for analysis (Figure 1). Mutations in 12 genes were strongly associated with shorter OS in univariate analyses (p<0.001 for each gene): ASXL1, CBL, EZH2, IDH2, NF1, NRAS, PTPN11, RUNX1, SRSF2, STAG2, TP53, and U2AF1. Only mutations of SF3B1 were associated with a longer OS at this significance threshold. The large size of the cohort allowed for more precise estimates of survival in less frequently mutated genes. For example, mutations of IDH2 (present in 3.4% of cases, n=103) were associated with shorter OS (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.26-2.05; p=0.0001) whereas IDH1 mutations (present in 2.4% of cases, n=77) were only marginal (HR 1.29, CI: 0.97-1.72; p=0.082), demonstrating the distinct impact of mutations in these highly related genes. IPSS-R risk groups could be determined for 2173 patients and were strongly associated with OS. Adjusting the hazard ratio of death for IPSS-R risk groups identified several mutated genes with independent prognostic significance: TP53 (HR 2.37, CI 1.94-2.90), CBL (HR 1.57, CI 1.22-2.03), EZH2 (HR 1.55, CI 1.22-2.03), and RUNX1 (HR 1.50, CI 1.24-1.83). Mutations of U2AF1 (HR 1.29, CI 1.06-1.58) and ASXL1 (HR 1.21, CI 1.04-1.41) retained a more modest association with shorter OS. Adjustment for IPSS-R risk groups also moderated the favorable risk associated with mutations of SF3B1 (HR 0.83, CI 0.70-0.99). Patients without mutations in any of the 6 adverse genes above represented 58% of the fully sequenced cohort and had a longer median survival than patients with adverse mutations (4.8 years vs. 1.6 years respectively, p < 0.0001; Figure 2) even after correction for IPSS-R risk groups (adjusted HR 0.59, CI 0.51-0.67). Multivariable analysis of this dataset will examine the combined contribution of mutated genes to prognosis. A mutation score based on survival risk will be proposed and internally validated. The impact of somatic mutation in patients traditionally considered lower risk will be explored. Conclusions This large study definitively validates the prognostic value of mutations in several MDS-associated genes while clarifying the significance of other, less frequently mutated ones. Mutations in several genes retain their prognostic significance after adjustment for IPSS-R risk groups, indicating that these select abnormalities could refine the prediction of prognosis when incorporated into a clinical scoring system such as the IPSS-RM. The results of this analysis will serve as the template with which to build an integrated molecular risk model for MDS. Disclosures Bejar: Alexion: Other: ad hoc advisory board; Celgene: Consultancy, Honoraria; Genoptix Medical Laboratory: Consultancy, Honoraria, Patents & Royalties: MDS prognostic gene signature. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Shih:Novartis: Research Funding. Komrokji:Celgene: Consultancy, Research Funding; Incyte: Consultancy; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau. List:Celgene Corporation: Honoraria, Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Campbell:14M genomics: Other: Co-founder and consultant. Ebert:Celgene: Consultancy; Genoptix: Consultancy, Patents & Royalties; H3 Biomedicine: Consultancy.

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Prevalence and prognostic impact of somatic mutations in patients with heart failure and reduced ejection fraction

European Heart Journal ◽

10.1093/ehjci/ehaa946.0966 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

D.J Vazquez Andres ◽

A Hernandez Vicente ◽

M Diez Diez ◽

M Gomez Molina ◽

A Quintas ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Somatic Mutations ◽

Myocardial Dysfunction ◽

Study Endpoint ◽

Prognostic Impact ◽

Reduced Ejection Fraction ◽

Increased Risk ◽

Patients With Heart Failure

Abstract Introduction Somatic mutations in hematopoietic cells are associated with age and have been associated with higher mortality in apparently healthy adults, especially due to atherosclerotic disease. In animal models, somatic mutations are associated with atherosclerosis progression and myocardial dysfunction, especially when gene TET2 is affected. Preliminary clinical data, referred to ischemic heart failure (HF), have associate the presence of these acquired mutations with impaired prognosis. Purpose To study the prevalence of somatic mutations in patients with heart failure with reduced ejection fraction (HFrEF) and their impact on long-term prognosis. Methods We studied a cohort of elderly patients (more than 60 years old) hospitalized with HFrEF (LVEF<45%). The presence of somatic mutations was assessed using next generation sequencing (Illumina HiSeq 2500), with a mutated allelic fraction of at least 2% and a panel of 55 genes related with clonal hematopoiesis. Patients were followed-up for a median of three years. The study endpoint was a composite of death or readmission for worsening HF. Kaplan-Meier analysis (log-rank test) and Cox proportional hazards regression models were performed adjusting for age, sex and LVEF. Results A total of 62 patients (46 males (74.2%), age 74±7.5 years) with HFrEF (LVEF 29.7±7.8%) were enrolled in the study. The ischemic etiology was present in 54% of patients. Somatic mutations in Dnmt3a or Tet2 were present in 11 patients (17.7%). No differences existed in baseline characteristics except for a higher prevalence of atrial fibrillation in patients with somatic mutations (70% vs. 40%, p=0.007). During the follow-up period, 40 patients (64.5%) died and 38 (61.3%) had HF re-admission. The KM survival analysis for the combined event is shown in Figure 1. Compared with patients without somatic mutations and after adjusting for covariates, there was an increased risk of adverse outcomes when the somatic mutations were present (HR 3.6, 95% CI [1.6, 7.8], p=0.0014). This results remains considering death as a competing risk (Gray's test p=0.0097) and adjusting for covariates (HR = 2.21 95% CI [0.98, 5], p=0.0556). Conclusions Somatic mutation are present in patients with HFrEF and determine a higher risk of adverse events in the follow-up. Further studies are needed to assess the clinical implications of these findings. Figure 1 Funding Acknowledgement Type of funding source: None

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Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-116496 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2149-2149

Author(s):

Romil Patel ◽

Neeraj Y Saini ◽

Ankur Varma ◽

Omar Hasan ◽

Qaiser Bashir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees ◽

First Remission ◽

Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

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Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-134237 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-14

Author(s):

Alexander Coltoff ◽

Joseph G. Jurcic ◽

Peter Campbell ◽

Daniel J. Lee ◽

Mark L Heaney ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Median Overall Survival ◽

Residual Disease ◽

Institutional Research ◽

Negative Group ◽

Advisory Committees ◽

Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis: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;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

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Effectiveness of Reduced Toxicity Conditioning Regimen with Intravenous Busulfan Plus Pentostatin (BUPENT) in Patients Older Than 50 Years with Advanced Hematologic Malignancies.

Blood ◽

10.1182/blood.v114.22.3331.3331 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3331-3331

Author(s):

Tulio E. Rodriguez ◽

Mala Parthasarathy ◽

Scott E. Smith ◽

David H. Vesole ◽

Zachary M. Earley ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Graft Failure ◽

Conditioning Regimen ◽

Advisory Committees ◽

Reduced Toxicity

Abstract Abstract 3331 Poster Board III-219 Introduction Current data suggests that recipient age above 50 is associated with an inferior outcome after myeloablative allogeneic stem cell transplantation (SCT). Overall survival (OS) of 31%, and transplant related mortality (TRM) of 17% at 100 days have been reported in this population (Ditchkowski, et al 2005; Yanada, et al. 2004). Encouraging results are observed with non-myeloablative conditioning regimens. However, for patients with a high relapse risk, this approach may not be sufficient to achieve long term disease control. In these cases, a reduced toxicity, yet ablative stem cell transplantation (RT-SCT) may give adequate time to the transplanted cells to mature and mount an immune-mediated antitumor response. This study evaluated the outcome after RT-SCT using a conditioning regimen consisting of intravenous busulfan (Bu) and pentostatin (Pent). Methods Consented adult patients up to 70 years with a fully-matched related (MRD) or unrelated donor (MUD) were screened for enrollment. Conditioning consisted of Bu 1.6 mg/kg every 12 hours days -7 to -4, and Pent 4 mg/m2 on day -3 and -2 prior to stem cell infusion on day 0. GVHD prophylaxis was methotrexate 10 mg/m2 on day 1, and 5 mg/m2 on days 3, and 6. Tacrolimus was started on day -2, and then tapered over 1 month after day +100. Characteristics Twenty six patients were analyzed. Male to female ratio was 1:1. Stem cell source was from MRD in 15 patients and MUD in 11. Median age was 62, with 92% of patients being older than 50 years. Indications for treatment were AML (35%), MDS (42%), Refractory CLL (23%), Relapsed NHL (12%), and Philadelphia (+) ALL (4%). All AML patients were high risk either due to poor cytogenetic, transformation, or relapse and only two of them were transplanted in first complete remission. MDS patients were RAEB (36%), secondary MDS (36%), or multilineage dysplasia (18%). Two patients had prior autologous transplants. Results No graft failure was observed. All patients achieved neutrophil (NEU) engraftment. Two patients expired prior to platelet (PLT) engraftment. Median engraftment days for NEU and PLT were 13 days. At a median follow up of 25 months, the OS and progression free survival for the entire group was 40% and 38% respectively. The OS in the MRD group was 58%. TRM at 100 days was seen in one patient (4%) due to veno-occlusive disease (VOD). Limited chronic GVHD was the most common observed toxicity (54%), followed by diarrhea (30%) and mucositis (23%). Mucositis was mainly grade 1 (8%) and grade 2 (8%). No grade 3 mucositis was observed. There was only one case of VOD and one case of acute GVHD. Conclusion To our knowledge, this is the first report of a RT-SCT using BuPent. This study demonstrates the efficacy of the regimen in patients older than 50 years. No graft failure was observed and the regimen related toxicity was acceptable in this high-risk population. The overall survival of 40% at a median follow up of 25 months compares favorably with prior reports of myeloablative allogeneic stem cell transplatation in patients older than 50 years. This regimen provides an exciting opportunity to extend the benefits of allogenic transplant to an older population, and warrants replication with larger controlled trials. Disclosures Rodriguez: Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vesole:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Millenium: Speakers Bureau; Centocor Ortho Biotech: Speakers Bureau.

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Long-Term Clinical Outcome of Patients with Acquired Aplastic Anemia In Brazil Using Cyclosporine-A (CSA) and Prednisone (PRED): 20 Years Follow-up From a Single Institution

Blood ◽

10.1182/blood.v116.21.2234.2234 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2234-2234

Author(s):

Larissa A Medeiros ◽

Samir K Nabhan ◽

Marco Antonio Bitencourt ◽

Michel M. Oliveira ◽

Vaneuza A M Funke ◽

...

Keyword(s):

Quality Of Life ◽

Overall Survival ◽

Aplastic Anemia ◽

Immunosuppressive Therapy ◽

Board Of Directors ◽

Clonal Evolution ◽

Severe Aplastic Anemia ◽

Advisory Committees

Abstract Abstract 2234 Introduction/Background: Immunosuppressive therapy is the best alternative for patients with severe aplastic anemia (SAA) without matched sibling donor or with age > 40 years. Since 1988, an alternative protocol was developed with cyclosporine (CSA) and prednisone (PRED) due to irregularity in distribution of anti-thymocyte globulin (ATG) in Brazil. This study aims to show the results of this treatment on the quality of response, overall survival and development of clonal evolution. Materials and methods: 384 patients diagnosed with SAA (Camitta and Bacigalupo criteria) were evaluable by medical records review from 12/1988 to 12/2008. The immunosuppressive therapy consisted of CSA: 12mg/kg/day BID from day (D)1- D8, then 7mg/kg/day BID until 1 year. After that CSA was progressively tapered (5% each month) and ultimately stopped usually by two years. CSA levels were kept between 200–400ng/ml. PRED: 2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on PRED dose was tapered 20% each week. Sulfamethoxazole-trimethoprim and fluconazole were used for prophylaxis against Pneumocystis jiroveci (P carinni) and fungal diseases, respectively. Treatment response was defined as Table 1. Treatment evaluation was performed at 6 weeks, 3, 6 and 12 months and then yearly. At diagnosis: median age was 21 years (2-75), disease duration 95 days (2-4749), and median number of transfusions were 12 (0-200). Etiology was idiopathic in 78%. In peripheral blood, median hemoglobin was 7.4g/dL, granulocytes 580/uL, platelets 12.000/uL and reticulocyte 0.5% (corrected value). 60% of the patients had not been treated previously. Results: Overall survival was 61% ± 3 with a median follow-up of 7 years (range: 2 months - 23 years). Response to treatment: 51% had some degree of response, with good quality of life and transfusions independent (143 patients with complete response and 53 partial response). 36 patients had no response and there were 96 deaths. Fifty six patients have lost follow-up. Most patients achieved response between 3 and 6 months of therapy. In multivariate analysis the number of neutrophils ≥ 200/uL (p = 0.009), platelets ≥ 12.000/uL (p = 0.018), reticulocyte ≥ 0.5% (p <0.001) and starting treatment after 1997 (p = 0.002) had an impact on overall survival. Patients with 15 or more previous transfusions (p = 0.006) and age ≥ 40 years (p = 0.003) had lower survival. Overall survival was 63% ± 4 and 42% ± 6 for for patients with severe disease and very severe aplastic anemia (p <0.001). The subgroup analysis of patients under 10 years old had similar results. Among patients with response, thirty-four remained dependent of CSA. Cumulative incidence of relapse was 28% ± 4 within a median of 4.4 years. Hypertension, gingival hypertrophy and diabetes mellitus were common, but easily controlled. The rate of clonal evolution among this cohort was 7.81% (16 patients developed Paroxysmal Nocturnal Hemoglobinuria, 9 Myelodysplastic Syndrome and 5 Acute Myeloid Leukemia). Conclusion: This study, with a long follow-up, has demonstrated that the overall survival using CSA and PRED is similar to that reported with ATG therapy. Even patients with partial responses had achieved good quality of life, free from transfusions and infections. Survival was influenced by the neutrophils, platelet counts, reticulocyte, number of transfusions, age at diagnosis, and therapy started after 1997. The incidence of clonal evolution was lower when compared to reported trials with ATG + CSA. Disclosures: Oliveira: Alexion: Speakers Bureau. Funke: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pasquini: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I

Blood ◽

10.1182/blood.v118.21.278.278 ◽

2011 ◽

Vol 118 (21) ◽

pp. 278-278 ◽

Cited By ~ 8

Author(s):

Srdan Verstovsek ◽

Ruben A. Mesa ◽

Jason Gotlib ◽

Richard S. Levy ◽

Vikas Gupta ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Symptom Severity ◽

Research Funding ◽

Risk Group ◽

Spleen Volume ◽

Advisory Committees ◽

Disease Subtype ◽

Baseline Hemoglobin

Abstract Abstract 278 Background: Overactive JAK-STAT signaling as a result of gain-of-function mutations (eg, JAK2V617F) and/or high circulating levels of inflammatory cytokines is considered to play a key role in the pathogenesis of myeloproliferative neoplasms. Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, demonstrated a significant reduction in spleen volume (SV) and improvements in myelofibrosis (MF)-related symptoms in a double-blind placebo-controlled trial (COMFORT-I). The objective of this analysis was to evaluate the efficacy of ruxolitinib across patient (pt) subgroups in COMFORT-I. Methods: Pts with MF were randomized to start placebo or ruxolitinib at a dose of 15 mg or 20 mg PO BID depending on baseline platelet count (100–200 ×109/L or >200 ×109/L, respectively). The dose was optimized for efficacy and safety during treatment. SV change was measured by MRI; MF symptoms were assessed using a daily diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0) over 1 wk prior to dosing and throughout the 24 wks of dosing. The percent changes from baseline to wk 24 in SV and MFSAF Total Symptom Score (TSS, a measure of combined scores for abdominal discomfort, pain under ribs on left side, early satiety, itching, night sweats, and bone/muscle pain) were compared for ruxolitinib and placebo pts across the following subgroups: MF disease subtype, age, International Prognosis Scoring System (IPSS) risk group, presence/absence of JAK2V617F mutation, baseline hemoglobin, baseline spleen size (palpable spleen length), and baseline TSS. Survival was estimated by Kaplan-Meier method. Changes in SV and TSS Across Subgroups: 309 pts were randomized: 155 to ruxolitinib and 154 to placebo. Ruxolitinib demonstrated consistent benefit compared with placebo in both SV and TSS across all subgroups evaluated (Table). The impact of symptom severity on response was evaluated by baseline TSS quartiles (maximum score for TSS = 60). Ruxolitinib pts with baseline TSS of <8.5, 8.5-<16.5, 16.5-<25.5 and ≥25.5 had mean percent changes in SV of −28.0, −31.4, −31.7 and −34.8, respectively, vs +8.1 for all placebo pts combined. The mean percent change in TSS for these same subgroups was −40.5, −47.2, −48.1 and −48.2 vs +41.8 for all placebo pts combined. These data indicate that pts with modest to marked symptoms all benefit from ruxolitinib therapy in terms of both SV and TSS. Survival Analysis: 13 ruxolitinib and 24 placebo pts died during the study or during extended follow-up (median follow-up of 52 and 51 wks, respectively), representing a hazard ratio (95% CI) of 0.499 (0.254, 0.98) (p=0.0395). For ruxolitinib- and placebo-treated pts, respectively, the probability of survival (95% CI) >48 wks was 0.98 (0.92, 0.99) and 0.90 (0.81, 0.95) for pts with baseline hemoglobin values ≥10 g/dL and 0.84 (0.72, 0.91) and 0.77 (0.63, 0.86) for pts with baseline hemoglobin <10 g/dL. Conclusions: Pts receiving ruxolitinib had higher response rates than placebo based on reductions in SV and improvements in TSS at wk 24 regardless of baseline subgroup: MF disease subtype, age (≤65 or >65 y), IPSS risk group (intermediate-2 or high-risk), presence or absence of JAK2V617F mutation, hemoglobin level (≥10 g/dL or <10 g/dL), palpable spleen length (≤10 cm or >10 cm), and symptom severity (TSS quartile). In addition, the overall survival analysis suggested a benefit with ruxolitinib therapy over placebo. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, 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. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: 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; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Alexion: Consultancy, Honoraria; Telik: Research Funding; Incyte: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

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