Mutational Type and Configuration of an Individual Gene May Differentially Impact the Clinical and Phenotypic Features

Myelodysplastic syndromes (MDS) arise in older adults through the stepwise acquisition of multiple somatic mutations. The genetic heterogeneity that results includes mutations of diverse genes and their combinations, clonal hierarchy, genetic configuration (e.g., bi-allelic or compound heterozygous, hemizygous lesions), specific positions within a gene including canonical hotspots vs. other positions, and types of mutation (truncations vs. missense), all of which could differentially affect pathogenesis. Given the binary status (e.g. mutated vs. wild-type) used in many clinical analyses, the true impact of specific types of mutations may be obscured and their specific roles underestimated. Deep targeted NGS was carried out for a panel of the 36 most frequently mutated genes in 1,809 MDS patients (low-risk MDS (n=839) vs. high-risk MDS (n=607), MDS/MPN (n=212), and sAML n=151). Copy number alterations (CNA) were also evaluated by combining karyotyping, microarray, and digital copy number analysis. With a mean coverage of 862x, after removing SNPs and errors, 3,971 somatic mutations were identified, the most common (>10% of cases) being TET2, SF3B1, ASXL1, del(5q), SRSF2, complex karyotype, and del(7q). For the purpose of this proof of concept analysis we focused on illustrative genes (TP53, RUNX1, TET2, and EZH2) affected by 2 recurrent hits. Bi-allelic TET2 or TP53 mutations were found in 15% (271/1,809) and 4% (72/1,809) of patients, respectively. TET2 and RUNX1 were most likely biallelic, whereas TP53 and EZH2 were most often affected by mutations and somatic deletion. Comparing the distribution of canonical vs. other types of mutations in genes, DNMT3A mutations affected the canonical site (R882) in 17% (35/203) of patients, were truncating in 39% (79/203) and missense in 44% (89/203) have also been found; deletions affecting the DNMT3A locus are rare. Within U2AF1, U2AF1Q157 are more frequent than U2AF1S34 (54% vs. 35%). Next, we checked correlation between these different types of mutations of one gene. 78 significant combinations were found. For instance, U2AF1Q157 mutations more commonly accompanied ASXL1 mutations and del(7q) and less frequently DNMT3A and BCOR mutations, trisomy8 and del(20) when compared to U2AF1S34 mutations [ASXL1 mutations 53% (42/80) in U2AF1Q157 vs. 16% (8/49) in U2AF1S34, P < .0001]. TET2 Bi-allelic mutations were more commonly associated with ZRSR2 and SRSF2 mutations, and less frequently del(5q) when compared to TET2 mono-allelic mutations [SRSF2 mutations 29% (80/276) in TET2-bi vs. 15% (34/227) in TET2-mono, P = .003]. In addition, patients with SRSF2 missense mutations were more likely to have RUNX1 bi-allelic mutations than those with SRSF2 in-frame mutations. We evaluated the impact of different types of mutations and combinations of them on disease phenotypes and survival. We then evaluated the impact of different types of mutations and their combinations on clinical phenotypes including dichotomous morphological (MDS vs. MDS/MPN) features, progressive (low- vs. high risk) subtypes. EZH2 bi-allelic alterations were more commonly associated with myleoproliferative features` compared to EZH2 mono-allelic alteration (q=.016). TET2 bi-allelic alterations and truncating mutations were found more frequently in higher-risk subtypes than TET2 mono-allelic and missense mutations (q<.001). In survival analyses, patients with DNMT3AR882 mutations had a poorer prognosis than those with truncating and the other missense mutations [P = .033, HR 1.86 (1.05-3.3)]. Next, using the PyClone bioanalytic pipeline, we recapitulated for each patient the clonal hierarchy and defined "dominant" vs. "secondary" mutations. DNMT3AR882 mutations were likely to be dominant/founder lesions compared to truncating or the other missense mutations: 77% (27/35) for R882 vs. 51% (40/79) for truncating vs. 45% (47/98) for the other missense, p=.0046. Specific dominant and secondary mutational pairs also differentially affected survival compared to the reverse configuration (q<.1) including EZH2 and RUNX1 or BCOR and U2AF1 or RUNX1 and BCOR. In conclusion, we report a comprehensive analysis of various types and configurations of lesions of individual commonly affected genes. Our results indicate that establishment of clinical or phenotypic correlations requires consideration of the type, rank and configuration of somatic mutations. Disclosures Mukherjee: McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy. Nazha:Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ogawa:Asahi Genomics: Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Qiagen Corporation: Patents & Royalties; RegCell Corporation: Equity Ownership; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Kan Research Laboratory, Inc.: Consultancy. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.

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Invariant Patterns of Clonal Succession Determines Specific Phenotypic and Clinical Features of Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood-2018-99-118861 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 104-104

Author(s):

Yasunobu Nagata ◽

Hideki Makishima ◽

Tetsuichi Yoshizato ◽

Hiromichi Suzuki ◽

Cassandra M. Hirsch ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Features ◽

Copy Number ◽

De Novo ◽

Hot Spot ◽

Missense Mutations ◽

Advisory Committees ◽

Targeted Ngs ◽

Different Types ◽

The Impact

Abstract MDS arises through stepwise acquisitions of multiple mutations. Mutation configuration (bi-allelic vs. mono-allelic), specific distributions (hot spot), timing of acquisitions/ranks within clonal hierarchies, and combinatorial spectra, can all affect the pathogenesis and clinical phenotype of this disease. We performed integrative analyses of these processes to determine which relationships are deterministic vs. random. We analyzed 1,809 clinically annotated MDS patients. Deep targeted NGS was applied to a panel of the 36 genes frequently mutated in myeloid neoplasms. Copy number alterations (CNA) were evaluated by combining karyotyping, microarray, and digital CNA analysis. With a mean coverage of 862x, after removing SNPs and errors, we identified 3,971 somatic mutations. Frequently mutated genes/CNAs were TET2 (27%), SF3B1 (23%), ASXL1 (19%), del(5q) (16%), SRSF2 (14%), DNMT3A (11%) and del(7q) (10%), each present in >10% of cases. DNMT3AMT affected the canonical site (R882) in 17% (35/203) of DNMT3AMT cases, were truncating in 39% (79/203) and were other missense mutations in 44% (89/203). Bi-allelic alterations of EZH2 and TP53 most commonly involved a mutation paired with a copy number deletion or UPD. In contrast, RUNX1 and TET2 commonly involved multiple mutations of the gene. Examining intragenetic relationships, we assumed that the impact of individual mutations depends on their clonal hierarchical position. To discriminate 1st hits ("dominant") from subsequent "secondary mutations", we used a stringent binominal distribution algorithm to compare the expected vs. observed VAFs using read counts (Figure 1). A mutation with the largest VAF in a sample was defined as "dominant". Mutations with overlapping 95% CI of expected VAFs were "co-dominant", and those with non-overlapping 95% CIs were "secondary". These assumptions were validated by Pyclone (concordance rate > 95%). Accordingly, 1,474 (36%) and 1,372 (35%) mutations were dominant and secondary, respectively. SF3B1, DNMT3A, U2AF1, and TP53 were more likely to be dominant, ASXL1, CBL, ETV6, and KRAS were more likely to be secondary. For example, SF3B1 mutations were dominant in 17% (303/1809) of patients and secondary in 2% (39/1,809), p<.0001, q<.01. 78 common combinations were identified among these different types of mutations. For instance, compared to U2AF1S34 mutations, U2AF1Q157 mutations were more associated with ASXL1 mutations and del(7q), and less with DNMT3A and BCOR mutations (p<.01). Compared to TET2 mono-allelic mutations, TET2 bi-allelic mutations co-existed more with ZRSR2 and SRSF2 mutations, but less with del(5q). DNMT3AR882 mutations at 77% (27/35) were more likely to be dominant than truncating or other missense DNMT3A mutations at 51% (40/79) and 45% (47/98), p=.0046, q=.07. We also evaluated the impact of different types of mutations and their combinations on disease phenotypes and survival. Many relationships were identified between mutations in different genes and bi-allelic vs. mono allelic hits. Among frequently correlated dominant/secondary pairs, pairs of dominant EZH2 mutations and secondary RUNX1 or ASXL1 mutations were associated with higher-risk subtypes (q=.08) (Figure 2), whereas patients with dominant SF3B1 mutations and secondary JAK2 mutations had myeloproliferative features and lower-risk subtypes (q<.001; q=.09). DNMT3AR882 mutations associated with worse overall survival than did truncating and other missense DNMT3A mutations. Five pairs of dominant and secondary mutations significantly affected survival (p<.01, q<.1). We hypothesized that if a fraction of MDS originates from clonal hematopoiesis of indeterminate potential (CHIP), the compositions of dominant mutations in MDS should be similar to those in CHIP. MDS patients with dominant mutations of TET2, DNMT3A, and ASXL1 were defined as "CHIP-derived MDS" and had more secondary TET2 and ZRSR2 mutations than "De novo MDS". In conclusion, we report a comprehensive analysis of various mutational scenarios and the resultant clinical features. Most significantly, our results demonstrate how invariant patterns of evolution evolve with certain dominant hits dictating high probabilities of specific secondary events. Such patterns coincide with unique combinations of clinical properties that arise with hits along specific pathways. Disclosures Nazha: MEI: 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. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy.

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Variation in Health-Related Quality of Life by ECOG Performance Status and Fatigue Among Patients with Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v118.21.4591.4591 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4591-4591 ◽

Cited By ~ 1

Author(s):

Chris L. Pashos ◽

Christopher R Flowers ◽

Mark Weiss ◽

Nicole Lamanna ◽

Charles M Farber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Clinical Practices ◽

Employment Equity ◽

Ecog Performance Status ◽

Advisory Committees ◽

Equity Ownership ◽

Ecog Ps ◽

The Impact

Abstract Abstract 4591 Introduction: Clinicians and investigators appreciate the value of measuring HRQOL for monitoring CLL and the impact of treatments, and commonly use ECOG performance status (PS) and clinician-reported patient fatigue as surrogates for HRQOL in clinical practice. However, limited data exist on the relationships between PS, fatigue, and HRQOL in CLL patients (pts) undergoing treatment in clinical practices. We examined the associations between these measures and 3 psychometrically validated, patient-reported, HRQOL instruments: the Brief Fatigue Inventory (BFI), EQ-5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Methods: Data were collected as part of Connect CLL®, a prospective observational registry initiated in March 2010 involving US practices. Data on pt demographics and clinical characteristics were provided by clinicians. HRQOL was self-reported by pts at enrollment using the BFI, EQ-5D, and FACT-Leu. Mean BFI, EQ-5D and FACT-Leu scores were analyzed by ECOG PS and clinician-reported fatigue. Differences in HRQOL scores between sub-cohorts were assessed by ANOVA. Results: HRQOL data were reported by 604 pts enrolled from 10 academic, 148 community, and 3 government centers. Pts were predominantly male (62%) and white (90%); mean age was 70 (standard deviation 11) years. BFI data (scale: 0 [no fatigue] - 10 [worst fatigue]) indicated that on average pts report that global fatigue, fatigue severity and fatigue-related interference worsen by ECOG severity (Table 1) and are statistically associated with clinician-reported fatigue (Table 2). Mean EQ-5D overall HRQOL as measured by a Visual Analogue Scale (VAS) from 0 (worst) to 100 (best) worsens by ECOG severity and is significantly worse in pts with fatigue. Mean EQ-5D domain scores (scale: 1 [no problem], 2 [some problems], 3 [incapacity]) indicated that pain/discomfort, mobility and usual activities increase in severity as ECOG worsens and in pts with fatigue. FACT-Leu domains except social/family were statistically worse with worse ECOG PS and in pts with fatigue. Conclusions: Initial results from Connect CLL® indicate that HRQOL worsens with worsening ECOG PS, especially in physical / functioning domains, pain/discomfort, and mobility, and worsens across multiple domains among pts whose physicians reported fatigue. Future analyses should be conducted on how HRQOL, PS and fatigue may change over time with changes in CLL, and how they are influenced by therapies. These results may serve as baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech/Roche (unpaid): Consultancy; Celgene: Consultancy; Millennium/Takeda: Research Funding; Wyeth: Research Funding; Novartis: Research Funding. Weiss:Celgene: Membership on an entity's Board of Directors or advisory committees. Lamanna:Celgene: Membership on an entity's Board of Directors or advisory committees. Farber:Celgene: Membership on an entity's Board of Directors or advisory committees. Kipps:Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Lerner:Celgene: Membership on an entity's Board of Directors or advisory committees. Kay:Celgene: Membership on an entity's Board of Directors or advisory committees. Sharman:Celgene: Membership on an entity's Board of Directors or advisory committees. Grinblatt:Celgene: Membership on an entity's Board of Directors or advisory committees. Flinn:Celgene: Membership on an entity's Board of Directors or advisory committees. Kozloff:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Kahn:Celgene Corporation: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Keating:Celgene: Membership on an entity's Board of Directors or advisory committees.

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Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽

10.1182/blood-2019-127435 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4248-4248 ◽

Cited By ~ 1

Author(s):

Uwe Platzbecker ◽

David P. Steensma ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: 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; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Colony Stimulating Factor 1 Receptor (CSF1R) As a Potential Novel Therapeutic Target in CLL

Blood ◽

10.1182/blood.v126.23.4439.4439 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4439-4439

Author(s):

Tyler Sweeney ◽

Stephen E Spurgeon ◽

Jeffrey W. Tyner ◽

Anupriya Agarwal ◽

Hibery Ho ◽

...

Keyword(s):

Cell Viability ◽

Board Of Directors ◽

Solid Tumor ◽

Therapeutic Target ◽

Research Funding ◽

Ex Vivo ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Macrophage Lineage

Abstract Introduction: Monocyte/macrophage lineage cells have been reported to provide a supportive signal in a variety of neoplastic settings. Tumor-associated macrophages (TAMs) have been shown to provide microenvironmental support that maintains tumor cell viability and growth for a variety of solid tumor types, and these TAMs have been shown to depend on the receptor tyrosine kinase, CSF1R (M-CSFR). Monocyte/macrophage lineage cells have also been implicated in the microenvironment of CLL and are termed nurse-like cells in this setting. However, the role of CSF1R in CLL including potential maintenance of these nurse-like cells has not been explored. Using an ex vivo, functional screening platform applied directly to primary specimens from CLL patients, we have identified recurrent sensitivity to CSF1R inhibitors as well as decreased viability after depletion of CSF1R-expressing monocytes, thereby depriving the CLL cells of an important, microenvironmental growth/survival signal. We also have seen synergistic anti-tumor activity when combining CSF1R inhibitors with idelaisib and ibrutinib which inhibit b-cell receptor (BCR) activated pathways. Methods: We evaluated the impact on cell viability of hundreds of CLL patient specimens against panels of targeted small molecule inhibitors. These panels include two small-molecules with exquisite specificity for CSF1R (GW-2580; ARRY-382). In addition, we evaluated the impact of antibody depletion of monocytes (CD14-depletion) on ex vivo CLL cell viability as well as the effect of monocyte cell depletion on response to CSF1R inhibitors. We also evaluated the combination of GW-2580 or ARRY-382 with idelalisib (PI3kδ inhibitor) and ibrutinib (BTK inhibitor). Results: We found that 20-30% of CLL specimens showed sensitivity to inhibition of CSF1R with good concordance between GW-2580 and ARRY-382. Analysis of clinical and demographic features of these patients failed to reveal correlation of CSF1R with any prominent disease subsets. Flow cytometry analysis revealed that CSF1R was not expressed on CLL cells but only on a subpopulation of CD14-expressing monocytes. Depletion of these monocytes with CD14 antibody had little to no impact on samples not exhibiting ex vivo sensitivity to CSF1R inhibitors, however, samples showing strong sensitivity to CSF1R inhibitors were also quite sensitive to depletion of this CD14-positive monocyte population. After CD14 depletion, the remaining CLL cells showed no further sensitivity to CSF1R inhibitors. Finally, when combined with ibrutinib or idelalisib synergy was seen. Conclusions: These results show that CSF1R is a potential therapeutic target in CLL and suggest that CLL supporting monocytes (nurse-like cells) express CSF1R and depend on CSF1R for viability in a similar manner as TAMs depend on CSF1R in a variety of solid tumor settings. As such, CSF1R inhibitors may deprive CLL cells of this supportive microenvironmental signal resulting in CLL cell death. Therefore, we propose that CSF1R inhibitors, such as ARRY-382, possibly in combination with ibrutinib, idelalisib, or other approved agents, may be a promising new line of therapy to target CLL cells by impacting the tumor microenvironment. Disclosures Spurgeon: Genentech: Honoraria; Acerta Pharma: Research Funding; Bristol Meyers Squibb: Research Funding; Gilead sciences: Honoraria, Research Funding; Janssen: Research Funding; Pharmacyclics: Honoraria. Tyner:Janssen Pharmaceuticals: Research Funding; Incyte: Research Funding; Aptose Biosciences: Research Funding; Constellation Pharmaceuticals: Research Funding; Array Biopharma: Research Funding. Agarwal:CTI BioPharma: Research Funding. Lee:Array Biopharma: Employment. Chantry:Array Biopharma: Employment. Druker:Fred Hutchinson Cancer Research Center: Research Funding; Bristol-Myers Squibb: Research Funding; Henry Stewart Talks: Patents & Royalties; Millipore: Patents & Royalties; Sage Bionetworks: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis Pharmaceuticals: Research Funding; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncotide Pharmaceuticals: Research Funding; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; ARIAD: Research Funding; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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The Impact of Allogeneic Hematopoietic Cell Transplantation (alloHCT) on the Outcome of Poor-Risk Non-Hodgkin Lymphoma (NHL): A Retrospective Intent-to-Transplant (ITT) Analysis

Blood ◽

10.1182/blood-2019-128352 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3328-3328 ◽

Cited By ~ 1

Author(s):

Lorenz Selberg ◽

Peter Stadtherr ◽

Sascha Dietrich ◽

Thomas Luft ◽

Andrea Bondong ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

The Other ◽

Advisory Committees ◽

Unrelated Donors ◽

The Impact

Although alloHCT is an accepted salvage treatment in defined settings of poor-risk NHL, its potential benefit in these indications remains controversial because virtually all published studies are uncontrolled and restricted to patients who were actually able to undergo transplantation. Here, we aimed at assessing the impact of alloHCT by measuring its outcome from the time of donor search indication rather than from the time of transplant, thereby taking into account those patients who fail to proceed to allografting for any reason. Study design and patients : In a single centre retrospective analysis, course and outcome of all patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) mantle cell lymphoma (MCL) and peripheral T-cell lymphoma (PTCL) who were considered as having an alloHCT indication according to accepted guidelines between 2004 and 2018 were recorded. Primary endpoint was overall survival (OS) from start of donor search. A key secondary endpoint was comparison of OS from the 3-month landmark by donor availability. Accepted donors were matched related donors (MRD), 10/10 matched unrelated donors (MUD), 9/10 compatible unrelated donors (MMUD), and mismatched related donors (MMRD), with haplo donors being used at our institution only since 2014. Results : Altogether a donor search was initiated in 187 patients (DLBCL 32%, FL 17%, MCL 23%, PTCL 28%). Median age was 54 (19-69) years with 74% being male. Within a median time from diagnosis to search initiation of 1.1 (0.1-19) years, a median of 4 (1-9) treatment lines had been administered, including an autoHCT in 50%. 69% of the patients had active disease at the time of search initiation. Only 2 patients underwent donor search in 1st remission (for Richter transformation and hepatosplenic T cell lymphoma, respectively). With a median follow-up of 6.2 (0.6-15.9) years, OS at 5 years after search initiation for DLBCL, FL, MCL, and PTCL was 25%, 44%, 52%, and 50%, respectively (Fig 1). 171 patients (91%) were alive at the 3-month landmark. For these, an MRD (20%), MUD (44%), MMUD (25%), or MMRD (7%) could be identified in 96% of the cases. AlloHCT was performed in 72% of all 187 patients, and in 79% of the patients alive at the 3-month landmark, with a significantly lower rate in DLBCL (69%) compared to the other entities. In patients who were actually transplanted, 5-year OS from landmark for DLBCL, FL, MCL and PTCL was 32%, 63%, 62%, and 62%, respectively, whereas only 5 of the 36 patients (14%) alive at the 3-month landmark not undergoing alloHCT for any reason survived long term. Due to the low rate of unsuccessful searches, donor vs no-donor landmark survival analyses were not possible. Conclusions: Despite donor search now being successful in virtually all cases, 20-30% of those patients intended for alloHCT for NHL will never proceed to transplant. However, long-term OS by ITT does not seem substantially worse than alloHCT outcome observed in registry studies restricted to patients actually transplanted, with DLBCL appearing inferior to the other 3 entities. Patients surviving the 3-month landmark but not undergoing alloHCT for any reason have a poor outlook. These results may serve as benchmark for novel therapeutic options entering the NHL treatment landscape. Disclosures Luft: Neovii: Research Funding; JAZZ: Research Funding. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support. Dreger:Neovii, Riemser: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy.

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Longitudinal Genomic Analyses In Chronic Lymphocytic Leukemia (CLL) Patients Reveal Clonal Relationship and Genomic Evolution In Disease Progression and After Therapy

Blood ◽

10.1182/blood.v116.21.3605.3605 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3605-3605

Author(s):

Esteban Braggio ◽

Neil E. Kay ◽

Scott Van Wier ◽

Stephanie Smoley ◽

Jeanette Eckel-Passow ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

Clonal Evolution ◽

The Other ◽

Genomic Evolution ◽

Advisory Committees ◽

Time Points ◽

Time Point

Abstract Abstract 3605 CLL is a malignant B-cell disorder characterized by the accumulation of small B lymphocytes with a mature appearance in blood, marrow and lymph nodes. Despite effective treatment options, all patients with CLL will eventually relapse after therapy. This could be due in part to the presence of subclones of the CLL cell population that harbor genetic abnormalities, which confer resistance to treatment. The aims of this study were to investigate the clonal evolution in longitudinal samples of CLL patients and to identify genetic alterations associated with disease progression and resistance to therapy. Sequential analyses were performed in 51 samples from 23 patients who were included in a previously reported clinical trial of pentostatin, cyclophosphamide and rituximab (PCR) given every 3 weeks for 6 cycles in previously untreated CLL (Blood 109:2007). In all cases the first sample analyzed was prior to therapy. In 5 of 23 patients, three time points were analyzed: >6 months prior to entry onto PCR trial (time point A), just before starting with the PCR regimen (time point B), and the time of relapse after PCR trial (time point C). Seven patients were analyzed at time points A and B; 9 at time points B and C and 2 at time points A and C. The median time between points A and B was 17.5 months (range 8–48 months) and between points B and C was 20.5 months (7–60 m). All samples were examined by array-based comparative genomic hybridization (aCGH) using the Agilent Sureprint G3 (1 million probe) array. aCGH findings were confirmed by interphase FISH using probes for D13S319 (MIR16–1/MIR15A), RB1, MDM2, CEP12, CEP6, MYB, TP53, NFKBIA, PERP and FGFR1 loci. Overall, we observed a small increase in the number of copy-number abnormalities (CNA) with disease progression. Twenty-two of the 23 patients with paired samples harbored at least one CNA that persisted in all samples, indicating clonal relationship between the sequential samples. In 15 of the 23 patients the tumor clone was stable and no CNA differences between time points were identified. Conversely, genomic evolution was found in 8 patients. In 3 cases the genetic differences were observed pre treatment (between time points A and B) and in the other 5 cases, the observed changes were found after therapy (between time points A and C or between B and C). One remarkable case with genome evolution exhibited two subclones sharing trisomies 12 and 19, but with several unique CNA confined to each subclone. The first subclone was characterized by deletions of 6q, RB1, MIR16-1/MIR15A and 3 other losses, while the second subclone showed homozygous deletion of MIR16–1/MIR15A and 5 other monoallelic deletions. The first subclone was predominant at time points A and B (60–70% of cells), but was present in only 10–20% of cells at time point C as confirmed by FISH. Conversely, the second subclone was observed in ~20% of cells at time points A and B and became predominant after therapy, found in ~80% of cells at time point C. Another case was characterized by deletion 11q32 (including ATM and others) as the sole abnormality at time point B. Significant genomic complexity was observed at time point C, including deletions of 11q32, 9p21 (CDKN2A), 9q12-q33, 14q13.2 (NFKBIA) and 17p (TP53), and gains of 2p16 (REL) and 9q34. Interestingly, the deletion 11q32 from both time points arose independently at each time point, as they exhibited different chromosomal breakpoints and copy number variants. Moreover, the other CNA found at relapse were not identified at diagnosis (confirmed by aCGH and FISH). For evolution of specific CNA, trisomy 12 was found in 5 cases at the first sample analyzed and was stable with no changes between time points. The frequency of deletions 13q14.3 (MIR16-1/MIR15A) and 17p increased at the later time points. Conversely, –6q decreased in frequency across time points (3 cases in time points A–B and 1 case in time point C). In summary, at least 35% of CLL patients exhibited clonal evolution and at least 9% showed evidence of multiple subclones. This subgroup of CLL patients provides an exceptional framework for comprehensive analysis of genome evolution during disease progression before and after therapy. Our observations also support the hypothesis of a common CLL progenitor cell can give rise to clonally related, but genetically evolving subpopulations of tumor cells. Finally, this study may bring novel information regarding the drug resistance pathways utilized by CLL B cell clones post therapy. Disclosures: Kipps: GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding; Memgen: Research Funding; Igenica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Research Funding; Abbott Laboratories: Research Funding. Fonseca:Genzyme: Consultancy; Medtronic: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Research Funding; Intellikine: Consultancy; Cylene: Research Funding; Onyx: Research Funding; FISH probes prognostication in myeloma: Patents & Royalties.

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The Effect of Ruxolitinib on White Blood Cell Counts in Patients with Polycythemia Vera: Results from the RESPONSE Trial

Blood ◽

10.1182/blood.v126.23.4070.4070 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4070-4070 ◽

Cited By ~ 1

Author(s):

Carole B. Miller ◽

Jean-Jacques Kiladjian ◽

Martin Griesshammer ◽

Ahmad B. Naim ◽

William Sun ◽

...

Keyword(s):

Blood Cell ◽

Board Of Directors ◽

Research Funding ◽

Thromboembolic Events ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Over Time ◽

Response Trial

Abstract Background: Age, prior thrombotic events, and an elevated hematocrit are established risk factors for increased risk of thrombosis in patients with polycythemia vera (PV). Evidence also suggests that elevated white blood cell (WBC) counts ≥ 11×109/L are a significant independent risk factor for thrombosis in patients with PV (P =0.02; Barbui T, et al. Blood. 2015; 126:560-561). Therefore, this analysis was conducted to evaluate the impact of ruxolitinib (Rux) and best available therapy (BAT) treatment on WBC counts among patients with Baseline WBC counts ≥ 11×109/L in the RESPONSE trial. RESPONSE is a global, multicenter, open-label phase 3 trial investigating Rux and BAT in patients with PV who are resistant to or intolerant of hydroxyurea (HU). In the RESPONSE trial, Rux was associated with durable improvements in hematocrit control without phlebotomy compared with BAT as well as reductions in WBC counts. Methods: Changes from Baseline in WBC counts in the Rux arm (n=110), BAT arm (n=112), and HU subgroup of the BAT arm (n=66) were evaluated as part of an exploratory analysis using the RESPONSE 80-Week analysis dataset. Patient subgroups with Baseline WBC counts ≥ 11×109/L and < 11×109/L were analyzed for changes in WBC counts at Weeks 12, 32, and 80. For patients with Baseline WBC counts ≥ 11×109/L, the proportion of patients who achieved a decrease in WBC counts to ≤ 10×109/L or a ≥50% reduction at Week 12 and Week 32, respectively, was summarized; time to achieve the decrease was analyzed by Kaplan-Meier method. Results: Baseline mean WBC counts were generally similar among patients in the Rux arm, BAT arm, and HU subgroup (17.6×109/L, 19.0×109/L, and 17.4×109/L, respectively). The proportion of patients with Baseline WBC counts ≥ 11×109/L was also similar among the Rux arm, BAT arm, and HU subgroup (75%, 71%, and 70%, respectively). In patients with Baseline WBC counts ≥ 11×109/L, patients treated with Rux had greater mean reductions in WBC counts compared with the BAT arm and HU subgroups, and these reductions were maintained over time; mean changes from Baseline in WBC values at Week 12/Week 32 (×109/L) were -7.7/-7.2 for Rux, -3.2/-4.2 for BAT, and -1.2/-2.2 for HU. In patients with lower Baseline WBC counts, mean values remained stable over time. The change from Baseline to Week 12 for individual patients with Baseline WBC counts ≥ 11×109/L is shown in Figure 1. In patients with Baseline WBC counts ≥ 11×109/L, worsening WBC counts were observed in 10.8% of patients in the Rux arm vs 35.4% in the BAT arm (P =0.0002) and 47.8% in the HU subgroup (P <0.0001). In this same subgroup with elevated WBC counts, a greater proportion of patients in the Rux arm achieved WBC counts ≤ 10×109/L or a ≥50% reduction compared with the BAT arm or HU subgroup (Week 12: Rux, 41% vs BAT, 19% vs HU, 13%; Week 32: Rux, 45% vs BAT, 22% vs HU, 9%); median time to this reduction was 8 weeks in the Rux arm and was not reached in the BAT arm or HU subgroup. Conclusion: Rux treatment resulted in better control of WBC counts compared to BAT in patients with PV. These changes in the Rux arm occurred early after study initiation (within a median of 8 weeks) and were durable over time. Although RESPONSE was not powered to assess the impact of Rux on thromboembolic events, the lower rate of thromboembolic events observed in the Rux arm vs the BAT arm (1.8 vs 8.2 per 100 patient-years of exposure) is consistent with the observed effects of Rux on hematocrit, WBC counts, and C-reactive protein levels, which are all associated with thromboembolic risk. Disclosures Miller: Incyte Corporation: Honoraria, Research Funding. Kiladjian:Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Incyte Corporation: Consultancy; Novartis: Consultancy. Naim:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Gadbaw:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau.

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Aberrant a-to-I RNA Editing and Prognostic Impact of Adar in Multiple Myeloma Patients with 1q Amplification

Blood ◽

10.1182/blood.v128.22.357.357 ◽

2016 ◽

Vol 128 (22) ◽

pp. 357-357

Author(s):

Alessandro Lagana ◽

Deepak Perumal ◽

Violetta V Leshchenko ◽

Pei-Yu Kuo ◽

Brian Kidd ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Rna Editing ◽

Copy Number ◽

Research Funding ◽

Cox Regression ◽

Advisory Committees ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Equity Ownership

Abstract Amplification of 1q is observed in 40% of Multiple Myeloma (MM) patients and is associated with a more aggressive clinical course of the disease. The frequency of 1q21 amplifications has been shown to increase significantly in the transition from monoclonal gammopathy of undetermined significance (MGUS) to overt myeloma and to relapse. Previous studies have reported genes on 1q such as ANP32E and CSK1B that have significant impact on survival. However, the biological mechanisms underlying disease aggressiveness associated to 1q amplification still remain unclear. ADAR (Adenosine Deaminase Acting on RNA) is an enzyme responsible for A-to-I editing, a post-transcriptional modification of double stranded RNA consisting in the conversion of specific Adenosines (A) into Inosines (I) by deamination. As Inosine is structurally similar to Guanosine (G), editing events can result in functional consequences in RNA and protein structure, including non-synonymous changes in protein coding sequences and creation/disruption of miRNA binding sites on UTRs. Dysregulation of A-to-I editing by ADAR has been recently linked to cancer. Since the ADAR gene is located in 1q21.3 (the critical minimally amplified region in MM), we asked whether 1q amplification affected ADAR expression, RNA editing and overall prognosis in MM patients. We identified 44 patients with 1q amplification from the IA6 release of the MMRF CoMMpass dataset. As a control group (wt), we selected an equal number of patients from CoMMpass without any 1q alteration. Gene expression analysis showed significantly higher expression of ADAR in 1q-amp patients compared to wt (q = 3.64e-7) (Fig. 1) and significant correlation between ADAR copy number and its expression (Spearman ρ=0.69, p = 4.52e-14). To evaluate the functional impact of ADAR up-regulation, we applied a computational pipeline based on the tool REDItools and our in-house scripts to detect A-to-I edited sites in RNA-Seq samples. The pipeline identified candidate A-to-G mutations in RNA sequences using corresponding Whole-Exome Sequencing data to filter out actual DNA mutations. We calculated sample-wise mean editing frequency across all edited sites and found significantly increased editing in 1q-amp patients compared to wt (p = 4.3e-5) (Fig. 2). Mean editing frequency was significantly correlated with ADAR expression (ρ = 0.62, p < 2e-16) and ADAR copy number (ρ= 0.5, p= 4.32e-7). Our analysis identified 3,286 sites residing in Alu sequences and 1,303 in non-Alu regions. A-to-I editing has been shown to occur predominantly in Alu elements, repetitive sequences abundantly interspersed throughout the human genome, mostly within introns and untranslated regions (UTRs). As expected, most sites were reported within 3' UTRs (66%) and introns (12%). Overall, at the site level, we observed increased editing in 1q-amp vs wt (p < 2e-16). We found that 2,173 sites (47%) had significant differential editing frequency between 1q-amp and wt patients (FDR < 20%). Next, we sought to assess the prognostic implications of ADAR activity. Cox regression analysis revealed a trend toward higher risk in terms of EFS (Event Free Survival) for 1q-amp vs wt (HR = 1.7, 95% CI = 0.83-3.59, p = 0.13), as well as for patients with higher expression of ADAR (HR = 2.4, 95% CI = 0.79-7.15, p = 0.11) and higher mean editing frequency (HR = 2, 95% CI = 0.72-5.59, p = 0.17). Since survival data in the CoMMpass dataset is not yet mature, we evaluated the effects of ADAR expression on survival on an independent dataset consisting of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658, Shaughnessy et al, Blood 2007; 109:2276-84). Cox regression analysis showed a significant difference in terms of overall survival between patients with low and high ADAR expression, the latter being correlated with higher risk (HR = 2, 95% CI = 1.18-3.66, p = 0.01) (Fig. 3). In conclusion, we found a significant increase in ADAR expression and aberrant A-to-I RNA editing in MM patients with amplification of 1q. These results demonstrate a novel mechanism by which 1q amplification can contribute to MM pathogenesis via induction of A-to-I RNA editing by ADAR. Figure 1 ADAR expression in 1q-amp vs wt patients. Figure 1. ADAR expression in 1q-amp vs wt patients. Figure 2 Difference in mean RNA editing frequency between 1q-amp and wt patients. Figure 2. Difference in mean RNA editing frequency between 1q-amp and wt patients. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by ADAR expression (GSE2658) Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by ADAR expression (GSE2658) Disclosures Chari: Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Array Biopharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cho:Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Agenus, Inc.: Research Funding; Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Jagannath:Janssen: Consultancy; Celgene: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Dudley:NuMedii, Inc.: Patents & Royalties; AstraZeneca: Speakers Bureau; Ontomics, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; Ayasdi, Inc.: Equity Ownership; Janssen Pharmaceuticals, Inc.: Consultancy; GlaxoSmithKline: Consultancy; Personalis: Patents & Royalties.

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Venetoclax Improves Quality of Life for Patients with Elapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-117127 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4858-4858 ◽

Cited By ~ 1

Author(s):

Tara Cochrane ◽

Tatiana Chagorova ◽

Tadeusz Robak ◽

Su-Peng Yeh ◽

Evgeny Nikitin ◽

...

Keyword(s):

Quality Of Life ◽

Board Of Directors ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Eortc Qlq ◽

The Impact

Abstract INTRODUCTION: Patients with chronic lymphocytic leukemia (CLL) have significantly decreased health related quality of life (HRQoL), particularly related to severe and progressive fatigue. Side effects of chemotherapies and the emotional burden of living with an often poor prognosis disease also negatively impact patient HRQoL. Venetoclax, an oral agent that targets the anti-apoptotic protein BCL2, has demonstrated high rates of deep and durable response in patients with relapsed/refractory (R/R) CLL, including those with 17p deletions, and has been shown to facilitate clinically relevant improvement in several key aspects of functioning and HRQoL. We evaluated the impact of venetoclax monotherapy on the quality of life of patients with R/R CLL. METHODS: VENICE II is an ongoing open-label, phase 3b, multicenter study (NCT02980731) that assessed patient-reported HRQoL in patients who were ≥18 years old with R/R CLL, including those with 17p deletion, TP53 mutations, and/or prior experience with B-cell receptor pathway inhibitor-containing (BCRi) therapy, treated with venetoclax monotherapy (5-week dose-titration, starting at 20mg once daily, then increased weekly to 50 mg, 100 mg, 200 mg, and 400 mg, followed by 400mg once daily). The primary endpoint was the mean change from baseline to Week 48 in the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) subscale. HRQoL subscales analyzed included: Global Health Status, Role Functioning, Emotional Functioning, Cognitive Functioning, Social Functioning, and Fatigue. The impact on QoL was also assessed on the CLL Module (EORTC QLQ-CLL16). Relevance of mean changes in HRQoL measures from baseline were analyzed based on minimum important difference (MID); a 5-10 point change was defined as MID, and >10 points was considered clinically meaningful.(Osoba, D., et al. J Clin Oncol. 1998;16:139-44. Osoba, D., et al. Qual Life Res. 1994;3:353-64.) Safety and adverse events (AEs) were also monitored. RESULTS: As of the data cutoff, April 30, 2018, the median time on study was 28 weeks (range: 1 - 73) and the median time on therapy was 23 weeks (range: 0.1 - 69) in this ongoing study. Of the 169 treated patients, 70% were male; the median age was 65 years (range: 24 - 86). Among those with available data, 17p deletions and TP53 mutations were confirmed in 34% (41/122) and 38% (19/50) of patients, respectively. Overall, 38%, 20%, and 42% of patients had one, two, and three (or more) prior lines of therapy respectively; 21% of patients had prior BCRi therapy. Clinically meaningful improvements from baseline were observed by week 12 and were sustained through week 48 in the EORTC-QLQ-C30 global health status and the role function, social function, and fatigue subscales (Table and Figure 1A) and EORTC-QLQ-CLL16 future health and disease effect subscales (Table and Figure 1B). Eighty-two percent of patients had at least 1 AE; most commonly observed AEs (≥10% of patients) were neutropenia (35%), diarrhea (17%), thrombocytopenia (15%), anemia (12%), nausea (12%), and upper respiratory infection (11%). Twenty-eight percent of patients had a serious AE, of which the most common were pneumonia (5%), febrile neutropenia (4%) and pyrexia (3%). Five percent of patients discontinued the study due to an AE. CONCLUSIONS: Preliminary data from this ongoing study suggest that patients with R/R CLL experienced improvement in several key aspects of functioning and quality of life with venetoclax monotherapy within the first 12 weeks which is sustained over time. Venetoclax monotherapy was well tolerated in R/R CLL patients. These findings are consistent with previous studies of R/R CLL patients who received venetoclax monotherapy. Disclosures Cochrane: Janssen: Membership on an entity's Board of Directors or advisory committees; Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Calgene: Honoraria; Amgen: Honoraria; Novartis: Honoraria; MSD: Honoraria. Robak:AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Nikitin:AbbVie, Inc: Speakers Bureau. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Masud:AbbVie, Inc: Employment, Equity Ownership. Sail:AbbVie, Inc: Employment, Equity Ownership. Komlosi:AbbVie, Inc: Employment, Equity Ownership. Anderson:Walter and Eliza Hall: Employment, Patents & Royalties; AbbVie, Inc: Research Funding; Genentech: Research Funding.

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Molecular Epidemiology of AML: Association of Somatic Gene Mutations with Epidemiologic Exposures and Outcomes in the Mayo Clinic AML Epidemiology Cohort

Blood ◽

10.1182/blood-2020-134353 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 35-36

Author(s):

Zaid Abdel Rahman ◽

Yesesri Cherukuri ◽

Michael G. Heckman ◽

Laura E. Finn ◽

Liuyan Jiang ◽

...

Keyword(s):

Exome Sequencing ◽

Board Of Directors ◽

Mayo Clinic ◽

Copy Number ◽

Research Funding ◽

Somatic Mutations ◽

Patient Characteristics ◽

Advisory Committees ◽

Risk Response ◽

Response To Chemotherapy

Introduction: Population studies have identified genes with germline polymorphisms associated with acute myeloid leukemia (AML) risk and outcome. However, somatic mutations in these genes have not been reported in an AML clinical population and whether they are associated with epidemiologic exposures, clinical AML phenotypes and outcome after therapy. Methods: We systemically interrogated PubMed database (1998-2018), to identify genes with germline polymorphisms associated with AML risk, response to chemotherapy or outcome. To determine the prevalence and relevance of somatic mutations in these genes in an unselected AML population, we performed an analysis using Whole-Exome Sequencing (WES) on remnant diagnostic cytogenetic pellets from 98 patients from the Mayo Clinic AML Epidemiology Cohort, a detailed and highly-annotated cohort of 295 consecutive AML patients treated at Mayo Clinic Florida & Arizona between October, 2000 and December, 2011. Patient characteristics are shown in Table 1. Samples were sequenced at a depth of ~100 million paired-end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Sequencing reads were aligned to human reference genome, and somatic mutations including non-synonymous and truncating single nucleotide variants and small INDELs were identified and filtered using Exome Sequencing Project, 1000 genome, HapMap, & Mayo Clinic internal biobank genetic variants database. Copy number aberrations were identified & filtered using public copy number polymorphism databases. The association analyses were performed at the gene level, with a primary endpoint of whether a given patient harbored a somatic mutation in any genes linked to AML risk or outcome in literature, and to determine the associations of these mutations with epidemiologic exposures, AML phenotype and clinical outcomes. Results: From the literature search, we identified 77 unique genes with known germline polymorphisms associated with AML risk, response to chemotherapy or outcome. Fifty-eight of these were found to be somatically mutated in our WES dataset, with subsequent analysis focusing on the 11 genes (ABCB1, CYP1A1, CYP2B6, EPHX1, ERCC1, ERCC2, ERCC5, JAK2, MEFV, MTRR, and TERT) that had greater than 5 patients with nonsynonymous somatic mutations in the given gene. Significant associations with epidemiologic exposures and outcomes were noted in patients with somatic mutations in ERCC2, CYP1A1 and ERCC5 genes. Table 2 shows a comparison of patient characteristics and associations according to the presence of somatic mutations in these genes. Patients with mutations in CYP1A1 had a significantly younger age at AML diagnosis (Median: 51.7 vs. 71.0 years, P=.02) and significantly shorter OS in age-adjusted analysis (HR=4.45, P=.003). The former is a novel finding, whereas the latter is consistent with previous reports. Patients with mutations in ERCC2 more commonly used statins (66.7% vs. 21.7%, P=.03). Patients with ERCC5 mutations had a lower rate of tobacco use (20.0% vs. 54.5%, P=.049). In unadjusted analysis, there was a significant association between presence of somatic mutations in JAK2 and poorer survival after AML diagnosis (HR=2.83, P=.017), but this attenuated and did not retain significance when adjusting for age at AML diagnosis (HR=2.22, P=.067). Conclusion: Our exploratory study describes a novel association of CYP1A1 somatic nonsynonymous mutations with age of AML onset, as well as novel associations of ERCC2 and ERCC5 mutations with epidemiologic exposures in an unselect cohort of patients with AML. We confirm the association of CYP1A1 with inferior overall survival after AML diagnosis. These findings suggest that some genes associated with AML risk may also harbor somatic mutations that are clinically relevant. These results will guide a planned confirmatory prospective study to determine frequency and impact of both germline and somatic mutations of risk genes in AML patients, and may contribute to a better understanding leukemia risk assessment and potentially to prevention strategies. Disclosures Finn: Jazz Pharmaceuticals: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Cerhan:BMS/Celgene: Research Funding; NanoString: Research Funding. Foran:Revolution Medicine: Consultancy; Servier: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Agios: Honoraria, Research Funding.

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