Non-del 5q Myelodysplastic Syndromes Research Articles

Research Progress of Thalidomide and Its Derivatives in Treatment of Myelodysplastic Syndrome--Review

Thalidomide and its derivatives have been used in the treatment of myelodysplastic syndrome (MDS) because of their anti-angiogenic and immunomodulatory effects. In recent years, some studies have found that thalidomide and its derivatives not only showed significant efficacy in lower-risk MDS patients with del (5q), but also showed advantages in non-del (5q) MDS patients. In addition, the discovery of its molecular targets and new substrates makes it possible to develop a new generation of immunomodulatory drugs (IMiDs) and to design IMiDs-based proteolysis-targeting chimeras. In this review, the new progress in mechanism and clinical application of thalidomide and its derivatives were summarized briefly, so as to provide a more scientific, reasonable and effective scheme to the treatment of MDS.

Icare 1: A Prospective Clinical Trial to Predict Treatment Response Based on Mutanome-Informed Computational Biology in Patients with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS)

Refractory disease remains a challenge in treating patients (pts) with MDS and AML. Despite their widespread use, cytotoxic agents (7+3, HiDAC) and hypomethylating agents (HMAs) fail in the majority of pts, and lenalidomide (LEN) fails in 75% of non-del(5q) MDS. 90% of MDS and AML pts harbor at least one somatic mutation, further contributing to disease complexity. Currently, no comprehensive method exists to predict disease response based on the entire mutational burden detected in malignant samples. Predicting response to treatment would improve effectiveness, limit treatment-related adverse events, and reduce health care costs. Hence, there is need to predict pt response based on disease biology.Aim: Determine the biological and clinical predictive values of a genomics-informed computational biology method (CBM) in pts who are treated with standard of care (SOC) therapy.Methods: Pts with AML or MDS were recruited in a prospective clinical trial (NCT02435550) designed to assess predictive values by comparing computer predictions of treatment response to actual clinical response. Genomic profiling was conducted by cytogenetics, whole exome sequencing (WES), and copy number variation (CNV) analysis. These genomic results were entered into a CBM software (Cellworks Group), which generates disease-specific protein network maps using PubMed and other online resources. Digital drug simulations were conducted by quantitatively measuring drug effect on a cell growth score, which is a composite of cell proliferation, viability and apoptosis. Each pt-specific protein network map was digitally screened for the extent to which each pt's therapy reduced simulated disease growth in a dose-respondent manner. Treatment was physician's choice of SOC. Before initiating treatment, treating physicians were masked to the results of WES and CBM predictions. Clinical outcomes were prospectively recorded by the physicians. To be eligible for efficacy assessment, MDS pts must have had at least 4 cycles of HMA treatment or 2 cycles of LEN treatment. For AML, CR+PR was used to define response (IWG 2003). For MDS, CR+PR+HI was used to define response (IWG 2006). AML pt response was determined at time of recovery bone marrow biopsy, post induction therapy and/or consolidation therapy. Western blot assays were performed to validate the predicted protein network perturbations. Comparisons of CBM versus actual responses were performed using 2x2 tables. Fisher's exact tests were used to compare prediction values of the genomics-informed computer method versus empiric drug administration.Results: Between June 2015 and July 2017, 120 pts were recruited, and 81 have had all genetic tests performed. At the time of this report, 42 pts were eligible for clinical response evaluation. 25/42 (60%) had AML, 15/42 had MDS (36%), and 2 pts had myelofibrosis. The median age was 65 (range 47-90). 24/42 (57%) were treatment-naïve and 18/42 (43%) were treatment-refractory. Laboratory validation study of computer-predicted, activated protein networks in 19 samples from 11 different pts showed correct prediction of 4 activated networks (Akt2, Akt3, PIK3CA, Erk1/2) in 17 samples, exhibiting 89% accuracy. At the time of this report, 42/81 pts received 52 treatments and were eligible for efficacy evaluation. 28/52 treatments resulted in clinical response to SOC therapy, while 24/52 did not achieve clinical response. 48 drug outcome predictions (92%) were correctly matched to their actual clinical outcomes, and 4/52 were incorrectly matched, resulting in 93% PPV, 92% NPV, 93% sensitivity, and 92% specificity (Table 1). Of note, CBM performed accurately in both treatment-naïve and relapsed/refractory pts.The accuracy of the CBM was significantly greater than empiric drug administration (p=6.034 E-08). Additionally, new genomic signature rules were discovered to correlate with clinical response after HMA or len.Conclusions: CBM that models multiple genomic abnormalities simultaneously showed high predictive value of protein network perturbations and clinical outcomes after SOC treatments. The network method uncovered molecular reasons for drug failure and highlighted resistance pathways that could be targeted to recover chemosensitivity. This technology could also be used to establish eligibility criteria for precision enrollment in drug development trials, and will be used in upcoming precision medicine trials. [Display omitted] DisclosuresSingh:Cellworks Research India Pvt. Ltd: Employment. Radhakrishnan:Cellworks: Employment. Ullal:Cellworks Research India: Employment. Talawdekar:Cellworks: Employment. Sikora:Cellworks: Employment. Nair:Cellworks: Employment. Bhowmick:Cellworks: Employment. Abbasi:Cellworks Group Inc.: Employment. Vali:Cellworks Group Inc.: Employment. Norkin:Celgene: Honoraria, Research Funding. Cogle:Celgene: Other: Membership on Steering Committee for Connect MDS/AML Registry.

IMerge: A phase 3 study to evaluate imetelstat in transfusion-dependent subjects with IPSS low or intermediate-1 risk myelodysplastic syndromes that are relapsed/refractory to erythropoiesis-stimulating agent treatment.

TPS7056 Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients (pts) 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 first-in-class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in MDS pts across all disease stages. IMerge (MDS3001) is a Phase 2/3 global study of imetelstat for TD pts with non-del(5q) LR MDS post ESA therapy. The results from Phase 2 part indicated that imetelstat achieved durable RBC transfusion independence (RBC-TI) and the most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. Among 38 pts with median follow-up of 24 months, 8-week, 24-week and 1-year TI rates were 42%, 32% and 29%, respectively; these responses were seen across different LR MDS subtypes. Median TI duration was 20 months and the longest TI was 2.7 years. A high and durable hematologic improvement-erythroid (HI-E) rate of 68% for a median duration of 21 months were also achieved. Reduction of variant allele frequency of mutations by imetelstat treatment was observed in some pts and correlated with clinical benefits (Platzbecker et al EHA 2020; Steensma et al JCO 2020). These results support the Phase 3 part of the trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 3 part of the study is open for enrollment to adult pts 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 pts and will be conducted at approximately 120 centers in North America, Europe, Asia and Middle East. Imetelstat is 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 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. The study is currently recruiting pts. Clinical trial information: NCT02598661.

Imerge: A Phase 3 Study to Evaluate Imetelstat in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

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 (Tefferi et al, Blood Cancer J 2016) supported initiation of a study in TD LR MDS patients. The Phase 2 part of IMerge demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 32%, with median duration of TI being 88 weeks. The responses were seen across different subtypes of LR MDS (Platzbecker et al, EHA 2020, S183). No new safety signal was identified. These results support the Phase 3 part of the 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 enrolment. 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 130 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 hematologic improvement-erythroid (HI-E), the amount and relative change in RBC transfusions, rate of complete response or partial response, 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: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Steensma:CRISPR: Current equity holder in publicly-traded company; Aprea Therapeutics: Research Funding; Takeda: Consultancy; BMS/Celgene: Consultancy; Onconova: Consultancy; Arena: Current equity holder in publicly-traded company; H3 Biosciences: Research Funding; Astex Pharmaceuticals, Otsuka: Consultancy; Arrowhead Pharmaceuticals: Current equity holder in publicly-traded company. Font:Abbvie: Other: Travel, accommodations, expenses; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diez-Campelo:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Jang:Bristol Myers Squibb: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Johnson & Johnson: Honoraria.

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

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.

The role of innate immunity in MDS pathogenesis.

The role of innate immunity in MDS pathogenesis.

Genomic Biomarkers Predict Response/Resistance to Lenalidomide in Non-Del(5q) Myelodysplastic Syndromes

Genomic Biomarkers Predict Response/Resistance to Lenalidomide in Non-Del(5q) Myelodysplastic Syndromes

SNP-Array Genome Wide Association Study Meta-Analysis Identifies Innate Immune Susceptibility Loci Associated with Non-Del(5q) Myelodysplastic Syndromes Predisposition

Background: Myelodysplastic Syndromes (MDS) are genetically and hematologically diverse stem cell malignancies pathogenetically linked to constitutive innate immune activation. Other than rare germline mutations and age, the only known predispositions to adult MDS include prior cytotoxic therapy, clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. Few studies investigating the genetic susceptibility to MDS have been performed owing to the limitations of SNP-array sample size. Here, we report the results from the first unbiased genome wide analysis of germline polymorphisms associated with non-del(5q) MDS using a multinational curated data set.Methods: Association analyses were performed on 2 sample sets (set 1: 555 cases, 2,964 controls; set 2: 352 cases, 2,640 controls) and combined by meta-analysis. Standard SNP- and sample-level QC was applied. Haplotype reference consortium (HRC) imputation was done by the Michigan imputation server (Rsq>0.4) providing 23,278,269 markers for analysis. Gene expression sequencing was performed on an independent sample set from the National Taiwan University Hospital (213 MDS cases, 20 healthy donors; HumanHT-12 v4 Expression BeadChip; Chuang et al. Leukemia 2015). Functional analyses were performed as described.Results: Eight MDS associated loci were identified with lead variants, rs6683416, rs34539210, rs341274, rs1634783, rs7099032, rs2947170, rs4404050, and rs1206818, at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2), respctively. Odds ratio (OR) and p-values of each are listed in Table 1. Using gene expression profiling in an independent MDS sample set, we found expression of these five candidate genes was significantly increased in MDS vs controls (p<0.01). Using the same independent sample set, we found higher PLA2G4A and lower EYA2 expression were associated with reduced overall survival (p=0.039 and p=0.037, respectively). Importantly, EYA2 was an independently favorable risk factor irrespective of age, gender and IPSS-R (RR, 0.665; p=0.048). High PLA2G4A expression was associated with NRAS (p<0.001), RUNX1 (p=0.012), ASXL1 (p=0.007), and EZH2 (p=0.038) somatic mutations whereas higher FAM19A4 expression associated with KRAS mutations (p=0.045). Importantly, PLA2G4A, FAM19A4, GRID1, and EYA2 are involved in the regulation of innate immune signaling. We previously reported that across all somatic gene mutation classes, MDS cases biologically converge upon the redox-sensitive, Nlrp3 inflammasome to drive pyroptosis, a caspase-1 mediated innate immune cell death (Basiorka et al. Blood 2016). PLA2G4A encodes phospholipase A2 (PLA2) that inhibits inflammasome activation. Further, PLA2 is required for MAPK phosphorylation of S100A9, a key danger associated molecular pattern (DAMP) and TLR4 ligand implicated in the induction of pyroptosis in MDS progenitors. FAM19A4 encodes a cytokine whose expression is upregulated in response to endotoxin exposure suggesting a role in immune modulation. EYA members activate innate immune response in part through recognition of cytosolic double-stranded DNA, which can serve as a DAMP triggering inflammasome assembly. To investigate the possible role of EYA2 in inflammasome activation in MDS, we overexpressed EYA2 in the monocytic cell line, THP1. EYA2 overexpression induced caspase-1 and maturation of IL-1β, indicating inflammasome activation. These findings were accompanied by NFκB phosphorylation consistent with innate immune signal priming. We next treated MDS primary bone marrow specimens (n=3) with the EYA2 inhibitor, MLS000544460, demonstrating a significant, dose-dependent improvement in colony recovery consistent with restoration of effective hematopoiesis.Conclusion: We describe here the first MDS susceptibility loci ever identified the majority of which have a direct relationship to innate immune activation, a driver of MDS pathogenesis. Expression of genes housing these loci is increased in MDS with demonstrable prognostic and biological relevance. Further, functional studies implicate EYA2 as a novel, biologically rational target for MDS treatment. The direct functions of each polymorphism as well as the potential relationship between these predisposition loci to age-related clonal hematopoiesis merits further investigation. [Display omitted] DisclosuresCluzeau:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau. Sallman:Celgene: Research Funding, Speakers Bureau. Sokol:Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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. List:Celgene: Research Funding.

The Effect of Lenalidomide on Health-Related Quality of Life in Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes: Results From the MDS-005 Study

BackgroundThe phase III MDS-005 study compared lenalidomide versus placebo in red blood cell transfusion-dependent (RBC-TD) patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS), ineligible/refractory to erythropoiesis-stimulating agents. Lenalidomide-treated patients were more likely to achieve transfusion independence (TI) ≥ 8 weeks (26.9% vs. 2.5%; P < .001) and hemoglobin increase ≥ 1.5 g/dL (19.4% vs. 2.5%) versus placebo. Patients and MethodsPatients were randomized 2:1 to oral lenalidomide 10 mg once daily or placebo once daily (both on 28-day cycles). Patients with creatinine clearance 40 to 60 mL/min were given lenalidomide 5 mg once daily. Health-related quality of life (HRQoL), a predefined secondary end point, was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 questionnaire at baseline, week 12, week 24, every 12 weeks thereafter, and at discontinuation. ResultsAt week 24, lenalidomide was associated with benefit versus placebo across all 5 preselected questionnaire scales (fatigue, dyspnea, global quality of life, physical functioning, and emotional functioning). After adjustment for baseline scores, only emotional functioning achieved significance (P = .047). Further improvement versus baseline was observed for patients who continued lenalidomide after week 24. In post hoc analyses, achievement of TI ≥ 8 weeks was associated with significant improvements across all scales (P < .01); an increase in hemoglobin level correlated with significant improvements in all scales at week 24, except emotional functioning (P < .05). ConclusionLenalidomide did not adversely affect HRQoL in RBC-TD patients with lower-risk non-del(5q) MDS and response to lenalidomide was associated with significant improvements in HRQoL.

Abstract 4545: A computational biology method to predict HMA or lenalidomide treatment response in non-Del(5q) MDS

Abstract 60% of myelodysplastic syndromes (MDS) patients fail to achieve clinical improvement with hypomethylating agents (HMAs). 26% of patients with non-del5q MDS respond to lenalidomide (LEN), but the mechanism of response is unknown. Treatment of non-del5q patients who fail HMA is challenging and predicting response to LEN would address this unmet clinical need. Methods: A retrospective analysis was performed on non-del5q MDS patient cytogenetics, gene mutations, treatments, and clinical response data. Using Cellworks Group software, genomic data was used to generate disease-specific protein network maps. Digital drug simulations were done by quantitatively measuring drug effect and calculating a MDS inhibition score. Each patient-specific map was digitally screened for the extent by which LEN and HMAs inhibited MDS in a dose-dependent manner and compared to the patient's clinical outcome. Results: Patient 1 is a non-del5q patient with trisomy 8 (+8) and an ASXL1 frameshift mutation. Simulation modeling revealed overexpression (OE) of MYC leading to IRF4 and IKZF expression, key pathways for LEN sensitivity. MYC OE also leads to CCND1 expression, aiding proliferation of MDS cells. Simulated LEN treatment targets MYC-induced upregulation of IKZF1, STUB1, CRBN, and CSNK1A1 to reduce MDS cell survival. Upregulated TP53 inhibits MYC expression, augmenting the patient's response to LEN. To compare response to other SOC drugs, azacitidine (AZA), was screened. The ASXL1 mutation led to loss of PRC2-mediated DNMT1 function. +8 results in OE of GGH, reducing methylation of CpG regions. Given loss of DNMT1 function, patient 1 was predicted be a non-responder to AZA. Patient 2 is a non-del5q patient with +8, add(14q)(11.1-11.2), add(8)(p23.3-q24.3), and an ASXL1 mutation. Modeling revealed the same dysregulated pathways as patient 1, predicting sensitivity to LEN and resistance to AZA. Patient 3 is a non-del5q patient with complex karyotype and mutations in IDH2, TET2, and SRSF2. Modeling revealed OE of CARD11 yielding sensitivity to LEN. OE of CDH1 and AXIN1 decreased beta-catenin activity, a known resistance mechanism to LEN. OE of apoptotic TP53, BAX, and BBC3 sensitize this patient's MDS cells to LEN. Modeling revealed reduced EZH2 mRNA levels due to the SRSF2 mutation, directly impacting the PRC2 complex needed for DNMT1-mediated CpG methylation. EZH2 is further down regulated by L3MBTL2 OE. TET2 is functionally challenged from the lack of CpG methylation, diminishing IDH activity, resulting in AZA resistance. Conclusions: Computer modeling of non-del5q MDS patient biology can deduce the abnormal protein networks and consequent drug effects. This method could be used to understand drug failure and highlight resistance pathways that can be targeted to recover chemosensitivity. This technology can also be used to predict MDS patient response prior to treatment, increasing drug effectiveness and reducing side effects and treatment costs. Citation Format: Leylah Drusbosky, Neeraj Kumar Singh, Shireen Vali, Taher Abbasi, Christopher R. Cogle. A computational biology method to predict HMA or lenalidomide treatment response in non-Del(5q) MDS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4545. doi:10.1158/1538-7445.AM2017-4545

Abstract CT085: iCare 1: A prospective clinical trial to predict treatment response based on mutanome-informed computational biology in patients with AML and MDS

Abstract Hypomethylating agents (HMAs) (azacitidine (aza), decitabine (dec)) and lenalidomide (len) are approved agents and used to treat patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Despite their widespread use, HMAs fail in the majority of these patients, and len fails in 75% of non-del(5q) MDS. Currently, no method exists to predict disease response, thus the management of MDS and AML patients is challenging. Methods: Patients with AML or MDS were recruited to a clinical trial (NCT02435550) designed to assess predictive values by comparing computer predictions of drug response to actual clinical response. Genomic profiling was conducted by cytogenetics, whole exome sequencing, and array CGH. Genomic results were inputted into a computational software (Cellworks), which generates disease-specific protein network maps using PubMed and other resources. Digital drug simulations were conducted by quantitatively measuring drug effect on a cell growth score (proliferation + viability + apoptosis). Each patient-specific protein network was screened for the extent by which aza, dec or len reduced disease growth in a dose-respondent manner. Treatment was physician’s choice of SOC. Clinical outcomes were prospectively recorded. IWG criteria were used to define response. Western blot assays were performed to validate the predicted protein network perturbations. Fisher’s exact test was used to compare prediction values of the genomics-informed computer method versus empiric drug administration. Results: 88 patients have had all molecular tests and computational modeling performed. Lab validation of computer-predicted, activated protein networks in 19 samples from 13 different patients showed correct prediction of 5 activated networks (Akt2, Akt3, PIK3CA, p38, Erk1/2) in 17 samples, with 89% accuracy. At the time of this report, 26/88 patients were eligible for efficacy evaluation. 8/26 patients showed clinical response to SOC therapy, 18/26 did not. 24/26 outcome predictions were correctly matched to their clinical outcomes, and 2/20 were incorrectly matched, resulting in 92% prediction accuracy, 80% PPV, 100% NPV, 100% sensitivity, and 89% specificity. The accuracy of the genomics-informed computer method was significantly greater than empiric drug administration (p=1.664e-05). New genomic signature rules were discovered to correlate with clinical response after aza, dec or len. Summary: A computational method that models multiple genomic abnormalities simultaneously showed high predictive value of protein network aberrations and clinical outcomes after SOC treatments. The network method uncovered molecular reasons for drug failure and highlighted resistance pathways that could be targeted to recover chemosensitivity. This technology could also be used to establish eligibility criteria for precision enrollment in drug development trials Citation Format: Leylah Drusbosky, Kimberly E. Hawkins, Shireen Vali, Taher Abbasi, Ansu Kumar, Neeraj Kumar Singh, Kabya Basu, Chandan Kumar, Amjad Husain, Caitlin Tucker, Randy A. Brown, Maxim Norkin, John Hiemenz, Jack Hsu, John Wingard, Christopher R. Cogle. iCare 1: A prospective clinical trial to predict treatment response based on mutanome-informed computational biology in patients with AML and MDS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT085. doi:10.1158/1538-7445.AM2017-CT085

Prevalence and complications associated with off-label use of lenalidomide in older patients with myelodysplastic syndromes (MDS).

7054 Background: Lenalidomide (LEN) is approved for patients with lower-risk MDS with del5q who are transfusion-dependent (TD). We aimed to assess the prevalence and complications associated with LEN use in non-TD older patients with MDS. Methods: Using the SEER-Medicare database we identified Medicare enrollees diagnosed with MDS from 2007-2011. Medicare part D claims were analyzed for evidence of LEN use. CPT, HCPCS, and ICD-9 codes were used to characterize TD MDS (claims for ≥ 2 RBC transfusions within 8 weeks prior to LEN), complications, and baseline risk per SEER-Medicare MDS Risk Score (SMMRS; Uno, Leuk Res 2014). Incident complications during LEN were noted if there were no prior claims for the same within a 1-yr look-back window. Results: Among 469 patients initiating LEN (median age 78 years), 77% received it first-line, and 23% after a hypomethylating agent. Among all, 19% had del5q, 37% had non-del5q MDS, and 44% no histology specified (MDS NOS). SMMRS risk was evenly distributed between low (36%), intermediate (30%), and high (34%). Only 42% of patients were TD at the time of first LEN prescription, and 26% had not been transfused within six months prior to LEN. Non-TD patients receiving LEN were more likely to have lower-risk disease (p = .004), and less likely to have pre-treatment thrombocytopenia (p = .005) or neutropenia (p = .003); they did not differ significantly in age (p = .85), documentation of del5q (p = .51), comorbidity (p = .65) or treatment center volume (p = .80). Median days on LEN for the non-TD was 121. Incident complications post-LEN among the non-TD are shown. Conclusions:These data suggest there is widespread off-label use of LEN in older patients with MDS, as many receive the drug who are not TD. Moreover, off-label exposure to LEN in these patients is associated with a sizable risk of incident complications, which is difficult to justify given they are already living free of transfusion dependence. [Table: see text]

Dyserythropoiesis of myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are heterogeneous diseases of the hematopoietic stem cell in the elderly. Anemia is the main symptom that mostly correlates with dysplastic erythropoiesis in the bone marrow. We will review the recent advances in understanding the diverse mechanisms of dyserythropoiesis. Dyserythropoiesis defined as 10% dysplastic erythroid cells in the bone marrow is found in more than 80% of early MDS. Immature erythroblasts accumulate at the expense of mature erythroblasts due to differentiation arrest and apoptosis. In early MDS with dyserythropoiesis, caspase-dependent cleavage of the erythroid transcription factor GATA-1 occurring in basophilic erythroblasts accounts for impairment of final maturation. Depending on initiating genetic alteration, specific mechanisms contribute to erythroid defect. In MDS with 5q deletion, the haploinsufficiency of ribosomal protein gene, RPS14, opposes the transition of immature to mature erythroblasts by inducing a p53-dependent ribosome stress, cell cycle arrest and apoptosis. Recent work identifies the activation of a p53-S100A8/9 innate immune pathway that both intrinsically and extrinsically contributes to defective erythropoiesis. In MDS with ring sideroblasts, a paradigm of dyserythropoiesis, a unique mutation in SF3B1 splicing factor gene induces a multiplicity of alterations at RNA level that deeply modifies the patterns of gene expression. Insights in the pathophysiology of MDS with dyserythropoiesis may guide the choice of the appropriate therapy, for instance lenalidomide in MDS with del(5q). A better understanding of the mechanisms of dyserthropoiesis is required to treat anemia in non-del(5q) MDS, especially in case of resistance to first-line therapy by erythropoiesis-stimulating agents.

Knockdown of HSPA9 induces TP53-dependent apoptosis in human hematopoietic progenitor cells.

Myelodysplastic syndromes (MDS) are the most common adult myeloid blood cancers in the US. Patients have increased apoptosis in their bone marrow cells leading to low peripheral blood counts. The full complement of gene mutations that contribute to increased apoptosis in MDS remains unknown. Up to 25% of MDS patients harbor and acquired interstitial deletion on the long arm of chromosome 5 [del(5q)], creating haploinsufficiency for a large set of genes including HSPA9. Knockdown of HSPA9 in primary human CD34+ hematopoietic progenitor cells significantly inhibits growth and increases apoptosis. We show here that HSPA9 knockdown is associated with increased TP53 expression and activity, resulting in increased expression of target genes BAX and p21. HSPA9 protein interacts with TP53 in CD34+ cells and knockdown of HSPA9 increases nuclear TP53 levels, providing a possible mechanism for regulation of TP53 by HSPA9 haploinsufficiency in hematopoietic cells. Concurrent knockdown of TP53 and HSPA9 rescued the increased apoptosis observed in CD34+ cells following knockdown of HSPA9. Reduction of HSPA9 below 50% results in severe inhibition of cell growth, suggesting that del(5q) cells may be preferentially sensitive to further reductions of HSPA9 below 50%, thus providing a genetic vulnerability to del(5q) cells. Treatment of bone marrow cells with MKT-077, an HSPA9 inhibitor, induced apoptosis in a higher percentage of cells from MDS patients with del(5q) compared to non-del(5q) MDS patients and normal donor cells. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to TP53 activation and increased apoptosis observed in del(5q)-associated MDS.

Outcome of patients treated for myelodysplastic syndromes without deletion 5q after failure of lenalidomide therapy.

Anemia is a key survival prognostic factor in lower-risk myelodysplastic syndromes (MDS). Lenalidomide (LEN) can correct anemia in 25% of MDS patients without deletion 5q (del5q). As this therapy will inevitably fail, understanding the outcome of these patients will facilitate development of subsequent treatment strategies. To answer this question, an international retrospective study focused on LEN-treated lower-risk, non-del5q, MDS patients was performed. We analyzed the overall survival after LEN failure, its prognostic factors and the impact of post LEN treatment options. We included a total of 384 patients. The median overall survival after failure of LEN was 43 months. In multivariate analysis, adverse cytogenetics, excess of blasts at the initiation of LEN, and the type of failure (classified as stable disease, relapse, intolerance, or progression) were the main determinants of outcome. Subsequent therapy with hypomethylating agents was associated with a prolonged survival compared to BSC (median OS= 51m vs. 36m, p=0.01). In conclusion, the survival for non-del5q MDS patients after failure of LEN remains relatively prolonged, though with a wide range. Clinical trial participation remains the recommendation for these patients even if options such as hypomethylating agents may be considered.

Effect of Lenalidomide (LEN) Exposure on Response and Outcomes in Patients (Pts) with Lower-Risk Non-Del(5q) Myelodysplastic Syndromes (MDS)

▪Introduction: In the phase 3 MDS-005 study, LEN treatment was associated with a significant increase in transfusion independence (TI) vs placebo (26.9% vs 2.5%; P < 0.001) (Santini et al. J Clin Oncol. 2016;pii:JCO.2015.66.0118) and greater clinical benefit vs placebo (31.9% vs 3.8%) (Garcia-Manero et al. Haematologica. 2016;101:abstract P252) in red blood cell (RBC) transfusion-dependent (TD) pts with lower-risk non-del(5q) MDS who were ineligible for or refractory to erythropoiesis-stimulating agents (ESAs). For pts with lower-risk del(5q) MDS, a starting dose of LEN 10 mg is recommended, followed by subsequent dose modifications in response to adverse events (AEs), in order to maximize duration of treatment and thereby improve pt outcomes. This study evaluated the relationship between LEN exposure, including dose reductions, and duration of treatment, and the clinical benefit to pts with lower-risk, non-del(5q) MDS in the multicenter, randomized, double-blind, phase 3 MDS-005 study.Methods: Eligible pts were age ≥ 18 years, had TD anemia due to International Prognostic Scoring System (IPSS)-defined Low- or Intermediate-1-risk MDS, lacked the del(5q) mutation, and were ineligible for or refractory to ESAs. Pts were randomized 2:1 to receive LEN 10 mg (n = 160) or placebo (n = 79) once daily (both in 28-day cycles). Pts randomized to LEN with creatinine clearance ≥ 40 to < 60 mL/min (n = 57) received LEN 5 mg. Cumulative dose, dose reductions, and discontinuations were recorded; association between these parameters and clinical benefit or RBC-TI was evaluated. Clinical benefit ≥ 8 weeks was defined as the composite endpoint of RBC-TI ≥ 8 weeks, or transfusion reduction of ≥ 4 units packed RBCs (pRBCs) ≥ 8 weeks, or hemoglobin (Hb) increase ≥ 1.5 g/dL ≥ 8 weeks (International Working Group 2006), or cytogenetic response (CyR). Rate of transfusion reduction was calculated using data collected during a 112-day assessment period to account for on-study differences in transfusion burden. LEN dose modifications due to AEs were defined in the study protocol. The analysis included all pts receiving LEN.Results: Of 160 LEN-treated pts included in the analysis, 77 (48.1%) underwent ≥ 1 LEN dose reduction. A total of 73 pts experienced ≥ 1 dose reduction due to AEs, amounting to 102 dose reductions overall. Of these AE-related dose reductions, 47 were due to neutropenia, 33 due to thrombocytopenia, and 2 due to other hematologic conditions. Median time to first dose reduction was 85 days (interquartile range [IQR] 50-114 days). A total of 145 LEN-treated pts discontinued therapy: 52 discontinued due to AEs; 32 discontinued before the end of cycle 3, of which 23 were due to AEs.Of the 77 pts who had ≥ 1 dose reduction, 6 (7.8%) pts had a dose reduction in the first cycle; 37 (48.1%) pts had dose reductions during cycles 1-3. During the first 3 cycles of LEN, pts with ≥ 1 dose reduction received a lower median dose than those with no dose reductions (385 mg [IQR 318-520 mg] vs 660 mg [IQR 415-840 mg]). However, when analyzed over the course of the entire study, pts undergoing ≥ 1 dose reduction received a higher median cumulative dose than those with no dose reductions (950 mg [IQR 595-1,435 mg] vs 715 mg [IQR 370-1,660 mg]). Duration of treatment was also longer for pts with ≥ 1 dose reduction vs those with no dose reductions (172 days [IQR 140-391 days] vs 92 days [IQR 46-168 days]).Pts with ≥ 1 dose reduction were more likely to achieve RBC-TI ≥ 8 weeks than pts with no dose reductions (39% vs 16%; odds ratio [OR] 3.44 [95% confidence interval {CI} 1.63-7.26]). Pts with ≥ 1 dose reduction were also more likely to achieve clinical benefit ≥ 8 weeks vs pts with no dose reductions (47% vs 18%; OR 3.98 [95% CI 1.94-8.15]).Conclusions: In this post hoc analysis of the MDS-005 study, pts undergoing ≥ 1 LEN dose reduction had a longer duration of treatment, and were more likely to achieve RBC-TI and the composite endpoint of clinical benefit (RBC-TI ≥ 8 weeks, transfusion reduction ≥ 4 units pRBCs ≥ 8 weeks, Hb increase ≥ 1.5 g/dL ≥ 8 weeks, or CyR) than pts with no dose reductions. DisclosuresSantini:Novartis: Consultancy, Honoraria; Onconova: Other: advisory board; Amgen: Other: advisory board; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex: Other: advisory board. Almeida:BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Shire: Speakers Bureau. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding. Gatterman:Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Heinrich-Heine-Universitat Dusseldorf: Employment. Ozawa:Sumitomo Dainippon Pharma Co. Ltd: Research Funding; JCR Pharmaceutical Inc: Consultancy; Celgene Japan: Consultancy; Takara Bio Inc: Research Funding. Goldberg:COTA Inc: Employment; Novartis: Consultancy; Pfizer: Honoraria; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership. Weaver:Celgene Corporation: Employment, Equity Ownership. Sugrue:Celgene Corporation: Employment, Equity Ownership.

Combined Treatment with Lenalidomide (LEN) and Epoetin Alfa (EA) Is Superior to Lenalidomide Alone in Patients with Erythropoietin (Epo)-Refractory, Lower Risk (LR) Non-Deletion 5q [Del(5q)] Myelodysplastic Syndrome (MDS): Results of the E2905 Intergroup Study-an ECOG-ACRIN Cancer Research Group Study, Grant CA180820, and the National Cancer Institute of the National Institutes of Health

▪Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo.Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin <9.5 g/dL who were unresponsive to rhEpo treatment or were TD (>2 units/mo) with serum Epo >500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers.Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (< median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of >Grade 3, non-hematologic AEs.Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. DisclosuresBennett:Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.

Icare 1: A Prospective Clinical Trial to Predict Treatment Response Based on Mutanome-Informed Computational Biology in Patients with AML and MDS

Background: Hypomethylating agents (HMAs) (e.g., azacitidine (aza), decitabine (dec)) and lenalidomide (len) are approved agents and used in the treatment of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Despite their widespread use, HMAs fail in the majority of MDS and AML patients, and len fails in 75% of non-del(5q) MDS. Unfortunately, no method exists to predict disease response, thus the management of MDS and AML patients is challenging. Predicting treatment response would improve treatment effectiveness, restrict treatment-related adverse events to those who would benefit, and reduce health care costs. Ideally, patient prediction would be based on disease biology.Aim: To determine the biological and clinical predictive values of a genomics-informed computational biology method in patients with AML and MDS who are treated with aza, dec or len.Methods: Patients with AML or MDS were recruited in a prospective clinical trial (NCT02435550) designed to assess predictive values by comparing computer predictions of treatment response to actual clinical response. Genomic profiling was conducted by conventional cytogenetics, whole exome sequencing (SureSelectXT Clinical Research Exome, Agilent), and array CGH (Agilent). These genomic results were inputted into computational biology software (Cellworks Group), which generates disease-specific protein network maps using PubMed and other online resources. Digital drug simulations were conducted by quantitatively measuring drug effect on a cell growth score, which is a composite of cell proliferation, viability and apoptosis. Each patient-specific protein network map was digitally screened for the extent by which aza, dec or len reduced simulated disease growth in a dose-respondent manner. Treatment was physician's choice based on SOC. Before initiating treatment, treating physicians were masked to the results of whole exome sequencing and computational predictions. Clinical outcomes were prospectively recorded. To be eligible for efficacy assessment, patients must have had at least 4 cycles of HMA treatment or 2 cycles of len treatment. For AML, CR+PR was used to define response (IWG 2003). For MDS, CR+PR+HI was used to define response (IWG 2006). To validate the predicted protein network perturbations, Western blot assays were performed on pertinent pathway proteins. Comparisons of computer-predicted versus actual responses were performed using 2x2 tables, from which prediction values were calculated. Fisher's exact test was used to compare prediction values of the genomics-informed computer method versus empiric drug administration.Results: Between June 2015 and June 2016, 80 patients were recruited. 40/80 (50%) had AML and 40/80 had MDS (50%). The median age was 66 (range 24-91). 44/80 (55%) were treatment-naïve and 36/80 (45%) were treatment-refractory. 99% completed all planned molecular tests and computational analyses. Laboratory validation study of computer-predicted, activated protein networks in 19 samples from 13 different patients showed correct prediction of 5 activated networks (Akt2, Akt3, PIK3CA, p38, Erk1/2) in 17 samples, exhibiting 89% accuracy. At the time of this report, 20/80 patients were eligible for efficacy evaluation. 6/20 patients showed clinical response to SOC therapy, while 14/20 did not achieve clinical response. 18 patients’ outcome predictions were correctly matched to their actual clinical outcomes, and 2/20 were incorrectly matched, resulting in 90% prediction accuracy, 75% positive predictive value (PPV), 100% negative predictive value (NPV), 100% sensitivity, and 86% specificity. The accuracy of the genomics-informed computer method was significantly greater than empiric drug administration (p=1.664e-05). New genomic signature rules were discovered to correlate with clinical response after aza, dec or len.Conclusions: A computational method that models multiple genomic abnormalities simultaneously showed high predictive value of protein network perturbations and clinical outcomes after standard of care treatments. The network method uncovered molecular reasons for drug failure and highlighted resistance pathways that could be targeted to recover chemosensitivity. This technology could also be used to establish eligibility criteria for precision enrollment in drug development trials. DisclosuresVali:Cellworks Group: Employment. Abbasi:Cellworks: Employment. Kumar:Cellworks group: Employment. Kumar Singh:Cellworks group: Employment. Basu:Cellworks Group: Employment. Kumar:Cellworks Group: Employment. Husain:Cellworks Group: Employment. Wingard:Ansun: Consultancy; Merck: Consultancy; Fate Therapeutics: Consultancy; Astellas: Consultancy; Gilead: Consultancy.

A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes.

Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.

Treatment-emergent adverse events (TEAEs) in lenalidomide (LEN)-treated Low-/Int-1-risk myelodysplastic syndromes (MDS) patients (pts) without del(5q) ineligible for or refractory to erythropoiesis-stimulating agents (ESAs).

7061Background: In the phase 3 MDS-005 study of LEN in RBC transfusion-dependent lower-risk non-del(5q) MDS pts ineligible for or refractory to ESAs, a significantly higher proportion of LEN-treated pts achieved RBC transfusion independence ≥ 8 weeks vs placebo (P< 0.001). Here, we describe frequency, timing, and management of TEAEs in pts from MDS-005. Methods: AEs of all 160 pts randomized to LEN who received ≥ 1 dose were reported per NCI-CTCAE v3.0. Results: Median duration of LEN treatment was 164 days (range 7–1,158). Grade (G)1/2 and G3/4 TEAEs were reported in 96.9% and 86.3% of pts, respectively. The most common G3/4 TEAEs were neutropenia (61.9%), thrombocytopenia (35.6%), anemia (5.6%), pneumonia (5.6%); G3/4 deep vein thrombosis (DVT) occurred in 1.9%. G3/4 neutropenia and thrombocytopenia generally occurred in cycles 1–4. The most common G1/2 TEAEs were diarrhea (42.5%), constipation (22.5%), asthenia (21.9%), rash (21.3%), fatigue (20.6%), peripheral edema (20.6%). TEAEs led to 54.4% dose in...