ALBERT

Description: Introduction PF-04449913 is a potent and selective inhibitor of the Hedgehog signaling pathway through binding to the target, Smoothened (SMO). PF-04449913 inhibits Hedgehog (Hh) signaling ex vivo and has demonstrated anti-tumor activity in vivo. PF-04449913 is currently under clinical evaluation in the AML and high risk MDS patient populations, who receive anti-fungal agents routinely as prophylaxis. The preferred anti-fungal agents are azoles which are known strong CYP3A4 inhibitors. Preliminary assessment using individual recombinant P450 enzymes suggests that CYP3A4 plays a major role in mediating the metabolism of PF-04449913. Preliminary results show that PF-04449913 does not inhibit CYPs .Thus, one of the goals of this study was to understand the potential drug-drug interaction (DDI) impact of a strong CYP3A4 inhibitor (ketoconazole) on PF-04449913 plasma exposure to provide dosing guidance. An additional objective was to estimate the effect of a high fat, high calorie meal on single dose PF-04449913 plasma pharmacokinetics (PK). Methods This was an open label, 2-sequence, 3-period, 3-treatment arm, single dose, crossover study in healthy volunteers. Subjects were randomized to receive single doses of 200 mg PF-04449913 in either the fasted or fed state during Periods 1 or 2 with a washout period of at least 8 days between treatments. Subsequently, in Period 3, all subjects received a fixed regimen of ketoconazole (400 mg/day) from Days 1 to 7 and a co-administered single 200 mg PF-04449913 dose on Day 4. Serial blood sampling to determine plasma concentrations of PF-04449913 was performed to 120 hours post dose in Periods 1 and 2, and to 144 hours post dose in Period 3. PF-04449913 in the fasted state was the Reference treatment for both comparisons, while PF-04449913 in the fed state and PF-04449913 + ketoconazole were the Test treatments. Natural log transformed AUCinf (area under the plasma concentration versus time curve from time zero to infinity) and Cmax (maximum observed plasma concentration) for PF-04449913 were analyzed using a mixed effects model with sequence, period and treatment as fixed effects and subject within sequence as a random effect for the effect of food. For the DDI, natural log transformed AUCinf and Cmax for PF-04449913 were analyzed using a mixed effects model with treatment as a fixed effect and subject as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences from both models were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. Results PF-04449913 exposure was increased in the presence of ketoconazole, with a geometric mean ratio for AUCinf of 2.40 (90% CI: 2.15 -2.68) and for Cmax of 1.40 (90% CI: 1.24-1.58). For PF-04449913 alone and with ketoconazole, Cmax occurred 1.0 and 2.0 hours after dosing, respectively. The geometric mean ratio for AUCinf for fed state compared to the fasted state was 0.87 (90% CI: 0.78 -0.97) and for Cmax was 0.66 (90% CI: 0.56-0.78). In the fasted and fed state, the PF-0444913 Cmax occurred at 1.0 and 4.0 hours after dosing, respectively. All adverse events (AE) were mild in severity except for one case of moderate AE accelerated idioventricular rhythm in an individual with underlying cardiac issues, which was classified as non-treatment related. Conclusions PF-04449913 plasma exposures and peak concentrations were increased (2.40-fold for AUCinf and 1.40-fold for Cmax) following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for the PF-04449913 plasma exposures expected with potent metabolic inhibition and define PF-04449913 dosing parameters in AML and high-risk MDS patient trials. While PF-04449913 plasma exposures and peak concentrations were decreased following administration of PF-04449913 in the fed state, the difference in exposures under the fed and fasted conditions was not considered clinically meaningful. Disclosures: Shaik: Pfizer: Employment, Stock Other. LaBadie:Pfizer: Employment, Stock Other. Rudin:Pfizer: Employment. Levin:Pfizer Oncology Business Unit: Employment.

Description: Introduction: Glasdegib is an inhibitor of the Hedgehog signaling pathway through binding to its target, Smoothened (SMO). B1371003 was a Phase 1b/2 study evaluating glasdegib in combination with chemotherapy in patients with acute myeloid leukemia (AML). In one part of the Phase 2 portion of B1371003, patients who were not candidates for more standard chemotherapy were randomized 2:1 to receive low-dose cytarabine (LDAC) with glasdegib or LDAC alone. The primary endpoint was overall survival (OS). A Cox regression analysis for overall survival (OS) was conducted, and median OS for AML patients treated with glasdegib plus LDAC was 8.3 months compared to 4.3 months with LDAC alone (hazard ratio [HR] 0.463). This analysis aimed to assess the potential relationship between glasdegib exposure and OS (exposure-response [ER]) and to evaluate the effect on OS of moderators/covariates, including treatment-response (TR) for glasdegib + LDAC vs. LDAC alone. Methods: The analyses included data from the Phase 2 non-intensive AML patients. Glasdegib was administered continuously at 100 mg once daily (QD) orally in 28-day cycles. LDAC was administered subcutaneously at 20 mg twice daily on Days 1-10 of each 28-day cycle. Glasdegib exposure from the glasdegib + LDAC treated arm was estimated utilizing a population pharmacokinetics (PK) model. Survival was assessed at every visit then every month for the first 2 months after discontinuation from study treatment and thereafter every 2 months until death or termination of the study. Parametric time-to-event survival models were used to assess the relationship between OS, treatment arm, and glasdegib exposure. Baseline characteristics (such as age, sex, body weight, and white blood cell count) and other prognostic factors (such as disease status and treatment arm) were evaluated as potential predictors of OS by forward inclusion and backward elimination. R statistical programming (version 3.2.2) and NONMEM software (version 7.3.0) were used for the analysis. Results: Glasdegib PK was adequately characterized by a 2-compartment model with first order absorption kinetics. Demographic and baseline characteristics such as age, sex, body weight, and renal and hepatic function were either non-significant or did not have a clinically relevant impact on glasdegib PK. The TR analysis included all Phase 2 AML patients with available OS data who were randomized to receive LDAC with (n=78) or without (n=38) glasdegib. Glasdegib-treated patients with at least one PK observation (n=75) were evaluated in the ER analysis. Exponential, Weibull, and log-logistic parametric distributions were explored, and the exponential distribution was selected as the model that best described the observed OS data (Figure). In the TR analysis, addition of glasdegib to LDAC resulted in longer OS with HR of 0.42 (95% confidence interval: 0.28-0.66). No ER relationship was identified in the analysis between glasdegib plasma exposures at 100 mg QD and OS. No other baseline characteristics were identified as potential predictors of survival in either the TR or ER analyses. Conclusions: Addition of glasdegib treatment to LDAC chemotherapy in AML patients who are not suitable for intensive chemotherapy significantly prolonged OS compared to LDAC chemotherapy alone. Across the range of plasma exposures for glasdegib 100-mg QD treatment, no ER relationship was identified. No other covariates were found to be predictors of survival, therefore supporting the broad use of glasdegib as an addition to chemotherapy in AML patients. Disclosures Lin: Pfizer: Employment. Shaik:Pfizer Inc: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding. Ruiz-Garcia:Pfizer: Employment, Equity Ownership.

Description: Abstract 3396 Chronic myeloid leukemia (CML) is characterized by the BCR/ABL fusion gene. However, secondary molecular events leading to accelerated (AP) or blast phase (BP) have not been sufficiently clarified. We hypothesized that, in analogy to other MDS/MPN or MPN, TET2, ASXL1, CBL and IDH family mutations may also occur in CML and contribute as secondary events leading to progression to AP or BP. Similarly, higher resolution of cytogenetic testing by single nucleotide polymorphism array (SNP-A)-based karyotyping may reveal additional chromosomal abnormalities associated with stepwise progression. This study is focused on the combined analysis of chromosomal lesions and mutations associated with AP, BP and Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL) and the association of these defects with clinical features. We screened TET2, ASXL1, CBL and IDH for mutations in AP (N=14) and BP (N=26) and Ph+ ALL (N=9). Chronic phase (CP) (N=14) and Ph negative ALL (N=9) served as controls. We identified 3 CBL family (9%), 7 TET2 (21%), 2 ASXL1 (6%) and 2 IDH family (6%) mutations in patients with AP and myeloid BP. Subsequently, we also detected a TET2 mutation in a case of Ph+ ALL. None of these mutations were found in patients with CP or Ph negative ALL. We also performed SNP-A-based karyotyping and only included lesions which did not overlap with copy number variations (CNVs) or germ line regions of homozygosity present in any of the controls. 23 gains, 21 losses and 4 regions of somatic UPD lesions were identified. By SNP-A, additional copy number abnormalities, including microdeletions were found in 67% and 50% of patients with AP and BP, respectively. Recurrent lesions were detected on chromosome 1, 8, 9, 17 and 22. Microdeletions on chromosome 17 and 21 involved tumor associated genes NF1 and RUNX1. Deletions flanking the ABL1 and BCR genes were observed in 3 cases with der(22)t(9;22) or der(9)t(9;22) by metaphase cytogenetics. Gains including 1q25.3q41, chromosome 8 and 17q24.3 were found in 3 cases. Regions of UPD included UPD5q, 8q, 11p and 17q but no UPD involving 11q (CBL) and 4q (TET2) regions were found confirming heterozygous nature of the corresponding mutations. Newly detected molecular lesions associated with AP and BP may change the biology and thereby clinical features of affected cases. Overall survival of patients with mutations did not differ from those without mutations. Of note is that BCR/ABL1 kinase domain mutations were detected in 9/10 patients with imatinib resistance. In these 9 cases, 3 TET2 and 2 CBLB mutations were detected (but no mutations in the other genes). In an imatinib-resistant patient without BCR/ABL1 kinase domain mutation, CBL mutation was present. In the patients with TET2 mutations, additional chromosomal lesions were found by SNP-A, significantly more frequently when compared with WT cases (P=0.017). Of the 9 TET2 variants in 8 cases, 7 (78%) were missense substitutions, 1 (11%) was frame shift and 1 (11%) produced a stop codon and were located within the N-terminus as well as in a conserved DSBH 2OG-Fe(II)-dependent dioxygenase domain. The presence of nonsense and frameshift mutations suggests that mutated lesions result in inactivation, consistent with putative tumor suppressor functions, while heterozygous mutations indicate that the wild type allele is not completely protective. Since no TET2 mutations were identified in chronic phase CML, these mutations might represent an additional pathogenic event and contribute to progression. In 3 cases we observed a combination of 2 mutations. Coincidence of CBLB and TET2 mutations in 2 cases suggests that these might cooperate in the evolution of advanced phase of CML. We also found a combination of IDH1 and ASXL1 mutations in a patient with BP, suggesting that both mutations contribute to clonal advantage. In conclusion, while CBL family, ASXL1 and IDH family mutations as well a additional unbalanced chromosomal abnormalities not seen by metaphase cytogenetics can occur in myeloid type advanced phase CML, TET2 mutations were identified in Ph+ ALL, as well as myeloid BP and AP. These mutations likely represent secondary lesions which contribute to either disease progression or more aggressive features and commonly occur in association with imatinib-resistant BCR/ABL mutations. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: The prevalence of iron deficiency (ID) without anemia is unknown. Iron is a vital constituent of hemoglobin, myoglobin, and some mitochondrial enzymes and its deficiency may result in reduced aerobic capacity. A few clinical studies have shown improvement in exercise performance after replacement of iron in subjects (subs) with ID and no anemia. As maximum oxygen consumption (Vo2 max) is the gold standard laboratory measure of cardiorespiratory fitness, in this study we investigated the prevalence of ID without anemia in general population and the effect of iron deficiency on Vo2 max in non-anemic subjects. Methods Data is obtained from continuous National Health and Nutrition Examination Survey (NHANES) 1999-2003, a nationally representative health survey combined with examination of non-institutionalized healthy subs. The data regarding demographics, age, race and smoking status, complete blood count, ferritin and estimated Vo2 max was obtained from questionnaires, laboratory and examination datasets respectively. The subs with normal hemoglobin were divided in to two groups based on ferritin level: Group A (GpA); ferritin ≤20 ng/mL, Group B (GpB); ferritin 〉20 ng/mL. Based on Vo2 max level subs were divided into: 'below average' (Vo2 max ≤ 30 ml/kg/min), and 'average' (Vo2 max 〉30 ml/kg/min). The prevalence of ID without anemia was obtained using chi-square test. The correlation of Vo2 max and ferritin was obtained using linear regression. Odds ratio (OR) of ID with low Vo2 max was obtained using logistic regression after adjusting to age, race, gender and smoking. NHANES is a complex multistage probability sampling, and sampling weights were used in this analysis. P-value 20) (n=2184) Median age 25 29 Median Hematocit 39.2 44.5 Median RDW 12.5 12.2 Median Platelets 281 262 Median WBC 6.9 6.9 Median Neutrophils 4.1 4.0 Vo2 max 36.5 40.8 Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Iron deficiency (ID) is the most common nutritional deficiency in the world and remains relatively common in at-risk groups in the United States. The development of (ID) is dependent upon the individual's iron stores which is a balance between iron absorption and loss. Commonly associated with (ID) is iron deficiency anemia (IDA) which has a well known association with fatigue. Fatigue is a common complaint in general, with a prevalence in population-based surveys in Great Britain and the United States of 6.0 and 7.5 % respectively. However it is not uncommon to have (ID) without subsequent anemia in females childbearing age group. Our study aims to evaluate the prevalence of ID in non anemic females of childbearing age and its association with fatigue. Methods: Data was obtained from continuous NHANES database, a nationally representative health survey conducted from 2005-2010. The data including age, race, complete blood count (CBC), ferritin and fatigue was obtianed from laboratory and questionnaire datasets, respectively. Subjects were further divided based on ferritin levels into two groups, Group A; ferritin ≤20 ng/mL and Group B; ferritin 〉20 ng/mL. The question regarding fatigue- "feeling tired or having little energy for past two weeks" was obtained from PHQ-9 scale. Univariate analysis was done comparing Group A and Group B using chi-square test and t-test for categorical and numerical variables, respectively. The effect of iron deficiency on fatigue was obtained using logistic regression to calculate odds ratio (OR) after adjusting for age and race. Results: Of 3230 female subjects( age 18yrs -49yrs), there were 809 with ID with no anemia. The weighted prevalence of iron deficiency in non-anemic women of childbearing age was 22.5% (95% CI 20.76-24.22). The weighted prevalence of fatigue in Group A and Group B was 61.8% (95% CI 56.4-67.2) and 59.7 % (95%CI 57-62.4) respectively (p=0.45)(table 1). In multivariate analysis, after adjusting for age and race, the odds ratio (OR) for fatigue with iron deficiency was 1.1 ( 95% CI 0.8-1.4). Conclusion: The prevalence of ID in non anemic females of childbearing age in the United States was 22.5 % .The percentage of subjects who reported fatigue was significantly high in both iron deficient and non-iron deficient subjects in this age group. There was no statistical difference in self-reported fatigue in both iron deficient and non-iron deficient women of childbearing age. Further studies are needed to validate our findings. Table 1. Comparision of GpA and GpB Variables Ferritin≤ 20 ng/mL (GpA) Ferritin 〉 20 ng/mL Fatigue - Yes 512 1452 Fatigue - No 297 986 Total 809 2421 Disclosures No relevant conflicts of interest to declare.

Description: T-cell large granular lymphocyte leukemia (T-LGLL) is characterized by chronic lymphoproliferation of cytotoxic T lymphocytes (CTLs) and is associated with lineage-restricted cytopenias. Introduction of T-cell receptor (TCR) variable β-chain (Vβ) monoclonal antibodies has facilitated identification and enumeration of clonal CTLs by flow cytometry. A highly skewed TCR Vβ repertoire identified by flow cytometry is strongly associated with monoclonal CDR3 regions by quantitative sequencing and positive TCRγ rearrangement assays. Therefore, Vβ expansions can serve as surrogate markers of CTL clonality to assess clonal kinetics in T-LGLL. We analyzed the TCR repertoire in 143 patients, 71 of which were available for serial measurements over 6 to 96 months. Although the majority (38/71, 54%) maintained a consistent monoclonal expansion, many (26/71, 37%) unexpectedly displayed a change in the dominant clone, whereby the original CTL clone contracted and another emerged as demonstrated by Vβ typing. Our results demonstrate that the T-cell repertoire is more dynamic in T-LGLL than recognized previously, illustrating the heterogeneity of disorders under this categorization.

Description: Platelet hyperactivity associated with hyperlipidemia contributes to development of a pro-thrombotic state. We previously showed that oxidized LDL (oxLDL) formed in the setting of hyperlipidemia and atherosclerosis initiated a CD36-mediated signaling cascade leading to platelet hyperactivity. We now show that the guanine nucleotide exchange factors Vav1 and Vav3 were tyrosine phosphorylated in platelets exposed to oxLDL. Pharmacologic inhibition of src family kinases abolished Vav1 phosphorylation by oxLDL in vitro. Coimmunoprecipitations revealed the tyrosine phosphorylated form of src kinase Fyn was associated with Vav1 in platelets exposed to oxLDL. Using a platelet aggregation assay, we demonstrated that Vav1 deficiency, Fyn deficiency, or Vav1/Vav3 deficiency protected mice from diet-induced platelet hyperactivity. Furthermore, flow cytometric analysis revealed that Vav1/Vav3 deficiency significantly inhibited oxLDL-mediated integrin αIIbβIII activation of platelets costimulated with ADP. Finally, we showed with an in vivo carotid artery thrombosis model that genetic deletion of Vav1 and Vav3 together may prevent the development of occlusive thrombi in mice fed a high-fat diet. These findings implicate Vav proteins in oxLDL-mediated platelet activation and suggest that Vav family member(s) may act as critical modulators linking a prothrombotic state and hyperlipidemia.

Description: Endorepellin, the C-terminal domain of perlecan, is a powerful angiogenesis inhibitor. To dissect the mechanism of endorepellin-mediated endothelial silencing, we used an antibody array against multiple tyrosine kinase receptors. Endorepellin caused a widespread reduction in phosphorylation of key receptors involved in angiogenesis and a concurrent increase in phosphatase activity in endothelial cells and tumor xenografts. These effects were efficiently hampered by function-blocking antibodies against integrin α2β1, the functional endorepellin receptor. The Src homology-2 protein phosphatase-1 (SHP-1) coprecipitated with integrin α2 and was phosphorylated in a dynamic fashion after endorepellin stimulation. Genetic evidence was provided by lack of an endorepellin-evoked phosphatase response in microvascular endothelial cells derived from integrin α2β1−/− mice and by response to endorepellin in cells genetically engineered to express the α2β1 integrin, but not in cells either lacking this receptor or expressing a chimera harboring the integrin α2 ectodomain fused to the α1 intracellular domain. siRNA-mediated knockdown of integrin α2 caused a dose-dependent reduction of SHP-1. Finally, the levels of SHP-1 and its enzymatic activity were substantially reduced in multiple organs from α2β1−/− mice. Our results show that SHP-1 is an essential mediator of endorepellin activity and discover a novel functional interaction between the integrin α2 subunit and SHP-1.

Description: Abstract 860 Background: PD 0332991, the only known selective inhibitor of cyclin-dependent kinase (CDK) 4/6, is reversible and orally bioavailable. Inhibition of CDK4/6 phosphorylation of retinoblastoma (Rb) induces prolonged early G1 cell cycle arrest and synchronous progression to S phase upon withdrawal, which sensitizes human multiple myeloma (MM) cells to killing by bortezomib (B) or dexamethasone (D) in vitro and in animal models. This multicenter phase I trial is investigating the combination of PD 0332991 with these agents in MM during prolonged G1 arrest alone (Schedule A) or together with synchronization into S phase (Schedule B). The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of PD 0332991 and the schedule for combination. Methods: Adults with Rb protein-positive, symptomatic, relapsed and/or refractory MM (International Myeloma Working Group [IMWG] definition) after ≥1 prior treatment were eligible. Patients (pts) received oral PD 0332991 once daily on Days 1–21 of a 28-day cycle (Schedule A) or Days 1–12 of a 21-day cycle (Schedule B) for a maximum of 10 cycles. The starting dose of PD 0332991 was 100 mg, with planned escalation to 125 mg or de-escalation to 75 mg. Intravenous B 1.0 mg/m2 (with planned escalation to 1.3 mg/m2) and oral D 20 mg were administered on Days 8, 11, 15, and 18 on both schedules. A 3+3 dose-escalation scheme was used. The MTD was defined as the dose level at which ≤1/6 pts experienced dose-limiting toxicity (DLT), with the next higher dose level having ≥2/3 or ≥2/6 pts with DLTs. The RP2D was determined based on the MTD and overall safety and tolerability. The primary endpoint was first-cycle DLTs; tumor response (per IMWGURC) and PD 0332991-mediated inhibition of CDK4/6 activity and cell proliferation by immunohistochemistry (IHC) of CDK4/6-specific phosphorylation of Rb (pSRb) and Ki67, respectively, in bone marrow MM cells were secondary endpoints. The effects of B and D on PD 0332991 pharmacokinetics were also evaluated. Results: Twenty-one pts were enrolled: 9 on Schedule A (3 on PD 0332991 100 mg and 6 on 75 mg); 12 on Schedule B (7 on 100 mg and 5 on 125 mg). Sixty-seven percent of pts had an Eastern Cooperative Oncology Group performance status of 1. At baseline, median β2 microglobulin was 3.9 (range 1.6–14.8), median hemoglobin was 10.9 (7.3–13.4), and median calcium was 9.1 (6.6–11.5). The median number of prior therapies was 4 (range 1–9); 86% had received prior B. Eighteen pts have discontinued (14 due to progressive disease; 4 due to an adverse event [AE]). On Schedule A, 2/3 pts on PD 0332991 100 mg and 2/6 pts on 75 mg experienced DLTs (inability to receive ≥80% of PD 0332991 or B doses due to treatment-related toxicity), thus the MTD was not determined. On Schedule B, 1/6 DLT-evaluable pts on 100 mg and 2/4 on 125 mg experienced DLTs, and the MTD was determined to be PD 0332991 100 mg plus B 1.0 mg/m2 and D 20 mg. The most common treatment-related AEs were grade ≥3 thrombocytopenia (n=13) and neutropenia (n=7). There were no pts with QTc intervals 〉500 msec observed on study. The mean plasma AUC(0–12) of PD 0332991 was 539 ng · h/mL in the absence and 555 ng · h/mL in the presence of B and D (n=6). IHC showed preferential and complete (13/16 pts) or 〉80% (3/16 pts) inhibition of both pSRb and Ki67 in bone marrow MM cells before initiation of B and D treatment on Day 8, and cell cycle progression following PD 0332991 withdrawal on Day 18 of Schedule B (7/7 pts). One pt achieved a very good partial response (VGPR), 1 achieved a PR, and 3 had stable disease ≥3 months. Conclusions: In this first phase I trial of PD 0332991 in combination therapy, the MTD and RP2D have been determined to be PD 0332991 100 mg plus B 1.0 mg/m2 and D 20 mg on Schedule B in MM. The most commonly reported AEs were cytopenias, consistent with the known safety profiles of PD 0332991 and B. B and D had no apparent impact on the plasma AUC(0–12) of PD 0332991. Regardless of treatment history, PD 0332991 preferentially and completely inhibited CDK4/6 and cell cycle progression in MM cells, and this was reversible. Encouraging antitumor activity was observed in this heavily pretreated MM population, including VGPR in a pt with t(4:14) who had relapsed on lenalidomide, bortezomib, and carfilzomib therapies and a stem cell transplant. The phase II portion of the trial to evaluate the antitumor activity of targeting CDK4/6 with PD 0332991 using the Schedule B combination is underway. Disclosures: Niesvizky: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Research Funding. Lentzsch:Celgene Corp: Research Funding. Singhal:Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding; Celgene: Speakers Bureau. Zonder:Millennium: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Consultancy, Research Funding; Celgene: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event; Novartis: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event; Proteolix: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event. Courtney:Pfizer: Employment, Equity Ownership. Shaik:Pfizer Inc: Employment, Equity Ownership. Kim:Pfizer Inc.: Employment, Equity Ownership. Randolph:Pfizer: Employment, Equity Ownership.

Description: In aplastic anemia (AA), contraction of the stem cell pool may result in oligoclonality, while in myelodysplastic syndromes (MDS) a single hematopoietic clone often characterized by chromosomal aberrations expands and outcompetes normal stem cells. We analyzed patients with AA (N = 93) and hypocellular MDS (hMDS, N = 24) using single nucleotide polymorphism arrays (SNP-A) complementing routine cytogenetics. We hypothesized that clinically important cryptic clonal aberrations may exist in some patients with BM failure. Combined metaphase and SNP-A karyotyping improved detection of chromosomal lesions: 19% and 54% of AA and hMDS cases harbored clonal abnormalities including copy-neutral loss of heterozygosity (UPD, 7%). Remarkably, lesions involving the HLA locus suggestive of clonal immune escape were found in 3 of 93 patients with AA. In hMDS, additional clonal lesions were detected in 5 (36%) of 14 patients with normal/noninformative routine cytogenetics. In a subset of AA patients studied at presentation, persistent chromosomal genomic lesions were found in 10 of 33, suggesting that the initial diagnosis may have been hMDS. Similarly, using SNP-A, earlier clonal evolution was found in 4 of 7 AA patients followed serially. In sum, our results indicate that SNP-A identify cryptic clonal genomic aberrations in AA and hMDS leading to improved distinction of these disease entities.