ALBERT

Description: Abstract 4010 Patients with IPSS intermediate or high risk myelodysplastic syndrome (MDS) have few treatment options once their disease fails to respond to hypomethylating agent therapy. The styryl sulfone mitotic inhibitor ON 01910.Na, inhibits Polo-1 kinase, PI3-kinase and AKT pathways, and the drug has shown promising results in patients (pts) with advanced solid tumors (Jimeno et al, J Clin Onc 26:5504, 2008) and in Phase I/II studies of MDS pts, including those with trisomy 8 (Sloand at al, Proc ASH 2007, #822, Proc ASH 2008, #1651). In an ongoing Phase II clinical trial, we have treated 10 MDS pts unresponsive to at least 4 cycles (range 4–12 cycles) of hypomethylating agent therapy (5 post-azacytidine, 4 post-decitabine, and 1 pt treated with both agents) with ON 01910.Na. The pts had IPSS Intermediate-1 (n=3), Intermediate-2 (n=4) and High (n=3) risk MDS. The study cohort comprised pts with RAEB-1 (4 pts), RAEB-2 (3 pts) and RAEB-T (3 pts), with a median age of 80 years (range 65–86) and 2.3 year median (range 0.4–5.4) prior duration of MDS. Their cytogenetic profile included 5 pts with Good, 4 with Intermediate [t(8,10), t(14,18), +8, and (8+, 19+)], 1 with Poor risk cytogenetics (+8, 5q-, 1p-). At baseline, all pts were red blood cell transfusion-dependent. After the initial 2 pts were treated with 800mg/m2/day × 2day continuous IV infusion (CIVI)/week × 3weeks/month, the subsequent 8 patients received 1800mg/day × 3day CIVI q2weeks/month × 2 months, then monthly. Patients underwent bone marrow sampling and evaluation after every other cycle of treatment. To date, 7 pts have completed at least 2 cycles of therapy, with 2 pts having completed the full treatment course of 7 monthly cycles (median 4.7 for all pts). Responses according to IWG 2006 criteria were: Marrow CR (mCR) (2), Partial response (1), stable disease (SD) with hematologic improvement (HI) (2; 1 HI-E, N, 1 HI-P, N) = 5/10 overall responses (50%). Four pts had SD without HI, 1 pt progressed to AML. mCRs occurred in those with

Description: Background Outcomes for patients with DLBCL have improved over the past decade, with the addition of rituximab to CHOP or CHOP-like multi-agent chemotherapy regimens improving the 3-year overall survival (OS) of patients by 10-16% compared to multi-agent chemotherapy alone (Coiffier 2002; Pfreundschuh 2010). However, patients with high-intermediate or high-risk disease have relatively poor outcomes with the standard RCHOP regimen (Ziepert 2010); in a recent prospective trial of intermediate- and high-risk DLBCL patients, complete response (CR) rate for RCHOP alone was 26% (Hainsworth 2011). Brentuximab vedotin (ADCETRIS®) is an antibody-drug conjugate comprising the antibody cAC10, specific for human CD30, covalently attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. Brentuximab vedotin has demonstrated compelling activity as a single agent in patients with relapsed or refractory DLBCL, even those with low CD30 expression (Bartlett 2013). This phase 2, randomized, open label study is designed to evaluate the antitumor activity and safety of brentuximab vedotin (1.2 or 1.8 mg/kg) when administered in combination with standard RCHOP chemotherapy (A+RCHOP) for the front-line treatment of patients with CD30-unselected high-intermediate/high-risk (standard IPI score 3–5 or age-adjusted IPI [aaIPI] score 2–3) DLBCL (ClinicalTrials.gov NCT01925612). Methods Patients were randomized to receive up to 6 cycles of either 1.2 or 1.8 mg/kg brentuximab vedotin administered IV on Day 1 of every 21-day cycle in combination with RCHOP; prednisone was administered orally on Days 1-5 of every 21-day cycle. Assessments included disease response per Cheson 2007, as evaluated by the investigator, surveillance of adverse events (AEs), physical examination findings, and laboratory testing. The primary endpoints for this study are the CR rate at the end of treatment (EOT) and the type, incidence, and severity of AEs. Key secondary endpoints include objective response rate (ORR), progression-free survival (PFS), and OS. Results At the time of the planned interim analysis, 33 patients were enrolled (17 patients, 1.2 mg/kg A+RCHOP; 16 patients, 1.8 mg/kg A+RCHOP). Median age for all patients was 66 years (range, 21 to 81). At baseline, 36% were high-risk (IPI 4-5, aaIPI 3) and 64% were high-intermediate risk (IPI 3, aaIPI 2). The majority of patients (73%) had Stage IV disease and 33% had an ECOG status of 2. At the time of interim analysis, a total of 12 patients (6 patients in each arm) had completed EOT. Across both dose levels, ORR was 92% (11/12), with 7 CRs (58%), 4 PRs (33%), and 1 PD. The patient with PD subsequently died. Patients with PR had a median reduction of baseline tumor size of 84% (range, 92% to 83%), as measured by SPD. The only patient with follow-up after EOT converted from PR to CR without subsequent therapy. Treatment-emergent AEs occurring in ≥30% of patients treated (26/33) were nausea, diarrhea, peripheral sensory neuropathy, fatigue, and decreased appetite. Grade 3 or higher events occurring in more than 2 patients were febrile neutropenia and neutropenia. Events of peripheral neuropathy occurred equally per arm (46%, 1.2 mg/kg A+RCHOP; 46% 1.8 mg/kg A+RCHOP) and were generally Grade 1 or 2 (15% and 23%, respectively); events were of similar grade across dose levels. The median time to onset of any grade of peripheral neuropathy was 6 weeks (range, 2 to 10 weeks). Five patients (19%) had dose reductions due to peripheral neuropathy and 3 patients (12%) had dose reductions due to febrile neutropenia. One patient who received 1.2 mg/kg A+RCHOP discontinued study drug due to an AE (thrombocytopenia). Conclusions At doses of 1.2 or 1.8 mg/kg, A+RCHOP exhibited manageable toxicity in the treatment of newly-diagnosed DLBCL; the incidence of peripheral neuropathy was similar to single-agent administration of brentuximab vedotin (Pro 2012, Younes 2012) and RCHOP alone (Rummel 2013, Flinn 2014). In 12 patients with response-assessable, high-intermediate and high-risk DLBCL, A+RCHOP showed encouraging antitumor activity, with an ORR of 92% and a CR rate of 58%. Disclosures Yasenchak: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. . Farber:Seattle Genetics, Inc.: Research Funding. Budde:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Advani:Takeda Pharmaceuticals International Co.: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Jansseen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Holkova:Seattle Genetics, Inc.: Research Funding. Halwani:Seattle Genetics, Inc.: Research Funding. Knapp:Takeda Pharmaceuticals International Co.: Research Funding; EMD Serono: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Merck: Research Funding; Heron Pharmaceuticals: Research Funding, Travel expenses, Travel expenses Other; Genentech: Research Funding, Travel expenses, Travel expenses Other; Seattle Genetics, Inc.: Research Funding; Pharmacyclics: Research Funding. Fayad:Seattle Genetics, Inc.: Consultancy, Research Funding. Kolibaba:Genentech: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Seetharam:Seattle Genetics, Inc.: Research Funding. Manley:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Genentech: Research Funding; ImaginAb: Research Funding; Celgene: Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Janssen: Research Funding; Astra Zeneca: Research Funding.

Description: Abstract 2638 Poster Board II-614 Background: The importance of cytogenetics in prognosis of AML is now widely recognized and accepted in clinical practice. A recent study found that autosomal chromosomal monosomy predicted for an adverse outcome. The goal of this study is to characterize patients with monosomal karyotype by mutation status and clinical features. Methods: One-hundred forty consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2008 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. An abnormality was considered clonal when at least two metaphases had the same aberration, except for clonal monosomy, which required at least three metaphases. The karyotype analysis was based on 20 or more metaphases. All samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 77 males and 63 females with a median age of 58 (range 17-83). Cytogenetic risk-group stratification resulted in 14 patients with favorable, 88 with intermediate and 28 with unfavorable risk status. Loss of one or more autosomal chromosomes was present in 18 /130 patients (13.8%) with available cytogenetic studies. A single autosomal monosomy was found in 5 patients while 13 patients had two or more autosomal monosomies. The most common chromosomes lost in these 18 patients included 7 (55% of 18 cases), 5 (50%), 17 (33%), 21 (22%), 20 (22%), 22 (17%) and 18 (11%). Using the 2008 WHO criteria, there were 66 AML with myelodysplasia-related changes (AML-MRC), 55 AML not otherwise specified (AML-NOS), 14 AML with either t(8;21), inv(16) or t(15;17) and 5 therapy related AMLs. Overall, 35 patients (25% of all patients) had a NPM1 mutation (19 of which were FLT3 mutated), 33 had FLT3-ITD mutation (24%), 11 had FLT3-D835 (8%) and 11 had a CEBPA mutation (8%) (4 of which were FLT3 mutated). Patients with monosomal karyotype were significantly older (83 vs. 59 years, p=0.0125) and presented with lower WBC (34 vs. 66 K/uL, p=0.0006), lower platelets (41 vs. 64 K/uL, p=0.0111), and lower blasts (38% vs. 65%, p=0.0030) as compared to the rest of AML patients. In addition, patients with monosomal karyotype were more frequently diagnosed with AML-MRC (16/18 vs. 48/107, p=0.0034) and exhibited a decreased frequency of NPM1 mutation (0/18 vs. 28/107, p=0.0138) and FLT3-ITD mutation (0/18 vs. 29/107, p=0.0117). Clinical outcome data showed that patients with monosomal karyotype had a significantly worse OS, PFS and CR compared to the rest of AML patients (OS p=0.001, PFS p=0.002 and CR p=0.0262). Dividing patients by number of monosomies showed that patients with 2 or more monosomies had a significantly worse OS (p=0.0001) and PFS (p=0.0045) than patients without any monosomies. However, no difference in OS or PFS was seen when comparing patients with 1 monosomy to those with 2 or more monosomies. Within the AML-MRC group, monosomal karyotype correlated with lower WBC (17 vs. 37 K/uL, p=0.0005), lower platelets (21 vs. 35 K/uL, p=0.0095), lower blasts (19% vs. 36%, p=0.0015) and shorter OS (p=0.0322) and PFS (p=0.0084). Conclusion: AML patients with monosomal karyotype exhibit a significantly worse OS, PFS and lower CR as compared to other AML patients. Most of patients fall within the newly defined AML-MRC group and are characterized by significant absence of NPM1 and FLT3-ITD mutations. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Although some studies have validated the 2001 WHO classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification system has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC) that now includes 1) AML arising from myelodysplastic syndrome (MDS), 2) AML with MDS-related cytogenetic abnormalities, and 3) AML with multilineage dysplasia. An individual case may fall into this category by meeting any of the criteria. The goal of the current study is to clinically characterize this newly defined AML-MRC subgroup. Methods: One-hundred consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2007 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. Available flow cytometry immunophenotyping results were reviewed and all samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate and multivariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 57 males and 43 females with a median age of 56 (range 17–81). Cytogenetic risk-group stratification resulted in 9 patients with favorable, 65 with intermediate and 19 with unfavorable risk status. Using the 2008 WHO criteria, there were 48 AML-MRC, 40 AML not otherwise specified (AML-NOS), 9 AML with either t(8;21), inv(16) or t(15;17), and 3 therapy related AMLs. Overall, 26 patients had a NPM1 mutation (16 of which were FLT3 mutated), 25 had FLT3-ITD, 8 had FLT3-D835 and 9 had a CEBPA mutation (3 of which were FLT3 mutated). Compared to AML-NOS, patients with AML-MRC were significantly older (59 vs 51 years, p=0.014) and presented with lower hemoglobin (9 vs 11.2 g/dL, p=0.044), lower platelets (47 vs 54 K/uL, p=0.059), unfavorable cytogenetics (14/46 vs 3/36, p=0.014) and exhibited a decreased frequency of CEBPA mutation (0/46 vs 7/40, p=0.001) as compared to AML-NOS. Based on the flow cytometry immunophenotyping, the blasts from patients with AML-MRC more frequently expressed CD14 compared to AML-NOS (10/46 vs 4/36, p=0.048). Clinical outcome data showed that patients with AML-MRC had a significantly worse OS, PFS and CR compared to AML-NOS (Figure, all p

Description: Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (〉20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.

Description: Introduction RCHOP is the standard frontline treatment for patients with DLBCL. However, for patients with high-intermediate or high-risk disease (IPI 3-5), outcomes are suboptimal, with an estimated 3-year PFS of about 55%. In addition to IPI, an additional factor associated with an increased risk include non-GCB cell of origin. Brentuximab vedotin, an ADC targeting CD30, has demonstrated single-agent activity in relapsed/refractory DLBCL patients. Of note, higher ORR and CR, as well as longer duration of PFS, were observed in those patients with CD30 detected on tumor cells by routine IHC. Methods This phase 2 study was designed to evaluate combination therapy using brentuximab vedotin (BV) and standard RCHOP chemotherapy as frontline treatment in patients with high-intermediate/high risk (standard IPI score 3-5 or age-adjusted IPI [aaIPI] score 2-3) DLBCL, regardless of CD30 expression (ClinicalTrials.gov NCT01925612). Patients were randomized to receive either 1.2 mg/kg BV+RCHOP or 1.8 mg/kg BV+RCHOP for up to 6 cycles of treatment. BV was given on Day 1 of every 21-day cycle. Response was assessed per investigator using Cheson 2007. AEs, physical examination findings, and laboratory testing were utilized to characterize safety. Tumor cell CD30 expression was measured by IHC and gene expression analysis; soluble CD30 was measured in plasma. Tumor microenvironment was also evaluated for frequency of immune-infiltrating cells. The primary endpoints for this study were the tolerability of each regimen and the CR rate at the end of treatment (EOT). Key secondary endpoints included progression-free survival (PFS). Additional exploratory endpoints included CD30 expression on tumor specimens (CD30- defined as

Description: Although some studies have validated the 2001 World Health Organization (WHO) classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC). We evaluated the clinical, pathologic, cytogenetic, and molecular features of 100 AML patients using the 2008 WHO criteria. Patients underwent genetic screening for NPM1, FLT3-ITD, FLT3-D835, and CEBPA mutations. Compared with patients with AML, not otherwise specified, patients with AML-MRC were significantly older (P = .014), presented with a lower hemoglobin (P = .044), more frequently expressed CD14 (P = .048), and exhibited a decreased frequency of CEBPA mutations (P = .001). Multivariate analysis indicated that patients with AML-MRC had a significantly worse overall survival, progression-free survival, and complete response compared with AML-not otherwise specified (all P 〈 .001). These data support the clinical, morphologic, and cytogenetic criteria for this 2008 WHO AML category.

Description: Transforming Growth Factor β (TGF-β) is a myelosuppressive cytokine that has been implicated in the ineffective hematopoiesis seen in myelodysplastic syndromes (MDS). Overactivation of TGF-β signaling in this disease was demonstrated immunohistochemically by significantly higher nuclear SMAD2 phosphorylation observed in 20 MDS bone marrows when compared with 7 non MDS anemic controls (P 〈 0.0001, 2 Tailed T Test, Image Pro Plus software). This data along with high levels of membrane-bound and plasma TGF-β observed in MDS patients in previous studies support the development of therapeutics targeting the TGF-β signaling pathways in this disease. SD-208 is a novel, potent and specific inhibitor of TGF-β Receptor I (TGFβ-RI) kinase. We demonstrate that SD-208 blocks the phosphorylation of SMAD2 in hematopoietic progenitors which are at the colony forming unit-erythroid (CFU-E) stage of differentiation. SD-208 also abrogates the G0/G1 cell cycle arrest induced by TGF-β in bone marrow progenitors. SD-208 treatment leads to reversal of the myelosuppressive effects of TGF-β on erythroid and myeloid colony formation from primary human CD34+ cells. Selectivity of SD-208 in inhibiting TGF-β-mediated effects on hematopoiesis was supported by similar results observed with siRNAs targeting SMAD2, a major component of the TGF-b signaling pathway. Finally, the efficacy of SD-208 in MDS was evaluated by treating bone marrow mononuclear cells from 15 patients with early low grade MDS. SD-208 treatment led to dose-dependent increases in erythroid and myeloid colonies after 14 days of in vitro culture. The effect was most notable in patients with high levels of activated SMAD-2, as assessed by immunohistochemical staining of bone marrow biopsies. Stimulation of hematopoiesis in MDS-derived marrow culture by SD-208 demonstrates a novel concept and potential therapeutic role for TGFβ-RI inhibition in this disease. Supported by VISN-17 grant, Harris Methodist Foundation Grant and ASCO YIA to AV