The limited effects of current treatments of primary myelofibrosis (PM) led us to prospectively evaluate recombinant interferon-␣ (rIFN␣) in "early" PM patients with residual hematopoiesis and only grade 1 or 2 myelofibrosis. Seventeen patients meeting World Health Organization PM diagnostic criteria received either rIFN␣-2b 500 000 to 3 million units 3 times weekly, or pegylated rIFN␣-2a

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In a series of 105 patients with polycythemia vera, we retrospectively determined whether the JAK2V617F mutation correlated with severity of disease phenotype. Higher JAK2V617F allele burden correlated with more advanced myelofibrosis, greater splenomegaly, and higher white blood cell count, but not with age, gender, hematocrit level, or frequency of phlebotomy prior to cytoreductive therapy. Although a subgroup at increased risk for thrombosis was not clearly defined, there was a suggestion that frequency of thrombosis increased as the JAK2V617F allele burden increased. The JAK2V617F allele burden did not change significantly in treated patients with serial JAK2 analyses.

We compare long-term outcomes in patients with node negative early stage breast cancer treated with breast radiotherapy (RT) without the axillary RT field after sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND). We hypothesize that though tangential RT was delivered to the breast tissue, it at least partially sterilized occult axillary nodal metastases thus providing low nodal failure rates. Between 1995 and 2001, 265 patients with AJCC stages I–II breast cancer were treated with lumpectomy and either SLND (cohort SLND) or SLND and ALND (cohort ALND). Median follow-up was 9.9 years (range 8.3–15.3 years). RT was administered to the whole breast to the median dose of 48.2 Gy (range 46.0–50.4 Gy) plus boost without axillary RT. Chi-square tests were employed in comparing outcomes of two groups for axillary and supraclavicular failure rates, ipsilateral in-breast tumor recurrence (IBTR), distant metastases (DM), and chronic complications. Progression-free survival (PFS) was compared using log-rank test. There were 136/265 (51%) and 129/265 (49%) patients in the SLND and ALND cohorts, respectively. The median number of axillary lymph nodes assessed was 2 (range 1–5) in cohort SLND and 18 (range 7–36) in cohort ALND (P < 0.0001). Incidence of AFR and SFR in both cohorts was 0%. The rates of IBTR and DM in both cohorts were not significantly different. Median PFS in the SLND cohort is 14.6 years and 10-year PFS is 88.2%. Median PFS in the ALND group is 15.0 years and 10-year PFS is 85.7%. At a 10-year follow-up chronic lymphedema occurred in 5/108 (4.6%) and 40/115 (34.8%) in cohorts SLND and ALND, respectively (P = 0.0001). This study provides mature evidence that patients with negative nodes, treated with tangential breast RT and SLND alone, experience low AFR or SFR. Our findings, while awaiting mature long-term data from NSABP B-32, support that in patients with negative axillary nodal status such treatment provides excellent long-term cure rates while avoiding morbidities associated with ALND or addition of axillary RT field.

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67 Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated, metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m2, LV 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/ m2 over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts (V/P 60/64) enrolled at 20 sites between 10/09-2/12. Pt characteristics (V/P): median age 58/62; ECOG PS 0: 23 (40%) / 30 (47%); male 39 (65%) / 53 (83%); GEJ 37 (62%) / 39 (61%); diffuse histology 20 (43%) / 14 (30%). Median number of FOLFOX cycles 9.5/11. Most common Gr ≥3 toxicities: (% pts V/P) neutropenia 50.0/31.7 (p=0.07), neuropathy 23.1/14.3 (p=0.33), fatigue 15.4/9.5 (p=0.50), thrombosis 13.5/11.1 (p=0.92), anemia 9.6/9.5 (p=0.99), hypokalemia 9.6/4.8 (p=0.52), nausea 7.7/9.5 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in ITT population 11.5/9.3 mo (95% CI 8.5-14.4/6.7-11.9; p=0.34) and median OS 12.2/13.9 mo (95% CI 10.2-14.3/11.5-16.3; p=0.48). Non-statistically significant trends toward improved PFS with V were noted in female pts, diffuse histology, and PS 1 (p≤ 0.08). RR (%) 33/27 (p=0.64). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06 Clinical trial information: NCT00982592.

4011 Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m2, LV 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/ m2 over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts enrolled at 20 sites between 10/09-2/12. 123 pts eligible for analysis (V/P 60/63). Pt characteristics (V/P): median age 58/62; ECOG PS 0: 24 (40%) / 30 (48%); male 39 (65%) / 52 (83%); GEJ 37 (62%) / 39 (61%); diffuse or mixed histology 19 (32%) / 10 (16%), recurrent disease 10(17%) / 16 (25%). Median number of FOLFOX cycles 10/11. Most common Grade ≥3 toxicities: (% pts V/P) neutropenia 50/32 (p=0.07), neuropathy 19/13 (p=0.49), fatigue 15/10 (p=0.50), thrombosis 14/11 (p=0.92), anemia 10/10 (p=0.99), hemorrhage-GI 8/11 (p=0.77), hypokalemia 10/5 (p=0.76), nausea 8/8 (p=0.99). Death on or within 30 days of treatment 6.7%/15.6% (p=0.20). Median PFS in intent to treat population 7.3/8.0 mo (95% CI 4.6-10.1/5.1-11.0; p=0.64) and median OS 11.5/14.9 mo (95% CI 9.6-13.4/11.3-18.4; p=0.23). Overall RR (%) 35/35 (p=0.99). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06. Clinical trial information: NCT00982592.

Although heterozygous mutations in RUNX1 are not sufficient for leukemogenesis, 1,2 somatically acquired secondary events may promote transformation leading to overt MDS and AML. As seen in the reported family, recruitment of different secondary alterations may partially explain the variable penetrance and clinical heterogeneity seen in FPD/MM. Cytogenetic investigations of leukemia patients with FPD/MM displayed chromosomal aberrations that frequently occur in sporadic MDS/AML, and vice versa, RUNX1 mutations were seen in sporadic MDS/ AML. 1 Consequently, rare FPD/MM-related myeloid malignancies may serve as a model for multistep leukemogenesis in MDS/AML 8 and, as illustrated here, aCGH may help to identify candidate genes involved in malignant transformation in familial and sporadic myeloid malignancies.