Hanson, Curtis A.

Abstract Backgrounds B cell receptor (BCR) signals and microenvironment protection have been recognized to have key influences on CLL survival and activation. Akt activation is down-stream of the BCR signaling cascade and is critical in the mediation of the bi-directional interactions between CLL B-cells and bone marrow stroma. MK2206 is an allosteric Akt inhibitor previously tested for safety in solid tumor patients. Our preclinical data has demonstrated the synergy of MK2206 with bendamustine (B) to induce CLL apoptosis in vitro. MK2206 also abolished the signal activation and cytokine production induced by BCR ligation in CLL leukemic cells (Ding, ASH 2012). Therefore, we conducted a phase 1 trial testing the safety and efficacy of MK2206 in combination with bendamustine and rituximab (BR) for patients with relapsed/refractory CLL. Methods A phase 1 dose-escalation study was designed to define the maximum tolerated dose (MTD) as well as the safety and efficacy of 3 dose levels (90 mg or 135 mg or 200 mg weekly) of the oral Akt inhibitor MK2206 in combination with bendamustine (70 mg/m2 daily for 2 days in each cycle) and rituximab (cycle 1: 375 mg/m2, cycle 2-6: 500 mg/m2) therapy in relapse/refractory CLL patients. To test the targeting efficacy of MK2206 on Akt and downstream signals, we designed a one-week “run-in” of single agent MK2206 before the initiation of BR during cycle 1. MK2206 was then given along with BR on day 1 of cycles 2-6. Tumor response was evaluated 2 months after the 6th/last cycle of therapy based on IWCLL 2008 criteria. Correlative laboratory studies included assessment of Akt signaling and the plasma cytokine levels (multiplex beads assay (Invitrogen)) at baseline and after one week of first dose of single agent MK2206. Results Nine patients (median age 68) were enrolled in the phase I portion of this trial. All 9 patients had unmutated immunoglobulin heavy chain variable region genes (IGHV) and 4 had del(11q). Six had received prior chemoimmunotherapy (CIT: FCR or PCR or PCO) and 5 had high risk disease defined as early progression within 26 months of the last CIT. Three had received alemtuzumab containing regimen. We have observed potent lymphocyte mobilization in all evaluated patients (n=7) after one-dose of MK2206 during week 1 (mean increase ALC: 35%) as well as reductions of plasma CCL3, CCL4 and CCL2 in the majority of the patients. A single dose-limiting toxicity (DLT) (febrile neutropenia and hemolytic anemia) was observed at dose level 1 (90 mg weekly) among 6 patients treated at this dose. Two patients with dose-limiting toxicities at dose level 2 (135 mg weekly) were observed where one patient had a rash and one patient had dehydration and febrile neutropenia among three patients treated at this dose. Accordingly, the 90 mg once weekly dose was determined to be the MTD for phase 2 trial testing. The most frequent grade 3 or 4 adverse events observed to date were neutropenia (44%) including febrile neutropenia (22%), rash (22%), diarrhea (22%), nausea and vomiting (11%), dehydration (11%), hemolytic anemia (11%) and thrombocytopenia (11%). The frequency of cytopenias was similar to the published German experience with BR (50% grade 3 or 4 hematological toxicities compared to 44% in N1087) in relapsed CLL patients (Fischer, JCO 2011). The median number of cycles received was 6 (range 1-6). Using an intent to treat analysis, two patients achieved complete response (CR, n= 2, 22%), one patient achieved nodular partial response (nPR, n=1, 11%) and five patients achieved a partial response (PR, n=5, 56%). The overall response rate (ORR) is 89%. Conclusion The Akt inhibitor MK2206 in combination with BR is well tolerated in patients with relapsed/refractory CLL. Single dose of MK2206 inhibits Akt phosphorylation, mobilizes leukemic cells and decreases plasma cytokines involved in BCR signals. The preliminary efficacy of this combination demonstrated promising results with a 89% ORR and 22% CR albeit in the small phase 1 cohort. These results compare favorably to BR alone (9% CR and 59% ORR) in relapsed/refractory CLL patients. Phase 2 testing of this combination is now underway. Acknowledgment This work was supported by the funding from NCI grant K23CA160345 (WD), NCI grant CA95241 (NEK) and Alliance for Clinical Trials in Oncology (CA025224 and CA33601). Disclosures: Off Label Use: MK2206, used in a phase 1 trial of relapsed CLL disease. Shanafelt:Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Zent:Novartis: Research Funding; GlaxSmithKline: Research Funding; Biothera: Research Funding; Genzyme: Research Funding; Genentech : Research Funding. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.

Abstract Background MBL is a precursor state to CLL, with a prevalence of ~5-8% in the general population and 15-18% in CLL families. To date, 41 single nucleotide polymorphisms (SNPs) have been found to be associated with CLL. We previously showed that a PRS of the weighted average of the number of risk alleles of these SNPs is associated with CLL risk using cases and controls from the International Lymphoma Epidemiology (InterLymph) Consortium. We validated this score in an independent sample of CLL cases and controls from the Genetic Epidemiology of CLL (GEC) Consortium, a cohort of families with ≥2 members with CLL. In the CLL families we also reported an association between the PRS and MBL risk, where 93% of MBLs were low-count MBL. Here we evaluate the PRS in an independent sample ascertained from the Mayo Clinic Biobank. Methods The Mayo Clinic Biobank is a large-scale bio-repository of adult patients assembled to provide a wide array of health-related research studies. Biobank participants (N=2530) were screened for MBL using a highly-sensitive, 8-color (CD38, CD45, Kappa, Lambda, CD19, CD23, CD5 and CD20) flow-cytometry assay on stored cryopreserved peripheral blood mononucleotide cells. Low-count and high-count MBL were defined as those individuals who had <85% and ≥85 clonal B-cells out of total B-cells, respectively. Individuals without MBL ("controls") were frequency matched to MBLs based on age and sex, after excluding non-Caucasian and non-interpretable flow results. Participants were genotyped using the Illumina OmniExpress array. Standard genotyping quality-control metrics were applied. We computed the PRS as previously published and categorized it by quintiles based on values previously used with InterLymph controls. The middle quintile served as the reference category. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age at consent, sex, and socioeconomic status. In addition, we compared the median PRS by low-count MBL and high count MBL using the Mann-Whitney U test. Results We identified 276 MBLs overall and 2109 controls; 97% (N=267) of MBLs had low-count MBL and only 3% (N=9) had high-count MBL. We then selected 844 controls frequency matched to the MBL cases on age and sex. Family history of leukemia/lymphoma was 11.3% among MBLs overall and 8.8% among controls. The median PRS was 7.88 and 7.46 (Figure) among MBLs overall and controls, respectively. The continuous PRS had a 1.75-fold increased risk for MBL overall (CI:1.5-2.1, P=2.65x10-12). Compared to the middle quintile, the highest quintile had 2.2-fold increased risk for MBL overall (CI:1.5-3.3, P=1.46x10-4) and the lowest quintile had 0.6-fold decreased risk (CI:0.4-0.96, P=0.03). The median PRS for low-count and high count MBL were 7.86 and 8.04, respectively. The continuous PRS had a 1.75-fold increased risk for low-count MBL (CI:1.5-2.1, P=4.81x10-12) and a 1.89-fold increased risk for high-count MBL (CI:0.8-4.2, P=0.13), however, the effect is not statistically significant between high-count and low-count MBL (P=0.89). Conclusion In this independent sample, we validated our previous findings that the CLL PRS is associated with MBL risk. Although the sample size of high-count MBL was limited (N=9), there is evidence of a weak trend towards a higher PRS compared to low-count MBL and controls Larger sample size of high-count MBL is warranted in order to stratify MBL risk by low-count and high-count MBL. These results may help identify individuals at higher risk of MBL including low-count and high-count MBL, beyond the risk associated with age and family history of CLL. Figure: Polygenic risk score distribution by control and MBL status Figure. Figure. Disclosures Parikh: Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding. Cerhan:Nanostring: Research Funding; Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Genentech: Research Funding; Pharmacyclics: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding.

Abstract This study evaluated the contributing roles of flow cytometric immunophenotyping of blood and bone marrow and immunohistochemical paraffin section staining of bone marrow biopsies in the staging of B-cell malignant lymphoma. Flow immunophenotyping was performed on a marrow specimen in 175 cases; a corresponding blood specimen was also immunophenotyped in 135 of these cases. Morphologic marrow involvement by lymphoma was found in 59 cases; flow immunophenotyping identified 54 cases with a monoclonal B-cell process: morphology-positive/flow-positive (n = 49), morphology-positive/flow-negative (n = 10), morphology-negative/flow-positive (n = 5), and morphology-negative/flow-negative (n = 111). The 10 morphology-positive/flow-negative cases included 5 follicular and 5 large-cell lymphomas with minimal marrow involvement. All 5 morphology-negative/flow-positive cases were from patients with large-cell lymphomas and bulky clinical disease. Because the blood contained the same B-cell clone in 2 of 2 morphology-negative/flow-positive cases studied, blood contamination of marrow may account for these findings. Blood flow cytometric immunophenotyping studies were positive in 32 cases; 30 had marrow involvement by morphology and were from patients with follicular, mantle cell, lymphoplasmacytic, small lymphocytic, or marginal zone lymphomas. From our results, we conclude that (1) bone marrow flow cytometric immunophenotyping is not a cost-effective replacement for good morphologic evaluation in lymphoma staging and that (2) a positive peripheral blood flow cytometric immunophenotyping study when performed in low-grade lymphomas correlates with marrow involvement.

Abstract Abstract 2835 Background: Extrinsic growth and survival signals provided by nonneoplastic cells present within the tumor microenvironment promote the growth and survival of CLL cells. For example, bone marrow stromal cells, blood-derived “nurse-like” cells and follicular dendritic cells have been shown to promote the survival of CLL cells via the provision of both soluble and cell-contact dependent factors. More recently, monocytes were convincingly shown to support the survival of CLL cells during in vitro culture, and many of the factors (e.g. BLyS/BAFF, SDF-1, CD14) previously implicated in supporting the growth and survival of CLL cells are produced by monocytes. To explore the potential clinical implications of these in vitro findings, we evaluated the relationship between the absolute monocyte count (AMC) at diagnosis and disease progression in a well defined cohort of CLL patients. We hypothesized that the presence of a relative monocytosis at presentation in patients newly diagnosed with CLL may create a nurturing environment for CLL cells and be associated with more rapid disease progression. Methods: Previously untreated patients diagnosed with CLL/SLL within 12 months of presentation to the Mayo Clinic (from 1/1/2000-8/31/2010) were identified (n=1396). The AMC was obtained from routine complete blood counts (CBC) with automated or manual differentials that were performed within 3 months of diagnosis (n=947). The primary study objective was to determine whether the AMC is associated with time to first treatment (TTFT) in CLL. The secondary objective was to determine whether the AMC had independent prognostic value after adjusting for CD38/CD49d/Zap-70 expression, IGHV gene mutation status, and cytogenetic (11q-, 17p-) findings by FISH analysis. Results: The median age was 66 years and the median AMC was 550/μL (380–812/ μL, 1st-3rd quartile) at diagnosis (normal range: 300–900/μL). No significant difference in the median AMC was observed by age, gender; CD38, CD49d, or Zap-70 expression; IGHV gene mutation status or cytogenetic findings. Patients were followed for a median of 3.2 years (range: 0–10.3), with disease progression requiring the initiation of treatment observed in 268 (28%) patients. On multivariate analysis using a Cox proportional hazards model which incorporated age, gender and Rai stage, the AMC (as a continuous variable) was associated with TTFT with a hazard ratio (HR) of 1.099 (per unit change; 95% CI, 1.003–1.205; p=0.04). The optimal cutpoint for the association between AMC and TTFT was determined to be ≥1, 170/μL, a threshold that remained an independently significant predictor of TTFT after adjusting for age, gender and Rai stage with a HR of 5.1 (95% CI, 2.56–10.10, p<0.0001). The median TTFT was 1.0 year for patients with an AMC ≥1, 170/μL and 7.4 years for those with an AMC <1, 170/μL (p<0.0001). In order to evaluate whether the AMC had independent prognostic value after adjusting for other prognostic biomarkers, CD38, CD49d, Zap-70, IGHV gene mutation status and cytogenetic findings (11q- or 17p-), were individually incorporated into the multivariate analysis. In each case, the AMC remained an independent predictor of TTFT, with HRs ranging from 4.31 to 5.43 (p<0.0001 for all analyses). Conclusions: The AMC at the time of diagnosis as measured by a routine CBC is associated with accelerated disease progression in CLL/SLL independent of other prognostic biomarkers. These results suggest that the in vitro observation that nonneoplastic cells present in the tumor microenvironment promote CLL cell survival may have direct clinical implications for the prognostic evaluation of CLL patients and further substantiate the pathogenic role of monocytic cells in CLL. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 971 Unlike the case in acute myeloid leukemia, there is limited information on the prognostic impact of IDH mutations in myelodysplastic syndromes (MDS). In the current study of 277 patients with MDS, IDH mutations were detected in 34 (12%) cases: 26 IDH2 (all R140Q) and 8 IDH1 (six R132S and two R132C). Mutational frequency was 4% (2 of 56) in refractory anemia with ring sideroblasts (RARS), 12% (16 of 130) in refractory cytopenia with multilineage dysplasia, 14% (2 of 14) in MDS-unclassifiable, 14% (6 of 42) in refractory anemia with excess blasts (RAEB)-1, and 23% (8 of 35) in RAEB-2. Normal karyotype was noted in all but one IDH1-mutated cases and 13 IDH2-mutated cases. Multivariable analysis identified presence of mutant IDH1 (p=0.0004; HR 4.0, 95% CI 1.9–8.8), revised International Prognostic Scoring System (IPSS-R) risk category (p<0.0001), and red cell transfusion need (p=0.002) as independent predictors of inferior survival (Figure 1). In a similar multivariable analysis, mutant IDH1 was the only variable associated with shortened leukemia-free survival (p=0.001; HR 7.0, 95% CI 2.3–20.8). The presence of IDH2 R140Q did not affect overall (p=0.54) or leukemia-free (p=0.81) survival (Figure 2). The current study suggests a powerful adverse prognostic effect for mutant IDH1 in MDS. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2806 Background: A high degree of prognostic certainty is required to recommend or discourage high risk treatment procedures in primary myelofibrosis (PMF). The Dynamic International Prognostic Scoring System (DIPSS-plus) uses eight risk factors to predict overall survival (OS) in PMF: unfavorable karyotype, peripheral blood (PB) blast count ≥1%, platelet count <100 × 109/L, white blood cell count (WBC) >25 × 109/L, hemoglobin level <10 g/dL, red blood cell transfusion need, constitutional symptoms, and age >65 years (Gangat et al. JCO 2011;29 :392). The presence of four or more of these risk factors defines high-risk disease. purpose: The purpose of the current study was to enhance the prognostic weight of some of the DIPSS-plus risk factors with the intent to identify one or two parameters that can reliably predict death in the first two years of disease. Methods: An updated Mayo Clinic database of 884 karyotypically-annotated patients with PMF was used. Calculations of 2-year mortality rates and variables considered for prognostic value were from time of referral to the Mayo Clinic. Cytogenetic risk categorization per DIPSS-plus was further refined to capture additional prognostic information from monosomal karyotype (MK) (Vaidya et al. Blood 2011;117 :5612) and inv(3)/i(17q) abnormalities (Caramazza et al. Leukemia 2011;25 :82). Receiver operating characteristic (ROC) analysis was employed to define best discriminant levels. Results: To date, 564 (64%) deaths have been documented. Each one of the aforementioned DIPSS-plus risk factors was associated with a 2-year mortality rate that ranged from 42% (PB blast count ≥1%) to 60% (unfavorable karyotype). High-risk disease per DIPSS-plus was associated with 57% two-year mortality. The only risk factors that were associated with >80% two-year mortality were MK (n =19) and inv(3)/i(17q) abnormalities (n =8) and both were associated with significantly worse survival, compared to other unfavorable karyotype (n =102): HR (95% CI) of 5.1 (3.1−8.4) and 3.9 (1.7−8.8), respectively. ROC analysis identified PB blast counts of 2% and 9% (AUC 0.62) and WBC of 43 × 109/L (AUC 0.66) as best discriminant levels for predicting 2-year mortality; OS was significantly worse in the presence of PB blast >9% (HR 4.1, 95% CI 2.8–6.1) vs. 2% to 9% (HR 1.8, 95% CI 1.5–2.2) vs. <2%; the corresponding 2-year mortality rates were 73%, 46% and 25%. OS was also significantly worse in the presence of WBC ≥40 × 109/L (HR 2.8, 95% CI 2.2–3.6) vs. 26–39 × 109/L (HR 1.6, 95% CI, 1.2–2.1) vs. <26 × 109/L; the corresponding 2-year mortality rates were 63%, 42% and 28%. Two-year mortality rates exceeded 80% in the presence of any two of the following: PB blast count >9%, WBC ≥40 × 109/L or unfavorable karyotype other than MK or inv(3)/i(17q). Conclusions: A greater than 80% 2-year mortality in PMF is predicted by the presence of MK, inv(3)/i(17q) abnormalities, or any two of the following: PB blast >9%, WBC ≥40 × 109/L, other unfavorable karyotype. Such patients and those with high DIPSS-plus risk should be referred to allogenic stem cell transplantation earlier than later. Disclosures: No relevant conflicts of interest to declare.

Abstract BACKGROUND: Information regarding risk factors for leukemic transformation (LT) in primary myelofibrosis (PMF) is limited, although both leukocytosis and abnormal cytogenetics have previously been implicated. The current retrospective study examines clinical variables at diagnosis as well as specific treatment modalities for their effect on LT in PMF. METHODS: Diagnoses of PMF and LT were based on World Health Organization criteria. In addition, study inclusion required availability, for review, of bone marrow histology and clinical data obtained at or within 6 months of diagnosis but prior to treatment intervention. Statistical methods used were standard and included Cox regression analysis of leukemia-free survival (LFS). RESULTS: A master database of PMF patients seen at the Mayo Clinic from 1976 through 2006 was queried to identify 311 patients who fulfilled the aforementioned stipulated criteria for study inclusion; median age was 57 years and 41% were females. At presentation, 30% of the patients displayed a hemoglobin level (Hgb) of < 100 g/L, 20% a leukocyte count of < 4 or > 30 x 109/L, 18% a platelet count of < 100 x 109/L, 12% an absolute monocyte count (AMC) of ≥ 1 x 109/L, 28% hypercatabolic symptoms and 35% a peripheral blood (PB) blast percentage of ≥ 1; 27 patients (9%) had a PB blast percentage of ≥ 3. Dupriez prognostic scoring system distribution for high, intermediate, and low risk disease was 30 (10%), 94 (30%), and 187 (60%) patients. Among 182 and 139 evaluable patients, 74 (41%) and 80 (58%) displayed cytogenetic abnormalities and JAK2V617F, respectively. At a median follow-up of 27 months (range 0–282), 27 cases (9%) of LT were documented at a median time from diagnosis to LT of 26 months (range 0.8–266). Effect of clinical and laboratory variables at diagnosis on leukemic transformation By univariate analysis, LFS was negatively affected by anemia (p=0.04), leukocytosis (p=0.04), PB monocyte count ≥ 1 x 109/L (p=0.02), platelet count of < 100 x 109/L (p=0.004), hypercatabolic symptoms (p=0.03) and PB blast percentage of ≥ 3 (p<0.0001); LFS was not affected by PB blast percentage of > 1 but < 3 (p=0.49). By multivariable analysis, significance was sustained only for PB blast percentage of ≥ 3 (p = 0.0002) and platelet count of < 100 x 109/L (p = 0.02) with hazard ratios (HR) of 5.8 and 2.8 and 95% confidence intervals (CI) of 2.3–14.6 and 1.2–6.6, respectively. The presence of JAK2V617F did not affect LFS (p=0.98). Effect of specific treatment on leukemic transformation By univariate analysis, LT was significantly associated with history of splenectomy (p=0.01) and treatment with erythropoiesis stimulating agents (ESA; p=0.004), danazol (p=0.007), and androgens (p=0.03) but not with hydroxyurea (p=0.17), interferon alpha (p=0.95), thalidomide (p=0.26) or other drugs. On multivariable analysis, significance was sustained for both ESA (p = 0.005; HR 3.1, CI 1.4–6.8) and danazol (p = 0.01; HR 3.4, CI 1.3–8.5), even when the aforementioned prognostic indicators at diagnosis were added as covariates to the multivariable model. CONCLUSIONS: The current study identifies PB blast percentage of ≥ 3% and platelet count of < 100 x 109/L, at presentation, as independent risk factors for LT in PMF. Unexpectedly, the study also revealed an association between LT and treatment history with ESA or danazol. These observations are intriguing, considering recent reports on the possible harmful effects of ESA in certain solid tumors.

AbstractRecent observations have underscored the biologic relevance of intratumoral angiogenesis and its potential impact on prognosis. Increased bone marrow angiogenesis has been demonstrated in a variety of hematologic disorders, including multiple myeloma. The extent and prognostic significance of bone marrow angiogenesis in 114 patients with myelofibrosis with myeloid metaplasia (MMM) was investigated. A control group of 44 patients without bone marrow disease, 15 patients with polycythemia vera, and 17 patients with essential thrombocythemia was also studied. Bone marrow microvessel density was assessed by a semiquantitative method, visual microvessel grading, and 2 separate quantitative methods, visual count and computerized image analysis. Angiogenesis estimation by all 3 methods was highly comparable. On visual microvessel grading, a grade 3 or 4 increase in bone marrow angiogenesis was demonstrated in 70% of patients with MMM, 33% of patients with polycythemia vera, 12% of patients with essential thrombocythemia, and 0% of normal controls. In a multivariate analysis, increased angiogenesis in MMM correlated significantly with increased spleen size and was found to be a significant and independent risk factor for overall survival. Increases in marrow angiogenesis correlated with hypercellularity and megakaryocyte clumping. In contrast, these 2 features were inversely proportional to reticulin fibrosis, whereas increases in marrow angiogenesis were independent of reticulin fibrosis. These preliminary findings suggest that neo-angiogenesis is an integral component of the bone marrow stromal reaction in MMM and may provide useful prognostic information and a rationale for the therapeutic investigation of anti-angiogenic agents.

Abstract Abstract 3814 Poster Board III-750 Introduction The 1997 IPSS remains the most widely used prognostic scoring system for patients with MDS, and it has important strengths, but several other prognostic systems have been proposed recently to overcome some of the well-recognized IPSS limitations. These systems include a new risk model for patients with MDS and CMML – including previously treated patients and those with secondary (treatment-related) MDS – proposed by Kantarjian and colleagues at the MD Anderson Cancer Center (MDACC) (Cancer 2008; 113:1351), as well as the WPSS, proposed by Malcovati and colleagues in Europe (J Clin Oncol 2007; 25:3503) To date, the MDACC risk model has not been validated in a large external independent cohort or directly compared to the WPSS. We assessed the performance of the MDACC model compared to the WPSS and the IPSS in a 12-year Mayo Clinic MDS/CMML cohort. Patients and Methods We reviewed the medical records of 1,503 adult patients (pts; 984 males; median age 71 years, range 17-98) with MDS (n=1,249) or CMML (n=254) evaluated at Mayo Clinic between January 1996 and December 2007. Pediatric pts (age ≤16 and pts with ≥30% marrow blasts were excluded. IPSS and WPSS scores were calculated, and data collected for MDACC risk model assignment (age, performance score, platelet count, hemoglogbin, marrow blast proportion, white blood cell count, karyotype, and transfusion history). Data were analyzed using Kaplan-Meier survival analysis and Cox proportional hazards regression models. Results The overall median survival was 17.8 months (mos) – 13.7 mos for CMML, 19.1 mos for WHO-defined MDS, and 9.6 mos for RAEB-t – similar to the 14.1 mos observed in the test cohort used to derive the MDACC risk model. Follow-up was complete until death in 1,122 (74.7%) pts. Pts excluded from the cohort stratified using IPSS included 122 patients with CMML and leukocytosis (>12 × 109/L), and 176 pts with secondary MDS/CMML (there were 12 pts with secondary CMML with leukocytosis) – total excluded, 286 pts. Patients excluded from the WPSS cohort included 27 pts with RAEB-t, 254 pts with CMML, and 148 pts with secondary MDS – total excluded, 429 pts. Survival by IPSS risk group was 38.9 mos for Low (n=413), 17.9 mos for Int-1 (n=541), 9.6 mos for Int-2 (n=206), and 6.6 mos for High (n=57). Survival by WPSS risk group was 39.0 months for Very Low (n=352), 26.6 months for Low (n=276), 15.9 months for Intermediate (n=185), 11.2 mos for High (n=221), and 4.9 months for Very High (n=40). Survival by MDACC risk group was 45.6 mos for Low (n=426), 20.0 mos for Int-1 (n=552), 12.3 mos for Int-2 (n=325), and 4.9 mos for High (n=200). When the MDACC risk model was used to classify only the 1,074 pts with conditions for which the WPSS has been validated, survival was 51.4 mos for Low (n=336), 21.2 mos for Int-1 (n=411), 13.3 mos for Int-2 (n=213), and 4.6 mos for High (n=114) (p<0.001 for all comparisons). In a multivariable proportional hazards model, all of the MDACC risk model components except WBC>20 × 109/L retained independent prognostic significance. Conclusions All 3 systems stratify patients accurately, but the MDACC risk model best identifies the lowest-risk patients, and also classifies the broadest group of patients (i.e., primary and secondary MDS, and primary and secondary CMML with or without leukocytosis). The revised IPSS that is currently in development should include the patient factors accounted for by the MDACC risk model, with the possible exception of leukocytosis. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 3937 Poster Board III-873 Introduction Mantle cell lymphoma (MCL), defined by the pathognomic CCND1/IGH translocation, commonly presents with lymphadenopathy and has an aggressive clinical course with poor survival. However, a minority of patients with MCL present with lymphocytosis without substantial adenopathy. The clinical and pathologic features of this group of patients are not currently well understood. Methods Patients with monoclonal B-cell lymphocytosis, positive CCND1/IGH translocation status by FISH analysis and absence of lymphadenopathy were identified in our institutional B-cell lymphoproliferative disorder database. A comprehensive review of clinical, laboratory, and histopathologic features was conducted. Results of ancillary immunophenotypic, molecular genetic, and cytogenetic studies were reviewed. Univariate survival analysis was performed using the method of Kaplan and Meier. Result We identified a total of 35 patients meeting the selection criteria (10 female and 25 male; median age 66 yrs, range 41-86). The median absolute lymphocyte count at presentation was 8.7 × 109/L (range 2.7-180). Eleven patients subsequently developed adenopathy (MCL-LN) while 24 patients had persistent lymphocytosis without adenopathy (MCL-PB). There were no significant differences in age, gender, absolute leukocyte count, percent bone marrow involvement by lymphoma, or immunophenotypic features of the neoplastic B-cells between these 2 subgroups at initial evaluation. All 11 MCL-LN (100%) and 14 of the 24 MCL-PB patients (58%) had splenomegaly at presentation. Morphologic and immunophenotypic features in peripheral blood (n=35), bone marrow (n=34), lymph node (n=7), spleen (n=7) and other involved tissues (n=4) were typical of MCL in 34 patients. One patient had an unusual disease recurrence resembling hairy cell leukemia, but was retained in the analysis given the persistence of the CCND1/IGH abnormality and molecular evidence of clonal identity with previous specimens. All patients with MCL-LN and 12/24 (50%) of patients with MCL-PB received therapy including R-CHOP, cladribine, or rituximab. The remaining 12 MCL-PB patients (50%) were managed expectantly. Patients with MCL-PB (median survival of 156 months from diagnosis) had a significantly better survival than patients with MCL-LN (13 months) regardless of splenic involvement (P=0.0002) (Figure 1). Conclusion Among patients with MCL presenting in leukemic phase without adenopathy, we have identified 2 subgroups with distinct clinical outcomes. Patients who do not develop subsequent lymph node involvement (MCL-PB) have a generally more favorable clinical outcome. These findings imply fundamental differences in the pathobiology and molecular oncogenesis between these subgroups, suggesting the presence of distinct MCL entities. Disclosures: Zent: Genentech, Bayer, Genzyme, Novartis: Research Funding. Shanafelt:Genentech: Research Funding; Hospira: Membership on an entity's Board of Directors or advisory committees, Research Funding; Polyphenon E International: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Bayer Health Care Pharmaceuticals: Research Funding. Kay:Gnentch: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospire: Research Funding; Polyphenon Pharma: Research Funding; Sanofi-Aventis: Research Funding; Biogenc-Ides: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees. Witzig:Novartis: Research Funding.