Hussein, Kebede

Abstract BACK GROUND Primary myelofibrosis (PMF) leads to weight loss, splenomegaly and constitutional symptoms (Cancer2007;109:68–76) and hypocholesterolemia associated with decreased survival (Blood2007;110:a2548). Initial trials of JAK2 inhibitors have demonstrated improvements in these (JCO2008;26:a7004), yet little objective data exists regarding the dynamic changes in weight and spleen size during the course of PMF. METHODS We analyzed the Mayo PMF database for patients with information on disease prognosis, presentation, therapies, height and weight at diagnosis, and outcomes. Additionally, when available, we analyzed additional weights during the clinical course, the body mass index (BMI- (weight/(height*height)), spleen size, and peripheral blood studies including lipids. Results: 370 patients with PMF were identified with 193 (52%) having a weight at the time of diagnosis, the remainder had a weight obtained a median of 10.0 months (range 1.8–159) after diagnosis. Additionally, 210 patients (57%) had a weight value available from 1–3 additional time points during the course of their disease. At PMF diagnosis patients had a median BMI of 25.3 (range 17.6 to 38.4), with 53% considered overweight (USA Norms (NHANES 2004): 66% and 32.2% are considered overweight or obese). Although weight lost prior to diagnosis unclear, only 2% of patients would be deemed “underweight” at diagnosis. Serial analysis demonstrated 67% experienced a decrease in weight over time, with 23% and 6% experiencing a >10% or 20% decrease, respectively. Overall during the course of illness 65% of patients remained in the same BMI category with 27% dropping to a lower category and 8% gaining in a category (Table 1). Table 1. Distribution of Body Mass Index and Spleen Size in 370 PMF patients followed serially DX of PMF Weight 2 Weight 3 Weight 4 Underweight BMI<18.5 2% 1% 2% 2% Normal BMI=18.5–24.9 45% 41% 41% 54% Overweight BMI=25–29.9 33% 42% 41% 35% Obese BMI>30 20% 16% 16% 10% Spleen Size (cm BLCM) (median: range) 5.0 (0–30) 6 (0–33) 7 (0–33) 7.5 (0–28) Time from PMF DX (median(range) months) 0 10.3 (1.8–159) 28.3 (6–191) 57 (15–258) Major weight increases were rare <1%, and might include buildup of fluid or splenic mass. Indeed spleen sizes generally increased during the course of the illness, with 51% having “massive” splenomegaly (either >10 (45%) or >20 (20%) cm below left costal margin or requiring splenectomy (19%)). Massive splenomegaly was not associated with weight loss or weight gain, suggesting increasing splenic mass came at the expense of alternate tissue mass (muscle and or fat). Median survival for the entire cohort was 77 months and PMF prognostic scores being valid (Lille PMF score p<0.01; IWG-MRT PMF Score - Submitted separately Cervantes et. al. p<0.01), however BMI number and category was not independently predictive of survival. Additionally, neither percentage of weight loss nor changing BMI category were associated with decreased survival. Although splenomegaly was not independently associated with decreased survival, the need for splenectomy clearly was (p=0.02). Consistent with our prior observation hypocholesterolemia (total <150 (median of 151 (range 12–366) or a HDL cholesterol of <60 (median 77 (range 25–248)) were associated with decreased survival (p<0.01 and =0.05, respectively). Decreasing weight in PMF patients was most highly correlated with decreases in HDL (p=0.03). Hypocholesterolemia was highly associated with splenomegaly (p<0.001 for spleen size >10 cm at any point during disease course). Conclusions: Weight loss is common in most PMF patients, despite the confounders of edema and increasing splenomegaly which could mask the degree of loss of lean body mass. Although few PMF patients are considered “underweight” by BMI standards, the distribution compared to USA norms suggest a lower weight distribution. Additionally, patients during the course of their illness are most likely to fall from a BMI overweight category to a “normal” category which may underestimate the true degree of catabolism of muscle mass occurring. Although not independently associated with decreased survival, weight loss remains common and a sign of advancing disease in this terminal illness. More precise methodology to estimate true lean muscle mass lost or gained may yield a better understanding of the hypercatabolic state seen in PMF. Efficacious therapy (such as potentially a JAK2 inhibitor) will likely reverse the trend of weight loss in these patients.

Abstract BACKGROUND: In myelodysplastic syndromes (MDS) without excess blasts, red blood cell (RBC) transfusion requirement has been associated with poorer overall (OS) and leukemia-free (LFS) survival, suggesting that transfusion dependency is a marker of more severe disease (JCO2005;23:7594). We recently reported similar results in refractory anemia with ring sideroblasts (RARS): RBC transfusion requirement was an IPSS-independent adverse prognostic factor, but neither serum ferritin nor transfusion burden had prognostic value (AJH2008;83:611). Here, we examine the prognostic relevance of serum ferritin, need for RBC transfusions at time of diagnosis, and total transfusion burden in primary myelofibrosis (PMF). METHODS: We reviewed medical records to ascertain the clinical and laboratory features of 185 consecutive patients diagnosed with PMF according to the 2001 World Health Organization (WHO) criteria. Patients were excluded if ferritin measurements at time of diagnosis were unavailable. OS and LFS curves were constructed by Kaplan-Meier method, taking the interval from the date of diagnosis to death, leukemic transformation, or last contact. Log-rank test was used to test the homogeneity of survival curves over different groups. Cox proportional hazards model was utilized to determine the impact of various clinical and laboratory variables on OS and LFS. RESULTS: Clinical characteristics at diagnosis: Median age was 58 years (range 15–81; 110 males). Median serum ferritin level at diagnosis was 164 ng/mL (range 1–3903) and was ≥1000 ng/mL in 22 patients (12%). 101 (55%), 65 (35%) and 19 (10%) patients were assigned low, intermediate- and high-risk disease category (Blood1996;88:1013). In addition, 32 (17%) patients required RBC transfusions, 33% had constitutional symptoms and 39% displayed ≥ 1% circulating blasts. Where evaluated, 40% of the patients had cytogenetic abnormalities and 56% JAK2V617F. Events during the disease course: At a median follow-up of 28 months (range 0.5–231), 79 (43%) deaths and 15 (8%) leukemic transformations were documented. During this period, 126 (68%) patients required some form of therapy other than transfusion, including splenectomy in 33 (18%); only 4 underwent allogeneic stem cell transplantation. Causes of death were documented in 33 instances and none were attributed to iron overload. Median peak serum ferritin level during the disease course was 231ng/mL (range 9–13,080); 144 (78%) patients had peak levels <1000 ng/mL, 28 (15%) between 1000 and 3000 ng/mL, and 13 (7%) above 3000 ng/mL. Number of total RBC transfusions ranged from none to 121. Iron chelation therapy was reported in 62 patients (34%). Prognostic factors for OS and LFS: Kaplan-Meier projected median survival was 72 months. By univariate analysis, increased serum ferritin level at diagnosis considered as either a continuous (p<0.0001) or categorical (≥ 1000 ng/mL) variable (p<0.0001), RBC transfusion requirement at diagnosis (p<0.0001) and higher number of total RBC units transfused during the course of the disease (p=0.004) were all associated with inferior survival. However, only RBC transfusion requirement at diagnosis sustained its prognostic significance when age and conventional prognostic risk scores were added to the multivariable model as covariates. Similarly, a peak serum ferritin level of > 3000 ng/mL documented during the disease course was not detrimental to survival. History of iron chelation therapy was associated with shortened survival (p=0.003). Multivariable analysis that included previously described risk factors for LFS also identified RBC transfusion requirement at diagnosis as an additional and independent risk factor. CONCLUSIONS: Serum ferritin level at time of diagnosis or during the disease course of PMF lacks independent prognostic value for either OS or LFS. The same is true for total transfusion burden. However, although hemoglobin <10 g/dL is a component of all currently utilized prognostic scoring systems for PMF, the presence of a more severe erythropoietic defect as indicated by RBC transfusion need at time of diagnosis has an additional adverse prognostic value for both OS and LFS.

Abstract Background: Myelofibrosis (MF) shortens survival but also compromises quality of life from disease associated splenomegaly and constitutional symptoms (fatigue, weight loss, night sweats, and bone pain). No current validated instrument of patient reported outcomes (PRO) captures the spectrum of MF associated symptoms. In an era of rapid development and testing of therapeutic agents which may impact the natural history and symptoms associated with MF (such as JAK2 inhibitors) a uniform and validated instrument for capturing the presence, severity (and potentially improvement) of MF symptoms is needed. We sought to develop and validate such an instrument, the myelofibrosis symptom assessment form (MFSAF). Methods: Based upon the results in our MF QOL survey (Cancer2007;109(1):68–76), we developed the MFSAF to assess fatigue (via the brief fatigue inventory (BFI-Cancer1999;85:1186)), additional symptoms were independently assessed for presence and severity on a scale from 0 (absent) to 10 (worst possible) for splenomegaly associated symptoms (early satiety, pain, inactivity, cough) night sweats, itching, bone pain, fever, unintentional weight loss as well as an estimate of overall quality of life. Additionally, patients provided feedback on the quality and nature of the MFSAF, and also completed for comparison validated instruments including the Memorial Symptom Assessment Scale (MSAS), the Insomnia Severity Index (ISI), and the Brief Pain Index. Physician input was included including their assessment of patient’s fatigue, spleen symptoms, and quality of life (blinded to patient’s responses) as well as clinical history, lab and exam findings. Results: MFSAF Results 34 MPD patients were enrolled (24 MF, 10 in the comparison group (4 polycythemia vera (PV), 6 essential thrombocythemia (ET)). the MFSAF was rated by patients as easy to understand (median score 1, range 0–6), and “addressed most of my symptoms” (median score 1, range 0–6) both on a scale of 0 (as good as possible to 10 as bad as possible). When asked if a symptom was not addressed (open ended response) no single symptom was named more than once. As we have previously reported fatigue was common with BFI scores (median 3.6 (0–10) for MF and 2.5 (range 0.2–3.8) for the ET/PV group (increasing BFI score associated with worsening fatigue) worse than median score of published “healthy” controls 2.2. Additional MF associated symptoms were captured well by the MFSAF with splenic, constitutional symptoms, and QOL (median 3 (range 0–7) MF, median 2 (0–3) ET/PV) documented easily and worse than ET/PV controls. Physicians estimation of QOL was excellent (median 3 (0–8) for MF, median 2 (0–4) for ET/PV). MFSAF Comparison to other Instruments: The MSAS demonstrated more adverse values for MF (than ET/PV) in the PSYCH (psychologic stress; mean-1.27 (STD DEV 0.80), PHYS (physical symptoms; mean 0.90 (STD DEV 0.53)), GDI (Global Distress Index mean-1.29 (STD DEV 0.77)) and a total MSAS symptom score (mean 0.85 (std dev (0.49)) comparable with advanced renal disease (PSYCH 0.99, PHYS 0.99, GDI 1.27, and MSAS of 0.81; J of Pall Med2007;10(6):1266), as well as advanced lung disease, AIDS, and various advanced malignancies. Individual, previously validated MSAS questions were all highly correlated (all p<0.01) with MFSAF (in italic) counterparts including lack of energy (fatigue), cough (same), pain (both abdominal pain and bone pain), sweats (night sweats), itching (same), and weight loss (same). Further validation of pain measurements in the MFSAF came from comparison to the BPI where both individually the presence, and intensity of pain (both abdominal and bone) were highly correlated (all p<0.01). Insomnia, not yet included in the MFSAF, was present in 68% and 63% of patients (MSAS and ISI, respectively). Additionally, problems with sexual interest, or activity, was noted in 35% of patients to the MSAS. Conclusions: Currently available instruments of PRO and symptoms are lengthy, and individually incomplete for assessing the presence and severity of the diverse nature of symptoms associated with MF. The proposed MFSAF, was comprehensive and well understood by patients and the results for the individual symptoms assessed were highly correlated with previously validated instruments for other conditions as well as with physicians perceptions of fatigue and QOL. The MFSAF, with the addition of questions regarding insomnia and sexuality, should be utilized in all trials of therapeutic agents in MF patients in which symptomatic improvements are an endpoint.

Abstract BACKGROUND: We sought to determine the prognostic relevance of aberrant serum lipid values in the myeloproliferative disorders (MPDs) of primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). METHODS: The Mayo MPD patient institutional database was queried to identify clinical history and lipid profiles (within a year of diagnosis). Serum cholesterol (CHOL), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C), and triglycerides (TRI) were assessed compared to clinical outcomes. RESULTS: 558 patients with MPDs (PMF 28%, PV 27%, and ET 45%) (median age at diagnosis of 56 (range18–81)) were identified. A lipid profile obtained a median of 0.0 months from diagnosis (range (-8 to 12 months) from MPD patients displayed low CHOL, LDL-C, and higher HDL-C than typical for the USA. Amongst MPD disease types PMF patients had lower CHOL (p<0.001) and HDL (p<0.001) compared to ET and PV (see table). Amongst PMF patients, although hypocholesterolemia was not a surrogate for malnutrition (p=0.13) median serum albumin 4.1 g/dL (range 2.7–4.8)), there was correlation with the presence of weight loss, hypercatabolic symptoms, and worse Mayo-CBC myelofibrosis prognostic scores (Cancer2006;106:623; p<0.01). Amongst the study group PMF patients had the poorest survival (followed by PV then ET; p<0.001). Decreased cholesterol (CHOL <150mg/dL, or HDL <60 mg/dL) was associated with decreased survival (P<0.001), but only in PMF patients (see figure). Decreased PMF survival was also associated with traditional PMF risk factors of hemoglobin <10g/dL, leukocytes <4 or >30 × 10(9)/L, platelets <100 × 10(9)/L, and circulating blasts. In multivariate analysis (Cox-Proportional Hazard) only the Mayo-CBC score, hemoglobin <10g/dL, circulating blasts and decreased CHOL remained significant for decreased survival (p<0.001). CONCLUSIONS: The presence of hypocholesterolemia is very common in patients with PMF and is independently associated with inferior survival. Survival by HDL-C and Serum Cholesterol (CHOL) in 154 patient’s with Primary Myelofibrosis Survival by HDL-C and Serum Cholesterol (CHOL) in 154 patient’s with Primary Myelofibrosis Lipid Distributions in 558 MPD patients VALUE/ NCEP CATEGORY PMF (N=154) PV (N=149) ET (N=255) NHANES (USA MEANS;95th CI) NCEP: National Cholesterol Education Program: NHANES (National Health and Nutrition Examination Survey (values for all races ages 65–74) Serum Cholesterol (Median) 149 mg/dL 179 mg/dL 199 mg/dL 221 mg/dL (153–301) −>200mg/dl (Desirable) 10% 31% 48% −150–200mg/dL (Desirable) 39% 25% 41% −100–149mg/dL (Desirable) 41% 41% 9% −<100mg/dL (Low) 10% 3% 2% LDL Cholesterol (Median) 33 mg/dL 41 mg/dL 49 mg/dL 149 mg/dL (87–217) −>100mg/dL (Low to high risk) 1% 1% 1% −<100mg/dL (Optimal) 99% 99% 99% HDL Cholesterol (Median) 79 mg/dL 118 mg/dL 108 mg/dL 45.7 mg/dL (29–71) −>60mg/dL (Optimal) 74% 90% 91% −40–60mg/dL (Normal) 16% 10% 8% −<40mg/dL (Low) 10% 0% 1% Triglycerides (Median) 151 mg/dL 89 mg/dL 116 mg/dL 145 mg/dL (62–285) −>200mg/dL (High) 28% 0% 3% −150–199mg/dL (Borderline) 23% 6% 14% −<150mg/dL (low) 49% 94%% 83%

Abstract Background: Peripheral blood (PB) is sometimes used in place of bone marrow (BM) for cytogenetic studies in either primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis. In a retrospective study, we examined overall yield from PB cytogenetic studies in MF and where possible compared the results with those obtained by BM cytogenetic analysis. Methods: Standard laboratory techniques were used to perform cytogenetic studies in both the PB and BM. A successful study constituted the acquisition of at least two analyzable metaphases and an abnormal clone required the presence of a specific cytogenetic abnormality in at least two metaphases. Clinical and laboratory correlations were made using variables collected at the time of cytogenetic studies. Results I: A total of 242 PB cytogenetic studies were reviewed to identify 59 MF cases; 39 were PMF and 20 post-PV/ET MF. Median age was 60 years (range 36–77) and 37 were male patients. The median duration of the disease at the time of PB cytogenetic studies was 3.5 years (range 0.2–35). At least two analyzable metaphases (median 20, range 2–31) were obtained in 49 (81%) of the 59 study patients; in univariate analysis, this was predicted by presence and degree of circulating myeloid progenitor cells (p < 0.0001), higher PB CD34 count (p < 0.0001), higher leukocyte count (p = 0.0008), and absence of myeloid growth factor therapy (p = 0.005). In multivariable analysis, only the presence of circulating myeloid progenitor cells sustained its significance. Results II: Twenty two cases had concomitant PB and BM cytogenetic studies performed. Of these, 9 patients had abnormal BM cytogenetic findings; the concomitant PB cytogenetic studies were also abnormal in 5 (56%) patients but normal in the other 4. Conversely, PB cytogenetic studies were abnormal in 12 patients; the concomitant BM cytogenetic studies were abnormal in 5 (41%) and normal in the remaining 7. PB cytogenetic studies were not successful in 4 of the 22 total cases; BM studies were successful in 3 of these 4 cases and the results were normal in all. Conclusion: In the presence of circulating myeloid progenitor cells, PB can be considered as an alternative to BM for cytogenetic studies in MF patients, especially in view of the difficulty getting BM aspirates in this disease. However, considering the prognostic value of specific cytogenetic abnormalities in MF, the non-trivial discordance between the BM and PB cytogenetic findings, observed in the current study, warrants a prospective evaluation for further clarification.

Abstract BACKGROUND: Splenectomy is performed for palliating symptoms in patients with primary myelofibrosis (PMF; as well as post essential thrombocythemia myelofibrosis/ post polycythemia myelofibrosis (Mesa et. al. Cancer2006;107(2):361–70). Pre-operative computed tomograms (CTs) of the spleen are frequently performed for estimating spleen size and anatomy, but sometimes raise concern over radiographic splenic masses. We performed a retrospective analysis of splenectomized PMF patients to determine the predictive value of CT in these patients. METHODS: Splenectomized patients, with confirmed PMF (and POST ET/PV MF), with an available pre-operative CT scan were included. Pre-operative CT scans were reviewed in a blinded fashion by a radiologist (B.B.), and histopathology was concurrently reviewed in a blinded fashion by a hematopathologist (C.Y.L.), with attention for radiographic evidence of splenic masses, splenic infarction and hemorrhage, evidence of extra-splenic masses. Additionally splenic volume was calculated by CT through an algorithm using maximal splenic length, width, and slice size (prorated ellipsoid where volume = (30+.58(XxYxZ)). Results from each review were compared and analyzed against clinical outcomes and documented splenic mass. RESULTS: Thirty-eight patients had concurrent CT and splenic pathology available underwent splenectomy for myelofibrosis (20 PMF; median age at diagnosis 64.6 years (range (46–79), 52% males). Splenic volume estimations by CT correlated well with splenic mass measurements. Splenic volume estimation by CT was 2365 CC (range 736–11355 CC), compared with a measured median splenic mass of 2000 mg (range 730–11750 mg) (bivariate analysis p<0.001). Splenic lesions were identified in a total of 33 patients (87%), 10 only by histopathology (30%), 3 only by CT (9%), and 20 by both (61%). Histopathologically 15 patients had localized hemorrhage, 13 had splenic infractions, and 8 had nodular foci of extramedullary hematopoiesis. Only 2 patients had evidence of an alternative malignancy (concurrent chronic lymphocytic leukemia (CLL, n =1) or systemic mast cell disease (n = 1). CT was very sensitive for detecting focal low density lesions (LDLs), which are roughly spherical regions of decreased contrast enhancement in the spleen, and detected the majority of macroscopic lesions. The presence of splenic infarctions histologically was associated with decreased post splenectomy survival (p=0.02; median 7.2 months vs. 15.0 months), however the sensitive (but not specific) presence of LDL lesions by CT did not have prognostic significance. The CT appearance of splenic hemorrhage was nonspecific, and since these areas of parenchymal hemorrhage were likely subacute/chronic, they could not be reliably distinguished from other LDLs. CONCLUSIONS: Pre-operative CT in patients whom undergo palliative splenectomy for myelofibrosis is a sensitive tool for determining the presence of small splenic lesions (hemorrhage, infarction and EMH). Additionally splenic volume estimation by CT, correlates well with measured splenic mass and may assist in operative planning. Splenic lesions in PMF (post ET/PV MF) by CT rarely represented an alternative malignant process, and should likely not be the sole indication for splenectomy. Splenic infarctions were associated with decreased survival after splenectomy, however CT is not always able to distinguish these lesions from EMH and hemorrhage.

Abstract Background: JAK2V617F is a recurring mutation in patients with polycythemia vera (PV) (95%) and essential thrombocythemia (ET) (50%), diseases that are frequently complicated by arterial and/or venous thrombosis. JAK2V617F is also frequently identified in patients with splanchnic vein thrombosis, including in those with occult myeloproliferative disorder (MPD). We previously reported a low prevalence of JAK2V617F in thrombosis patients - only 2% of 210 patients with non-splanchnic vein thrombosis (Leukemia, 2007 Aug;21(8):1828–9), and <1% of 136 patients with arterial stroke (J Thromb Haemost. 2007 Aug;5(8):1784–5). Here, we expanded the analysis to 664 thrombosis patients to describe: JAK2V617F prevalence, and clinical course of patients harboring this mutation. Methods: In Phase I, we screened 439 consecutive patients who underwent thrombophilia testing at our institution in early 2005 - patients with splanchnic vein thrombosis or overt MPD were excluded. In Phase II, we identified 228 additional patients considered to be at high risk for harboring JAK2V617F, who were seen at our institution from 2004 to 2006. JAK2V617F screening (assay sensitivity <1%) was performed as described in the aforementioned references. Results: In the initial cohort of 439 patients (median age=56 years; range 17–93 years; 222 female), 136 (31%) presented with stroke, 114 (26%) with deep venous thrombosis (DVT), 95 (22%) with pulmonary embolism (PE), 50 (11%) with DVT and PE, 10 (2%) with central retinal vein occlusion (CRVO), 7 (2%) with cerebral vein thrombosis, and the remaining 27 (6%) with other thromboses. Five patients (MC1-MC5; median age=78 years) were found to harbor JAK2V617F (prevalence=1%) - none had overt clinical features of MPD and all harbored a low level of JAK2V617F in peripheral blood (median=5–2%; range=2.2–7.5%) (Table). One patient (MC2) carried the Prothrombin G20210A mutation In the subsequent cohort, we studied 197 patients (median age=39 years; range=16–84 years) with recurrent DVT and/or PE, and 28 patients (median age=27 years; range=31–49 years) with acute myocardial infarction at a young age (<50 years). One patient (MC6) who presented with recurrent idiopathic DVT was found to harbor JAK2V617F (prevalence <0.5%) (Table) - this patient had no features of underlying MPD and the mutation burden was low (9%). After a median follow up of 27 months (range=4–66 months), none of the 6 patients harboring JAK2V617F has developed overt MPD. Conclusions: In patients with thrombosis, JAK2V617F is infrequently detected in the absence of overt MPD and/or involvement of splanchnic veins. Thus, JAK2V617F screening cannot be recommended as part of the hypercoagulable workup in routine clinical practice in this setting. The risk of developing overt MPD may be quite low for patients harboring a low JAK2V617F burden at the time of thrombosis although longer follow up is needed in this regard. Furthermore, the thrombosis risk may be well controlled with standard warfarin therapy, and the role of myelosuppressive agents (eg. hydroxyurea) is unclear in these patients. Characteristics of patients harboring JAK2V617F Patient Age Sex Thrombosis JAK2V617F allele burden MPD Follow up (months) Status MC1 84 M PE, DVT 5.3% No 66 Alive MC2 82 F PE, cerebral vein 5% No 38 Alive MC3 74 F PE 2.2% No 4 Dead MC4 78 F Central retinal vein 5.2% No 22 Alive MC5 63 M Stroke 7.5% No 30 Alive MC6 69 M Recurrent DVT No No 24 Alive

Abstract Abstract 3918 Poster Board III-854 BACK GROUND We have previously demonstrated that the myeloproliferative neoplasms (MPNs) of primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) can lead to weight loss, splenomegaly and constitutional symptoms (Cancer 2007;109:68–76). Additionally we have demonstrated that hypocholesterolemia in MPN patients is associated with decreased survival (Blood 2007;110:a2548). Given that current JAK2 inhibitor trials are demonstrating the ability to reverse MPN associated splenomegaly (Haematologica 2009;94(Suppl 2)439 a1088) and cachexia (Blood 2008;112(11):a1760) we sought to determine the baseline natural history for these variables in patients treated prior to the JAK2 inhibitor era. METHODS We analyzed the Mayo MPN database for patients (not treated with JAK2 inhibitors) with information on disease prognosis, presentation, therapies, height and weight at diagnosis, and outcomes. Additionally, when available, we analyzed additional weights during the clinical course, the body mass index (BMI- (weight/(height*height)), spleen size, and peripheral blood studies including lipids. Results: Patients 783 patients with MPNs (followed for a median of 51 months (range 1-871 months); 60% having expired) were identified for the analysis (PV=158, ET=255, PMF=370) with 541 (69%) having a weight at the time of diagnosis, the remainder had a weight obtained a median of 7.8 months after diagnosis. Additionally, 508 patients (65%) had a weight value available from 1–3 additional time points during the course of their disease. Corresponding measurements of splenomegaly, or absence thereof, were noted in 766 cases (98%). Lipid panels (obtained within 18 months of diagnosis) were available in 264 patients. Results by MPN disease type are listed in the Table. Impact on prognosis Univariate analysis of variables discussed which negatively impacted survival included the subtype of MPN (not surprisingly worse for PMF p<0.001), weight loss of greater than 10% during the course of follow-up (P<0.001), or development of splenomegaly of >10 cm below the left costal margin (p=0.004) whereas hypocholesterolemia was significant only for the subset of PMF patients (P=0.03). The IWG-MRT International Prognostic Score (IPSS - Cervantes et. al. Blood 2009) was the only variable prognostically relevant in multivariate analysis (P<0.001). Conclusions Progressive splenomegaly, weight loss, and hypocholesterolemia are common across all MPNs but are most prognostically detrimental in PMF. Ongoing and future trials of JAK2 inhibitors will answer whether reversal of these latter hypercatabolic and proliferative manifestations of disease will improve outcomes for MPN patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Peripheral blood (PB) is sometimes used in place of bone marrow (BM) for cytogenetic studies during the evaluation of hematologic malignancies. We looked for clinical or laboratory features that predict success in obtaining analyzable metaphases during PB chromosome studies. Methods: The Mayo Clinic cytogenetics database was queried to identify adult cases (age > 18 years) with suspected or established hematologic neoplasm in whom PB cytogenetic studies were performed. Success defined as the acquisition of at least two metaphases, was correlated with clinical and laboratory information corresponding to the time of the PB cytogenetic study. Results: A total of 242 PB cytogenetic studies were performed: clinical diagnosis was a myeloid neoplasm in 169 patients (70%), lymphoid neoplasm in 50 (21%), and unexplained cytopenia or leukocytosis in 23 (9%). The 169 myeloid cases included 59 patients with either primary (n=39) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis (n=20), 42 with acute myeloid leukemia (AML), 15 with chronic myeloid leukemia, 9 with myelodysplastic syndrome (MDS), 8 with ET, 6 with PV, and 30 with other MPDs. The 50 lymphoid cases included 19 with chronic lymphocytic leukemia, 12 with lymphoma, 11 with acute lymphocytic leukemia (ALL), and 8 with plasma cell proliferative disorders. PB cytogenetic studies resulted in at least two analyzable metaphases (median 20, range 2–31) in 142 of the 242 study cases (59%); in univariate analysis, this was predicted by the specific clinical diagnosis (p<0.0001), presence and degree of circulating myeloid progenitor cells (p<0.0001), higher leukocyte count (p<0.001), lower platelet count (p=0.003), lower hemoglobin level (p=0.002), and presence of palpable splenomegaly (p=0.002). In multivariable analysis, only the presence of circulating myeloid progenitor cells sustained its significance and this was consistent with the high yield rates seen in PMF (80%), post-PV/ET MF (85%), AML (76%), and ALL (80%) as opposed to the low rates seen in ET (0%) and PV (2%). In 104 cases, BM cytogenetic studies were performed within one month of the PB cytogenetic studies; an abnormal BM cytogenetic finding was another independent predictor of a successful PB study (p=0.002). Conclusion: PB cytogenetic studies are most appropriate in diseases characterized by presence of circulating myeloid progenitors or blasts (e.g. PMF, AML, ALL); the yield otherwise is too small to be cost-effective. The current study also suggests a higher likelihood of a successful PB cytogenetic study in the presence of an abnormal bone marrow karyotype.

Abstract Abstract 1909 Poster Board I-932 Background: The International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) utilizes five independent predictors of inferior survival; of these, a hemoglobin level <10 g/dL has the highest impact on survival (Cervantes et al. Blood 2009;113:2895). In the current study, we examined the additional prognostic impact of transfusion need at diagnosis or becoming transfusion-dependent in the first year of diagnosis. These events were also correlated with JAK2 or TET2 mutational status. Methods: Patients were selected from the Mayo Clinic PMF database based on availability of bone marrow histology and IPSS-relevant information at diagnosis and follow-up transfusion history at one year from diagnosis. WHO criteria were used for PMF diagnosis. Patients who underwent allogeneic hematopoietic cell transplantation were censored at time of transplant. Patient records were updated in July, 2009. Survival curves were constructed using the Kaplan-Meier method and compared by the log-rank test. Multivariable survival was analysed using Cox regression model. Results: A consecutive cohort of 254 patients was studied (median age 59 years; range 28-87; 159 males). IPSS risk category was low, intermediate (int)-1, int-2 and high in 75, 71, 62 and 46 patients, respectively. JAK2V617F was present in 118 (62%) of 192 patients and TET2 mutations in 6 (13%) of 45 patients evaluated. Transfusion need at diagnosis was documented in 62 patients whereas an additional 22 patients became transfusion-dependent during the first year of their diagnosis. The remaining 170 patients remained transfusion-independent for at least one year post-diagnosis. To date, 139 patients have died. In patients who are alive, median follow-up was 5.3 years. Median survivals in IPSS high, Int-2, Int-1 and low risk patients were, 3, 3.9, 6.8 and 12.8 years, respectively (p<0.0001). Median survival for patients requiring transfusions at diagnosis was similar to that of patients who became transfusion-dependent in their first year of diagnosis, and both were significantly shorter than the median survival seen in patients who remained transfusion-free during the first year post-diagnosis: 2.9, 2.2 and 9.7 years, respectively (p<0.0001; figure). Multivariable analysis confirmed the IPSS-independent prognostic value of transfusion status-based risk stratification. Neither JAK2 nor TET2 mutational status correlated with transfusion need. Conclusions: In PMF, becoming transfusion-dependent in the first year of diagnosis is prognostically as detrimental as requiring transfusions at initial presentation. These events are not affected by JAK2 or TET2 mutational status and confer an IPSS-independent adverse prognosis. The ability to identify Int-1 risk patients with shortened survival (Figure) holds major treatment implications. Disclosures: No relevant conflicts of interest to declare.