Mesa, Ruben A.

Abstract Abstract 5146 Background: Myelofibrosis (MF) is characterized by splenomegaly, debilitating symptoms, hematologic abnormalities, and shortened survival. COMFORT-I is a Phase III randomized, double-blind, placebo-controlled study of the JAK1 and JAK2 inhibitor ruxolitinib in patients (pts) with MF. The placebo arm of this ongoing study provides a unique population in which to assess the clinical burden of MF in a controlled setting. Methods: 151 pts with intermediate-2 or high-risk primary-MF (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thombocythemia-MF (PET-MF) who were not candidates for other therapies were randomized to receive placebo in COMFORT-I after a 28-day washout of previous MF therapies. Assessments included MF symptoms measured daily using an electronic diary (modified Myelofibrosis Symptom Assessment Form [MFSAF] v2.0), spleen volume measured every 12 wks by blinded abdominal MRI or CT scans, and laboratory measures at least monthly through wk 24. The Patient-Reported Outcomes Measurement System (PROMISE) Fatigue and Patient Global Impression of Change (PGIC) questionnaires were administered at each visit. Pts with missing data (baseline or post-baseline assessment measured), or pts who withdrew or crossed over to active treatment before a study visit were not included in analyses. Results: 151 pts received 1 or more doses of placebo (median exposure 204 days). The study included 65% high-risk and 35% intermediate-2 risk pts, with a median of 2.5 years since diagnosis. 55% had PMF, 31% PPV-MF, and 14% PET-MF. Regardless of prior MF therapy (57% were on hydroxyurea), there was continual worsening of symptoms over time as assessed by the MFSAF Total Symptom Score (TSS, comprised of scores for night sweats, itching, abdominal pain and discomfort, early satiety and bone/muscle pain) (see Figure). At wk 24, mean/median spleen volume increased by +8.1%/+8.5%, and both intermediate-2 and high-risk pts demonstrated progressive disease over the course of the study. Mean/median PROMIS Fatigue score worsened by 9.1%/6.5%. Mean/median score for the PGIC (a 7-point scale ranging from 1 = very much improved to 7 = very much worse, with 4 = no change) was 4.2/4.0 at wk 24; 19.6% of pts reported feeling much worse or very much worse. Mean/median total body weight changed from 72.0 kg/72.2 kg to 70.1 kg/69.7 kg at wk 24. Hematology assessments (median, baseline vs wk 24) were as follows: hemoglobin, 105 vs 106 g/L; platelets, 233 vs 219 x109/L; neutrophils, 14.8 vs 16.0 x109/L; white blood cell count, 18.4 vs 20.1 x109/L. Two of 151 pts had new-onset (new or worsening) grade 3 or grade 4 thrombocytopenia, and 23/151 pts had new-onset grade 3 or grade 4 anemia. 16 pts met protocol-specified criteria for unblinding and crossover to active treatment before wk 24, which was a 25% increase in MRI-based spleen volume either with or without increased pain or weight loss; thus, mean and median values reported at wk 24 may represent an underestimate of the degree of worsening in disease parameters. Conclusion: The signs and symptoms of MF continued to worsen over a 6-month time frame in this placebo population. The data illustrate the progressive nature of MF and support the need for effective therapeutic interventions. Moreover, treatment benefit must be benchmarked against continual evolution of the disease in the absence of treatment. Early recognition of the debilitating symptoms of MF and intervention with effective therapy to prevent continual worsening of the disease should be strongly considered. Disclosures: Verstovsek: Incyte: Research Funding. Mesa:Incyte: Research Funding; Lilly: Research Funding; SBio: Research Funding; Astra Zeneca: Research Funding; NS Pharma: Research Funding; Celgene: Research Funding. Gotlib:Incyte: Consultancy, Research Funding. Levy:Incyte: Employment, Equity Ownership. Gupta:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Catalano:Incyte: Honoraria; Novartis: Honoraria. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Winton:Incyte: Consultancy. Arcasoy:Incyte: Research Funding. Lyons:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Telik: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Research Funding. Vaddi:Incyte: Employment. Erickson-Viitanen:Incyte: Employment. Sun:Incyte: Employment. Sandor:Incyte: Employment. Kantarjian:Incyte: Research Funding; Novartis: Consultancy, Research Funding.

Abstract Background: A mutation in the Janus tyrosine kinase 2 gene (JAK2 V617F) has been recognized in Philadelphia chromosome-negative myeloproliferative disorders, including PV (∼95% of patients), ET (∼50%) and PMF (∼50%). INCB018424 is a potent and orally bioavailable selective JAK2 inhibitor with >80-fold selectivity against a broad panel of kinases, including JAK3. INCB018424 potently inhibits JAK2 V617F mediated signaling and malignant cell survival in vitro and in vivo in mice. Preclinical safety studies with INCB018424 demonstrated an excellent safety profile with no off-target toxicities. Methods: A phase I/II trial of INCB018424 given orally BID is being conducted in patients with PMF and Post-PV/ET MF. Both JAK2 V617F and JAK2 wild type patients are eligible. PK and PD data are being collected. Responses are being evaluated using the International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT) (Tefferi et al., Blood, 108, 1497–1503, 2006). Results: The initial dose of 25 mg PO BID resulted in a rapid and marked reduction in splenomegaly. All 3 patients in the first cohort of patients achieved a reduction in spleen size that is consistent with a clinical improvement response provided it is sustained for 8 weeks; spleen sizes of 25, 22, and 7 cm below the left costal margin have decreased to 8, 10, and 0 cm in the first month of therapy. At two months follow-up, the patient with a baseline spleen size of 22 cm is now down to 2 cm. All 3 patients also noted significant symptomatic improvement. The second cohort of 3 patients started therapy at an increased dose (50 mg PO BID) and at one week follow-up, the initial two patients (one JAK2 wild type, one JAK2 V617F) had decreases in spleen size from 22 cm to 17 cm and from 22 cm to 16 cm, respectively. No dose-limiting toxicities or other significant adverse events occurred in any patients to date. PK/PD analyses demonstrated that administration of INCB018424 resulted in plasma drug concentrations sufficient to markedly inhibit JAK2, as shown by suppression of phosphorylated STAT3 (a substrate of JAK2) in whole blood cells in all 3 patients in the first cohort. The 3 patients in the first cohort were all JAK2 V617F mutation positive: percentages of JAK2 V617F positive whole blood cells before therapy were 79%, 49% and 91%, and after one month of therapy, they were 59%, 48% and 78%, respectively. Conclusions: Initial results show marked reduction in splenomegaly and symptomatic improvement, without significant toxicity. The percentage of blood cells with JAK2 V617F mutation appears to be decreasing in patients on therapy. Updated results on current and future patients will be presented at the meeting.

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 3917 Poster Board III-853 Background Patients with Myelofibrosis (MF) suffer from significant fatigue, constitutional symptoms and splenomegaly (Mesa et. al. Cancer 2007) not improved by current therapy. The MF-SAF is a 19 item self administered instrument specific to MF associated symptoms previously validated for use at a single time point (Mesa et. al. Leukemia Research 2009). We sought to assess the performance characteristics of the MF-SAF when administered sequentially in the context of a prospective clinical trial. Methods Sequential MF patients enrolled in the prospective, uncontrolled Phase II, trial were given a 15 item modified MF-SAF to complete at enrollment, and after 15 days, 1 month, 2 months, 3 months and every 3 months thereafter. The MF-SAF was scored as previously published on a 0 (absent) to 10 (maximal) scale. Cross validation of serial change in MF-SAF scores was undertaken by comparison to objective measurements made as part of the therapeutic drug trial. Results Patients Eighty six MF patients were enrolled and had 2 or more MF-SAF instruments completed to allow for sequential analysis. Patients were of a median age (65 years), gender distribution (35 % females), and disease subtype (53 % PMF) typical for a clinical trial in MF. Baseline MF-SAF Responses: Baseline assessment of the most frequent MF abnormalities reported by patients completing the MF-SAF (see Table 1) confirmed the wide prevalence of MF associated symptoms, and their significant severity. General fatigue was the most frequent symptom cited (91%), while cough was the least frequently observed symptom (44%). 95% of patients had at least 2 symptoms present on the MF-SAF. Serial MF-SAF Changes in Response to Therapy Therapy with INCB018424 resulted in a significant and rapid reduction in MF associated symptoms with 46% to 85% of patients experiencing improvement in a given symptom. The greatest improvements in MFSAF score improvements were reported by patients experiencing abdominal discomfort, night sweats, pruritus and fever (see Table 1), and corresponded to significant improvements in the individual MF symptom scales as well as the patient's overall assessment of quality of life (QOL). Correlation of MF-SAF to Objective Changes during INCB018424 Therapy Objective measurements obtained on the INCB018424 trial included MRI measurements of splenic reduction, the six minute walk test (6MWT) for inactivity, and serial weights. Reduction in spleen size (by ≥ 35% by volume or ≥ 50% by palpable length) corresponded to improvement in MF-SAF scores of abdominal discomfort and fatigue (50% of patients, median score decrease of -1.2, and -1.8, respectively). Improvement in the 6MWT by > 50 meters was associated with a 2-fold greater improvement in inactivity score on the MF-SAF compared to subjects who improved 6MWT performance by <50 meters. Finally, improvements in weight loss and fever were corroborated by objective measurements made at physician visits on the trial. Conclusions The MF-SAF is a brief, easily self administered, MF specific instrument which was successfully administered sequentially in the conduct of a large Phase II clinical trial. The significant symptomatic improvements reported by patients in the open label trial of INCB018424 corresponded to both improvements in symptom specific scores on the MF-SAF and objective measurements. Further validation of the MF-SAF will be possible by inclusion in upcoming randomized placebo controlled trials in MF patients. Parallel trials performed in MF patients should consider use of this instrument to allow for comparisons. Disclosures: Levy: Incyte Corporation: Employment, Equity Ownership. Vaddi:Incyte Corporation: Employment, Equity Ownership. Erickson-Viitanen:Incyte Corporation: Employment, Equity Ownership. Verstovsek:Incyte: Research Funding.

Abstract Background: Previously established adverse prognostic factors in myelofibrosis with myeloid metaplasia (MMM) include anemia (hemoglobin < 10 g/dL), leukocytosis or leukopenia, presence of circulating blasts, and hypercatabolic symptoms (Dupriez et al. 1996;88:1013, Cervantes et al. BJH1998;102:684). Measurement of peripheral blood (PB) CD34 count has been shown to have diagnostic as well as possible prognostic value in MMM (Barosi et al. Blood2001;98:3249). Methods: A concurrent evaluation of PB CD34 count, bone marrow histology, and other clinical and laboratory parameters was conducted in a consecutive cohort of both newly and previously diagnosed patients with MMM. The study patients were prospectively followed for a minimum of 3 years in order to determine the prognostic value of PB CD34 count on survival, leukemic transformation, and disease progression from the time of PB CD34 analysis. Results: i. Patient cohort: A total of 94 patients (median age 61 years, range 26–81; 61 males) were accrued between January 2000 and August 2001 and subsequently followed through July 2004. MMM subtypes included agnogenic myeloid metaplasia (AMM; 58 patients), post-polycythemic myeloid metaplasia (PPMM; 12 patients), post-thrombocythemic myeloid metaplasia (PTMM; 12 patients), cellular phase MMM (8 patients) and hypocellular variant MMM (4 patients). At the time of study entry, 19 patients (20%) were newly diagnosed and 75 were established cases (median of 36 months from initial diagnosis, range 4–221). The Dupriez prognostic scores were 0 in 37 (39%), 1 in 37 (39%), and 2 in 20 patients (21%). ii) Clinical correlates of PB CD34 count: The median PB CD34 count for the entire study cohort was 54.7 x 106/L (range 0–5345) with 85% patients having increased values (> 5 x 106/L). Cellular phase MMM and PPMM had significantly lower PB CD34 counts compared to the other MMM subtypes. On univariate analysis, PB CD34 count significantly correlated with Dupriez prognostic score, leukocyte count, circulating blast or immature myeloid cell percentage, and presence of hypercatabolic symptoms but not with age, gender, anemia (hemoglobin < 10 g/dL), abnormal cytogenetics, disease duration, treatment history, splenectomy status, nucleated RBC count (NRBC), platelet count, or bone marrow histology including fibrosis, osteosclerosis, and angiogenesis. On multivariate analysis, only leukocyte count and PB blast or immature myeloid cell percentage retained their significance. iii) Prognostic evaluation of PB CD34 count : As of July 16, 2004, 43 patients (46%) have died and median duration of follow up in the surviving patients was 41 months (range 36–54). The projected overall survival at 5 years was 50%. On Cox proportional regression analysis, individual variables that correlated with inferior survival included anemia (hemoglobin < 10 g/dL), advanced age, presence of hypercatabolic symptoms, abnormal cytogenetics, and increased leukocyte count, circulating blast percentage, Dupriez prognostic score, and NRBC. PB CD34 count displayed borderline significance (p=0.06). However, on multivariate analysis, only anemia, leukocytosis, and age retained prognostic significance. Similarly, PB CD34 count did not predict either subsequent leukemic transformation or disease progression. Conclusion: PB CD34 count is often but not always increased in MMM and correlates significantly with leukocytosis and degree of PB myeloid immaturity. The current prospective study does not support an independent prognostic value for PB CD34 count in MMM.

Abstract Introduction: Several groups are developing orally bioavailable small molecule JAK2 inhibitors as an approach to targeted therapy of myeloproliferative disorders. We previously reported that one such inhibitor (TG101209) potently inhibits JAK2V617F in vitro, and was effective in reducing tumor growth in a mouse xenograft model (Leukemia, 2007 Aug;21(8):1658–68). Here, we expand our analysis using TG101348, a highly selective JAK2 inhibitor currently in preclinical development, using cell lines and primary cells harboring JAK2V617F, MPLW515L/K, or JAK2 exon 12 mutations. Methods: Cell proliferation was assessed using the XTT assay. For primary cell experiments, PBMCs were plated in methylcellulose medium at 0, 300nM, 600nM, and 1200nM TG101348, both with and without erythropoietin (Epo). Hematopoietic colonies were scored after 12–16 days culture, and harvested for genotyping. Results: TG101348 inhibits growth of human erythroleukemia (HEL) and Ba/F3-V617F cells (IC50=300nM and 580nM, respectively), as well as Ba/F3-(MPL)W515L cells (IC50=620nM). JAK2:JAK3 selectivity of TG101348 was demonstrated by its 10-fold more potent inhibition of CHRF (JAK2T875N) as compared to CMK (JAK3A572V) cell proliferation. TG101348’s inhibitory effect on ex vivo hematopoietic colony growth was studied in 12 MPD patients (JAK2V617F=9, MPLW515L/K=1, JAK2 exon 12 mutation [N542-E543del]=1, no mutation=1), and 2 healthy controls (Table). Conclusions: (1) TG101348 inhibits colony growth from MPD patients more potently than healthy controls, reflecting its potential therapeutic window. (2) Endogenous colony growth is inhibited at nanomolar concentrations in all cases, with some alleles showing greater sensitivity than others (MPLW515K = exon 12 mutation > JAK2V617F). The corresponding Epo-supported erythroid colonies are less potently inhibited, reflecting the generally lower prevalence of JAK2 mutations in such colonies. (3) EEC growth in the absence of known JAK2 or MPLW515 mutations is also inhibited, indicating a similar dependence on dysregulated JAK-STAT signaling in such cases. (4) The ability of TG101348 to selectively suppress mutation-positive hematopoietic colonies will be discussed. Inhibitor effect on ex vivo hematopoietic colony growth Paient Mutation IC50 (nM) % Mutation-positive colonies Epo No Epo Epo No Epo (EEC) Normal 1 None >1200 n/a n/a n/a Normal 2 None >1200 n/a n/a n.a PV1 V617F 600 <300 5 40 PV2 V617F 600 300 33 50 PV3 V617F 600–1200 300–600 9 70 PV4 V617F 300–600 600 0 15 PV5 V617F 600–1200 300 80 100 PV6 V617F 600 300–600 7 19 PV7 V617F 600–1200 600 32 36 PV8 V617F 600–1200 <300 45 37 PV9 V617F 600 600–1200 20 12 PV10 Exon 12 (N542–E543del) 900 <300 9 60 PMF1 W515K 300–600 <300 100 33 PMF2 None >1200 300 n/a n/a

Abstract BACKGROUND: Both thalidomide (Br J Haematol2002;117:288) and lenalidomide (Blood2006;108:1158) are effective for alleviating anemia in approximately 20% of patients with myelofibrosis (MF). However, the value of these drugs is undermined by their respective potential for peripheral neuropathy and severe myelosuppression. In the current study, we evaluated the safety and efficacy of the new immunomodulatory drug, pomalidomide (POM) in MF. METHODS: This is a phase-2 randomized, multicenter, double-blind, active-control, parallel-group study to determine safety and select a “Best” dose of POM alone or combined with prednisone (PRED). Patients were equally randomized to 4 treatment groups: POM (2 mg/day) + placebo, PRED (30 mg/day) + placebo, POM (2 mg/day) + PRED (30 mg/day), and POM (0.5 mg/day) + PRED (30 mg/day). POM therapy was given for up to twelve 28-day treatment cycles. PRED therapy was given in a tapering dose schedule during the first three of these 12 treatment cycles. Protocol eligibility criteria included absolute neutrophil count of ≥ 1 × 109/L, platelet count of ≥ 50 × 109/L and hemoglobin level of < 10 g/dL including red blood cell (RBC) transfusion requirement. Patients with prior thalidomide or lenalidomide therapy and/or venous thrombosis were excluded from study participation. Response was assessed by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria (Blood.2006;108:1497) and by independent analysis of the component variables. RESULTS: A total of 104 patients with MF were assessed for eligibility; 85 were randomized and 84 received the assigned therapy. Blinded data for the first 82 patients are presented here; median age was 67 years and MF subtype was PMF in 70% of the patients and post-PV/ET MF in 30%. All patients belonged to either intermediate or high risk disease category (Blood1996;88:1013); 42 (51%) were RBC transfusion-dependent. Median duration of disease before randomization was 3 years (range 2–14). The number of patients assigned to each arm was relatively balanced: 21, 20, 19 and 22, respectively. After a median treatment duration of 3 months, 42 (51%) patients have discontinued protocol therapy because of lack of therapeutic effect (n=19), withdrawal of consent (n=11), adverse event (n=11) or death (n=2). Grade 3/4 adverse events (regardless of attribution) included anemia (10%), thrombocytopenia (9%), leukopenia (9%), fatigue (7%), dyspnea (5%), thrombosis (4%), diarrhea (4%) and hyperglycemia (4%). Combined response rate using IWG-MRT criteria was 25% (95% CI, 16–34%) and ranged between 11% and 42% among the four treatment arms. CONCLUSION: Pomalidomide, with or without concomitant prednisone therapy, is well tolerated in patients with MF, especially from the standpoint of myelosuppression. Response rates are high. Additional, unblinded, information regarding response details, remission duration and laboratory correlative studies will be presented at the meeting.

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 Survival of patients with primary myelofibrosis (PMF) is highly variable, ranging from months to even decades. Although treatment of PMF remains mostly palliative, the increasing use of allogeneic hemopoietic stem cell transplantation and introduction of newer therapies has raised the need for a better prognostic stratification of these patients. The initial features of 1,054 patients (638M/416F; median age 64 years, range 10–90) consecutively diagnosed with PMF in seven institutions from Europe and USA between 1980 and 2007 were evaluated for prognostic significance. Patients with the so-called “pre-fibrotic” form of PMF were not considered. The variables assessed were those previously shown to be of prognostic value in PMF, those clinically meaningful, and possible confounders (namely, diagnostic period and series of origin). The effect of the potential prognostic factors on survival was evaluated by the Cox proportional hazards regression and the proportional hazards assumption checked in every model by graphical methods and the Grambsch-Therneau test. A prognostic model was identified through a stepwise selection process, based on a z-test of the regression coefficients, and evaluated by calculating its discriminating power (measured by Harrell’s C concordance index), as compared to that of current PMF prognostic systems, and its positive predictive accuracy for actual survival longer (or shorter) than definite periods of time from diagnosis. The replicability of both the prognostic variables and the new prognostic score was tested by bootstrap re-sampling, in which 1,000 samples of the same size than the original series were built by random extraction with reposition. Median survival of the overall series was 69 months (95% CI: 61–76), with 49% of patients having died at the time of study. At multivariate analysis, five initial variables were associated with shorter survival: age > 65 years, constitutional symptoms (weight loss, fever, sweats), Hb < 10 g/dL, leukocyte count > 25×109/L, and blood blasts 1%. The hazard ratios of these variables did not differ substantially, ranging from 2.89 (95% CI: 2.46–3.61) for Hb < 10 g/dL to 1.80 (95% CI: 1.50–2.17) for blood blasts 1% and, therefore, one point was assigned to each one. Based on this, among the 1,001 patients of the series with all the necessary data available, four risk groups were identified with no overlapping in the 95% CI of their survival curves (figure): low risk (no factor, 22% of patients; median survival 135 months); intermediate risk-1 (one factor, 29% of patients; median survival 95 months); intermediate risk-2 (two factors; 28% of patients; median survival 48 months); and high risk (three factors, 21% of patients; median survival 27 months). The new prognostic score showed high predictive accuracy and replicability and had higher discriminating power than current risk-based PMF classifications. In the 409 patients with assessable metaphases, presence of cytogenetic abnormalities (observed in 30% of cases) was associated with shorter survival and contributed to prognosis, but only in patients in the intermediate-risk groups. No prognostic influence for either JAK2 V617F mutational status (n= 345) or blood CD34+ cell count (n= 150) was noted. This new prognostic scoring system substantially improves existing risk-based classifications of PMF and may help in treatment-decision making and in the design and analysis of newer therapies for the disease. Figure Figure

Abstract Background: In both polycythemia vera (PV) and essential thrombocythemia (ET), aspirin and/or hydroxyurea therapy provide adequate protection from thrombosis but not from disease transformation into acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or myelofibrosis (MF). In designing clinical trials with new drugs, including the use of small molecule JAK2 inhibitors, in either ET or PV, it is important to identify patients who are at a higher risk of early transformation into AML/MDS/MF as well as those in whom the long-term risk of these complications is too low to justify exposure to experimental drugs with unknown short-term and long-term toxicity profile. Methods: Information on an institutional database of 1061 patients with either PV (n=458) or ET (n=603) was updated in July of 2007. The World Health Organization criteria were used for diagnosis of PV, ET, AML, MDS, and MF. Two different approaches were used to assess both early and overall risk of AML/MDS/MF development in both ET and PV. In the first approach, three distinct groups were delineated and their presenting features compared; group A was comprised of patients who have remained AML/MDS/MF free after a minimum follow-up of 20 years whereas groups B and C included patients who developed either AML/MDS or MF, respectively, in the first decade of their disease. In the second approach, prognostic factors for AML/MDS/MF-free survival were examined among the entire cohort of 1061 patients. Results : In ET, the number of patients that fulfilled the above-mentioned criteria for inclusion in groups A, B, and C were 40, 12, and 8; the three groups displayed significant differences in the prevalence, at diagnosis, of lower than normal hemoglobin level (8% vs. 58% vs. 38%; p=0.0004), male sex (18% vs. 58% vs. 50%; p=0.01), and arterial thrombosis at diagnosis (p=0.03), respectively. However, only the former two remained significant during multivariable analysis that included age as a covariate. In PV, the number of patients in groups A, B, and C were 23, 18, and 12; the only difference between the three groups was the association between group B and leukocytosis (p=0.02). Cox regression analysis of the entire 1061 ET/PV patients cohort, including 65 AML/MDS/MF events in ET and 36 AML/MDS events in PV, confirmed the inferior AML/MDS/MF-free survival in ET associated with lower than normal hemoglobin and AML/MDS-free survival in PV associated with leukocytosis (Figure). Conclusion : The current study identifies PV patients with leukocytosis as being the most appropriate and ET patients without anemia as the least appropriate for consideration of participation in experimental drug treatment trials. Figure Figure Figure Figure