Tefferi, Ayalew

Abstract Background: The recent discovery of JAK2V617F, as an activating mutation in the majority of patients with myeloproliferative neoplasms, has spurred development of JAK2-selective small molecule inhibitors for the treatment of these diseases. TG101348 is a potent (enzyme IC50=3 nM) and selective (35- and 334-fold selectivity over JAK1 and JAK3, respectively) orally bioavailable JAK2 inhibitor that is effective in treating a murine model of Polycythemia vera (PV) (Cancer Cell. 2008 13:311). TG101348 selectively inhibits growth of hematopoietic colonies harboring V617F, MPLW515K, or JAK2 exon 12 mutations (Leukemia. 2008 Mar 20, Epub). Methods: A Phase I dose-escalation study of TG101348 is ongoing for patients with high- or intermediate-risk (with symptomatic disease) primary myelofibrosis (PMF) and post-PV or post-essential thrombocythemia (ET) myelofibrosis (Cancer.2007109:2083). TG101348 was administered orally once daily in 28-day cycles in cohorts of at least 3 patients. Additional eligibility criteria included absolute neutrophil count of ≥1 × 109/L and platelet count of ≥50 × 109/L, but a JAK2 mutation was not required. Primary objectives were determination of safety and tolerability, as well as pharmacokinetic behavior of TG101348. The secondary objectives were evaluation of treatment response (Blood.2006108:1497), pharmacodynamic activity, and drug effect on V617F allele burden and plasma cytokine levels. The spleen response was documented as change in palpable spleen tip from the costal margin. For patients achieving less than a complete remission after 3 cycles of treatment at their initial dose, step-wise escalation was permitted at each cycle if a cohort had been shown to have tolerated that dose. Results: Fifteen patients (9 males; median age=66 years; range=53 to 79 years) have been enrolled in the study to date – 10 with PMF (8 V617F+) and 5 with post-PV MF (all V617F+). The median follow-up to date is 13 weeks (range 1–28). Treatment was discontinued in 1 patient, in cohort 1, on the 2nd day of dosing after it was discovered that the patient had baseline QTcF prolongation (Grade 1). In the remaining 14 patients, no dose-limiting toxicities or other significant non-hematological adverse events have been observed to date. The pharmacokinetic parameters of TG101348 in plasma were well characterized following single daily oral doses of 30 mg, 60 mg, 120 mg or 240 mg. Dose-proportional pharmacokinetics were observed following single and multiple doses of TG101348. Treatment response data are as follows: Cohort 1 (starting dose=30 mg; 3 patients; median follow-up=26 weeks): 2 of the 3 patients had improvement in constitutional symptoms including fatigue, night sweats and pruritus. No other benefits were noted. These patients have now been dose escalated to either 120 or 240 mg/day. Cohort 2 (starting dose=60 mg; 3 patients; median follow-up=18 weeks): 1 patient had a 40% decrease in spleen size (18 to 10 cm). All 3 patients have now been dose escalated to 120 or 240 mg/day. Cohort 3 (starting dose=120 mg; 3 patients; median follow-up=13 weeks): 2 of the 3 patients reported improvement in constitutional symptoms including fatigue, night sweats, and pruritus. 1 patient had a 25% decrease in spleen size (28 to 21 cm). 2 patients have been dose escalated to 240 mg/day. Cohort 4 (starting dose=240 mg; 3 patients; median follow-up=8 weeks): 1 patient developed Grade 3 anemia (baseline Grade 1) at the end of the first cycle. 1 patient reported decreased fatigue. All 3 patients have experienced a 20 to 53% reduction in spleen size; baseline measurements were 10, 13, and 17 cm. Cohort 5 (starting dose=360 mg; 2 patients; median follow-up=1 week). Both patients had decreased splenomegaly within 1 week of therapy, including 1 with disappearance of palpable splenomegaly from a baseline of 20 cm; this patient also reported significant improvement in constitutional symptoms. Conclusions: Preliminary findings indicate that TG101348 is well tolerated in patients with myelofibrosis. Although it is too early to make valid conclusions, a decrease in spleen size has been noted at higher dose levels. Similarly, improvement in constitutional symptoms has been reported by some patients. Updated results on current and future patients, including data on pharmacokinetics, pharmacodynamics, and changes in V617F allele burden and plasma cytokine levels will be presented at the meeting.

We review the clinical manifestations and long-term outlook of patients with chronic natural killer (NK) cell lymphocytosis. After reviewing more than 1,500 peripheral blood lymphoid flow cytometry reports and molecular genetics data from patients with suspected large granular lymphocyte (LGL) proliferation, we identified 10 patients (median age at diagnosis, 60 years; range, 35 to 76 years; male:female ratio, 3:2) with persistent (greater than 6 months) increase in phenotypically determined NK cells (CD3-CD16+). Southern blot analysis performed on 9 patients showed no clonal T-cell receptor gene rearrangements. Disease duration was measured from time of initial recognition of LGL or NK cell excess (greater than 40% of the lymphocyte fraction). Clinical data from these 10 patients were compared with those from 68 patients with T-cell LGL (T-LGL) leukemia. Currently, all patients are alive (median disease duration, 5 years; range, 0.8 to 8 years). Associated disease manifestations included pure red blood cell aplasia, recurrent neutropenia, recurrent neutropenic sepsis, and vasculitic syndromes, all of which were responsive to immunosuppressive therapy. No patient had palpable lymphadenopathy or splenomegaly. Compared with the patients with T-LGL leukemia, patients with chronic NK cell leukemia has similar lymphocyte counts, associated conditions, treatment responses, and survival but had less neutropenia and anemia.

A favorable prognosis and a low rate of leukemic transformation has been attributed to the 5q- syndrome, a myelodysplastic syndrome (MDS) characterized by macrocytic anemia, hypolobulated micromegakaryocytic hyperplasia, and an interstitial deletion of chromosome 5. We examined the characteristics and outcome of 43 consecutive patients in our institution strictly defined by morphologic criteria and a solitary 5q- cytogenetic defect. The median age at diagnosis was 68 years, with a clear female predominance (7:3). Eighty percent of the patients were red blood cell transfusion-dependent at diagnosis and all untransfused patients had macrocytic indexes. In contrast, significant neutropenia or thrombocytopenia was rare. The French-American-British (FAB) class distributions were RA (72%), RARS (7%), RAEB (16%), and RAEB-IT (5%). At a median follow-up of 31 months, 56% of the patients survive, with a projected median survival of 63 months. The incidence of acute leukemia was 16% and was uniformly fatal. Clinical hemosiderosis occurred in 28% of the patients, resulting in two deaths. Neither survival nor the risk of leukemic transformation was predictable from initial clinical parameters, including FAB classification, Bournemouth score, and degree of aneuploidy. The lack of significant neutropenia and thrombocytopenia seemed to account for a very low incidence of infection and bleeding resulting in a prognosis equal or superior to historical patients with MDS. Therapeutic endeavors, including the use of corticosteroids, androgens, cis-retinoic acid, pyridoxine, and danazol, were largely unsuccessful.

Abstract Recent studies have shown decreased megakaryocyte expression of the thrombopoietin receptor (c-mpl) in patients with polycythemia vera (PV) but not in those with reactive erythrocytosis. We examined the diagnostic utility of this observation in 22 patients with PV, 7 patients with secondary erythrocytosis (SE), and 10 normal controls. Commercial antibodies against c-mpl were used with standard immunoperoxidase methods. Megakaryocyte c-mpl staining intensity was uniformly moderate-to-strong in the healthy controls and in all the patients with SE. In contrast, staining intensity in 9 patients with PV (41%) was uniformly weak. Furthermore, in 12 of the remaining 13 patients with PV, the c-mpl staining pattern in each case was heterogeneous and was associated with weak staining intensity in more than 20% of the megakaryocyte population. These preliminary data suggest that c-mpl immunostains may complement bone marrow histopathology in distinguishing PV from nonclonal causes of erythrocytosis.

We identified 68 patients with clonal T-large granular lymphocyte (T- LGL) proliferations who were seen at the Mayo Clinic between 1984 and 1992. Nineteen (28%) were asymptomatic at diagnosis, while the rest experienced fatigue (60%), B-symptoms (12%), and recurrent infections (15%). Associated comorbid conditions included rheumatoid arthritis (RA) in 26%. Severe anemia (hemoglobin [Hb] < 8g/dL) and neutopenia (absolute neutrophil count [ANC] < 500/microL) were seen in 19% and 40% of patients, respectively. Immunophenotypic studies showed CD3+, CD8+ phenotype in the majority (72%). Twenty-one patients (31%) have required no therapy, and remain relatively stable with a median follow- up period of 50 months. Treatment was required at either diagnosis (36 patients) or at subsequent follow-up (11 patients). Initial response rates were similar in patients treated with cyclophosphamide (CTX) with or without prednisone (69%), or prednisone alone (73%). Overall, 61 patients (90%) are alive with a median follow-up of 44 months. Actuarial median survival of this entire cohort is 161 months. The presence of anemia or symptoms does not appear to correlate with the tumor burden. In patients requiring therapy, a lower ANC and the presence of B-symptoms/infection were independently associated with a significantly lower probability of achieving a molecular or hematologic complete remission (H-CR). Intermittent immunosuppressive therapy is effective in achieving durable responses in a number of patients. T-LGL proliferations are associated with a favorable prognosis and response to therapy. However, significant heterogeneity exists in clinical presentation and associated comorbid conditions. These disorders should be included in the differential diagnosis of patients with unexplained cytopenias, particularly in the setting of RA and other autoimmune disorders. Analogous to the situation with monoclonal gammopathies, a term such as T-cell clonopathy of undetermined significance (TCUS) may be more appropriate to describe these patients.

Abstract Background Severe anemia with RBC-transfusion-dependence is common in persons with advanced MPN-associated myelofibrosis. Pomalidomide, an immune-modulating drug with pleiotrophic bone marrow effects, improved anemia in several phase 2 studies. Method Phase 3 double-blind, placebo-controlled trial of pomalidomide (0.5 mg/d) in subjects with MPN-associated myelofibrosis and RBC-transfusion-dependence. The primary endpoint was RBC-transfusion-independence. Criteria for RBC-transfusion-dependence and -independence were based on results of an expert consensus panel RAND-Delphi study. Subjects 252 subjects were randomized 2:1 to receive pomalidomide or placebo with stratifications for age, type of myelofibrosis, and intensity of RBC-transfusions. Median age was 70 y. 75% had primary myelofibrosis. Median units (U) RBC-transfusions/28 d pre-randomization was 3 (range, 2-13). Results Response rates in the cohorts were similar (16% [95% CI, 11-23%] vs 16% [8-26%]), as were response durations. However, median time to response for pomalidomide was 7 w (range, 0-20 w) vs only 2 w (range, 0-15 w) for placebo (p=0.22). Response in both cohorts was more common in subjects with ≤4 vs >4 U RBC/28 d pre-randomization (OR=3.1 [p=0.09] and OR=8.6 [p=0.06]). However, other variables associated with response to pomalidomide: age ≤65 vs >65 y (OR=2.4; p=0.07) and primary myelofibrosis vs other (OR=2.6; p=0.14) and response to placebo: (WBC >25 vs ≤25 x10E9/L; OR=5.0; p=0.08) and interval from diagnosis to randomization >2 vs ≤2 y (OR=5.0; p=0.04) differed. These differences would not be expected were response to pomalidomide identical to response to placebo. Also, a center effect was found in placebo but not pomalidomide responders, which persisted after adjusting for predictive associations. Several pomalidomide responders lost response when therapy was stopped but regained it when pomalidomide was re-started. No pre-randomization therapy (iron-chelation, hydroxyurea, busulfan, folate) was consistently correlated with response to placebo, and durations of RBC-transfusion-dependence pre-randomization were similar between the cohorts. In contrast, platelet response rates, a 2̍° endpoint, were significantly different between the cohorts: pomalidomide, 22% (95% CI, 11-35%) vsplacebo, 0 (0-12%; p=0.006). Platelet response was not correlated with RBC-transfusion-independence response. Conclusion There was no significant difference in rate or duration of RBC-transfusion-independence response to pomalidomide vsplacebo despite using what were thought to be sensitive and specific entry- and response-criteria. Unexpectedly, however, most variables associated with response to pomalidomide and placebo differed between the cohorts, as did distribution of times to response. These data suggest responses to pomalidomide and placebo differ but were not distinguished by our response-criteria. Pomalidomide appears to reverse RBC transfusion dependence in some persons with MPN associated MF. However, additional research designs are needed to study this impression. This abstract is presented on behalf of all RESUME Investigators. Study registration: NCT01178281. Disclosures: Cervantes: Novartis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Gisslinger:AOP Orphan Pharmaceuticals: Advisory Board Meeting Other, Honoraria; Novartis: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria; Sanofi-Aventis: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria; Shire: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria; Celgene: Advisory Board Meeting Other, Honoraria; Janssen: Advisory Board Meeting, Advisory Board Meeting Other, Honoraria. Gupta:Incyte Corporation: Consultancy, Grant support through institution Other; Novartis: Consultancy, Grant support through institution, Grant support through institution Other, Honoraria. Harrison:SBio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kiladjian:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; AOP Orphan: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schiller:Celgene: Research Funding. Mesa:Gilead: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Lilly: Research Funding; Genentech: Research Funding; Celgene: Research Funding.

Abstract Background : Current prognostication in primary myelofibrosis (PMF) utilizes international prognostic scoring systems that rely on clinical parameters that are sensitive to day-to-day variations and subjective interpretation. Recent studies in PMF have disclosed important prognostic information attached to additional cytogenetic details (Blood. 2011;118:4595) and somatic mutations, including CALR and ASXL1 (NEJM. 2013;369:2379; Leukemia. 2013;27:1861). Methods : PMF diagnosis and definition of blast transformation (BT) were according to World Health Organization criteria (Blood. 2009;114:937). Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature (Cytogenetic and genome research. 2013. Prepublished on 2013/07/03 as DOI 10.1159/000353118). Previously published methods were used for analyses of CALR, JAK2, MPL and other prognostically-relevant mutations, including ASXL1, SRSF2, EZH2 and IDH(Leukemia. 2014;28:1472). Results : The training set included 964 Mayo Clinic patients (median age 65 years; 62% males) in whom informative karyotype or mutation information was available; cytogenetic information was available in 903 (94%) cases, JAK2/CALR/MPL mutational status in 532 (55%), ASXL1 in 425 (44%), SRSF2 in 434 (45%), IDH1/2 in 376 (39%) and EZH2 in 268 (28%). DIPSS-plus (JCO. 2011;29:392) risk distribution was high in 37% of patients, intermediate-2 in 37%, intermediate-1 in 15% and low in 11%. We used a revised risk stratification for cytogenetics (see accompanying ASH 2014 abstract) to distinguish four distinct cytogenetic risk categories: very high (monosomal karyotype, inv(3), i(17q), -7/7q-, 11q or 12p abnormalities; n=67), high (complex non-monosomal, two abnormalities not included in very high risk category, 5q-, +8, other autosomal trisomies except +9, and other sole abnormalities not included in other risk categories; n=164), intermediate (sole abnormalities of 20q-, 1q+ or any other sole translocation, and -Y or other sex chromosome abnormality; n=133) and low (normal or sole abnormalities of 13q- or +9; n=539). Mutational frequencies were 58% for JAK2, 25% CALR, 7% MPL, 36% ASXL1, 11% SRSF2, 5% IDH1/2 and 6% EZH2. The 131 cases with CALR mutations were further subclassified into two prognostically different groups: type 1/type 1-like (n=110) and type 2/type 2-like (n=21) (see accompanying ASH 2014 abstract). At a median follow-up time of 4.2 years for patients who are alive, 664 (69%) deaths and 70 BT (7%) were recorded. Age-adjusted multivariable analysis that included cytogenetic and mutational risk groups disclosed the following as independent predictors of shortened survival: very high risk karyotype (HR 4.2; 3 points), high risk karyotype (HR 1.9; 1 point), triple-negative (HR 2.8; 2 points), JAK2 (HR 3.1; 2 points), MPL (HR 3.1; 2 points), type 2/type 2-like CALR (HR 3.6; 2 points), ASXL1 (HR 1.9; 1 points) and SRSF2 (HR 1.9; 1 point); EZH2 (p=0.24) and IDH1/2 (p=0.68) and intermediate risk karyotype (p=0.87) were not significant. The above-mentioned significant variables and age demarcated at 60 years (2 points), were subsequently used to develop an HR-derived, genetics-based prognostic scoring system (GPSS) for 369 patients who were fully informative for both karyotype and all significant mutations: low risk (0 points; n=31), intermediate-1 (1 or 2 points; n=90), intermediate-2 (3 or 4 points; n=133) and high (5 or more points; n=115); the corresponding median survivals were >17, 9 (HR 4.7, 95% CI 1.7-13.0), 5 (HR 10.7, 95% CI 3.9-29.3) and 2.2 (HR 29.2, 95% CI 10.6-80.0) years (Figure 1). High risk GPSS was also associated with higher BT rate (HR 7.4, 95% CI 2.1-26.3). The prognostic distinction between high/intermediate-2 and low/intermediate-1 risk GPSS, in terms of both overall (median 5 vs 26.4 years; HR 7.1, 95% CI 3.3-14.9) and leukemia-free survival (median 11.6 years vs not reached; HR 9.4, 95% CI 2.2-41.0) was validated in an independent cohort of 183 patients from the University of Florence (Figure 2). Conclusions : The current study demonstrates the feasibility of genetics-based prognostic models in PMF that rely on objective parameters that are amenable to further refinement as new genetic information becomes available. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 3795 Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (IL-2R, IL-8, IL-12, IL-15 and CXCL10) and large cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). In order to examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex ELISA to measure 30 plasma cytokines in 78 patients with primary MDS. Compared to normal controls (n =35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (p<0.01), IL-7 (p=0.02) and IL-6 (p=0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the international prognostic scoring system (IPSS), age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (p<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (p=0.01). Comparison of plasma cytokines between MDS (n =78) and primary myelofibrosis (n =127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically-relevant plasma cytokine signatures in hematologic malignancies.Figure:Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002).Figure:. Survival data for 78 patients with de novo myelodysplastic syndrome (MDS) stratified based on plasma levels of CXCL10, IL-7 and IL-6: (i) normal levels of all 3 cytokines (top curve), or (ii) increased (> 3 standard deviations of the normal mean level) level(s) of one or more of the aforementioned cytokines (bottom curve) (p=0.002). Disclosures: No relevant conflicts of interest to declare.

Abstract BACKGROUND. In primary myelofibrosis (PMF), survival from time of diagnosis is predicted by the international prognostic scoring system (IPSS), and from time of referral, by the dynamic IPSS (DIPSS) or DIPSS-plus. JAK2/CALR/MPL mutational status and presence and number of other prognostically-relevant mutations (ASXL1, SRSF2, EZH2, IDH1/2) provide IPSS/DIPSS-plus independent prognostic information. The objective in the current study was to revise IPSS, by including mutation-relevant prognostic information. METHODS. The study included 986 PMF patients divided into learning (n=588) and validation (n=398) cohorts. Previously published methods were used to screen for mutations involving JAK2,MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. The clinical variables assessed were those previously identified as being prognostically-relevant by IPSS or DIPSS-plus. The prognostic model (MIPSS) was developed through a stepwise selection process, based on a z-test of the regression coefficients, and its relative quality was measured by means of the Akaike information criterion. RESULTS. In the Italian learning cohort (n=588),median follow-up was 3.6years (95% CI, 0.03-30.8) for alive patients and 196 (33.3%) deaths and 67 leukemic transformations were documented. IPSS risk distribution was low in 26%, intermediate-1 in 30%, intermediate-2 in 24% and high in 20%. Mutational frequencies were approximately 63% for JAK2, 20% CALR, 6% MPL, 7% EZH2, 22% ASXL1, 2.5% IDH1/2 and 9% SRSF2. Constitutional symptoms were recorded in 28.6% of patients, splenomegaly 75% (18% >10cm from LCM) and grade 3 fibrosis 21%. Overall 252 patients were evaluable for karyotype and abnormalities were detected in 35%, including 9.5% unfavorable. Univariate analysis identified the following risk factors for inferior survival: age >60 years, constitutional symptoms, hemoglobin <100g/L, leukocytes >25x109/L, platelets <200x109/L, circulating blasts 1% or greater, splenomegaly >10cm, grade 3 fibrosis, unfavorable karyotype, triple-negativity for JAK2, MPL and CALR (TN), JAK2 or MPL mutation, and mutations in ASXL1, SRSF2, EZH2 or IDH1/2. In multivariable analysis, age >60 years, constitutional symptoms, hemoglobin <100g/L, platelets <200x109/L, TN, JAK2 or MPL mutation, ASXL1 and SRSF2 mutation remained significant; these variables were subsequently assigned the following HR-weighted adverse points: 1.5, 0.5, 0.5, 1.0, 1.5, 0.5, 0.5 and 0.5, respectively. Subsequently, four risk groups with no overlap in the 95% CI of their survival curves were delineated (Figure 1A): low (score 0-0.5); Intermediate-1 (score 1-1.5); Intermediate-2 (score 2-3.5); and high (score 4 or greater). The number of patients in each risk category, median survivals and HR and 95% CI values are included in figure 1A. Akaike information criterion indicated that MIPSS performed better than IPSS in predicting survival (1611.6 vs 1649.0). Leukemia-free survival was also predicted by high (p<0.01) and intermediate 1/2 (p<0.01) risk MIPSS. In the Mayo Clinic validation cohort (n=398), median age 63 years; males 64%,median follow-up for alive patients was 7.5 years and 271 (68%) deaths and 51 (13%) leukemic transformations were documented. DIPSS-plus risk distribution was low in 13%, intermediate-1 18%, intermediate-2 37% and high 32%. Mutational frequencies were approximately 51% for JAK2, 30% CALR, 7.5% MPL, 5% EZH2, 36% ASXL1, 5.6% IDH1/2 and 13% SRSF2. MIPSS performed equally well in this cohort, as illustrated in figure 1B, which includes number of patients in each risk category with their median survival and HR and 95% CI values. Leukemia-free survival in the Mayo cohort was also predicted by high (p<0.01) and intermediate-2 (p=0.04) risk MIPSS. Patients in the Mayo cohort were fully annotated for karyotype, which was MIPSS-independent in its prognostic value for both overall (p<0.01) and leukemia-free (p<0.01) survival. CONCLUSIONS. MIPSS addresses the mutation-relevant prognostic information gap in IPSS and performs equally well in the setting of patients seen at time of diagnosis or referral. Karyotype carries MIPSS-independent prognostic value that is recognized in an alternative GIPSS prognostic model (see accompanying ASH 2014 abstract), which complements MIPSS. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract SCI-36 Myeloproliferative neoplasms (MPN) are stem cell-derived clonal (or oligoclonal) hemopathies and are phenotypically characterized by abnormally increased left-shifted myeloproliferation. “BCR-ABL1-negative MPN” is an operational sub-category of MPN that includes polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Beginning in 2005, novel mutations involving JAK2, MPL, TET2, ASXL1, IDH1, IDH2, CBL, IKZF1, or LNK have been described in a variable proportion of patients with BCR-ABL1-negative MPN. The evidence so far suggests that none of these mutations garner the disease specificity or pathogenetic relevance otherwise displayed by BCR-ABL1. Nevertheless, considering the fact that some of these mutations exhibit high mutational frequency (e.g. JAK2 mutations) and either directly (e.g. JAK2 or MPL mutations) or indirectly (e.g. LNK or CBL mutations) induce JAK-STAT hyperactivation, it is reasonable to evaluate the therapeutic value of anti-JAK drugs in these disorders. In this regard, the ATP-mimetic small molecule kinase inhibitors have so far been the focus and those that have made it into clinical trials include TG101348, INCB018424, CEP-701, CYT387, AZD1480, SB1518, XL019 and LY2784544 (clinicaltrials.gov). Preliminary results from clinical studies suggest notable differences among these drugs in their toxicity and efficacy profiles, some of which might be linked to their variable in vitro activity against other JAK and non-JAK kinase targets and the resultant effect on JAK-STAT-dependent cytokines. For example, off-target FLT3 inhibition displayed by TG101348, CEP-701 and SB1518 might contribute to their common side effect profile of nausea, vomiting and diarrhea. Similarly, the impressive activity of INCB018424 in alleviating constitutional symptoms has been correlated with marked reduction in serum pro-inflammatory cytokines and therefore possibly related to its primarily anti-JAK1 activity whereas serum cytokine levels did not appear to be affected by either TG101348 or CEP-701. More selective anti-JAK2 drugs, such as TG101348, might be preferable in the setting of PV or ET because of their superior activity in controlling leukocytosis, thrombocytosis and JAK2V617F allele burden. Regardless, because most MPN-associated mutations do not necessarily represent the primary clonogenic event, we should curb our expectations from anti-JAK2 treatment trials and continue to pursue other treatment strategies. Furthermore, in considering the prospect of anti-JAK therapy in MPN, one should recognize the fact that life expectancy in the majority of patients with PV or ET is near-normal and disease complications are effectively managed by treatment with low-dose aspirin, phlebotomy or hydroxyurea. Therefore, controlled studies are needed to show added value and justify the risk of unknown long-term health effects associated with new drugs, including JAK inhibitors, in PV and ET. The unmet need for new treatment is in PMF where survival and quality of life are significantly worse and current therapy is inadequate. This session will i) summarize results of current anti-JAK clinical trials in MPN, ii) discuss putative mechanisms of action in terms of both therapeutic benefit and toxicity and iii) define the potential role of JAK inhibitors in the context of current therapeutic approaches for MPN. Disclosures: Off Label Use: Hydroxyurea to control myeloproliferation in myeloproliferative neoplasms Interferon-alfa to control myeloproliferation in myeloproliferative neoplasms Busulfan to control myeloproliferation Pipobroman to control myeloproliferation.