Siragusa, Sergio

Abstract Abstract 4971 Background Marked splenomegaly severely compromises quality of life in primary myelofibrosis (PMF). Preliminary results from the use of small molecule JAK2 inhibitors suggest prominent activity in reducing spleen size. In order to put such salutary effect of investigational drug therapy in context, it is important to determine the value of conventional therapy in this regard. Methods Study population was selected from the Mayo Clinic PMF database and consisted of patients treated with hydroxyurea (HU) as first-line therapy for symptomatic, marked splenomegaly (palpable at >10 cm below the left costal margin) and in whom follow-up information was available to assess response. Palpable spleen size measurements were recorded before and after 3, 6 and 12 months of HU therapy. Spleen response was defined as minimal (< 25% reduction), minor (25-50%), or major (>50%). Standard statistical procedures were used to correlate spleen response with other clinical and laboratory parameters, including cytogenetic and JAK2V617F mutational status. Results 46 consecutive patients (median age, 62 years; range 38-75; 30 males) met the above stipulated eligibility criteria for study inclusion. Pre-treatment IPSS risk categories were low, intermediate-1 (int-1), int-2 and high in 4, 13, 10 and 19 patients, respectively; 7 patients were transfusion-dependent. Quantitative JAK2V617F and pre-treatment cytogenetic information were available in 25 and 36 patients, respectively; 15 (60%) patients were positive for JAK2V617F and mutant allele burden was > 50% in 6 patients; 17 (47%) patients carried either favorable (n=5) or unfavorable (n=12) cytogenetic abnormalities. Overall response rate (major and minor) was 35% (16 of 46 patients) and major response rate 17%. Overall response rates were 10%, 67% and 33% in patients with undetectable JAK2V617F or mutant allele burden of < or ≥ 50%, respectively (p=0.04). Overall response rates in patients with normal, favorable and unfavorable karyotype were 32%, 40% and 33%, respectively (p=0.9). Response was not affected by age, sex, HU dose or pretreatment status regarding spleen size, IPSS score or transfusion need. Conclusions The current study provides background information on the value of conventional chemotherapy for controlling PMF-associated marked splenomegaly. The study also suggests a positive effect of JAK2V617F on treatment response to HU, a detail that needs to be considered when assessing the corresponding effect from a JAK2 inhibitor therapy. Disclosures Off Label Use: Hydroxyurea use in myelofibrosis.

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.

Abstract Abstract 2910 Poster Board II-886 Background: Polycythemia vera (PV) and primary myelofibrosis (PMF) are stem cell-derived myeloproliferative neoplasms characterized clinically by increased red cell volume and bone marrow fibrosis, respectively. Phlebotomy is the cornerstone of treatment in PV whereas hydroxyurea has been the traditional drug of choice in both PV and PMF. Over the last 20 years, several new treatment approaches have been introduced and promoted (e.g. interferon-alpha, anagrelide, thalidomide, allogeneic stem cell transplantation) but their benefit in terms of survival has not been confirmed in controlled studies. Methods: Study patients were recruited form the Mayo Clinic database for myeloproliferative neoplasms. Diagnosis was based on 2001 WHO criteria. Follow-up information was updated in July, 2009. In order to assess changes in survival over time, patients were stratified into two groups by year-of-diagnosis: 1970-1990 and 1991-2005. Survival analysis was performed by the Kaplan-Meier method and comparisons made by the log-rank test. Cox regression model was used for multivariable analysis. Results: 652 patients were studied, including 314 with PMF (median age 57 years, range 18-88; 193 males) and 338 with PV (median age 63 years, range 18-93; 183 males). Overall median survivals were 6.5 years for PMF and 12.2 years for PV (p<0.0001); ten- and twenty-year survival rates were 37% and 13% in PMF and 60% and 18% in PV (Figure). Both the International Prognostic Scoring System for PMF (IPSS; Cervantes et al. Blood 2009;113:2895) and the age/leukocyte count-based PSS for PV (Gangat et al. BJH 2007;138:354) were validated in the current series of patients. Considering all patients, there was no significant difference in survival when either PMF (p=0.91) or PV (p=0.73) patients were stratified according to year-of-diagnosis (Figure); median survivals were 4.7 and 6.6 years in PMF patients diagnosed 1970-1990 (n=54) and 1991-2005 (n=260), respectively; the corresponding median survival figures for PV were 11.8 (n=170) and 12.2 (n=168) years. These results did not change when adjusted for age and sex and, in PV, for age/leukocyte count-based PSS. In PMF, however, borderline significance (p=0.05) was noted when IPSS scores were introduced into the Cox model with further analysis showing improved survival in Int-2/high risk patients with PMF diagnosed after 1990 (p=0.01). Conclusion: The current study provides mature survival data in PMF and PV using large cohorts of consecutive patients seen at a single institution. Although median survival is significantly better in PV compared to PMF, their survival curves converge after 20 years of follow-up, underscoring the poor long-term prognosis in PV patients. The study also suggests improved survival for high/intermediate-2 risk PMF in recent years. Disclosures: Off Label Use: hydroxyurea use in myelofibrosis.