Gender Is a Core Modifier of Disease Outcomes and Survival in the MPN

Introduction: Host modifiers contribute to variation in disease pathogenesis and clinical features in the myeloproliferative neoplasms (MPN), essentialthrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF).Gender modifies the JAK2 V617F allele burden (women had lower levels and lower annual increases), influences PV gene expression (men had twice as many differentially-regulated genes as women) and influences thrombotic events (a predominance of abdominal vein thrombosis in women). The MPN symptom burden also appears to differ by gender. In this analysis, we describe gender differences in disease presentation and outcome in relation tomutational status. Methods: We analyzed a prospective cohort of 612 PV, ET and MF patients enrolled between 2005 and 2013 to study genomic modifiers of the MPN and disease outcomes. We stratified disease evolution and survival by both gender and mutational status. Results: In this cohort, 26% were newly diagnosed, and 61% were female. The current median follow-up is 8 years (> 4800 patient-years) and 110 have died. Prevalence of Molecular lesions JAK2 V617F was identified in 468/612 MPN patients (76%; 61% female), and comprised the majority of ET (62%; 70% female), PV (99.5%; 59% female), MF (62%; 39% female) and post MPN AML (80.7%; 38% female) patients. CALR mutations were identified in 81/612 MPN patients (13%; 58% female), representing 23% of all ET (59% female), and 21 % of all MF (52% female) and 3.8% of post MPN AML. MPL mutations were identified in 9 MPN patients (1.5%): 7 females with ET, and 2 males with MF. Disease presentation Among JAK2 V617F positive patients, more females presented with ET compared to males (43% vs 29%; p=0.002) and more males presented with MF (21% vs 9%; p=0.001). Gender differences in presentation were less apparent in those with CALR -mutated ET (59% women) and MF (53% women). Disease transformation By gender, among 197 women with an original diagnosis of ET, 62% retained their phenotype, whereas 20%, 17%, and 1.5% evolved to PV, MF, and AML, respectively. Among men with ET, 63% retained their phenotype, while 16%, 20%, and 1.1% evolved to PV, MF, and AML. Among MF patients, regardless of mutational status, 1 (3%) women and 5 (10%) men evolved to AML (p=0.39). With regard to transformations by gender, rates of MF (16% in both) and AML (2.6% and 5.5%p=0.083) were similar between women and men. Among 123 JAK2V617F- positive ET women, during the follow-up period, 66 (54%) retained an ET phenotype, while 32%, 14%, and 0.8% evolved to PV, MF, and AML, respectively. Among 53 JAK2V617F-positive ET men, 54% retained an ET phenotype; 25%, 17%, and 4% evolved to PV, MF, and AML, respectively. Among 141 JAK2V617F-positive PV females, 109 (77%) retained PV, 26 (18%) evolved to MF, and 6 (4%) evolved to AML (1 via MF, 5 PV to AML); among 100 JAK2V617F-positive males, 73% retained a PV phenotype, 20% evolved to MF, and 7% to AML (3 PV to AML, 4 via MF phase). Among JAK2V617F -positive patients with an original MF diagnosis, 1/20 (5%) and 3/31 (10%) women and men evolved to AML (p=NS); 22% vs. 18% of JAK2V617F -positive men versus women evolved to MF or AML (p=0.28). No CALR -mutated ET patient evolved to PV. Of 38 CALR- ET women, 27 (71%) retained their phenotype, 10 evolved to MF (26%), and 1 to AML (3%). Among the 26 CALR -mutated ET men, 81% retained their phenotype, while 19% evolved to MF (no AML transformations). Survival The proportion of deaths differed by gender; of the 612 patients, despite the predominance of females in the cohort, at the time of last follow-up, there were 110 deaths (18%): 50/375 women died, compared to 60/237 men (13% vs. 25%; p value=0.0002). A larger proportion of male deaths were due to MF and MF to AML, but this was not statistically different (male deaths in MF/AML phase: 54/60; (90%); women 38/50 (75%); p=0.0692)). Conclusion: We identified a gender influence on disease distribution at presentation, particularly in the JAK2V617F-positive subset with females presenting more commonly with ET and males more commonly with MF. Despite the predominance of females in this MPN cohort, the distribution of females at presentation and evolution into more indolent phenotypes compared to males and a trend toward lower rates of AML evolution may have accounted for longer disease duration and fewer deaths in females compared to males. This trend in MPN evolution complements a theme of gender differences in symptom burden, clinical consequences, and genomic changes. Disclosures Stein: Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Spivak:Incyte: Membership on an entity's Board of Directors or advisory committees. Moliterno:Incyte: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Ruxolitinib Therapy in Myelofibrosis: Analysis of 241 Patients Treated in Compassionate Use (French “ATU” program) by the French Intergroup of Myeloproliferative Neoplasms (FIM).

Blood ◽

10.1182/blood.v120.21.2841.2841 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2841-2841

Author(s):

Annalisa Andreoli ◽

Jerome Rey ◽

Charles Dauriac ◽

Raoul Herbrecht ◽

Franck E. Nicolini ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Neoplasm ◽

Costal Margin ◽

Spleen Size ◽

Compassionate Use ◽

Advisory Committees ◽

Mutational Status

Abstract Abstract 2841 Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, splenomegaly, cytopenias and constitutional symptoms. Ruxolitinib was recently approved by the FDA for the treatment of MF in the USA; its approval in Europe is still pending. However, EU patients may access to ruxolitinib through compassionate programs. In France, health authorities opened a compassionate patient-named program (Authorization for Temporary Utilization [ATU] program. Methods: 241 French patients (pts) with MF, including primary (PMF), post-polycythemia vera (PPV) and post-essential thrombocythemia (PET) MF were granted ruxolitinib therapy through ATU program, independently of their JAK2 mutational status, between April 15, 2011 and May 31, 2012. Physicians were asked to provide information on disease characteristics, treatment history, constitutional symptoms, spleen size, platelet and neutrophils count, as well as the ruxolitinib dose prescribed and adverse events (AE). Request forms had to be submitted at the time of initial application and every 3 months upon drug resupply or in case of treatment discontinuation. This analysis has been performed based on data available at baseline (n= 241), after 3 months (n= 101), 6 months (n= 57), 9 months (n= 21) and 12 months (n= 4). Results: In the entire cohort, 138 pts were men and 103 women. Median age was 68.3 years. 51.5% of pts had PMF, 22.8% PPV-MF and 23.8% PET-MF. 99.2% of pts had received ≥1 lines of therapy for MF prior to ruxolitinib (hydroxyurea: 56%; pipobroman: 15.4%; iMIDs: 13.7%; interferons: 13.7%; erythropoietins: 6.6%; spleen irradiation: 6.6%; anagrelide: 5.8%; corticosteroids: 4.9%). Despite these therapies, 93.7% had constitutional symptoms and 94.2% of patients presented a palpable splenomegaly (median 15 cm below costal margin) at inclusion. Efficacy: According to the baseline platelet count, ruxolitinib therapy was initiated at 15 mg BID in 132 pts (54.8%) or 20 mg BID in 103 pts (42.7%), or other doses in a minority of pts (n=6). Among the pts who were evaluable after 3 and 6 months of therapy, 96.5% and 90% presented a mean reduction in the spleen size (by palpation) by 47.2% and 46% from baseline, respectively. Constitutional symptoms resolved in 65.3% and 70.2% of pts at the aforementioned time points, respectively. In pts who completed 9 months follow-up (n=21), benefits in spleen size reduction and symptoms resolution were durable (95% and 71.4%). Safety: Since the beginning of the ruxolitinib ATU program, 83 pts presented at least one AE, including 27 pts with serious AE (SAE), with or without causal relationship to ruxolitinib therapy. AE, all grades, were essentially hematologic abnormalities (51.6%), gastro-intestinal 6.3%, cardiac 3.1%, musculoskeletal 3.1%, hepatic 2.3%, infection 2.3%. Dose adjustments were reported in 60 pts, mainly due to thrombocytopenia (n=36) and anemia (n=13). However, no patient discontinued ruxolitinib therapy because of cytopenia. Treatment was discontinued in 11 patients after a median duration of 2.6 months (range 0.3–7.9 months). Reasons for discontinuation were death (n=6), AE (n=2), inefficacy (n=2), and patient decision (n= 1). Conclusion: In this large, unselected population of heavily pretreated MF pts, ruxolitinib therapy appeared to be effective in treating both constitutional symptoms and splenomegaly, in line with previously reported efficacy in clinical trials. The safety profile seems also comparable. Comprehensive data and updated follow-up of the cohort will be presented. Disclosures: Off Label Use: compassionate use of ruxolitinib for myélofibrosis in France (indication not yet approved by EMEA). Rey:Novartis: Consultancy. Nicolini:novartis, Bristol myers Squibb, Pfizer, Ariad and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgène, Genzyme, Sunesis, Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other. Ranta:Novartis: Membership on an entity's Board of Directors or advisory committees. Legros:Novartis, Bristol Myers-Squibb: Research Funding, Speakers Bureau, Travel to meeting Other. Viallard:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dupriez:novartis: Membership on an entity's Board of Directors or advisory committees. Coiteux:Novartis, Bristol Myers-Squibb: Speakers Bureau. Demory:Novartis: Honoraria. Giraudier:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ugo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel to ASH Other. Kiladjian:Incyte: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Roy:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel to ASH Other.

Download Full-text

Myeloproliferative Neoplasms in Patients below 25 Years Old at Diagnosis: A Retrospective International Cooperative Work

Blood ◽

10.1182/blood-2018-99-112374 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1759-1759

Author(s):

Ianotto Jean-Christophe ◽

Jean-Jacques Kiladjian ◽

Marta Sobas ◽

Parvis Sadjadian ◽

Lee-Yung Shih ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Young Patients ◽

Complication Rates ◽

Vascular Events ◽

Advisory Committees ◽

Disease Evolution

Abstract Myeloproliferative neoplasms (MPN) are most common in old people (>60 years) and are rarely identified in children and young adults where information about complication rates and long-term data are lacking. To improve our knowledge, we retrospectively collected cases of young patients diagnosed with MPN before 25 years of age and analysed data of their disease to date, including vascular events and disease evolution. Data were collected in 29 hospital centres from 12 countries. Between 1971 and 2018, 335 young patients were diagnosed for an MPN before the age of 25. They were mostly females (n=246; 73.4%) with a median age of 20.3 years at diagnosis (2.5 months-25 years). Essential thrombocythemia was diagnosed in 234 patients (69.8%), polycythemia vera in 60 (17.9%) and myelofibrosis or unclassified MPN in 41 (12.3%). Most of the diagnoses were made following a coincidental blood count analysis (n=75; 51%) some based on symptoms (n=57; 38.8%) or thrombotic events (n=15; 10.2%). In terms of complications before or at diagnosis, 31 (9.3%) patients experienced thrombosis, mostly venous (75%) and 13 (3.9%) had hemorrhage. At diagnosis, the median leukocyte count was 9x109/l (range: 3-22.8), median hemoglobin count 140 g/l (65-220) and median platelet count 900x109/l (99-3290). To assess the diagnosis, 158 patients (47.2%) had had bone marrow aspirates and 214 (63.9%) a bone marrow biopsy. Mutational status was available in 319 (90%) cases: 194 (60.8%) were JAK2V617F positive, 48 (15%) had a calreticulin mutation, 76 (23.8%) were triple-negative and 1 patient had MPL mutation. The median follow-up of the cohort was 7.7 years (0-46.8) with 134 patients (40%) having follow-up for more than 10 years. 81 female patients (32.9%) experienced pregnancies. During this period, 295 patients (88%) received at least one drug for their MPN: 254 patients (77.2%) received antithrombotic drug and 222 patients (66.5%) a cytoreductive drug. As first line of treatment, hydroxycarbamide was given to 111 patients (50%) whereas anagrelide was given to 56 patients (25.2%) and interferon to 50 (22.5%). During the follow-up, 97 patients (29%) experienced at least one complication. In terms of cardiovascular events, 38 (11.3%) patients experienced thromboses with 50 events in total (recurrences in 12 cases), including 33 venous events (66%) of which 15 were localized in the splanchnic territory (45.5%). Hemorrhagic events were recorded in 34 cases (10.1%). During the follow-up, 39 patients (11.6%) have evolved: 11 from ET to PV (28.2%), 26 into MF (66.7%) and 2 into AML (5.1%). All evolutions were exclusive: one event per patient. At the time of the analysis, 66 patients (19.7%) were declared as lost of follow up and 4 were dead (1.2%). This is the largest cohort of patients aged below 25 years at the time of diagnosis demonstrates that despite their youth most of them (88%) received drug(s) for the management of their MPN. There was a high incidence of complications (29%), with vascular events and disease evolution occurring at equal frequency although death was uncommon (1.2%). Rates of events were disease evolution: 1.51/100pts/y; thromboses: 1.47 and hemorrhages: 1.32. No specific national or international guidance exists for MPN patients of this age; but our data suggest that these are not benign conditions and patients need to be carefully followed and treated. Table. Table. Disclosures Kiladjian: Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Giraudier:Novartis: Research Funding. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria.

Download Full-text

SF3B1 mutations in the Driver Clone Increase the Risk of Evolution to Myelofibrosis in Patients with Myeloproliferative Neoplasms (MPN)

Blood ◽

10.1182/blood-2020-141296 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Lin-Pierre Zhao ◽

Rafael Daltro De Oliveira ◽

Clemence Marcault ◽

Juliette Soret ◽

Nicolas Gauthier ◽

...

Keyword(s):

Board Of Directors ◽

Response To Therapy ◽

Driver Mutation ◽

Advisory Committees ◽

Disease Evolution ◽

Free Survival ◽

Mutational Status ◽

Significant Difference ◽

The Impact

Introduction: Next generation sequencing (NGS) studies identified additional somatic mutations impacting disease evolution and prognosis in MPN. SF3B1, a component of the U2 small nuclear ribonucleoprotein splicing complex, is frequently mutated in myelodysplastic syndromes where it has been proposed to define a new entity (Malcovati et. al. Blood 2020). In MPN, SF3B1 is mutated in approximately 10% of patients with primary myelofibrosis (PMF) and 3-5% with polycytemia vera or essential thrombocytemia (ET). Recent reports suggested that spliceosome mutations may adversely affect myelofibrosis free survival (MFS) in ET (Tefferi et. al. Br J Haematol. 2020). The main objective of this study was to evaluate the impact of the concomitant presence of driver (JAK2, MPLor CALR) and SF3B1 clonal or sub-clonal mutations on MPN phenotype and evolution in a large single center cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria between January 2011 and May 2020 in our center, of whom 707 had molecular analysis by NGS targeting a panel of 36 myeloid genes performed at diagnosis and/or during follow-up. Significant variants were retained with a sensitivity of 0.5%. Patients were grouped according to variant allele frequencies (VAF) determined by NGS as "driver" SF3B1mutated patients when driver and SF3B1 mutations VAF were similar (double mutated clone), and as "non-driver" SF3B1 mutants when SF3B1VAF was lower than that of the driver mutation, suggestive of a sub-clone. 4 patients with SF3B1 mutations but no driver mutation were excluded. We then compared the characteristics and outcomes of 3 groups of patients according to their SF3B1 mutational status: wild type (WT), driver and non-driver SF3B1 mutations. Results: A total of 39/703 (5.6%) patients had SF3B1 mutations, of whom 11/39 (28.2%) and 28/39 (71.8%) harbored driver and non-driver SF3B1mutations, respectively. Driver SF3B1 mutations were associated with PMF (OR 6.1, 95%CI [1.1; 33.6], p= 0.039) and MPN unclassified (OR 15.6,95%CI [1.1; 116.5], p= 0.007) subtypes, presence of immature myeloid cells ≥ 2% (OR 9.3, CI [2.6; 32.8], p= 0.001) and peripheral blasts ≥ 1% (OR 5.0,95%CI [1.0; 24.7], p= 0.047) at diagnosis (Figure A). Other variables were not significantly different between patients with driver, non-driver and WT SF3B1, including age, driver mutation type, MPN-related symptoms, cytogenetics and high molecular risk mutations (ASXL1, EZH2, SRSF2, IDH1/2or U2AF1). There was no significant difference in the response to therapy: complete hematological response was seen in 5/11 (45.5%), 10/28 (35.7%) and 327/664 (49.3%) of patients with driver, non-driver and WT SF3B1 respectively. After a median follow-up of 103.7 months IQR [47.2; 175.6], evolution to myelofibrosis occurred in 5/7 (71.4%), 6/20 (30.0%) and 99/564 (17.6%) of patients with driver, non-driver and WT SF3B1 respectively. Interestingly, driver SF3B1 but not non-driver SF3B1 mutational status adversely impacted MFS (OR 7.56,95%CI[2.95; 19.38], p<0.001)(Figure B). Other variables independently associated with adverse MFS in multivariate COX regression analysis included age at MPN diagnosis (OR 1.02, 95%CI[1.00; 1.04], p=0.003), JAK2V617F allele burden (OR 1.03, 95%CI[1.02; 1.04], p<0.001), MPL (OR 13.94, 95%CI[4.90; 39.70], p<0.001) and CALR (OR 7.06, 95%CI[3.69; 13.51], p<0.001) mutations. SF3B1 mutational status had no impact on overall survival, transformation to MDS/AML or thrombotic/hemorrhagic events free survival. Conclusion: This study in a large cohort of MPN patients highlights for the first time to our knowledge the adverse impact on MFS of SF3B1 and MPN-driver co-mutated clones. In contrast, presence of an SF3B1 mutation at sub-clonal level didn't increase the risk of MF development. In line with our findings, a recent study reported an association between rapid progression to myelofibrosis and SF3B1 mutations in patients with age-related clonal hematopoiesis (Bartels et al. Leukemia 2020). Further studies are warranted to confirm our results on independent cohorts and to investigate the mechanisms of bone marrow fibrosis development in patients with SF3B1 and MPN-drivermutations. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

Download Full-text

Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽

10.1182/blood.v128.22.3180.3180 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3180-3180

Author(s):

Felix Lopez-Cadenas ◽

Blanca Xicoy ◽

Silvia Rojas P ◽

Kaivers Jennifer ◽

Ulrich Germing ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Univariate Analysis ◽

Rank Test ◽

Advisory Committees ◽

Disease Evolution ◽

Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Overall Survival in Patients with JAK2 and ASXL1 Positive Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-128309 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5383-5383

Author(s):

Murtadha Al-Khabori ◽

Shoaib Al-Zadjali ◽

Iman Al Noumani ◽

Khalil Al Farsi ◽

Salam Al-Kindi ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloproliferative Neoplasms ◽

Prognostic Significance ◽

Jak2 V617f ◽

World Health ◽

Prognostic Impact ◽

Advisory Committees ◽

Myeloid Neoplasms ◽

The Impact

Objectives: Mutations in additional sex combs-like transcriptional regulator 1 (ASXL1) have been previously described in myeloid neoplasms (21% in non-Myeloproliferative [MPN; Tefferi A, Leukemia, 2010) and have been associated with a more aggressive disease [Rocquain J et al, BMC Cacer, 2010]. They can also be found in patients with JAK2 positive MPN [Abdel-Wahab O et al, Cancer Research, 2010). Disruption of ASXL1 gene leads to MPN phenotype in zebrafish model (Gjini E, Dis Model Mech, 2019). The co-expression and the prognostic significance of ASXL1 in patients with JAK2 positive MPN are not yet fully defined. We therefore planned to define the prognostic impact of ASXL1 mutations on the Overall Survival (OS) of patients with JAK2 positive MPN. Methods: We included patients with JAK2 V617F positive MPN diagnosed according to the World Health Organization 2016 criteria and treated at the three largest hematology centers in Oman. The entire coding region of ASXL1 gene was sequenced using Next Generation Sequencing (NGS; Ion PGM Sequencer; Thermo Fisher Scientific®). The library was constructed and the templates were prepared using the PGM tool and the variants were annotated using the ClinVar database and the prediction from the Scale-Invariant Feature Transform (SIFT) and or Polymorphism Phenotyping (Polyphen) algorithms. The NGS analysis was done on the frozen diagnostic bone marrow samples. The survival probability was estimated using Kaplan-Meier estimator and Cox regression was used to assess the impact of predictors on the OS outcome. An alpha threshold of 0.05 was used. The R program (version 3.1.2) was used for all statistical analyses. Results: A total of 58 patients with JAK2 V617F positive MPN were included. All of these patients were found to have mutated ASXL1 using the NGS (ASXL1 p.Leu815Pro was found in all patients). The median age of this cohort was 62 years (InterQuartile Range [IQR]: 44 - 70) and female to male ratio was 25:33. The median hemoglobin, hematocrit, white blood cell count and platelet count was 14.7 g/dL, 58%, 11.5 x109/L and 518 x109/L respectively. Out of the 58 patients included, 28 had polycythemia vera, 20 had essential thrombocythemia, 8 had myelofibrosis and 2 had MPN-Unclassified. The median time from diagnosis to last follow up or death was 13 months (IQR: 3-39). During this period, 5 patients died. The probability of OS at 3 years was 88%. The median OS was not reached. In the univariable analysis, age was a statistically significant predictor of OS (p = 0.0355) but not gender (p = 0.434) and MPN subtype (p = 0.7). In the multivariable analysis model of the previous three factors, age remained statistically significant (Hazard ratio = 1.13, p = 0.041). Conclusions: ASXL1 is mutated in high proportion of patients with JAK2 positive MPN. Despite the negative impact of ASXL1 in patients with non-MPN myeloid neoplasms, the patients with combined positivity of JAK2 and ASXL1 in this study had a very good OS probability. Age was a predictor of OS in the univariable and multivariable models. We recommend the development and the assessment of ASXL1 inhibitors as therapeutic strategies in patients with MPN. Disclosures Al-Khabori: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

M3P Sequencing Panel Identifies TP53 Mutational Status As a Prognostic Factor in Chemotherapy-Naive Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.2984.2984 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2984-2984

Author(s):

Davine Hofste op Bruinink ◽

K. Martin Kortüm ◽

Mark van Duin ◽

Mathijs A. Sanders ◽

Remco Hoogenboezem ◽

...

Keyword(s):

Prognostic Factor ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Prognostic Markers ◽

P Value ◽

Advisory Committees ◽

Mutational Status ◽

Tp53 Mutational Status

Abstract Introduction Multiple myeloma (MM) is characterized by a highly variable disease course, which can be traced to initiating and acquired genomic events. Whole exome analysis of matched tumor and germline DNA from 287 MM patients identified recurrently somatically mutated genes (RSMGs) (Lohr et al. - Cancer Cell 2014, Bolli et al. - Nat Commun 2014). Despite the fact that these RSMGs affect pathways that are biologically important in MM, the clinical relevance of many of these genes in the context of conventional prognostic markers remains to be elucidated. Aims The aims of this pilot study were: (1) To validate the prevalence of RSMGs in our newly diagnosed MM patient cohort; (2) To assess the correlation between RSMGs, clinical parameters and outcome; (3) To thereby identify the potential clinical usefulness of introducing RSMG mutational profiling in larger MM trial cohorts. Material and Methods CD138+ enriched MM cells and peripheral blood were obtained with informed consent from chemotherapy-naive patients, participating in 3 clinical trials: HOVON-65/GMMG-HD4, HOVON-87/NMSG-18 and Carthadex (EudraCT number 2004-000944-26, 2007-004007-34 and 2009-014922-40, respectively). Matched tumor and germline DNA were sequenced on an Ion Torrent sequencing platform (PGM, Life Technologies), using the M3 P Mutational Panel v3.0, comprising 1327 customized oligos (Life Technologies), targeted at the coding sequences of 88 MM-relevant genes, including the RSMGs. Somatic mutations were considered positive when present in >=10% of tumor reads and <=10% germline reads, with a minimal coverage of 10x and being non-synonymous, or splice donor variants. All statistical analyses were performed in SPSS version 23, using the log-rank and Mann-Whitney U-test, with the Bonferroni test to correct for multiple comparisons. Results A total of 206 DNA samples were sequenced from 103 patients (HOVON-65/GMMG-HD4 (n=16), HOVON-87/NMSG-18 (n=67), Carthadex (n=20)) with an average coverage of 574x in tumor DNA, 451x in germline DNA and an overall coverage of 98%. We collected follow-up data from 102/103 patients, with a median follow-up time of 30 months. 168 somatic mutations were detected in 44/88 genes. 82% of patients had at least 1 somatic mutation. Genes most frequently mutated were: (1) NRAS (26%), (2) KRAS (22%), (3) DIS3 (14%), (4) FAM46C (9%), (5) TP53 (7%) and (6) BRAF (6%) (Figure 1). Of note, NRAS and KRAS mutations were mutually exclusive in our cohort. Moreover, all TP53 mutations were located in its DNA binding domain. Three out of 6 BRAF mutations were predicted to cause a V600E amino acid change. We focused on these 6 RSMGs in all further analyses. Correlating mutational status with Progression Free Survival (PFS) and Overall Survival (OS) showed that TP53 mutated patients had a significantly shorter PFS compared to those with wildtype TP53 (adj. p-value=0,018; n=7 versus n=95). Comparing the mutational status of the 6 RSMGs, transplant versus non-transplant protocol, number of mutated genes in the M3 P panel, del17p and t(4;14) status, EMC92 score and ISS stage between patients with a PFS <=1 year and >1 year (n=23 versus n=79), only showed a significant correlation with TP53 mutational status (adj. p-value=0,012). TP53 mutational status remained the only significant prognostic factor when comparing patients with an OS <=1 year and >1 year (adj. p-value=0,003; n=13 versus n=89). When comparing the number of mutated genes, del17p and t(4;14) status, EMC92 score, transplant versus non-transplant protocol and ISS stage between TP53 mutated and wildtype MM, TP53 mutated patients had a significantly higher number of mutated genes in the M3 P panel (adj. p-value=0,001). Conclusions (1) With the M3 P Mutational Panel, we confirm the published prevalence of RSMGs in MM in our cohort of chemotherapy-naive patients. NRAS, KRAS, DIS3, FAM46C, TP53 and BRAF are the most frequently mutated genes. (2) TP53 mutational status is the strongest unfavorable prognostic factor in our cohort and it seems to be associated with greater mutational burden. Validation in a more extensive population is planned. (3) This warrants further investigation of the mutational status of these genes in larger clinical trial cohorts, enabling a more robust comparison with conventional prognostic markers in a multivariate analysis. Disclosures Broijl: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Zweegman:Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Deciphering the Individual Contribution of Absolute Neutrophil, Lymphocyte and Monocyte Counts to Thrombosis Risk in Patients with Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-149207 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3651-3651

Author(s):

Faiqa Farrukh ◽

Paola Guglielmelli ◽

Giuseppe Gaetano Loscocco ◽

Animesh D. Pardanani ◽

Curtis A. Hanson ◽

...

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Board Of Directors ◽

Arterial Thrombosis ◽

Leukocyte Count ◽

Myeloproliferative Neoplasms ◽

Advisory Committees ◽

Free Survival ◽

The Individual

Abstract Background In addition to its influence on survival, leukocytosis in myeloproliferative neoplasms (MPN) has also been implicated as a risk factor for thrombosis, including venous thrombosis in PV (Blood Cancer J, 2017;7:662) and arterial thrombosis in ET (Blood. 2011;117:5857). In the current study, we sought to clarify the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC) and monocyte (AMC) counts, for arterial and venous thrombotic events in essential thrombocythemia (ET) and polycythemia vera (PV). Methods The current study included 487 patients with ET (n=349) or PV (n=138), recruited from the Mayo Clinic MPN database, based on availability of information on ANC, ALC and AMC. Conventional criteria were used for diagnosis (Blood 2016;127:2391) and definitions of major vascular events (Blood Cancer J. 2018;8:25). Conventional statistical models were applied using JMP Pro 14.0.0 software package, SAS Institute, Cary, NC. Multivariable analyses included previously established risk factors for arterial or venous thrombosis. Results Essential thrombocythemia patients: 349 patients (median age 57 years, range 18-89; females 61%) with ET were included in the study: 46% JAK2, 34% CALR, 16% triple-negative and 4% MPL mutated; IPSET risk category high 24%, intermediate 41%, and low 35%; presenting median (range) values were 13.8 g/dL (11.1-16.4) for hemoglobin, 8.2 x 10(9)/L (3.2-52) for leukocyte count, and 859 x 10(9)/L (451-3460) for platelet count; palpable splenomegaly was present in 48 (14%) patients and cardiovascular risk factors in 56%; median follow-up was 10 years (range 0-47). There were 38 (11%) documented venous events at diagnosis and 31 (9%) after diagnosis and 42 (12%) arterial events at diagnosis and 64 (18%) after diagnosis. Polycythemia vera patients: 138 patients (median age 62 years, range 20-94; females 50%) with PV were included in the study; presenting median (range) values were 17.9 g/dL (16.1-24) for hemoglobin, 11.8 x 10(9)/L (2.7-65.8) for leukocyte count, and 434 x 10(9)/L (44-1679) for platelet count; 57% of patients presented with leukocytosis >11 x 10(9)/L; palpable splenomegaly was present in 37 (27%) patients; abnormal karyotype was documented in 17% of patients. Median follow-up was 11 years (range 0.03-36.7). There were 22 (16%) documented venous events at diagnosis and 21 (16%) after diagnosis and 28 (20%) arterial events at diagnosis and 15 (11%) after diagnosis. ANC/ALC/AMC associations with thrombosis in ET and PV: In both ET and PV, ANC/ALC/AMC did not correlate with arterial thrombosis at/prior to diagnosis (p>0.1 in all instances). By contrast, in both ET and PV, higher ANC (p=0.05 and 0.04, respectively) and higher AMC (p=0.005 and 0.07), but not ALC (p=0.6 and 0.7), were correlated with venous thrombosis at/prior to diagnosis. Arterial thrombosis-free survival was not affected by ANC/ALC/AMC in either ET or PV (p>0.1 in all instances). By contrast, venous thrombosis-free survival in both ET and PV was compromised by higher ANC (p=0.05 and 0.003, respectively), but not ALC or AMC. The significant association between higher ANC and inferior venous thrombosis-free survival in both ET (p=0.01) and PV (p=0.007) was sustained during multivariable analysis that included history of venous thrombosis, age and sex; the only other variable of significance was older age in ET (p<0.001). The significant association between ANC and venous thrombosis-free survival was also noted in an external cohort of PV patients from the University of Florence (n=576). Conclusions: The current study identifies ANC as having a direct correlation with venous thrombosis in both ET and PV, independent of currently known risk factors. An additional risk contribution from AMC was apparent for events occuring at or prior to but not after diagnosis. Taken together, these observations flag both neutrophils and monocytes as potential contributors to venous but not arterial thrombosis in MPN, at least not by themselves. Additional collaborative studies are ongoing in order to integrate and reconcile our observations in the context of neutrophil/lymphocyte ratio (Carobbio et al) and JAK2V617F allele burden (Loscocco et al), on venous thrombosis-free survival in PV, reported in concomitantly submitted ASH 2021 abstracts, especially in light of the relatively small number of events in the current study. Disclosures Barbui: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Chronic Exposure to Cytoreductive Treatment Shapes Clonal Evolution in Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-152622 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3620-3620

Author(s):

Lin-Pierre Zhao ◽

Nabih Maslah ◽

Rafael Daltro De Oliveira ◽

Emmanuelle Verger ◽

Juliette Soret-Dulphy ◽

...

Keyword(s):

Board Of Directors ◽

Mutation Rate ◽

Chronic Exposure ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Clonal Evolution ◽

Advisory Committees ◽

Cytoreductive Treatment ◽

The Impact

Abstract Introduction: Myeloproliferative neoplasms (MPN) are a heterogeneous group of chronic myeloid malignancies resulting from the combination of a driver mutated gene (JAK2, MPL or CALR) and a variety of acquired additional somatic mutations. Although next-generation sequencing (NGS) has identified high molecular risk mutations associated with adverse prognosis (Vannucchi et al., Leukemia, 2013 , Guglielmelli et al., Leukemia, 2014 ), the clonal evolution of these mutations remains poorly described. Chronic exposure to cytoreductive treatment, especially genotoxic drugs such as hydroxyurea (HU), could impact clonal evolution. A previous study suggested that Interferon-α (IFN) could limit the accumulation of cytogenetic abnormalities compared to HU (Mondello et al., Blood, 2018). The objective of our study was to describe the long-term evolution of the mutational landscape in the era of NGS in a large cohort of MPN patients. Methods: A total of 1538 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and January 2021. This study included 1039 of them in whom a NGS molecular analysis targeting 36 myeloid genes with a sensitivity of 1% was performed at diagnosis and/or during follow-up. Patients with only one NGS (n=588), AML/MDS transformation at either the first (n=3) or the second NGS (n=2) were excluded from the analysis. Serial NGS data obtained in chronic MPN phase were thus analyzed for 446 patients. Clinical and biological characteristics at time of diagnosis and follow-up were collected from medical charts and electronic medical records. Mutation rates per year were calculated for each gene as the difference in the number of mutations between first and last NGS divided by the time interval (in years) between both NGS. Results : Median age at MPN diagnosis in our whole cohort was 51 years [IQR 41-60]. Our cohort included 167 (37%), 205 (46%) and 64 (14%) patients with Polycythemia Vera (PV), Essential thrombocythemia (ET) and primary myelofibrosis (MF) respectively. 279 patients (63%) had at least one additional mutation at first NGS, and respectively 27 (6%) and 104 (23%) patients had TP53 and high molecular risk mutations. Median interval between MPN diagnosis and the first NGS was 6.5 years [IQR 1.7-13] while median time between the first and the last NGS was 2.5 years [IQR 1.6-4, range 0.3-14.3]. Overall, 178 patients (39.9%) acquired an additional mutation at last NGS evaluation, most frequently involving TET2, DNMT3A, ASXL1, TP53 and NFE2 genes . To study the impact of chronic MPN therapy on clonal evolution, we focused on patients who electively received HU (n=112) or IFN (n=92) as a monotherapy, or did not receive any cytoreductive treatment (n=119) between the first and the last NGS. The remaining patients received ruxolitinib (n=44), anagrelide (n=10), vercyte (n=7) or polytherapy (n=62). At last follow-up, 74 patients receiving IFN (80.4%) and 65 (58%) treated with HU had a complete hematological response. When combining all additional mutations, the global mutation rate per year did not significantly differ between treatment groups. When analyzing individual genes, TP53 mutation rate was higher in patients treated with HU compared to the patients receiving IFN (p=0.014) or not treated (p=0.008) (Figure). MDS/AML evolution occurred in 4 patients (3.6%) treated with HU, 2 (1.7%) without cytoreductive therapy versus none of the 92 patients treated with IFN (ns). In the whole cohort, MDS/AML evolution was significantly increased in patients harboring TP53 mutations (p= 0.004). In contrast, DNMT3A mutation rate was significantly increased in patients receiving IFN compared to patients treated with HU (p=0.045) (Figure). The latest result is in line with previous observations showing that loss of DNMT3A could confer resistance to IFN in a JAK2-V617F mouse model (Stetka et al., Blood, 2020). Conclusion: Our results highlight the impact of chronic cytoreductive therapy on clonal evolution shaping in MPN. IFN limits the emergence of TP53 mutated clones compared to HU, thus potentially reducing the risk of leukemogenesis. Emergence of DNMT3A mutated clones under IFN therapy requires further exploration and could potentially play a role in therapeutic resistance. This study on a large clinically and biologically annotated cohort illustrates how serial NGS analysis may guide therapeutic options for MPN patients. Figure 1 Figure 1. Disclosures Raffoux: PFIZER: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Kiladjian: AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees. Benajiba: Pfizer: Research Funding; Gilead: Research Funding.

Download Full-text

Patients with Unexplained Thrombosis Require a Prompt Investigation to Search a Chronic Myeloproliferative Neoplasm (MPN), Even If Platelet Count Is <600x109/L. Analysis on 129 Patients from Registro Italiano Trombocitemie (RIT)

Blood ◽

10.1182/blood.v126.23.5181.5181 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5181-5181

Author(s):

Giulia Benevolo ◽

Alessandra Iurlo ◽

Gabriele Gugliotta ◽

Alessia Tieghi ◽

Gianluca Gaidano ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Jak2 V617f ◽

Jak2 V617f Mutation ◽

Advisory Committees ◽

Thrombotic Risk ◽

Cytoreductive Treatment ◽

Wbc Count

Abstract Background In patients with Ph-negative MPN, a prior thrombosis (PrTh) occurs in around 1/5 of cases, with variable platelet (PLT) count and variable distance from diagnosis. Objective To investigate the influence of PLT count at PrTh on diagnostic and therapeutic approach in MPN patients. Material and methods We evaluated 129 MPN patients from RIT, reclassified according to WHO 2008 criteria as ET (n70), initial-primary myelofibrosis (n29), early-PV (n10), and unclassifiable-MPN (n20). Results Patients, 60 males and 69 females, showed following PrTh: 91(71%) major arterial (37 AMI, 4 angina, 24 stroke, and 26 TIA); 12(9%) minor arterial; 22(17%) major venous (8 DVT, 7 splanchnic, 4 cerebral sinus, 3 pulmonary embolism); and 4(3%) minor venous events. PrTh occurred at a median distance of 4.1 months (range 0.1-118) from MPN diagnosis. This distance was >24 months in 21(16%) patients. At occurrence of PrTh, median age was 58 years. PLT count (x109/L) had a median value of 661 (range 150-2200), and was ≤450, 451-600, 601-700, 701-1000, and >1000 in 15(12%), 35(27%), 26(20%), 43(33%), and 10(8%) patients, respectively. Median white blood cell (WBC) count was 9.0 x 109/L and median hematocrit (HCT) value was 46% in males, and 41% in females. Median time (months) from PrTh to diagnosis of MPN was higher (p0.004) in patients with lower PLT count (x 109/L): ≤450 (50.2), 451-600 (11.7), 601-700 (2.7), 701-1000 (1.8), and >1000 (1.4). After occurrence of PrTh, all patients received conventional anti-thrombotic treatment, but in 7(5.4%) patients 9 recurrent thrombosis were reported before MPN diagnosis (11/100 pt-years). At MPN diagnosis, clonality was documented in 101(78%) patients (JAK2 V617F mutation in 96 cases, 74%). The age was >60 years in 61(47%) patients. PLT count (x109/L) had a median value of 720 (166-2440), and was ≤450 (n 7, 5%), 451-600 (n 21, 16%), 601-700 (n 28, 22%), 701-1000 (n 58, 45%), >1000 (n15, 12%). WBC count (109/L) had a median value of 8.9, and was >10 in 40 (31%) cases. Median HCT level (%) was 45.6 in males and 42.1 in females. Cardiovascular risk factors (CVRF), comorbidities and symptoms were documented in 103(80%), 97(75%), and 57(44%) cases, respectively. Thrombotic risk (IPSET-Th) was high in 97.5%, and intermediate in 2.5% of cases. All 129 patients received anti-thrombotic drugs (low dose aspirin in 95% of cases) and, immediately after the diagnosis, they started a cytoreductive treatment (hydroxycarbamide 89%, anagrelide 8%, interferon-alpha 3%). Patients with a PLT count (x109/L) at PrTh ≤600(n 50), as compared with those with a PLT count >600(n 79), showed a longer median time to the MPN diagnosis (16.7 vs 2.0 months, p<0.001). No significant difference was found in the rate of: arterial PrTh (80% vs 79.7%, p0.97); recurrence of thrombosis before the diagnosis (8% vs 4%, p0.69); JAK2 V617F mutation (80% vs 71%, p0.29); age >60 years (52% vs 44%, p0.39); CVRF (82%vs79%, p0.63); WBC >10 x109/L (23% vs 39%, p0.07); HCT high level [>47% in males, >44% in females](28% vs 36%, p0.37), and high thrombotic risk [IPSET-Th] (96%vs99%, p0.56). During follow-up (median 7.9 years) they showed a higher incidence of thrombosis recurrence (30%vs15%, p0.04; 4.5 vs 1.7/100 pt-y, p<0.01) Conclusion Time to MPN diagnosis was significantly longer in patients with PLT count (x109/L) at PrTh ≤600 vs >600, and this time to diagnosis was characterized by a not negligible thrombosis recurrence. Moreover, during follow-up they showed a higher incidence of thrombosis recurrence. This analysis strongly suggests that a PLT count <600 or even <450 x109/L, in patients with unexplained thrombosis, deserves the search of a probable MPN, in order to promptly start cytoreductive treatment in addition to a conventional anti-thrombotic therapy. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Ruxolitinib for the Treatment of Inadequately Controlled Polycythemia Vera without Splenomegaly: 156-Week Follow-up from the Phase 3 Response-2 Study

Blood ◽

10.1182/blood-2018-99-115350 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1754-1754 ◽

Cited By ~ 2

Author(s):

Francesco Passamonti ◽

Francesca Palandri ◽

Guray Saydam ◽

Giulia Benevolo ◽

Miklos Egyed ◽

...

Keyword(s):

Blood Cell ◽

Cell Count ◽

Board Of Directors ◽

Research Funding ◽

Jak2 V617f ◽

Blood Cell Count ◽

Advisory Committees ◽

Adjusted Rate ◽

Over Time

Abstract BACKGROUND Ruxolitinib (RUX), a potent Janus kinase (JAK)1/JAK2 inhibitor, is approved for hydroxyurea (HU)-resistant/-intolerant patients (pts) with polycythemia vera (PV) based on findings from the RESPONSE study (NCT01243944). RUX proved superior to best available therapy (BAT) in maintaining hematocrit (Hct) control without phlebotomy eligibility, normalizing blood cell count, reducing spleen volume, and improving symptoms in pts with PV with splenomegaly who are resistant to or intolerant of HU. RESPONSE-2 (NCT02038036) is a global, multicenter, open-label, phase 3 trial comparing RUX with BAT in HU-resistant or -intolerant pts with PV without splenomegaly. In the primary analysis at wk 28, RUX proved superior to BAT in controlling Hct without phlebotomy eligibility, normalizing blood cell count, and improving symptoms. Responses were durable at 80 wk of follow-up. Here we evaluate the long-term safety and efficacy of RUX after a follow-up of 156 wk. METHODS Patients were randomized 1:1 to RUX 10 mg twice daily or BAT; BAT patients could cross over to RUX starting at wk 28. The primary endpoint was Hct control at wk 28 (absence of phlebotomy eligibility [Hct >45% and ≥3% higher than baseline, or >48%] from wk 8 to 28, with ≤1 phlebotomy eligibility up to wk 8). The key secondary endpoint was complete hematologic remission (CHR; Hct control, white blood cell count <10×109/L, platelet count ≤400×109/L) at wk 28. Other endpoints included changes in patient-reported outcomes and in JAK2 V617F allele burden over time. Durability of Hct control (ie, primary response), CHR, and safety were evaluated at wk 156. RESULTS At data cutoff (April 6, 2018), 65/74 RUX pts were still on treatment. Primary reasons for discontinuation were adverse events (AEs; 5.4%), consent withdrawal (2.7%), death, disease progression, and physician decision (1.4% each). All 75 BAT pts had discontinued; 58 pts had crossed over to RUX; 46 were ongoing. Reasons for early discontinuation in crossover pts were AEs (13.8%), consent withdrawal (3.4%), death (1.7%), and disease progression (1.7%). Median exposure was 168.5 wk for RUX, 28.4 wk for BAT, and, in crossover pts, 137.0 wk for RUX. At wk 156, durable Hct control was achieved in 41.9% of RUX pts (31/74). The Kaplan-Meier estimated median duration of Hct control had not been reached (Figure A). Durable CHR was achieved in 24.3% of RUX pts (18/74; estimated median duration, 35.9 weeks; Figure B). RUX also led to durable improvements in PV-associated symptoms, with approximately half of RUX pts (48%) continuing to achieve a ≥50% reduction in MPN-SAF TSS at wk 156. Pts in the RUX arm also continued to experience improvements in all 5 dimensions of the EQ-5D-5L assessment. Pts who crossed over to RUX derived benefits from RUX therapy as well, achieving Hct control following crossover, with Hct decreasing over time. As seen in RUX pts, crossover pts experienced a reduction in JAK2 V617F allele burden over time from the time of crossover. The safety profile of RUX was consistent with previous reports. The most common AEs were anemia (exposure-adjusted rate per 100 pt-years, 10.7), increased weight (8.5), arthralgia (6.8), and hypertension (6.0) in the RUX arm and anemia (12.8), nasopharyngitis (7.1), and increased weight (6.4) in pts after crossover. Of interest, exposure-adjusted rates of herpes zoster were 3.8 with RUX and 5.0 in crossover pts. Overall, exposure-adjusted rates of AEs with RUX were lower than those reported at 80 wk of follow-up. The exposure-adjusted rate of thromboembolic events was higher in the BAT arm (3.7; RUX, 2.6). As expected given prior HU exposure, nonmelanoma skin cancer was the most common second malignancy in RUX-treated pts (randomized, 3.4; crossover, 2.8). No RUX-treated pts developed AML; 1 pt (RUX arm; 0.4) developed myelofibrosis. Three pts died on study: 1 in the RUX arm (metastatic melanoma), 1 in the BAT arm (septic shock), and 1 after crossover (general health deterioration). CONCLUSIONS In this 156-wk follow-up, RUX provided durable Hct control and CHR in pts with PV without splenomegaly. RUX was well tolerated, with 88% of randomized pts and 79% of crossover pts still receiving RUX at the time of this analysis. AEs were consistent with previous reports, and no new safety signals were observed. Overall, findings are consistent with those from RESPONSE and support RUX as the standard of care for second-line therapy in pts with inadequately controlled PV. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Palandri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Saydam:Gilead: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Devos:Novartis: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bensasson:Novartis: Employment. Kandra:Novartis: Employment, Research Funding. Morando:Novartis: Employment, Equity Ownership. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text