The Interaction between IPSS Score and JAK2 Mutation Identifies Patients at Different Vascular Risk in Primary Myelofibrosis

Abstract BACKGROUND The rate of major arterial and venous thrombosis in primary myelofibrosis (PMF) and post-ET (PET) and post-PV (PPV) secondary myelofibrosis has been evaluated in a limited number of studies. In the present paper we describe the clinical epidemiology of thrombosis in a large series of patients with overt PMF and PPV/PET MF looking at the rate and risk factors. Moreover, we report findings on thrombosis rate in two cohorts of patients treated with Hydroxyurea (HU) or Ruxolitinib (Ruxo). METHODS Patients were registered in the European Registry for Myeloproliferative Neoplasms (ERNEST). This project, promoted by the European LeukemiaNet, is coordinated by FROM - Foundation for Research, Papa Giovanni XXIII Hospital, Bergamo (Italy) and supported by Novartis through a research collaboration . Patients were diagnosed in 6 Centers from Italy, Spain and Sweden, between Jan, 2001 and Dec, 2012, with the required follow-up information. Patients (n= 1010) with PMF (n=584, 59%), PET-MF (n=207, 20%) and PPV-MF (n=219, 21%) were evaluated for incident thrombosis as primary endpoint. Considering death as a competitive event, uni-and multivariate analyses were performed by applying Fine & Gray competing-risk regression models. RESULTS After a median follow-up of 3.8 years (IQR: 1.8-7.1) from diagnosis, 108 thromboses (10.7%) occurred, for an overall incidence rate of 2.0% pts-yr (95% CI: 1.7-2.5). Arterial thromboses were found in 50 patients (46.3%) including cerebral (n=21, 19.4%), myocardial infarction (n=13, 12.0%) and peripheral events (n=9, 8.3%). Venous thromboses were 58 (53.7%), of which 25 (23.0%) were DVT ± PE and 11 (10.2%) were splanchnic. Thrombosis rate was 1.91, 1.60 and 2.79% pts-yr in PMF, PET-MF and PPV-MF, respectively. In univariate analysis, factors significantly associated with an increased thrombotic risk in PMF were age (p=0.013) and the presence of the JAK2 mutation (p=0.003); in addition, a significant higher proportion of PMF patients at low and intermediate-1 vs intermediate-2 or high risk IPSS score, had thrombosis during the follow-up (p=0.008). In multivariate analysis, only JAK2 mutation retained statistical significance (SHR=3.12, 95% CI: 1.40-6.94, p=0.005). Conversely, neither in univariate nor in multivariable analysis, significant risk factors were not found.To investigate the possible interaction of IPSS score and JAK2 mutation we created a model whose results are presented in Fig. 1A: the cumulative incidence function (CIF) of thrombosis was significantly lower in patients with JAK2 wild-type and intermediate-2 or high IPSS score (CIF: 4% projected at 10 years; SHR=1 [reference category]), while patients at the highest risk for thrombosis harbored JAK2 mutation and were categorized at low or intermediate-1 by IPSS score (CIF: 20% projected at 10 years, SHR=7.13, p=0.008). Of note, thrombosis had a significant impact on mortality. After adjusting for sex, age, year of diagnosis, type of MF and IPPS, HR was 1.51, (95% CI. 1.15-1.98, p=0.003).The influence of drug exposure to incident thrombosis was investigated in two cohorts of 559 consecutive patients exposed to HU (n=470) or to Ruxo (n=89), median treatment 2.6 and 3.0 years, respectively. HU- compared to Ruxo-treated patients were older (median age 67 vs. 63 years, p=0.001), more frequently triple negatives (12% vs. 2%, p=0.036), less splenomegalic (spleen length >10 cm: 30% vs. 88%, p <.001) and less symptomatic (49% vs. 79%, p=0.031). Of note, median time from MF diagnosis to therapy start in Ruxo group was 4 years, whereas patients started HU at MF diagnosis. In 56 of 89 Ruxo-treated patients (62.9%), the drug was given after a prior HU therapy. The thrombosis rate from the time of initiation of therapy was 2.40% pts-yr (95% CI 1.78-3.24) under HU and 1.28% pts-yr (95% CI 0.48-3.41) under Ruxo (CIF curves in Fig. 1B). In multivariate analysis corrected for MF type, DIPPS at first drug administration, JAK2 mutation and time from MF diagnosis, exposure to Ruxo showed a non-significant trend towards a protection of approximately 70% compared to HU (SHR=0.33, 95% CI: 0.08-1.32, p=0.117). CONCLUSION IPSS score, in addition to the survival risk assessment, may be useful, if associated with the JAK2 mutation, to recognize patients at vascular risk and to suggest appropriate anti-thrombotic prophylaxis. The trend towards a benefit of Ruxo, compared to HU, warrants a study in larger case series. Figure 1 Figure 1. Disclosures Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Vannucchi: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures.

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Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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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.

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Higher Incidence and Risk of Developing Second Solid Cancers (SSC) after Haematopoetic Stem Cell Transplantation (HSCT) As Compared to General Population

Blood ◽

10.1182/blood.v128.22.4610.4610 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4610-4610

Author(s):

Samar Kulkarni ◽

John Murray ◽

Charlotte Smith ◽

Stephanie Cleaver ◽

Michael Dennis ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Stem Cell ◽

General Population ◽

Board Of Directors ◽

Primary Site ◽

Single Centre ◽

Advisory Committees

Abstract Introduction: As the number of long-term survivors following HSCT is increasing, the long-term risks and associated morbidity has become important component of survivorship program. The known risk factors for developing cancer include use of chemotherapy agents, radiation exposure, immune dysfunction, previous malignancy in addition to other factors and as HSCT process involves all these factors, this single centre retrospective analysis was undertaken to evaluate the risk of developing SSC in the patients receiving transplant. Methods: From February 1982 to February 2016, 2231 patients received 2495 transplants (median age: 46yr., range: 14-76 yr.; M: 1586, F: 909) for haematological malignancies (Leuk: 744, lymphoma:767, myeloma:848, solid tumours/other:136). Donor was allogeneic (n=744) or autologous (n=1751) and conditioning was with (n=614) or without TBI (n=1881). Donor was sibling (n=375), matched unrelated (n=355), haploidentical relative (n=3) or umbilical cord blood (n=11). Source of stem cell was marrow (n=367), PBSC (n=2086), both (n=31) or cord blood (n=11). GVH prophylaxis included Campath or ATG in 369 cases. Of all the patients 1985 received single transplant, 231 had two, 13 had 3 and 2 had 4 HSCT procedures. Data was analysed as of 15/04/2016 using competing risk model with death as the competing event. Comparison of incidence to general population was performed by computing standardized incidence rates (SIR). Patients with second haematological malignancy were not included in this analysis. Results: Median follow-up was 5.3 years (range: 0-32 years). Patient follow-up was more than 10 years in 467 cases (19%), between 5 to 10 years in 430 (17%), 2 to 5 years in 607 (24%) and less than 1 year in 997 cases (40%). 36% patients were followed-up for more than 5 years. Second solid cancers developed in 116 patients with the incidence of 1% at 5yr (95% CI: 0.5-2.6), 3% at 10 yr (95% CI: 1.6-5.3), 6% at 15yr (95%CI: 3.6-8.8) and 10% (95% CI: 5.9-15.5) at 20 years. Median time to develop SSC from date of HSCT was 11 yr (range: 0.4-28.1 yr). Primary site for SSC included skin (n=37), breast (n=22), GI (n=15), GU (n=16), H&N (n=10), lung (n=6), CNS (n=4), Endocrine (n=4) & HPB (n=2). There was no difference with type of transplant i.e. auto or allograft. Autograft and allograft groups were analysed separately. In univariate analysis, allograft group showed higher cumulative incidence of SSC with use of PBSC (p<0.0001), campath/ATG (p=0.0002), donor other than sibling (P=0.0004), RIC (p<0.0001), non-TBI conditioning (p=0.007), older age at transplant (0.008), development of agvhd or cgvhd (p=0.023) and transplant year after 2000 (p=0.01). In multivariate analysis age above 50 (RR: 1.8, 95%CI: 1.2-1.8, p=0.046) and RIC (RR: 4.4, 95% CI: 1.2-8.3, p=0.03) were independently associated with higher risk of SSC. In autograft group, there were no independent risk factors in univariate or multivariate analysis. As compared to general population incidence was higher for all cancers (SIR=7.4) and also cancers at every primary site. Risk was highest for breast (SIR=14.3), Head/neck (SIR=25.6), brain (SIR=17.4) and colon (SIR=6.2). Overall survival is significantly shorter in patients who develop SSC (median: 12 yr vs. not reached, p<0.0001). The median time to develop SSC from the date of HSCT has significantly shortened over last three decades (years 1982-1990: 21yr, 1991-2000: 11.1 yr, 2001-2010: 6.34 yr, 2011-2016: 2.2 yr; p=0.0001) Conclusion: This single centre analysis confirms that the risk of developing SSC increases with advancing age, use of RIC allograft, longer follow-up and leads to inferior survival. Since the year 2000, SSC are developing early after transplant and it needs to be evaluated if this is a trend seen at other centers and if so, is it related to increasing use of RIC, increasing number of elderly patients, severity of immune-suppression or higher incidence of GVHD. Disclosures Somervaille: Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Bloor:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; GSK: Consultancy, Speakers Bureau; Gilead: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Risk Factors for Severe Form of COVID-19 after Allogeneic Hematopoietic Stem Cell Transplantation: A SFGM-TC Multicentre Cohort Study

Blood ◽

10.1182/blood-2020-138411 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Alienor Xhaard ◽

Constance Xhaard ◽

Maud D'Aveni ◽

Hélène Salvator ◽

Marie-Laure Chabi-Charvillat ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Intensive Care ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Immunosuppressive Treatment ◽

Severe Form ◽

Advisory Committees

COVID-19 greatly affected Europe between March and May 2020. Initial reports suggest cancer and haematological malignancies as risk factors for severity and mortality, but the role of allogeneic stem cell transplantation (alloHSCT) remains unclear. The Société Francophone de Greffe de Moelle et Thérapie Cellulaire conducted a multicentre retrospective study of alloHSCT recipients diagnosed with COVID-19. We described the COVID-19 disease characteristics in this population and examined risk factors for severity and mortality. Data were collected retrospectively from the patients' charts and the ProMISe database. Diagnosis was retained only if a reverse transcription polymerase chain reaction assay test from a nose swab was positive for SARS-CoV-2. Patients were classified as severe if they were transferred to an intensive care unit (ICU) due to COVID-19 or died of COVID-19, and non-severe in other cases. Comparisons of characteristics were performed using student's t-tests and Mann-Whitney U tests for normally and abnormally distributed data, respectively, for continuous variables and χ2 or Fisher's exact tests, when appropriate for categorical variables. Risk factors associated with a severe form of COVID-19 were assessed using both univariate and multivariate logistic regressions. All analyses were performed using SAS version 9.4.6 (SAS Institute Inc., Cary, NC, USA. A two-tailed significance level p<0.05 was used. Fifty-four patients were diagnosed, including 21 with severe forms (intensive care transfer and/or death). Haematological characteristics did not vary between patients with severe or non-severe forms of COVID-19. Patients with a severe form of COVID-19 were more likely to be diagnosed earlier after alloHSCT (0.78 vs. 2.1 years, p=0.01), to have comorbidities (80.9% vs. 54.5%, p=0.05) and to receive immunosuppressive treatment (81% vs. 51.5%, p=0.03). Severe COVID-19 patients were more likely to have symptoms at COVID-19 diagnosis (100% vs. 81.8%, p=0.04), especially pneumonia and symptoms other than respiratory or digestive (asthenia, neurological symptoms, myalgia, dysgeusia, skin lesions and arthralgia), and to experience co-infection during the course of the disease (52.4% vs. 21.2%, p= 0.001). At COVID-19 diagnosis, patients with a non-severe form were more likely to have a higher platelet count (226 G/L vs. 98 G/L, p= 0.01), while other biological characteristics did not vary between the two cohorts. In univariate analysis, shorter time from transplant to COVID-19 (before 211 days, p=0.01), pneumonia (OR 12.21 [95% CI 2.43 - 61.46], p=0.002), symptoms other than pulmonary or digestive (OR 1.21 [95% CI 1.02 - 11.16], p=0.04), immunosuppressive treatment (OR 5.97 [95% CI 0.75 - 47.42], p=0.03) , co-infection (OR 5.84 [95% CI 1.65-20.63], p=0.006) and comorbidity (OR 3.54 [95% CI 0.98-12.83], p=0.05) were associated with severe COVID-19. The only biological parameter associated with severity was a lower platelet count <71G/L (OR 28.00 [95% CI 2.07-379.25]), p=0.008. In multivariate analysis, pneumonia and other symptoms retained a significant association with severe COVID-19. Thirteen patients died of COVID-19: in univariate analysis, risk factors for death from COVID-19 were similar to the risk factors for severe COVID-19 (i.e. shorter time from alloHSCT, p=0.03; pneumonia, p=0.01; co-infection during the course of COVID-19, p<0.01, and lower platelet count, p<0.01). In multivariate analysis, none of the above mentioned factors remained significantly associated with death from COVID-19. As SARS-CoV-2 continues to spread internationally, given the lack of vaccine or treatment, alloHSCT recipients should maintain a high level of awareness to avoid contamination. Figure Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rubio:MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding; Medac: Consultancy; Gilead: Honoraria.

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Connect MM®—the Multiple Myeloma (MM) Disease Registry: Incidence of Second Primary Malignancies (SPM)

Blood ◽

10.1182/blood.v124.21.4749.4749 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4749-4749

Author(s):

Robert M. Rifkin ◽

Rafat Abonour ◽

Jatin J. Shah ◽

Jayesh Mehta ◽

Mohit Narang ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Solid Tumor ◽

Research Funding ◽

Significant Risk ◽

Significant Risk Factor ◽

Prior History ◽

Advisory Committees ◽

History Of

Abstract Background: Increased rates of SPM have been observed as newer cancer treatments have improved survival over the past 2 decades (Fraumeni et al. NCI, 2006). Higher incidence of specific types of hematologic SPM following MM, especially acute myeloid leukemia and myelodysplastic syndromes, have been reported relative to the general population (Dores et al. NCI, 2006; Mailankody et al. Blood, 2011; Ravazi et al. Blood, 2011; Landgren and Mailankody. Leukemia, 2014). A complex interplay between myeloma-, host-, environmental-, and treatment-related factors likely contributes to the increased incidence of SPM in MM. Connect MM is the first and largest prospective, observational, US-based, multicenter registry designed to characterize patients (pts), treatment patterns, and outcomes in newly diagnosed MM (NDMM) pts. Methods: Between September 2009 and November 2012,a total of 1493 NDMM pts were enrolled from 234 US sites within 2 mos of the first diagnosis of MM. Patient data were collected at baseline and each subsequent quarter using a standardized form. Invasive SPM included hematologic and solid tumor second cancers and non-invasive SPM were defined as non-melanoma skin cancers (NMSC). SPM incidence and incidence rate (IR; number of pts with SPM per 100 patient-yrs [PY]) were calculated for all pts and by exposure to specific treatments, including lenalidomide (LEN). PYs were calculated as the observation period from the start of treatment until the detection of the first reported SPM (per category), death, or end of follow-up (pt lost or data cutoff). Results: As of Dec 10, 2013, SPM data were available for 1493 NDMM pts. The median age was 67 yrs (range, 24-94 yrs), 82% of patients were white and 57% were male. Median follow-up was 29.0 mos (0-49 mos). The median OS of treated pts was 44.4 mos. Fifty pts did not receive treatment and had no SPM reported. A total of 74 of the 1443 treated pts (5.1%) reported SPM. Invasive SPM were observed in 51 pts (3.5%): 37 pts (2.6%) with solid tumors and 14 pts (1.0%) with hematologic SPM. Lung/bronchus and myelodysplastic syndromes were the most frequently reported solid tumor and hematologic SPM respectively. NMSC were reported for 26 pts (1.8%). 3 pts had both an invasive SPM and NMSC. The IRs for invasive, hematologic, and solid tumor SPM by LEN exposure are listed in Table 1. By multivariate analysis, the only significant risk factor for the occurrence of SPM was prior history of invasive malignancy. Demographics (including age, ethnicity, race, and gender), International Staging System stage, family history of myeloma or other cancers, history of smoldering MM or monoclonal gammopathy of unknown significance, or prior radiation therapy were not associated with the occurrence of SPM. Conclusions: This analysis shows that there was no increased risk of invasive SPM in this disease-specific registry of pts with NDMM. The risk of SPM for LEN exposed pts was not greater than that for pts not exposed to LEN. In addition, multivariate analysis indicated the only significant risk factor for SPM was prior history of invasive malignancy. As additional agents are approved for the treatment of MM and the length of pt survival increases, longer prospective observation with expanded enrollment on the registry will better characterize the occurrence of SPM in this pt population. Correlations with risk factors including age, pre-existing MDS, risk status, as well as type and duration of therapy will continue to be investigated. Table 1. Incidence rates (per 100 PYa) by treatment exposure IR per 100 PY (95% CI) SPM LEN-Exposed (n = 977) Non–LEN Exposed (n = 466) Invasive 0.85 (0.61-1.19) 1.16 (0.72-1.86) Hematologic 0.17 (0.08-0.36) 0.47 (0.22-0.99) Solid tumor 0.67 (0.46-0.98) 0.68 (0.36-1.26) NMSC 0.50 (0.32-0.77) 0.41 (0.18-0.91) a PY of exposure is the sum of exposure of all pts. Disclosures Rifkin: Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Shah:Celgene Corp: Consultancy, Research Funding. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Lu:Celgene Corp: Employment. Kenvin:Celgene Corp: Employment. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Durie:Celgene Corp: Expert Board Committee Other; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees.

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Eculizumab Protects Against TE and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study

Blood ◽

10.1182/blood.v120.21.3480.3480 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3480-3480

Author(s):

Gérard Socié ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Jeffrey Szer ◽

Alvaro Urbano-Ispizua ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Advisory Committees ◽

Significant Protective Effect ◽

Rbc Transfusion

Abstract Abstract 3480 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. PNH, in large part due to chronic hemolysis and platelet hyperactivation, is associated with thromboembolism (TE), one of the leading causes of disease mortality. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown in clinical trials to reduce hemolysis and the incidence of TE. The International PNH Registry provides the opportunity to understand from real world experience the impact of eculizumab on TE reduction in PNH patients. Aim: To assess the risk factors for TE and mortality in PNH patients enrolled in the Registry and to assess the effectiveness of eculizumab in reducing PNH-associated TEs. Methods: Patients are eligible for the Registry if they have a detectable PNH clone, regardless of disease severity, comorbidities, or treatments (past, current or planned). As of June 30, 2012, there were 1547 patients enrolled from 25 countries on 5 continents. Patients were excluded from analysis if they were missing key demographic variables or dates of eculizumab use, or did not yet have follow-up information. The cumulative incidence of TE was determined using competing risks methods to take into account bone marrow transplantation and death, while Kaplan-Meier methods were used for the cumulative incidence of mortality. Risk factors for TE and mortality were explored using a Cox proportional hazards model with stepwise selection (the significance level was relaxed to P=0.20 due to the small number of events for analysis). Variables examined in the models included: ethnicity; prior TEs, bone marrow disorders, impaired renal function, impaired hepatic function (IHF), abdominal pain, dysphagia, dyspnea, easy bruising/bleeding, fatigue, headache, hemoglobinuria, Karnofsky performance score, granulocyte clone size and lactate dehydrogenase (LDH) at enrollment, red blood cell (RBC) transfusions 6 months prior to enrollment as a marker for hemolysis, and treatments after enrollment (eculizumab and warfarin/heparin). Results: The mean age of the 1047 patients eligible for analysis was 45 years; 537 patients (51.3%) were female and 868 were Caucasian (82.9%). Anti-coagulants (heparin/warfarin) were used by 28% of patients and eculizumab was used by 51% during follow-up (18% used both). During a mean (SD) follow-up of 22.5 (18.4) months, 16 patients had a TE and 51 were deceased. Patients taking eculizumab during follow-up had a cumulative incidence of TE at 1 year of 0.41% and 1.35% at 2 years, while patients not taking eculizumab had TE incidence of 1.70% and 2.61% at 1 and 2 years, respectively. In the multivariate Cox model, the greatest associations with TE were RBC transfusions in the 6 months before enrollment (hazard ratio [HR]=9.61), history of IHF (HR=4.78), dyspnea (HR=2.42) and headache (HR=2.33) at enrollment. While controlling for these variables, eculizumab had a significant protective effect (HR=0.23, 95% CI = 0.08–0.66). The cumulative incidence of mortality in eculizumab-treated patients was 2.31% and 4.21% at 1 and 2 years, while in untreated patients it was 4.40% and 7.01%, respectively. In the multivariate model of mortality, the greatest associations were age 60+ years (HR=4.72), Karnofsky score <80 (HR=2.34), fatigue at enrollment (HR=1.94), and recent RBC transfusion (HR=1.75). While controlling for these variable, eculizumab had a significant protective effect (HR=0.41, 95% CI = 0.23–0.73). Conclusions: This analysis of a large international cohort of ‘real world’ patients with PNH showed that eculizumab is associated with a significantly reduced risk of TE and mortality, consistent with prior research. Recent RBC transfusion, a surrogate marker for hemolysis, was associated with increased risk of TE and mortality. Several symptoms and hepatic dysfunction also showed increased risks for these outcomes. As might be expected, older age and low performance status were associated with mortality. These data should be interpreted within the context of a contemporary cohort of PNH patients who may or may not be treated (with either eculizumab and/or anticoagulation). These analyses are limited due to small number of TE and mortality outcomes. Disclosures: Muus: Alexion Pharmaceuticals : Sat on advisory board of Alexion Pharmaceuticals. Other. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Kanakura:Shire: Consultancy. Rosse:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion Pharmaceuticals, Inc: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Could Chronic Gvhd Overcome the Poor Prognosis of Patients with MDS and TP53 Undergoing Allogeneic HSCT?

Blood ◽

10.1182/blood.v126.23.2890.2890 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2890-2890

Author(s):

Juan Carlos Caballero ◽

Mercedes Sánchez-Barba ◽

Mónica Del Rey ◽

Kamila Janusz ◽

Eva Lumbreras ◽

...

Keyword(s):

Multivariate Analysis ◽

Stem Cell ◽

High Risk ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Somatic Mutations ◽

Advisory Committees ◽

Poor Outcome

Abstract Background and Aim Although new agents have been approved for the treatment of MDS, the only curative approach for these patients is allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, in these patients this approach has only obtained 40-60% of overall survival. Somatic mutations in MDS have recently been analyzed in order to confirm clonally and also prognostic impact in MDS patients. In this regard, TP 53 mutated gene is present in MDS in less than 10% of patients and is associated with advanced disease and high-risk features. Recent studies confirms poor outcomes in patients with TP 53 mutated receiving allogeneic stem cell transplantation1,2. The present study try to analyze if the development of chronic graft versus host disease (cGVHD) could modify, due to graft versus leukemia effect, the adverse prognosis of these high-risk patients (TP53 mutated patients). Design and Methods <>Results of HSCT in 92 MDS patients from 5 centers in Spain were retrospectively studied. Samples were collected 1 month prior to transplant. 280ng of the genomic DNA from BM cells was screened for somatic mutations in TP53 gene. The study was done by NGS on a GS Junior Instrument (Roche) according to an amplicon sequencing design. For each sample, eight exons (4-11) were amplified with preconfigured primer plates provided within the IRON II study network. Data analysis, were carried out using the Sequence Pilot software version 3.5.2 (JSI Medical Systems) and GS Amplicon Variant Analyzer software, versions 2.7 and 2.9 (Roche Applied Science). Minimum coverage of sequenced exons was 100 reads and the sensitivity of variant detection was set to a lower limit of >2% for bidirectional reads. Only those variants that resulted in amino acid change in the protein sequence were considered. OS and RFS were calculated using the Kaplan-Meier method. The log-rank test was used for comparisons. All calculations were done using SPSS 18.0. Cumulative incidence of relapse was also calculated by xlstat version 2014 program. <>Results Median age was 54 years (17-69), 71.7% were "de novo" MDS and regarding IPSS, 53% were in the int-2/high-risk category. Other characteristics were in Table 1. In the pre-transplant evaluation, 15 patients out of 92 (16,3%) were TP 53 mutated. The mutations were located in exons 5, 6, 7, 8 and 10. These variations were present in a variable percentageof the cell population (3 to 84%). All mutations were specific nucleotide changes except for two cases. At the time of the last update, 16 patients had relapsed (17.4%) and 40 had died (43.5%). After a median follow up of 15.5 months, OS was 56.5%. Median OS for patients with mutated TP53 trend a toward to be shorter than survival for patients without mutated TP53 (median of 7 mo vs median not reached, respectively, p=0.156). Multivariate analysis for OS confirmed complex karyotype (HR 5,588, 95CI 1,794-17,407, p=0.003) and no developement of cGVHD (HR 3,531, 95IC 1,634-7,632, p=0.001) as predictors for poor outcome. Cumulative incidence of relapse was 20.3% (+/-4.3%) at 1 years. Mutational status of TP53 significantly influenced on relapse (53.3% +/-12.9% vs 13.7% +/-4% at 1 year for patients with vs without TP 53 mutation (Gray test=0.001, Figure 2). Regarding Relapse Free Survival (RFS), after a median of follow up of 17 months, RFS was 67.9% and as previously suggested, the presence of TP 53 mutation had an impact on RFS (41.7% for mutated (median RFS of 6 months) and 75% for non mutated patients (median RFS not reached), p=0.009). Multivariate analysis for RFS confirmed age (HR 1.054, 95CI 1.005-1.106, p=0.032) and TP 53 mutated (HR 3.054, 95IC 1.145-8.149, p=0.026) as predictors for lower RFS. Regarding 15 patients with mutated TP 53, 7 did relapsed and 9 had died. Developement of cGVHD showed a trend toward to improve outcome among TP 53 mutated patients, with a better OS and RFS for those developing cGVHD as compared to those who did not (OS of 55% vs 17% for patients with and without cGVHD, p=0.039, Figure 2 and RFS of 71% vs 50%, respectively, p=0.3). <>Conclusions Mutated TP53 pre-allo patients presents poor outcome as compared to not mutated, as previously described Bejar1 and Kim2. Nevertheless, the developement of cGVHD could overcome the adverse impact of this factor due to the developement of graft versus tumor efect, improving survival curves (OS and RFS) as compared to previous published results. Study supported by GRS-1033/A/14 P53. 1.-BŽjar, JCO 2014, 32(25). 2.-Kim, BBMT 2015, Epub ahead of print. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Sanz: JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau. Valcarcel:AMGEN: 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; GSK: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Díez-Campelo:CELGENE: Research Funding, Speakers Bureau; JANSSEN: Research Funding; NOVARTIS: Research Funding, Speakers Bureau.

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Prognostic Impact of Bone Marrow Fibrosis in Primary Myelofibrosis: A Study of Agimm Group on 540 Patients

Blood ◽

10.1182/blood.v126.23.351.351 ◽

2015 ◽

Vol 126 (23) ◽

pp. 351-351 ◽

Cited By ~ 1

Author(s):

Paola Guglielmelli ◽

Giada Rotunno ◽

Annalisa Pacilli ◽

Elisa Rumi ◽

Vittorio Rosti ◽

...

Keyword(s):

Bone Marrow ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Primary Myelofibrosis ◽

Driver Mutations ◽

Prognostic Impact ◽

Advisory Committees ◽

The Impact

Abstract Background. The prognostic significance of bone marrow (BM) fibrosis grade in pts with primary myelofibrosis (PMF) is debated. A fibrosis grade greater than 1 was associated with a 2-fold higher risk of death compared with pts with early/prefibrotic MF (grade 0) [Thiele J, Ann Hematol 2006]. Recent data suggest that more accurate prediction of survival is achieved when fibrosis grade is added to IPSS [Verner C, Blood 2008; Giannelli U, Mod Pathol 2012]. Aim. To analyze the prognostic impact of fibrosis in diagnostic BM samples of 540 WHO-2008 diagnosed PMF pts with extensive clinical and molecular information collected in 6 Italian centers belonging to AGIMM (AIRC-Gruppo Italiano Malattie Mieloproliferative). Methods. The clinical variables assessed were those previously identified as prognostically relevant in the IPSS score. Published methods were used to screen mutations of JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. European consensus scoring system was used to grade fibrosis (on a scale of MF-0 to MF-3). The prognostic value of fibrosis with regard to overall survival (OS) was estimated by Kaplan-Meier method and Cox regression. Results. Pts' median age was 61y; median follow-up 3.7y; median OS 10.5y; 184 pts (34.1%) died. IPSS risk category: low 33.7%, Int-1 27.7%, Int-2 19.1%, High-risk 19.5%. Mutational rate: JAK2 V617F 62.6%, CALR 20.7% (type-1/1-like 77.7%, type2/2-like-2 21.4%), MPL W515 5.9%; 62 (11.5%) were triple negative (TN). 171 pts (31.7%) were High-Molecular Risk (HMR) category (Vannucchi AM, Leukemia 2013); mutation rate: EZH2 7.2%, ASXL1 22.2%, IDH1-2 2.4%, SRSF2 8.3%. According to fibrosis grading, 50 pts were MF-0 (9.3%), 180 MF-1 (33.3%), 196 MF-2 (36.3%), 114 MF-3 (21.1%). Compared with both MF-0 and MF-1, MF-2 and MF-3 pts presented more frequently constitutional symptoms (P<.0001), larger splenomegaly (P<.0001), greater risk of developing anemia (P<.0001) or thrombocytopenia (P=.003). We found a significant association (P<.0001) between IPSS higher/Int-2 risk categories and MF-2 and -3 (20.5% and 37.8%, respectively, vs 14.8% and 6.0% for MF-0 and -1). There was no correlation between fibrosis grade and phenotypic driver mutations; in particular, TN pts were equally distributed among MF fibrosis grades (10%, 10.6%, 14.3% and 8.8% from MF-0 to -3, respectively). Conversely, the frequency of HMR pts increased progressively according to fibrosis grade: 8 pts MF-0 (16%), 46 MF-1 (25.6%), 66 MF-2 (33.7%) and 51 MF-3 (44.7%) (P<.0001). In particular, we found a significant association between fibrosis grade and ASXL1 (12%, 15%, 23.5% and 36% from MF-0 to -3; P<.0001) and EZH2 (2%, 3.9%, 8.2%, 13.2%; P=.01) mutations. Also, pts with 2 or more HMR mutated genes were preferentially MF-2 or -3 ( 0%, 4.4% 10.2% and 10.5% from MF-0 to -3; P=.001). Median OS was significantly shorter in pts with MF-2 (OS 6.7y, HR 7.3, IC95% 2.7-20.0; P<.0001) and MF-3 (OS 7.2y, HR 8.7, IC95% 3.1-24.2; P<.0001) compared with MF-1 (14.7y; HR 3.9, IC95% 1.4-10.9, P=.008) and MF-0 (P<.0001) used as reference group (OS not reached) (Figure). Excluding MF-0, MF-2 and -3 maintained negative prognostic impact with HR 1.9 (1.3-2.6; P=.001) and 2.2 (1.5-3.3; P<.0001) respectively vs MF-1. The impact of fibrosis on OS was maintained when analysis was restricted to younger (≤65y) pts. In multivariate analysis using the individual IPSS variables, grade MF-2 and -3 were independently predictive of survival (HR 3.9 (1.4-10.8), and HR 4.2 (1.5-12.0), respectively, P=.008 for both). The negative impact on survival of MF-2/-3 was maintained regardless of IPSS category, HMR status, number of HMR mutated genes and driver mutations, included as covariates (Table). In low, Int-1 and Int-2, but not high-risk IPSS categories, MF-2/-3 associated with reduced survival (P<.03). Conclusions. Overall, these results indicate that higher grades (MF-2 and MF-3) of fibrosis correlate with defined clinical and molecular variables and independently negatively impact on OS in PMF, suggesting the opportunity to explore its value in the setting of clinical and molecular prognostic scores for PMF. Table. Multivariate Analysis Variables HR 95% CI P value HMR status 2.4 1.5-3.7 <.0001 HMR≥2mutations 4.3 2.8-6.4 .009 IPSS scoring Int1 2.9 1.6-5.1 <.0001 Int2 10.0 5.6-17.7 <.0001 High 9.7 5.5-17.2 <.0001 Driver mutations CALR type2 3.4 1.3-8.6 .010 JAK2/MPL 2.4 1.4-4.3 .003 TN 4.5 2.3-8.8 <.0001 Fibrosis MF-2/MF-3 3.8 1.4-10.6 .010 Figure 1. Figure 1. Disclosures Passamonti: Novartis: Consultancy, Honoraria, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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A Ruxolitinib Individual Supply Program for Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post-Essential Thrombocythemia Myelofibrosis

Blood ◽

10.1182/blood.v118.21.5170.5170 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5170-5170 ◽

Cited By ~ 1

Author(s):

Giovanni Barosi ◽

Francisco Cervantes ◽

Dina Ben-Yehuda ◽

Panagiotis Panagiotidis ◽

Jose Ricardo Perez ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Treatment Options ◽

Primary Myelofibrosis ◽

Patient Characteristics ◽

The United States ◽

Comparable Efficacy ◽

Phase 3 ◽

Advisory Committees ◽

Jak2 Mutation

Abstract Abstract 5170 Background: There are currently no approved, effective drug therapies for myelofibrosis (MF). Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, has recently demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life in 2 phase 3 studies in patients with MF. Both studies met their primary endpoint of the proportion of patients with ≥35% reduction in spleen volume at 24 weeks (COMFORT-I) and at 48 weeks (COMFORT-II): 41.9% vs 0.7% (ruxolitinib vs placebo, P <.0001) and 28.5% vs 0% (ruxolitinib vs best available therapy, P <.0001), respectively. The most common grade ≥3 hematologic adverse events (AEs) were thrombocytopenia and anemia, which were manageable and rarely led to discontinuation (COMFORT-I: n=1 each; COMFORT-II: thrombocytopenia, n=1; anemia, n=0). Because of the limited available treatment options and medical need, ruxolitinib has been made available through an individual supply program (ISP) outside the United States. Methods: Patients with PMF, PPV-MF or PET-MF who are determined by their physicians to be in need of treatment are considered for eligibility, irrespective of JAK2 mutation status. As in the COMFORT studies, the starting dose of ruxolitinib is determined on the basis of baseline platelet count and can be adjusted for efficacy and safety. Dose changes during treatment are registered, and AEs and serious AEs (SAEs) are monitored throughout the study. Results: To date, 231 patients have been screened at more than 150 study sites in 28 countries, including Canada, Australia, and locations in Europe, Latin America, the Middle East, and Asia. The baseline characteristics for patients whose requests for access were approved/enrolled (n=200) and denied/pending (n=31) are shown below (Table). The patient characteristics are generally similar to those expected in the overall MF patient population. To date, the proportion of patients with the JAK2V617F mutation enrolled in this ISP (68.5%) is higher than that for the general MF population (50–60%) and may reflect the tendency of physicians to include more JAK2V617F-positive patients in the ISP, even though ruxolitinib has demonstrated comparable efficacy in both patient types (Verstovsek S, et al. N Engl J Med. 2010;363(12):1117–1127). Thrombocytopenia and herpes zoster were each reported as an AE in 1 patient, and no SAEs have been reported. Conclusions: Ruxolitinib is currently the only drug to have completed phase 3 studies for the treatment of MF and has garnered a substantial number of requests for access through the individual supply program. Disclosures: Barosi: Novartis: Consultancy. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Panagiotidis:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Research Funding; GSK: Honoraria. Perez:Novartis: Employment. Orlando-Harper:Novartis: Employment. Martin:Novartis Pharma AG: Employment. Willenbacher:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AESCA: Honoraria, Research Funding. Ojeda:Novartis: Consultancy. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Knoops:Novartis: Consultancy.

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The Burden of Atrial Fibrillation in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-150564 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3119-3119

Author(s):

Chinonso Ukeje ◽

Bahaa Al-Azzam ◽

Santosh L. Saraf ◽

Dawood Darbar ◽

David Tofovic

Keyword(s):

Risk Factors ◽

Life Expectancy ◽

Board Of Directors ◽

Research Funding ◽

Observation Time ◽

Hemoglobin Level ◽

Categorical Variables ◽

Cell Disease ◽

Advisory Committees

Abstract Introduction Life expectancy amongst individuals with sickle cell disease (SCD) has plateaued, with cardiopulmonary complications now becoming a leading cause of death (Fitzhugh et al. Am. J. Hematology 2010). Indeed, SCD is associated with increased rates of pulmonary hypertension (pHTN) and diastolic dysfunction (Sachdev et al. Blood 2005). In the general population, atrial fibrillation (AF) is associated with an increased mortality in the setting of either pHTN or diastolic dysfunction. Although cardiac structural and biochemical changes likely create an electrophysiological substrate for AF in SCD, the prevalence and risk factors for AF in SCD remain unclear. We determined the prevalence, incidence, and clinical characteristics of AF in a large cohort of patients with SCD. Methods We conducted a retrospective, longitudinal cohort study of all adult patients with SCD seen at our large, urban single center from January 2008 to December 2017. SCD patients were identified using a previously described semi-automated system with a subset with direct chart review (Srisuwananukorn et al. Blood Advances 2020). We performed manual review of ~17,000 available electrocardiograms of all enrolled subjects to look for AF. For univariate analyses, the associations of linear and categorical variables with AF were assessed using the Kruskal-Wallis test and Pearson's χ 2 test, respectively. We used Bonferroni correction for categorical variables with greater than two groups. Logistic regression analysis with stepwise addition of variables (p>0.15) was used to evaluate for the effects of previously described AF risk factors, degree of anemia, hydroxyurea use, and genotype on AF development. Results Our cohort consisted of 763 adult SCD patients with a median age of 27.95 years, 59.50% female, 72.4% with Hb SS or Sβ 0-thalassemia genotype, and 61.2% were prescribed hydroxyurea. Mean observation time for the cohort was 8.3 ± 6.3 yrs. We identified AF in 30 out of 763 adult SCD individuals with a mean age onset of 51 ± 10 years (median age 52 years). The period prevalence of AF was 3.93% and the incidence density was 3.02 per 1000 patient years observed. Individuals with AF tended to be older at initial (40 vs. 25 years, p<0.0001) and follow-up (53 vs. 35 years, p<0.0001) visits and were observed for a longer period (13.3 vs. 9.5 years, p=0.0014). There was no difference in gender (p=0.7), ethnicity (p=0.5), or SCD genotype (p=0.03) between groups (see Table 1). Those with AF were more likely to carry diagnoses of chronic obstructive pulmonary disease (p=0.0004), hypertension (p<0.0001), chronic kidney disease (p<0.0001), type 2 diabetes (p<0.0001), and any cancer (p=0.04). However, hydroxyurea use was not associated with AF development (p=0.3). SCD patients with AF were more likely to receive diuretics, atrioventricular nodal blocking agents, antihypertensives, antiplatelets, and statin therapies (see Table 1). AF was associated with worse anemia and reduced renal function. Regression analysis identified significant odds ratios (ORs) for age at initial visit (OR 1.06, p=0.03), serum creatinine per 1 mg/dL increase (OR 2.34, p=0.02), hemoglobin level per 1 g/dL increase (OR 0.52, p=0.0009), fetal hemoglobin level per 1% increment (OR 0.81, p=0.008), and total observation time per year follow up (OR 1.26, p=0.0006). Conclusion We showed that the prevalence and incidence of AF is high in patients with SCD with the median age of onset occurring 1-2 decades earlier than in the general populace (Feinberg et al. JAMA Internal Medicine 1995). AF in patients with SCD is associated with advanced age, worse renal function, a higher degree of anemia, and greater usage of cardio- and nephro-active medications. The high incidence of AF in patients with SCD may contribute to the plateauing of life expectancy and identifying the causative risk factors and the underlying mechanisms may not only improve life expectancy but also the quality of life. Further study is warranted. Figure 1 Figure 1. Disclosures Saraf: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.

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