Integration of Mutations and Karyotype Towards a Genetics-Based Prognostic Scoring System (GPSS) for Primary Myelofibrosis

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

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Patterns of care of subjects with type 1 and type 2 diabetes according to their cardiovascular risk

The Journal of AMD ◽

10.36171/jamd20.23.4.12 ◽

2021 ◽

Vol 24 (1) ◽

pp. 30

Author(s):

Pintaudi, B.

Keyword(s):

Risk Factors ◽

Quality Of Care ◽

Cardiovascular Risk ◽

High Risk ◽

Quality Indicators ◽

High Cardiovascular Risk ◽

Very High

AIM OF THE STUDY To explore the distribution by cardiovascular risk groups according to the classification promoted by the ESC (European Society of Cardiology) of subjects with type 1 (T1D) and type 2 (T2D) diabetes cared for by Italian diabetologists and to describe the quality indicators of care, with particular regard to cardiovascular risk factors. DESIGN AND METHODS The study is based on data extracted from electronic medical records of patients treated at the 258 diabetes centers participating in the Annals AMD initiative and active in the year 2018. Patients with T1D or T2D were stratified by cardiovascular risk, in accordance with the recent ESC guidelines. General descriptive indicators and measures of intermediate outcomes, intensity/appropriateness of pharmacological treatment for diabetes and cardiovascular risk factors, presence of other complications and overall quality of care were evaluated. RESULTS Overall, 29,368 adults with T1D and 473,740 subjects with T2D were evaluated. Among subjects with T1D: 64.7% were at very high cardiovascular risk, 28.5% at high risk and the remaining 6.8% at moderate risk. Among subjects with T1D at very high-risk: 54.7% had retinopathy, 29.0% had albuminuria, 7.3% had a history of major cardiovascular event, 47.3% had organ damage, 48.9% had three or more risk factors, and 70.6% had a diabetes duration of over 20 years. Among subjects with T2D: 78.5% were at very high cardiovascular risk, 20.9% at high risk and the remaining 0.6% at moderate risk. Among those with T2D at very high risk: 39.0% had organ damage, 89.1% had three or more risk factors, 18.7% had a previous major cardiovascular event, 26,4% had retinopathy, 39.5% had albuminuria. With regard to the glucose-lowering drugs: the use of DPPIV-i increased markedly as cardiovascular risk increased; the use of secretagogues also increased and, although within low percentages, also the use of GLP1-RA tended to increase. The use of SGLT2-i is also still limited, and only slightly higher in subjects with very high cardiovascular risk. In both types of diabetes, the overall quality of care, as summarized by the Q score values, tended to be lower as the level of cardiovascular riskincreased. CONCLUSIONS The analysis of a large population such as that of the AMD Annals database allowed to highlight the characteristics and quality indicators of care of subjects with T1D and T2D in relation to cardiovascular risk classes. A large proportion of subjects appear to be at high or very high risk. Glucose-lowering drug therapies seem not to be adequately used with respect to the potential advantages in terms of reduction of cardiovascular risk of some drug categories (GLP1-RA and SGLT2-i) and, conversely, with respect to the potential risks related to the use of other pharmacological classes (sulfonylureas). Several actions are necessary to optimize care and improve the quality of care for both subjects with T1D and T2D. KEY WORDS type 1 diabetes; type 2 diabetes; cardiovascular risk; quality indicators of care.

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Predictors of Spleen and Anemia Response to Specific Drugs in Primary Myelofibrosis

Blood ◽

10.1182/blood-2018-99-119910 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4300-4300

Author(s):

Domenico Penna ◽

Natasha Szuber ◽

Terra L. Lasho ◽

Christy Finke ◽

Rangit Reddy Vallapureddy ◽

...

Keyword(s):

Conflicts Of Interest ◽

Response Duration ◽

Primary Myelofibrosis ◽

World Health ◽

Clinical Markers ◽

Strict Adherence ◽

Predictors Of Response ◽

Very High ◽

Jak2 Inhibitors

Abstract Background: Current drug therapy in primary myelofibrosis (PMF) offers palliative value only, including alleviation of splenomegaly, constitutional symptoms and anemia; hydroxyurea (HU), JAK2 inhibitors and interferon (IFN)-α are used for splenomegaly; JAK2 inhibitors for constitutional symptoms; and immunomodulatory drugs (IMiDs), erythropoiesis-stimulating agents (ESAs) and androgens for anemia. The current study constitutes a retrospective evaluation of specific drug response in anemia or splenomegaly in PMF. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). For the purposes of the current study, conventional response criteria were modified to reflect clinical benefit assessment without strict adherence to criteria designed for clinical trials; accordingly, spleen response was evaluated only in patients with palpable splenomegaly and was defined as a minimum 50% reduction in palpable spleen size, regardless of response duration; anemia response was evaluated only in patients with hemoglobin level <10 g/dl and was defined as achieving transfusion-indpendence lasting for at least one month or an increase in hemoglobin of 2 g/dl, regardless of response duration. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all statistical calculations. Results: 432 cytogenetically- and molecularly-annotated patients with PMF were accessed in order to identify 333 patients who received first-line treatment with HU (n=97), JAK2 inhibitors (n=41), IFN-α (n=22), IMiDs (n=58), androgens (n=19), ESAs (n=54) and various other drugs (n=42), and were evaluable for response; driver mutational status was JAK2 59%, CALR type 1/like 20%, CALR type 2/like 4%, MPL 7% and triple-negative 10%; karyotype included very high risk (VHR) 6%, unfavorable 18% and favorable 76%; 60% of the patients harbored high molecular risk (HMR) mutations including ASXL1 (45%), SRSF2 (18%), U2AF1Q157 (10%), EZH2 (4%), IDH2 (4%) and IDH1 (2%). MIPSS70+ version 2.0 risk distribution was very high 17%, high 46%, intermediate 21%, low 14% and very low 2%. Overall, 249 patients were evaluable for spleen response, including 218 that were treated with the specific drugs analyzed in the current study. Anemia response was evaluated in 222 patients, including 194 (105 transfusion-dependent) that were treated with the specific drugs analyzed in the current study. Predictors of response to HU: Spleen response to HU was more likely in the presence of HMR mutations (37% vs 11%; p=0.02); however, responses were mixed and limited to presence of ASXL1 (40% vs 17%; p=0.06) or SRSF2 (47% vs 22%; p=0.1) mutations while none of 8 patients with either U2AF1Q157 or IDH2 mutations responded. None of 5 patients with VHR karyotype and only 1 (9%) of 11 patients with platelet count <100 x 109/l responded. Anemia responses to HU were infrequent. Overall response rate to HU was predicted by the absence of U2AF1Q157 mutations (64% vs 0%; p=0.007). Predictors of response to JAK2 inhibitors: Spleen response to JAK2 inhibitors was more likely in female patients (87% vs 50%; p=0.01) and in the presence of CALR type 1/like mutations (90% vs 57%; p=0.06). Anemia responses to JAK2 inhibitors were largely unpredictable. In order to further verify the aforementioned observed associations, we accessed data from a previous formal clinical trial of momelotinib (JAK2 inhibitor); among 91 evaluable patients, spleen response was higher in the presence of CALR mutations (73% vs 37%; p=0.009) and female sex (49% vs 39%, p=NS). Predictors of response to other agents: Spleen response to IFN-α was unlikely in the presence of ≥2% circulating blasts (0/6 responded) or presence of ASXL1 mutations (0/7 responded). IFN-α was ineffective for the treatment of anemia. Spleen responses to treatment with IMiDs, androgens or ESAs were unusual while anemia response to all three agents was not predicted by either genetic or clinical markers. Conclusions: Our observations, which require additional examination in a prospective setting, suggest limited value of genetic and clinical markers in predicting response to currently available drugs for PMF; this is consistent with the non-specific mechanism of action for these drugs. CALR (JAK inhibitors) and U2AF1Q157 (HU) mutations respectively predict favorable or unfavorable spleen response. Disclosures No relevant conflicts of interest to declare.

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U2AF1 Mutation Variants and Their Phenotypic and Prognostic Relevance in Primary Myelofibrosis

Blood ◽

10.1182/blood.v128.22.4248.4248 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4248-4248 ◽

Cited By ~ 1

Author(s):

Ayalew Tefferi ◽

Daniela Barraco ◽

Terra L. Lasho ◽

Christy Finke ◽

Sahrish Shah ◽

...

Keyword(s):

Univariate Analysis ◽

Multivariable Analysis ◽

Normal Karyotype ◽

Primary Myelofibrosis ◽

Older Age ◽

Severe Anemia ◽

Mutational Status ◽

Survival Effect

Abstract Background U2AF1 mutations occur in approximately 16% of patients with primary myelofibrosis (PMF) and were significantly associated with anemia, thrombocytopenia, older age, JAK2V617F, ASXL1 mutations and normal karyotype (Leukemia 2014;28:431); furthermore, U2AF1 mutations were associated with inferior survival in univariate but not multivariable analysis. In the current study, we looked for the possibility of a differential effect from U2AF1 mutation variants on these observations in PMF. Methods Study patients fulfilled the 2016 WHO criteria for the diagnosis of PMF (Blood. 2016;127:2391). Additional selection criteria included the availability of U2AF1 mutational status. Previously published methods (Leukemia 2014;28:431), including targeted next generation sequencing (Blood 2015 126:354), were used to screen for U2AF1 and other prognostically-relevant mutations. Statistical analyses considered clinical and laboratory parameters obtained at time of initial referral to the Mayo Clinic. Results Patient characteristics: U2AF1 mutational status was available for 457 patients and 72 (16%) harbored one of several mutation variants: these mutations affected residue Q157 in 44 (10%) patients, S34 in 24 (5%) and the remaining 1% displayed other variants. The 44 patients with U2AF1Q157 mutations included 23 with Q157P, 18 with Q157R and 3 with Q157-Y158insYE. The 24 patients with U2AF1S34 included 16 with S34F and 8 with S34Y. Only one patient harbored both Q157 and S34 mutations (Q157R, S34Y). Among all 457 study patients, median age was 63 years, 64% were males, dynamic international prognostic scoring system (DIPSS)-plus (JCO 2011;29:392) risk distributions were 13% low, 18% intermediate-1, 38% intermediate-2 and 32% high and driver mutation distributions were 54% JAK2, 22% CALR type 1/ type1-like, 4% CALR type 2/type 2-like, 7% MPL and 13% triple-negative. Cytogenetic studies were available in 449 patients: 39% abnormal and 10% unfavorable. All 457 patients were screened for ASXL1 mutations with 37% mutated, 450 for SRSF2 mutations with 15% mutated, 403 for SF3B1 with 8% mutated, 366 for IDH1/2 with 5% mutated and 369 for EZH2 with 4% mutated. Median follow-up was 4.4 years and during this period, 318 (70%) deaths and 53 (12%) leukemic transformations were documented. Phenotypic correlates of U2AF1 mutation variants: Because of the relatively small number of informative cases with specific mutations, we classified all patients into Q157 (n=44) and S34 (n=24) mutation variants and compared them with the 385 U2AF1 un-mutated cases. First, we confirmed our previous observations regarding the association between U2AF1 mutations in general and older age (p=0.0003), JAK2V617F (p<0.0001), ASXL1 mutations (p=0.0002), normal karyotype (p=0.03), hemoglobin <10 g/dL (p<0.0001) and platelet count <100 x 10(9)/L (p<0.0001); when the two U2AF1 mutation categories were analyzed separately, the corresponding p values for Q157 were 0.0005, 0.001, <0.0001, 0.04, <0.0001 and <0.0001 and for S34 were 0.12, 0.001, 0.41, 0.41, <0.0001 and 0.67. Phenotypic correlates of U2AF1 mutation variants: In univariate analysis, survival was adversely affected by U2AF1Q157 (p<0.0001; HR 2.2, 95% CI 1.6-3.1) but not by U2AF1S34 (p=0.8; HR 1.1, 95% CI 0.6-1.8) mutations (Figure 1a). Furthermore, the negative survival effect of U2AF1Q157 mutations was independent of anemia, thrombocytopenia, ASXL1, SRSF2, IDH1/2 and EZH2 mutations, as well as driver mutational status; multivariable analysis that included all molecular alterations identified U2AF1Q157 (HR 1.6, 95% CI 1.1-2.3), ASXL1 (HR 2.3, 95% CI 1.8-3.5), SRSF2 (HR 1.6, 95% CI 1.2-2.2) and absence of CALR type-1/like (HR 2.6, 95% CI 1.8-3.5) mutations as independent risk factors for survival. Finally, the survival effect of U2AF1Q157 mutations was independent of DIPSS-plus in patients with hemoglobin ≥10 g/dL (HR 2.6, 95% CI 1.3-5.3; p=0.007) (Figure 1c) but not in those with hemoglobin <10 g/dL (p=0.98) (Figure 1b). Conclusion Both U2AF1Q157 and U2AF1S34 mutation variants in PMF are associated with JAK2V617F and severe anemia whereas only the former is associated with ASXL1 mutations and thrombocytopenia. More importantly, U2AF1Q157, but not U2AF1S34, mutation variants in PMF are predictive of inferior survival, independent of other adverse mutations, and, in the absence of severe anemia, independent of DIPSS-plus. Disclosures No relevant conflicts of interest to declare.

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MIPSS70+ V2.0 and Revised Cytogenetics Changes Predict Outcomes of Allogeneic Transplantation with Fludarabine and Melphalan Conditioning in Patients with Myelofibrosis

Blood ◽

10.1182/blood-2018-99-112239 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1752-1752

Author(s):

Haris Ali ◽

Ibrahim Aldoss ◽

Dongyun Yang ◽

Saloomeh Mokhtari ◽

Samer K. Khaled ◽

...

Keyword(s):

High Risk ◽

Risk Group ◽

Multivariable Analysis ◽

Prognostic Models ◽

Intermediate Risk ◽

Transplant Outcomes ◽

Cytogenetic Changes ◽

The Impact ◽

Very High

Abstract Several prognostic models have been developed to predict survival outcomes and response in patients with myelofibrosis (MF). MIPSS70 prognostic system, developed by incorporation of all the key clinical characteristics, cytogenetics, and mutational factors into one system, has recently been revised to MIPSS70+ v2.0 with refinements in degrees of anemia, cytogenetics, and HMR. While allogeneic hematopoietic cell transplantation (alloHCT) is the only curative treatment for patients with MF, limited data exists on the impact of molecular markers on transplant outcomes. Here, we evaluated the transplant outcome in MF patients who uniformly received fludarabine/melphalan (FluMel) conditioning at City of Hope and assessed the impact of cytogenetics, somatic mutations on transplant outcomes based on a 72 gene next-generation sequencing (NGS) panel and MIPSS 70+ v2.0. A total of 110 consecutive MF patients (primary: n=58, secondary: n=52) without prior acute leukemic transformation, underwent alloHCT between 2004 and 2017. Median age at the time of transplant was 58.5 years (range: 38-72 years) with median interval from diagnosis of primary or secondary MF to HCT of 15.2 months (range: 1.6-332.5 months). AlloHCT donors were matched related (n=51), matched unrelated (n=44), and mismatched unrelated (n=15). Intermediate-2 and High risk by DIPSS accounted for 83 (76%) of patients at the time of transplant. Tacrolimus/Sirolimus-based GVHD prophylaxis was used in 100 (91%) patients, and 16 had splenectomy prior to alloHCT. Pre-transplant DNA sample were available for 93 patients and cytogenetics information was available for 106 patients; among which 60 had abnormal cytogenetics. Based on recently developed revised cytogenetic risk stratification on transplant outcomes, we identified 67 patients (61%) in favorable, 24 (22%) in unfavorable, and 15 (14%) in very high risk groups. Median number of 2 mutations were detected with at least one mutation in 95% (n=88) of patients. JAK2 V617F was the most common alteration noted in 54 (58.1%) patients. Other common mutations were ASXL1 (n=41, 44%), CALR type 1 (n=15, 16.1%), TET2 (n=12, 13%) SRSF2 and DNMT3A (each n=10, 11%). No detectable mutations were found in 5 (5.4%) patients. HMR genes (ASLX1, EZH2, IDH1/2, SRSF2, and U2AF1) were identified in 48 patients (52%), with 30 patients (32%) carrying one and 18 patients (19%) carrying more than 1 HMRs. With a median follow-up of 63.7 months (range: 11.9-158.5), 5 year overall survival (OS) and non-relapse mortality (NRM) were 65% (95% CI: 54-73) and 17% (95%CI: 10%-24%), respectively. Detailed transplant outcomes were previously reported (Ali et al. American Society of Hematology. Vol. 130. Atlanta, GA: Blood; 2017:199) (Figure 1a). On multivariable analysis, unfavorable and VHR cytogenetic changes had significantly shorter OS and PFS (p=0.001 and 0.008), and relapse risk (p=0.035) (Figure1b). Triple negative status (p=0.063), HMR (p=0.73), and more than 1 HMR (p=0.59) did not significantly impact survival post-HCT. (Figure1c) Similarly, CALR type 1 (p=0.42), and ASXL1 (p=0.29) mutations also did not impact survival after HCT. Only CBL mutation was significantly associated with lower OS (HR=2.64, 95% CI: 1.09-6.38, p=0.032) and lower DFS (HR=4.35, 95% CI: 1.83-10.36, p<0.001), largely attributable to increased NRM (HR=3.68, 95% CI: 1.45-9.35, p=0.004). In addition U2AF1 mutations were significantly associated with NRM (HR=3.42, 95%CI: 1.50-7.80, p=0.009). Per MIPSS70+ 2.0, patients were classified into intermediate (n=11), high (n=47), or very high-risk (VHR) (n=35). MIPSS70+ 2.0 predicted OS, DFS, and NRM. Compared to high risk group, intermediate risk patients had better OS (HR=0.291, 95% CI: 0.04-2.26) and DFS (HR=0.24, 95% CI: .03-1.91), whereas VHR group had much lower OS (HR=5.05, 95% CI: 2.39-10.74, p=<0.001) and DFS (HR=3.87, 95% CI: 1.9.0-7.88 p<0.001). (Figure 1d) Compared to high risk, intermediate risk group had lower and VHR had higher NRM (HR=0.51, 95% CI: 0.06-4.23), and (HR=3.24, 95% CI: 1.47 - 7.13, p=0.004), respectively. In summary, we are presenting one of the largest single center experiences of FluMel-based alloHCT for MF patients, demonstrating revised cytogenetic changes and MIPSS70+ v2.0 accurately predicts transplant outcomes, thus would better inform physicians and patients in discussing and decision making about alloHCT. Figure. Figure. Disclosures Ali: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Khaled:Juno: Other: Travel Funding; Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy. Salhotra:Kadmon Corporation, LLC: Consultancy. Stein:Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

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P810Novel scoring system for takotsubo syndrome

European Heart Journal ◽

10.1093/eurheartj/ehz747.0409 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

D Di Vece ◽

K Kato ◽

B Bacchi ◽

A Candreva ◽

V L Cammann ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

Scoring System ◽

Multivariable Analysis ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Takotsubo Syndrome ◽

Triggering Factors ◽

Very High ◽

Overall Mortality

Abstract Background Scoring systems for risk stratification in takotsubo syndrome (TTS) are lacking. Purpose The present study aimed to develop a score to predict the overall mortality in TTS. Methods TTS patient were enrolled from a multicenter registry. Parameters known to be associated with adverse outcomes in TTS were identified based on current literature. A multivariable analysis including these parameters was conducted and those which were found to be significantly associated with mortality were considered in the scoring system. For each patient, the prognostic score was derived by summing the respective points of each prognostic factor. Based on cut-off values, patients were categorized into four groups including low, intermediate, high, and very high risk. Results A total of 1160 patients (90.8% females; mean age 66.5±13.0 years) were included in the present study. Regarding triggering factors, an emotional trigger was identified in 32.6% of TTS patients while 32.1% had preceding physical activities, medical conditions, or procedures and 5.7% had preceding neurologic disorders. The remaining patients (29.7%) had no identifiable triggering factors. According to the results from multivariable analysis, points were assigned to each parameter that was independently associated with long-term mortality: 15 points for neurologic trigger, 10 points for the other physical trigger, 8 points for Age >70 years, 7 points for male sex, 7 points for left ventricular ejection fraction ≤45%, 6 points for diabetes mellitus, 5 points for heart rate >94 bpm on admission, 5 points for systolic blood pressure >140 mmHg on admission, and 2 points for no identifiable trigger. Based on the total points, patients were categorized into four prognostic groups: low-risk ≤15 points (43.5%), intermediate-risk 16–22 points (28.0%), high-risk 23–29 points (18.0%), and very high-risk >29 points (10.5%). Conclusion This novel score for risk stratification in TTS only requires easy-obtainable variables to clinicians even in the acute phase and could identify low to very high risk of overall mortality. Thus, it could potentially serve as a useful clinical tool to predict prognosis in patients with TTS.

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The Germline JAK2 GGCC (46/1) Haplotype and Survival Among 414 Molecularly-Annotated Patients with Primary Myelofibrosis

Blood ◽

10.1182/blood-2018-99-110046 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1761-1761

Author(s):

Ayalew Tefferi ◽

Terra L. Lasho ◽

Christy Finke ◽

Mythri Mudireddy ◽

Natasha Szuber ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Genetic Risk ◽

Triple Negative ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Version 2.0 ◽

Survival Effect

Abstract Background: We have long introduced the concept of host genetic variations in the phenotypic diversity of myeloproliferative neoplasms (MPN) (Blood 2008;111:2785). Previous studies have established an association between JAK2 mutations in myeloproliferative neoplasms (MPN) and the germline GGCC (46/1) haplotype, which constitutes a string of single nucleotide polymorphisms (SNPs) near the JAK2 gene that are inherited together on chromosome 9p (reviewed recently;Int J Mol Sci. 2018; 19: 1152). In 2010, we reported an association between shortened survival in primary myelofibrosis (PMF) and nullizygosity for the JAK2 46/1 haplotype (Leukemia 2010; 24:105), although our findings were not confirmed in another study (Leukemia 2010; 24:1533). Others have reported an association with splanchnic vein thrombosis, that was not accounted for by JAK2 mutations (Ann Hematol 2014;93:1845). In the current study, we have increased the number of informative cases to 414 (from 130 reported in 2010), in order to revisit with the phenotypic and prognostic relevance of the JAK2 46/1 haplotype in PMF. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses PMF and its leukemic transformation were confirmed by both clinical and bone marrow examinations, in line with the 2016 World Health Organization criteria (Blood. 2016;127:2391). Screening for the JAK2 46/1 haplotype included rs12343867 SNP genotyping, as previously detailed (Leukemia 2010; 24:105), and using a commercially available TaqMan SNP genotyping assay (Applied Biosystems Inc., Foster City, CA, USA). Statistical analyses considered clinical and laboratory data collected at the time of initial PMF diagnosis or Mayo Clinic referral point. Conventional statistics was used for confirming phenotypic associations and calculation of overall (OS) and leukemia-free (LFS) survival. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 414 patients with PMF (median age 63 years; 63% males) were included in the current study; among 324 evaluable cases, MIPSS70+ version 2.0 risk distribution was 18% very high risk, 41% high risk, 19% intermediate risk, 18% low risk and 4% very low risk. Driver mutation distribution was 63% JAK2, 17% type 1-like CALR, 3% type 2-like CALR, 7% MPL and 10% triple-negative. JAK2 46/1 haplotype was documented in 69% of the study patients, including 25% in homozygous and 44% in heterozygous state. Driver mutation frequency in patients homozygous/heterozygous/nullizygous for the 46/1 haplotype was 78%/60%/56% JAK2, 10%/20%/18% type 1-like CALR, 3%/2%/5% type 2-like CALR, 4%/8%/7% MPL and 6%/10%/14% triple-negative (p=0.02). The three 46/1 haplotype groups were phenotypically mostly similar, with the exception of platelet count (p=0.02) and leukocyte count (p=0.003), which were both higher with homozygous 46/1 haplotype. In univariate analysis, nullizygosity for the JAK2 46/1 haplotype was associated with inferior overall survival (HR 1.5, 95% CI 1.1-1.9; figure 1a); this survival effect was most pronounced in JAK2 mutated cases (figure 1b; p<0.001), as opposed to CALR/MPL mutated cases (figure 1c; p=0.48) or triple-negative cases (figure 1d; p=0.27). Multivariable analysis that included age and other genetic risk factors, including karyotype, driver mutational status and presence of high molecular risk mutations, such as ASXL1 and SRSF2, confirmed the independent prognostic contribution of nullizygosity for the 46/1 haplotype (p=0.02; HR 1.4, 95% CI 1.1-1.8). Nullizygosity for 46/1 also remained significant in the context of the recently unveiled genetics-based prognostic model, GIPSS (genetically-inspired prognostic scoring system) (p=0.04) (Leukemia.2018 doi: 10.1038/s41375-018-0107-z), but not in the context of MIPSS70+ version 2.0 (karyotype and mutation-enhanced international prognostic scoring system for transplant-age patients) (p=0.4). (JClinOncol.2018 doi: 10.1200/JCO.2018.78.9867). Leukemia-free survival was not affected by the 46/1 haplotype (p=0.6). Conclusions: The current study confirms the association of nullizygosity for the JAK2 GGCC (46/1) haplotype with inferior survival in PMF, primarily in JAK2-mutated cases; the observed survival effect was independent of currently acknowledged genetic risk factors, including karyotype and high molecular risk mutations. Disclosures No relevant conflicts of interest to declare.

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Driver Mutations and Prognosis in 1118 Patients with Primary Myelofibrosis

Blood ◽

10.1182/blood.v126.23.2801.2801 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2801-2801 ◽

Cited By ~ 1

Author(s):

Ayalew Tefferi ◽

Paola Guglielmelli ◽

Terra L. Lasho ◽

Yoseph Elala ◽

Tiziana Fanelli ◽

...

Keyword(s):

Research Funding ◽

Triple Negative ◽

Multivariable Analysis ◽

Primary Myelofibrosis ◽

Driver Mutations ◽

Leukemic Transformation ◽

Advisory Committees ◽

University Of Florence

Abstract Background : In primary myelofibrosis (PMF), ̴ 88% of patients harbor JAK2, CALR or MPL, with respective mutational frequencies of approximately 60%, 22% and 6%; ̴ 12% are wild type for all three driver mutations and are labelled as being "triple negative" (Blood. 2014;124:2507). It is now well-established that CALR-mutated patients with PMF display significantly better survival, compared to all the other mutational categories; in addition, preliminary data have suggested inferior survival for "triple-negative" cases (Leukemia. 2014;28:1472; Blood. 2014;124:1062) and the possibility that the favorable impact of CALR mutations might be restricted to CALR type 1 or type 1-like variants (Blood. 2014;124:2465). In the current study, we sought to clarify the prognostic impact of driver mutations, and CALR variants, on overall (OS) and leukemia-free (LFS) survival, in a two-center study involving 1118 patients. Methods: A total of 1118 patients with PMF from the Mayo Clinic (n =722) and University of Florence, Italy (n =396) were included in the current study. Study patients were selected based on availability of mutation information. PMF diagnosis was according to World Health Organization criteria (Blood. 2009;114:937). Previously published methods were used for CALR, JAK2 and MPL mutation analyses and determination of CALR variants (Blood. 2014;124:2465). Kaplan-Meier survival analysis was considered from the date of first referral for the Mayo cohort and date of diagnosis for the Florence cohort. Leukemic transformation events replaced death as the uncensored variable during LFS analysis and Cox proportional hazard regression model was used for multivariable analysis. Results : Analysis was first conducted on the Mayo cohort of 722 patients (median age 64 years; 64% males). DIPSS-plus risk distributions were 14% low, 17% intermediate-1, 37% intermediate-2 and 33% high. All patients were annotated for JAK2/CALR/MPL mutations as well as CALR variants; 477 harbored JAK2, 139 CALR and 41 MPL mutations; 65 patients were triple-negative. The 139 CALR -mutated patients included type 1/type 1-like (n =115) and type 2/type 2-like (n =24). At a median follow-up time of 3.1 years, 439 (61%) deaths and 63 (8.7%) blast transformations were documented. In univariate analysis, survival in patients with CALR type 1/type 1-like mutations was significantly longer than every other mutational category: HR (95% CI) were for triple-negative 2.7 (1.8-4.0), JAK2 2.7 (2.0-3.7), CALR type 2/type 2-like 2.3 (1.3-4.2) and MPL 1.9 (1.1-3.1) (Figure 1); these differences were sustained during multivariable analysis that included ASXL1 mutations (n =480) and DIPSS-plus, and were also apparent in the Florence cohort of 396 cases that included 251 JAK2, 53 CALR type 1/type 1-like, 21 CALR type 2/type 2-like, 50 triple-negative and 21 MPL mutated cases (Figure 2). There was no difference in survival among the Mayo cohort across mutational categories not including CALR type 1/type 1-like variants (p=0.33). Because specific driver mutations in PMF differentially cluster with age and sex, multivariable analysis including these two parameters was also performed and confirmed the significant survival advantage of CALR type 1/type 1-like over triple-negative, JAK2 and CALR type 2/type 2-like mutated cases. Based on the above information, we divided driver mutational categories into "type 1/type 1-like" (median survival 10.3 years) and "all other mutational categories" (median survival 3.9 years; p<0.01). The difference in survival between these two groups remained significant (HR 2.1, 95% CI 1.5-2.9) during multivariable analysis that included both DIPSS-plus (P<0.01) and ASXL1 mutation (HR 1.8, 95% CI 1.4-2.2). LFS was similar between these two groups (p=0.4) but it was inferior in triple-negative cases compared to CALR type 1/type 1-like variants (HR 2.8, 95% CI 1.3-6.2), MPL (HR 4.6; 95% CI 1.04-20.4) and JAK2 (HR 2.5, 95% CI 1.3-4.8) but not CALR type 2/type 2-like variants (p=0.56). There was no difference in LFS among mutational categories not including triple-negative cases (p=0.33). Conclusions : In PMF, driver mutations might be classified into two prognostically distinct categories: "favorable" (type 1/type 1-like) and "unfavorable" (all other mutational categories). In addition, triple-negative cases might be at a higher risk of leukemic transformation. Disclosures Pardanani: Stemline: Research Funding. Vannucchi: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; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Molecular Correlates of Anemia in Primary Myelofibrosis

Blood ◽

10.1182/blood.v126.23.4068.4068 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4068-4068

Author(s):

Daniela Barraco ◽

Terra L. Lasho ◽

Kebede H. Begna ◽

Naseema Gangat ◽

Christy Finke ◽

...

Keyword(s):

Triple Negative ◽

Primary Myelofibrosis ◽

Hemoglobin Level ◽

Older Age ◽

Driver Mutation ◽

World Health ◽

Driver Mutations ◽

Severe Anemia

Abstract Background : Anemia is one of the most prominent symptoms in primary myelofibrosis (PMF) and is often associated with inferior quality of life and survival. Current drugs, including JAK inhibitors, are suboptimal in the treatment of PMF-associated anemia and better information on its pathogenesis is critical for the development of more effective drugs. In the current study of JAK2/CALR/MPL annotated patients with PMF, we examined its correlation with both "driver" and "non-driver mutations", as well as cytogenetic abnormalities, in order to gain better insight into its pathogenesis. Methods: Study patients were selected based on availability of "driver" mutation information. PMF diagnosis was according to World Health Organization criteria (Blood. 2009;114:937). Previously published methods were used for CALR, JAK2 and MPL mutation analyses and determination of CALR variants (Blood. 2014;124:2465). Considering their relatively high mutational frequency in PMF, subsets of patients were also screened for ASXL1, spliceosome component (SF3B1, U2AF1, SRSF2, ZRSR2) and TET2 mutations. Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature. Statistical analyses considered clinical and laboratory parameters obtained at time of first referral at the Mayo Clinic. Results : Analysis was conducted on 722 patients (median age 64 years; 64% males). DIPSS-plus risk distribution was 14% low, 17% intermediate-1, 37% intermediate-2 and 33% high. All patients were annotated for JAK2/CALR/MPL mutations as well as CALR variants; 477 harbored JAK2, 139 CALR and 41 MPL mutations; 65 patients were triple-negative. The 139 CALR -mutated patients included type 1/type 1-like (n =115) and type 2/type 2-like (n =24). Non-driver mutations screened included ASXL1 (n =480; mutated 38%), SRSF2 (n =474; mutated 14%), U2AF1 (n =457; mutated 16%), SF3B1 (n =328; mutated 8%), ZRSR2 (n =180; mutated 11%) and TET2 (n =180; mutated 18%). Karyotype was normal in 60%, favorable in 28% and unfavorable in 12%. Anemia was defined as being absent (normal sex-adjusted hemoglobin level; n =110; 15%), mild (hemoglobin level of ≥10 g/dL but below sex-adjusted normal value; n =263; 36%), moderate (hemoglobin level below 10 g/dL but not transfusion-dependent; n =108; 15%) and severe (transfusion-dependent anemia; n =241; 33%). Presence of at least mild anemia was associated with abnormal karyotype (p=0.006) with no difference between favorable and unfavorable abnormalities, U2AF1 (p=0.002), TET2 (p=0.02) and ASXL1 (p=0.04) mutations; other significant associations included male sex and older age. Presence of moderate to severe anemia was associated with U2AF1 (p<0.0001), SRSF2 (p=0.007) and driver mutations other than CALR type 1/type 1-like (p<0.0001). Presence of severe anemia was associated with U2AF1 (p<0.0001), SRSF2 (p=0.003) and non-CALR driver mutations (17% incidence in both types of CALR variants vs 51% in triple negative, 35% JAK2, 39% MPL mutated cases; p<0.0001). An association with older age but not gender was also noted for both moderate to severe and severe anemia (p<0.0001). During multivariable analysis, independent associations with moderate to severe anemia were confirmed for U2AF1 (p<0.0001), SRSF2 (p=0.007) and age (p=0.0001), but not driver mutation profile (p=0.30). A similar analysis for severe anemia also identified U2AF1, SRSF2 and age as being significantly relevant. Conclusions : The current study identifies older age and the spliceosomal mutations U2AF1 and SRSF2 as having strong and independent association with moderate to severe anemia in PMF. Targeting the spliceosome machinery or its mutant components offers a potential approach in the treatment of PMF-associated anemia. Disclosures Pardanani: Stemline: Research Funding.

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MIPSS70: Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients With Primary Myelofibrosis

Journal of Clinical Oncology ◽

10.1200/jco.2017.76.4886 ◽

2018 ◽

Vol 36 (4) ◽

pp. 310-318 ◽

Cited By ~ 136

Author(s):

Paola Guglielmelli ◽

Terra L. Lasho ◽

Giada Rotunno ◽

Mythri Mudireddy ◽

Carmela Mannarelli ◽

...

Keyword(s):

High Risk ◽

Prognostic Score ◽

Multivariable Analysis ◽

Significant Risk ◽

Primary Myelofibrosis ◽

Low Risk ◽

Prognostic Models ◽

Intermediate Risk ◽

Mutation Data ◽

Risk Categories

Purpose To develop a prognostic system for transplantation-age patients with primary myelofibrosis (PMF) that integrates clinical, cytogenetic, and mutation data. Patients and Methods The study included 805 patients with PMF age ≤ 70 years recruited from multiple Italian centers and the Mayo Clinic (Rochester, MN), forming two independent learning and validation cohorts. A Cox multivariable model was used to select from among a list of 22 variables those that were predictive of overall survival (OS). Integrated clinical and genetic prognostic models with (MIPSS70-plus) or without (MIPSS70) cytogenetic information were developed. Results Multivariable analysis identified the following as significant risk factors for OS: hemoglobin < 100 g/L, leukocytes > 25 × 109/L, platelets < 100 × 109/L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms, absence of CALR type-1 mutation, presence of high–molecular risk mutation (ie, ASXL1, EZH2, SRSF2, IDH1/ 2), and presence of two or more high–molecular risk mutations. By assigning hazard ratio (HR)–weighted points to these variables, three risk categories were delineated for the MIPSS70 model; 5-year OS was 95% in low-risk, 70% in intermediate-risk, and 29% in high-risk categories, corresponding to median OS of 27.7 years (95% CI, 22 to 34 years), 7.1 years (95% CI, 6.2 to 8.1 years), and 2.3 years (95% CI, 1.9 to 2.7 years), respectively. In the MIPSS70-plus model, which included cytogenetic information, four risk categories were delineated, with 5-year OS of 91% in low-risk, 66% in intermediate-risk (HR, 3.2; 95% CI, 1.9 to 5.2), 42% in high-risk (HR, 6.4; 95% CI, 4.1 to 10.0), and 7% very high–risk categories (HR, 17.0; 95% CI, 9.8 to 29.2). Both models remained effective after inclusion of older patients in the analysis. Conclusion MIPSS70 and MIPSS70-plus provide complementary systems of risk stratification for transplantation-age patients with PMF and integrate prognostically relevant clinical, cytogenetic, and mutation data.

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Re-Evaluation of the Efficacy of Azacitidine (AZA) In Patients From the AZA-001 Study with Higher-Risk Myelodysplastic Syndromes (MDS) Classified by WHO Criteria and WPSS Risk

Blood ◽

10.1182/blood.v116.21.4031.4031 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4031-4031

Author(s):

Norbert Gattermann ◽

Guillermo F. Sanz ◽

Aristoteles Giagounidis ◽

John F Seymour ◽

Pierre Fenaux ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Scoring System ◽

Research Funding ◽

Who Classification ◽

Hematologic Malignancies ◽

World Health ◽

International Prognostic Scoring System ◽

Advisory Committees ◽

Very High

Abstract Abstract 4031 Introduction: Because MDS are clinically heterogenous, classification and prognostic tools are essential to guide disease management decisions. The international, multicenter, phase 3 trial (AZA-001) enrolled 358 pts with higher-risk MDS as defined by French-American-British (FAB) criteria and International Prognostic Scoring System (IPSS) (Lancet Oncol 2009;10:223). The recent World Health Organization (WHO) classification of hematologic malignancies criteria (JCO 1999;17:3835) and the WHO Classification–Based Prognostic Scoring System (WPSS) (JCO 2007;25:3503) are increasingly being used in clinical practice. Aim: To evaluate whether overall survival (OS), hematologic improvement (HI), and transfusion independence (TI) in the subgroup of patients (pts) from AZA-001 who met WHO classification and WPSS criteria for higher-risk MDS are consistent with overall findings from AZA-001. Methods: According to protocol, AZA-001 enrolled pts with FAB-defined RAEB, RAEB-t, or CMML with more than 10% blasts, and IPSS Int-2 or High risk (Lancet Oncol 2009;10:223). Pts were randomized to AZA 75 mg/m2/d SC × 7d q 28d (n=179) or to a conventional care regimen (CCR; n=179), which included supportive care, low-dose ara-C, or intensive chemotherapy. This analysis included pts with WHO-defined RAEB-1 or RAEB-2 (pts with WHO-AML, CMML-1, CMML-2, or indeterminate classification were excluded) who had baseline WPSS risk of intermediate, high, or very high. Kaplan-Meier methods were used to estimate median OS and 95% CIs. HI and TI were defined by IWG-2000 criteria and results for AZA vs CCR were compared by Fisher's exact test. P values can only be used as a reference because these analyses were performed post hoc on a selected pt population that met WPSS criteria (40% of all AZA-001 pts did not meet these criteria and were excluded from analyses). Results: Overall, 215 pts in AZA-001 (106 AZA, 109 CCR) met a WHO classification for higher-risk MDS (RAEB-1: 13 AZA, 16 CCR; RAEB-2: 93 AZA, 93 CCR). Baseline WPSS risk was intermediate (1 AZA pt), high (66 AZA, 59 CCR), or very high (39 AZA, 50 CCR), with proportionately more CCR pts at very high risk than AZA pts (46% vs 37%, respectively). Median age was 68 years (range 42 – 83) in the AZA group and 70 years (range 38 – 88) in the CCR group. At baseline, 63% of both the AZA and CCR cohorts were RBC transfusion-dependent and 19% and 15%, respectively, were platelet transfusion dependent. Median OS was 26.3 months (95%CI: 17.2, not reached) with AZA vs 13.9 months (95%CI: 8.9, 18.8) with CCR, (log-rank p=0.016) (Figure). Rates of any HI and major erythroid and platelet lineage responses were better with AZA vs CCR (Table). RBC TI was also more frequent with AZA than with CCR (Table), but the platelet TI rate did not differ between treatment groups. Conclusion: These results are highly consistent with reported OS and hematological response outcomes for the entire AZA-001 population of higher-risk MDS pts classified by FAB and IPSS risk. The efficacy of AZA is consistently superior to CCR in pts with higher-risk MDS, irrespective of the classification and prognostic criteria used to describe them. Disclosures: Gattermann: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Giagounidis:Celgene: Consultancy, Honoraria. Seymour:Celgene: Honoraria, Speakers Bureau. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria; J&J: Honoraria. Santini:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Ramos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment. Silverman:Celgene: Honoraria.

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