Cytogenetics in Essential Thrombocythemia: Phenotype and Molecular Correlates and Prognostic Relevance in 818 Informative Cases

Abstract Background Cytogenetic abnormalities at diagnosis are relatively uncommon in essential thrombocythemia (ET). In the current study of 818 consecutive patients with ET who were fully annotated for karyotype, we describe the spectrum and prevalence of cytogenetic abnormalities at diagnosis, followed by a comprehensive assessment of phenotypic and molecular correlates and prognostic relevance. Methods The study cohort consisted of 818 consecutive patients with ET that were diagnosed according to the World health Organization 2016 criteria and underwent evaluation between 1967-2021. In order to minimize the inadvertent inclusion of patients with masked polycythemia vera, JAK2 mutated cases with hemoglobin (Hb) level >16 g/dL in women and 16.5 g/dL in men were excluded; similarly, cases with anemia defined by sex adjusted Hb level of <11 g/dL in women and <12.5 g/dL in men were also excluded, in order to avoid inadvertent inclusion of patients with prefibrotic myelofibrosis. Cytogenetic studies were performed either at or within one year of diagnosis and reported according to the International System for Human Cytogenetic Nomenclature. Disease status and survival information was updated in May 2021. JMP Pro 16.0.0 software package, SAS Institute, Cary, NC was utilized for all analyses. Results Prevalence and spectrum of cytogenetic abnormalities Karyotype was normal in 755 patients (92%), showed loss of Y chromosome (-Y) in 16 (2%), and showed abnormalities other than -Y in 47 (5.7%); most common abnormalities included del(20q) (n=10, 21%), trisomy 9 (n=8, 17%), trisomy 8 (n=2, 4%), del(5q) (n=2, 4%), and del(3p) (n=2, 4%). Other sole cytogenetic abnormalities were identified in 18 (38%) patients. Phenotypic and molecular correlates Abnormal karyotype, other than -Y, in comparison with normal karyotype was associated with older age (median age; 63 vs 58 years, p=0.02), lower hemoglobin level (p=0.003), and a higher incidence of arterial thrombosis prior to/at diagnosis (25% vs 13%; p=0.03). 603 patients were annotated for driver mutations; abnormal/normal/-Y frequencies were 78%/60%/71% for JAK2, 22%/26%/14% CALR, 0%/3%/0% MPL and 0%/10% /14% triple negative (p=0.31). NGS information was available in 226 patients and showed absence of ASXL1 mutation in all patients with abnormal karyotype vs 8/211 (4%) with normal karyotype vs 2/4 (50%) with -Y (p<0.0001). Disease transformation and overall-survival. At a median follow-up of 9.6 years (range; 0.01-49.4 years), a total of 96 patients (12%) underwent fibrotic transformation: 6 (13%) with abnormal karyotype, 89 (12%) with normal karyotype and 1 (6%) with -Y (p=0.77). Leukemic transformation rates were also similar with respective frequencies of 4%, 3% and 0% (p=0.71). Abnormal karyotype and -Y were associated with inferior survival with median of 12 years (range; 0.1-34) and 9 years (range; 0.01- 19.9), respectively, compared to 21 years (range; 0.01-49.4) for normal karyotype (p<0.0001) (Figure). In univariate analysis, risk factors for overall survival included abnormal karyotype (p=0.001), - Y (p=0.004), age >60 years (p<0.0001), leukocytosis >11 x10 9/L (p<0.0001), male gender (p=0.0003), and history of thrombosis (p=0.001). During multivariable analysis, abnormal karyotype other than -Y (p=0.003), age >60 years (p<0.0001), leukocytosis >11 x10 9/L (p=0.001), and male gender (p=0.01) remained significant. Additional analysis suggested individual prognostic impact for del(20q) (p=0.04) and also for trisomy 9 (p=0.09) and other abnormalities (p=0.07), with borderline significance. Conclusion The current study confirms the association of abnormal karyotype in ET with older age, lower hemoglobin level, and history of arterial thrombosis, and its mutual exclusivity with ASXL1 mutations. Our observation regarding the independent adverse impact of abnormal karyotype other than -Y, on overall survival, in the absence of association with fibrotic or leukemic transformation, requires clarification from additional studies, which should also investigate the effect of specific abnormalities. Figure 1 Figure 1. Disclosures Szuber: Novartis: Honoraria.

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The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication

Blood ◽

10.1182/blood-2008-12-194704 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5090-5093 ◽

Cited By ~ 58

Author(s):

Aline Renneville ◽

Nicolas Boissel ◽

Nathalie Gachard ◽

Dina Naguib ◽

Christian Bastard ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Confidence Interval ◽

Myeloid Leukemia ◽

Normal Karyotype ◽

Favorable Outcome ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities ◽

The Impact ◽

Acute Myeloid

AbstractMutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), but mainly in those with a normal karyotype. Here, we analyzed the impact of associated cytogenetic abnormalities or bad-prognosis fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 53 patients with CEBPA+ de novo AML treated in the Acute Leukemia French Association trials. We found that only those with a normal karyotype and no FLT3-ITD displayed the expected favorable outcome. In this context, relapse-free, disease-free, and overall survival were significantly longer than in corresponding patients without the CEBPA mutation (P = .035, .016, and .047, respectively). This was not observed in the context of an abnormal karyotype or associated FLT3-ITD. Furthermore, after adjustment on age, trial, and mutation type, these features were independently predictive of shorter overall survival in the subset of patients with CEBPA+ AML (multivariate hazard ratio = 2.7; 95% confidence interval, 1.08-6.7; and 2.9; 95% confidence interval, 1.01-8.2; with P = .034 and .05, for abnormal karyotype and FLT3-ITD, respectively).

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Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes

Blood ◽

10.1182/blood.v67.6.1765.1765 ◽

1986 ◽

Vol 67 (6) ◽

pp. 1765-1772 ◽

Cited By ~ 193

Author(s):

RH Jacobs ◽

MA Cornbleet ◽

JW Vardiman ◽

RA Larson ◽

MM Le Beau ◽

...

Keyword(s):

Median Survival ◽

Myelodysplastic Syndromes ◽

Chromosomal Abnormalities ◽

Bone Marrow Cells ◽

Normal Karyotype ◽

Refractory Anemia ◽

Survival Times ◽

Trisomy 8 ◽

Leukemic Transformation ◽

Abnormal Karyotype

Abstract Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.

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Frequency of Clonal Evolution by FISH in Untreated, Early Stage Patients with CLL: A Prospective, Longitudinal Study with Long Clinical Follow-Up.

Blood ◽

10.1182/blood.v106.11.2098.2098 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2098-2098 ◽

Cited By ~ 3

Author(s):

Tait D. Shanafelt ◽

Stephanie Fink ◽

Tom E. Witzig ◽

Sarah F. Paternoster ◽

Stephanie Smoley ◽

...

Keyword(s):

Overall Survival ◽

Median Time ◽

Early Stage ◽

Clonal Evolution ◽

Normal Karyotype ◽

Risk Category ◽

Fish Analysis ◽

Cytogenetic Abnormalities ◽

Study Participants

Abstract Background: Using fluorescent in-situ hybridization (FISH), a number of investigators have identified specific cytogenetic abnormalities that identify CLL patients with a more aggressive (17p-, 11q-) or indolent (13q-) disease course. Some have suggested patients who initially have a normal karyotype may acquire new chromosome abnormalities during the course of their disease. Since patients with specific cytogenetic abnormalities (17p-, 11q-) are less likely to respond to purine nucleoside analogues, such clonal evolution has potential implications for treatment as well as prognosis. No study has prospectively investigated the frequency of clonal evolution in a cohort of patients with newly diagnosed untreated CLL. Methods: Between 1994 and 2000, we enrolled 167 patients with previously untreated CLL seen at Mayo Clinic in a prospective trial evaluating the prognostic importance of cytogenetic abnormalities and clonal evolution detected by FISH. All patients provided a baseline blood specimen for FISH testing and follow-up specimens over the following 24 months. Other research samples from later timepoints were tested where available. Study participants were contacted by mail in 2004 to update vital and treatment status. Of 83 living responders, 70 (84%) indicated they would be willing to provide an additional follow-up sample for cytogenetic analysis of whom 48 have returned a sample to date. Results of clinical FISH testing during the follow-up interval were also abstracted. FISH was performed on interphase nuclei from blood as we have previously described (BJH 121:287). Results: Median age at diagnosis was 64. Median time from diagnosis to study enrollment was 3.3 months. 94% of patients had early stage disease at enrollment (88 Rai 0; 48 Rai I, 18 Rai II, 2 Rai III; 8 Rai IV). Median follow-up time from diagnosis for all 164 eligible study participants was 8.5 years (range: 0.33–22.9 yrs). As of last follow-up, 48% of patients have received treatment and 57 (35%) have died. 75% of patients had chromosome abnormalities on FISH testing at baseline. The frequency of individual cytogenetic abnormalities on baseline FISH analysis along with overall survival by hierarchical FISH risk category are shown in Table I. 106 patients had sequential samples for FISH analysis at least 2 years apart, 61 had samples at least 5 years apart, and 22 had samples at least 10 years apart. 15 patients had evidence of clonal evolution during follow up as evidenced by a new FISH anomaly not present on the baseline specimen. No clonal evolution was observed in the first 2 years of follow-up (n=106), however of 61 patients with samples at least 5 years apart, 14 (23%) had evidence of clonal evolution. Median time for development of a new cytogenetic abnormality among these patients was 9.3 years. Conclusions: Clonal evolution occurs during the course of disease for approximately 25% of patients with early stage CLL. Clonal evolution appears to occur at low frequency during the first 2 years of follow-up but increases in frequency after 5 years. This finding has potentially significant implications for prognosis and treatment of patients with CLL. FISH Risk Category* N (Baseline) Median Overall Survival (Years) * Difference between groups significant p=0.0038 13q- x 1 37 14.4 13q- x2 35 17 Normal Karyotype 40 13.2 12+ 24 11.1 11q- 12 8.6 17p- 10 10.5 6q- 2 4.1 Other 2 Not reached

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Risk Factors for Thrombosis Among 1,545 Patients with Polycythemia Vera: An International Study.

Blood ◽

10.1182/blood.v120.21.2849.2849 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2849-2849

Author(s):

Guido Finazzi ◽

Elisa Rumi ◽

Alessandro M. Vannucchi ◽

Maria Luigia Randi ◽

Ilaria Nichele ◽

...

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Board Of Directors ◽

Arterial Thrombosis ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Abnormal Karyotype ◽

Advisory Committees ◽

Free Survival ◽

History Of

Abstract Abstract 2849 Background We have previously reported on the natural history of polycythemia vera (PV), focusing primarily on overall and leukemia-free survival (ASH Annual Meeting Abstracts. 2011;118(21):277-). In the current study, we present, on behalf of the International Working Group for Myeloproliferative neoplasms Resarch and Treatment (IWG-MRT), our analysis regarding risk factors for thrombosis. Methods Under the auspices of IWG-MRT, seven international centers of excellence for myeloproliferative neoplasms participated in the current study. The two principle investigators (AT and TB) reviewed all the cases and selected 1,545 patients who met the 2008 WHO criteria for PV, were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting Features Median age was 61 years (range, 18–95; 51% females). Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) patients and 114 (7.4%) patients, respectively. Major hemorrhage hemorrhage before or at diagnosis was documented in 17 (4.5%) patients. Other features at diagnosis included pruritus (36%), microvascular disturbances (28.5%), palpable splenomegaly (36%), abnormal karyotype (12%), leukoerythroblastosis (6%), increased LDH (50%), thrombocytosis (53%), extreme thrombocytosis (platelets >1 million mm3; 4%) leukocytosis (49%), JAK2 V617F (95%), other JAK2 mutations (3%), subnormal serum erythropoietin (Epo) level (81%), and endogenous erythroid colonies (EEC; 73%). History of hypertension (46%), hyperlipidemia (18.3%), diabetes (8.4%), and tobacco use (16%) was also obtained. Results II: Clinical Course To date, 347 (23%) deaths, 50 (3%) leukemic progressions, and 138 (9%) fibrotic transformations have been recorded. Overall, cytoreductive treatment was not used in 416 (27%) patients and the remaining were exposed to different agents based on physician discretion. Post-diagnosis arterial or venous thrombosis occurred in 184 (12%) and 137 (9%) patients, respectively. Results III: Risk Factors for thrombosis Arterial and venous thrombosis-free survival, from time of diagnosis, were separately analyzed using the occurrence of thrombosis as the endpoint (uncensored variable) and last follow-up or death before thrombosis as the censored variable. In univariate analysis, the following were significantly associated with post-diagnosis arterial thrombosis: advanced age, leukocyte count, presence of a leukoerythroblastic smear (LES), history of hypertension and history of arterial thrombosis before or at diagnosis; multivariable analysis using all these five parameters identified arterial thrombosis history (RR 2.5, 95% CI 1.6–4.0; p<0.0001), LES (RR 2.3, 95% CI 1.3–4.2; p=0.005) and history of hypertension (RR 1.6, 95% CI 1.1–2.4; p=0.02) as independent predictors of post-diagnosis arterial thrombosis. Only two parameters predicted post-diagnosis venous thrombosis, in univariate analysis, and both remained significant during multivariable analysis: abnormal karyotype (RR 3.1, 95% CI 1.7–5.4; p=0.0001) and history of venous thrombosis (RR 2.4, 95% CI 1.2–4.9). Of note, the type of JAK2 mutation or presence of either subnormal Epo or EEC did not influence either arterial or venous thrombosis. Results IV: Risk Stratification for arterial and venous thrombosis The figures below illustrated arterial or venous thrombosis-free survival of patients stratified by the absence of all risk factors or presence of one or ≥2 risk factors. For arterial thrombosis, the presence of ≥2 risk factors clearly delineated a high risk group (RR 3.1, 95% CI 1.9–5.0) whereas the presence of one (RR 2.4, 95% CI 1.4–4.2) or two risk factors (RR 10.1, 95% CI 3.6–28.2) for venous thrombosis delineated an intermediate and high risk group, respectively. Conclusions: History of arterial thrombosis and venous thrombosis are key risk factors, respectively, for recurrent arterial and venous thrombosis in PV. In addition, abnormal karyotype is a strong independent risk factor for venous thrombosis and the presence of leukoerythroblastosis and hypertension, for arterial thrombosis. This information allows for a simple and practical risk stratification and raises interesting pathogenetic implications that require further clarification. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees. Gisslinger:Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Molecular and Prognostic Correlates of Cytogenetic Abnormalities in Chronic Myelomonocytic Leukemia: A Mayo Clinic-French Consortium Study

Blood ◽

10.1182/blood.v124.21.412.412 ◽

2014 ◽

Vol 124 (21) ◽

pp. 412-412

Author(s):

Emnet A Wassie ◽

Raphael Itzykson ◽

Terra L Lasho ◽

Olivier Kosmider ◽

Christy Finke ◽

...

Keyword(s):

Mayo Clinic ◽

Risk Model ◽

Normal Karyotype ◽

Chronic Myelomonocytic Leukemia ◽

Older Age ◽

World Health ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities ◽

Myelomonocytic Leukemia ◽

Monosomal Karyotype

Abstract Background: The prognostic significance of cytogenetic abnormalities in chronic myelomonocytic leukemia (CMML) was recently revisited (AJH, 89; 813-818, 2014 and Blood April, 2013). Using a large Mayo Clinic-French Consortium database, we analyzed the molecular and prognostic correlates of cytogenetic abnormalities in CMML. Methods: CMML diagnosis was according to World Health Organization criteria. 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 cytogenetic studies. Results: Spectrum and frequency of cytogenetic abnormalities: A total of 409 patients participated in this study including, 268 (66%) from the Mayo Clinic and 141 (34%) from the French CMML consortium. Of these, 396 (97%) had ≥20 metaphases and 13 (3%) had ten to 19, analyzed. One hundred and fifteen (30%) patients displayed an abnormal karyotype, including 82 (71%) sole, 20 (17%) two and 13 (11%) complex abnormalities. The most common abnormalities were; +8 (23%), -Y (20%), -7/7q- (14%), 20q- (8%), +21 (8%) and der (3q) (8%). Other cytogenetic abnormalities included 5q-, 12p-, 13q- and i(17q), present at a much lower frequency (0.9-4%). Phenotypic correlates: Abnormal vs normal karyotype was associated with older age (p=0.03), hemoglobin<10 g/dL (p=0.0009), white blood cell count (WBC) >15 x 109/L (p=0.02), absolute neutrophil count (ANC) >10 x 109/L (p=0.03), absolute lymphocyte count (ALC) >2.5 x109/L ( p=0.04), peripheral blood (PB) blast ≥1% (p<0.0001), bone marrow (BM) blast ≥10% (p<0.0001) and circulating immature myeloid cells (IMC) (p=0.0003). +8 (p=0.01), +21 (p=0.03) and der (3q) (p=0.03) were associated with hemoglobin <10 g/dL. -Y was associated with older age (p=0.04), lower PB (p=0.04) and BM (p=0.02) blasts. -7/7q was associated with leukocytosis (p=0.005), neutrophilia (p=0.04), and higher PB blasts (p=0.004). 20q- was associated with thrombocytopenia (p=0.04). Molecular correlates: ASXL1 mutations were associated with abnormal karyotype (p=0.04) and SRSF2 with normal karyotype (p=0.02). In comparison to other abnormal karyotypes, the incidence of ASXL1 mutations was lower in –Y (P=0.04) and der(3q) (p=0.03). U2AF1 mutations were associated with monosomal karyotype (p=0.03) and SF3B1 with der (3q) (p<0.0001). Prognostic relevance : Median follow-up was 1.8 years with 244 (60%) deaths and 79 leukemic transformations (19%). A step-wise survival analysis resulted in three distinct cytogenetic risk categories (Figure 1): high (complex and monosomal karyotype), intermediate (all abnormalities not in high or low risk) and low (normal, sole -Y and sole der (3q)); the corresponding median survivals were 0.2 (HR 8.1, 95% CI 4.6-14.2), 1.7 (HR 1.7, 95% CI 1.2-2.3). In multivariable analysis, the particular cytogenetic risk stratification remained significant in the context of Mayo molecular model (p<0.0001), MDAPS (p<0.0001), and the GFM risk model (P<0.0001). The Mayo-French cytogenetic risk model was also effective in predicting leukemic transformation with HR of 10.9 (95% CI 4.2-27.8) for high and 2.2 (95% CI 1.3-3.7) for intermediate risk groups. Conclusion: Cytogenetic abnormalities are seen in approximately 30% of patients with CMML and display significant associations with certain molecular and phenotypic characteristics. We describe a novel cytogenetic prognostic model for both over-all and leukemia free survival in CMML. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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The Impact of 20q Deletion on Clinical Presentation, Treatment Response and Survival in Patients with Acute Myeloid Leukemia (AML): The University of Texas MD Anderson Cancer Center Experience

Blood ◽

10.1182/blood.v126.23.1369.1369 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1369-1369

Author(s):

Jad Chahoud ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Koji Sasaki ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Overall Survival ◽

Treatment Response ◽

Research Funding ◽

Objective Response ◽

Normal Karyotype ◽

Prognostic Indicators ◽

Cancer Center ◽

Cytogenetic Abnormalities ◽

Md Anderson ◽

The Impact

Abstract Background: Karyotype classification is one of the strongest independent prognostic indicators in AML. The majority of recurring chromosomal aberrations are associated with an individual prognosis, other less frequent like the Del (20q), have been minimally evaluated and classified as intermediate risk in AML. Multiple studies established isolated 20q deletion as a good prognostic marker in MDS, with lower AML transformation rates and longer median overall survival (OS) in comparison with complex 20q deletion. Objective: The aim of this study is to determine the frequency and the impact on outcome of 20q deletion alone or with additional cytogenetic abnormalities in adult patients with AML. Patients and Methods: AML patients with chromosome 20 abnormalities were identified between 2000 and 2012 through the MD Anderson Cancer Center AML database (n=1741). Collected data included baseline demographics, number and type of additional cytogenetic abnormalities, disease characteristics, treatment and outcome. OS was defined as time from hematological diagnosis to death or last follow-up and relapse-free survival (RFS) was measured from time of hematological response to relapse. The Kaplan-Meier product limit method was used to estimate overall survival and the log-rank tests were employed for statistical comparisons between the OS curves. Results: From a total of 1741 adult AML patients, we identified 35 with Del (20q), representing 2% of our cohort. The distribution of cytogenetic abnormalities was as follows: isolated Del (20q) in 5 (14%), +8 in 3 (9%), +8 complex in 2 (6%), -5 complex in 8 (23%), -7 complex in 5 (14%), -7 not complex in 1 (3%), -5 and -7 complex in 6 (17%), other complex in 1 (3%), and other not complex in 4 (11%). Patients with Del (20q) were older (p=0.04), with lower bone marrow blast numbers (p<0.001), and lower WBC (p=0.001) compared to patients without Del (20q) (Table 1). Median RFS and OS for patients with Del (20q) were 16.8 and 7.5 months (mos), respectively. Objective response rates were 43% and 65% for patients with and without Del (20q), respectively (p=0.04) and the CR rates were 36% and 58%, respectively (p=0.01). Significant benefit was observed for OS in patients without Del (20q) (13.5 mos; 95% CI, 13.45-13.49; p=0.011), but not in RFS (19.52 mos; 95% CI, 19.48-19.55; p=0.376) in comparison with patients with Del (20q) (16.8 mos; 95% CI, 16.41-17.23; and 7.5 mos; 95% CI, 7.26-7.73). Patients with Del (20q) were compared to the remaining patients with leukemia classified as unfavorable cytogenetic status; the median survival for Del (20q) patients was similar by OS (OS 6.9 mos, 95% CI, 6.82-6.91). On the other hand, patients with Del (20q) had a significantly decreased overall survival (7.5 mos; 95% CI, 7.26-7.73, p=0.002) in comparison to patients with normal karyotype (17.7 mos; 95% CI, 17.64-17.71). No difference in survival was observed between patients with isolated Del (20q) and those with additional cytogenetic abnormalities: the median OS were 5 and 7.5 mos, respectively (p=0.964) (Figure 1). Conclusion: Our data demonstrated that Del (20q) occurs in 2% of previously untreated AML patients, with around 63% of these patients showing complex karyotype. Patients with Del (20q) have lower response rate and worse outcome, similar to patients with unfavorable cytogenetics. Table 1. Clinical descriptors, hematologic parameters and outcome of each set of patients Del 20qin Karyotype All othersnon-Del 20q P N = 35 N = 1706 Age (y), median (range) 65 (35-83) 61 (12-89) 0.04 Baseline hematologic data median (range) WBC × 109/L 2.7 (0.7-32.6) 5.8 (0.3-433) 0.001 Hemoglobin, g/dL 8.1 (5.6-14.2) 8.7 (2-93.3) 0.29 Platelet count, × 109/L 40 (7-254) 49 (2-676) 0.21 Neutrophil 29 (4-88) 16 (0-94) <0.001 PB blasts 9 (0-50) 16 (0-99) 0.02 BM blasts 30 (7-98) 47 (0-99) <0.001 Treatment Response and Survival Prior Chemo/XRT 7 301 0.72 CR 13 (37%) 990 (58%) 0.01 CRp 3 (9%) 88 (5%) 0.03 Cri 0 18 (1%) - RFS median, mo (95% CI) 17.22 (16.81-17.62) 25.59 (25.56-25-62) 0.55 OS median, mo (95% CI) 7.49 (7.26-7.73) 13.47 (13.45-13.49) 0.01 Disclosures Chahoud: American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. Off Label Use: Inotuzumab.. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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Eradication and Reduction of the Abnormal Chromosome 7 Clone with Azacitidine (AZA C) Is Achievable for One-Third of Patients (pts) with Myelodysplastic Syndrome (MDS).

Blood ◽

10.1182/blood.v110.11.5181.5181 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5181-5181

Author(s):

Vesna Najfeld ◽

Angela Scalise ◽

Rosalie Odchimar-Reissig ◽

Lewis R. Silverman

Keyword(s):

Longitudinal Study ◽

Stable Disease ◽

Normal Karyotype ◽

Cytogenetic Response ◽

Abnormal Chromosome ◽

Chromosome 7 ◽

Abnormal Karyotype ◽

Monosomy 7 ◽

Cytogenetic Abnormalities ◽

Results Of Treatment

Abstract The two most frequent cytogenetic abnormalities in pts with MDS involve rearrangements of chromosomes 5 and 7. Monosomy 7 or deletion 7q, alone or in a complex karyotypes are poor-risk abnormalities and associated with a low response rate to conventional therapies. As a part of our comprehensive longitudinal study of 220 patients treated with AZA C, we asked the question whether pts with −7/del(7q) alone or as a part of the complex clone, may achieve hematological and/or cytogenetic response. A minimum of three follow-up cytogenetic and FISH analyses were required as an inclusion criterion. A normal karyotype was observed in 129 of 229 pts (56%) and 100 pts (44%) had an abnormal karyotype at baseline. Among the 100 pts with an abnormal karyotype 29 pts (29%) had chromosome 7 abnormalities prior to the AZA C treatment. In an additional 12 pts chromosome 7 abnormalities developed during the course of disease and AZA C therapy (range 4 months to 5 years). Response of the abnormal chromosome 7 clone to AZA C therapy was observed in 3 patterns: pts who had −7/del(7q) present at baseline without any further cytogenetic change during the AZA C treatment (20 pts; 69%). Eight of these pts had hematological improvement (HI); Pts who had either reduction or elimination (complete cytogenetic response=CCR) of the abnormal chromosome 7 clone as a results of treatment (9 pts, 31%). Four of 29 pts (14%) had a reduction in the size of the abnormal clone from 100% to a mean of 23% (range 8%–50%) as judged by conventional cytogenetics. The median time to achieve reduction was 6 months (range 2 to 9 months) with median duration of 10.5 months (range 6 to 24 months) during maintenance therapy with AZA C. CCR was observed in 5 of 29 pts (17%) and occurred within a mean of 4.2 months (range 3–6 months). Repeated cytogenetic studies showed a normal karyotype and the CCR lasted a mean of 5.2 months (range 3–9 months) during therapy. FISH studies showed 2–5% cells with −7/del(7q) during the CCR. Four of the 5 pts had HI and one pt had CR. These patients relapsed with the diagnostic −7/del(7q) clone without additional cytogenetic abnormalities. 3) Of the 12 pts who developed −7/del(7q) while on Aza C therapy, 4 pts had a normal karyotype at baseline and developed −7/del(7q) after a mean of 16 months (range 6–39 months) therapy. One had PR and 3 pts had a stable disease. The other 8 pts were cytogenetically abnormal at baseline and developed −7/del(7q) as a subclonal evolution during therapy in 4 pts (range 4 months to 5 years) and following disease progression in 4 pts. Six pts had HI and two had a stable disease. In conclusion, our longitudinal study allowed us to delineate 3 categories of AZA C response to abnormal chromosome 7 clone: 31% had cytogenetic response: 17% complete and 14% major and 69% had no change in the abnormal −7/del(7q) clone. In additional 5% (12/229) pts, −7/del(7q) emerged either as a new abnormal clone or as a subclonal evolution during therapy or at progression. AZA C-based therapy can either stabilize or reduce/eradicate the abnormal chromosome 7 clone as determined by both, cytogenetics and FISH.

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A Compendium of Cytogenetic Abnormalities in Myelofibrosis: Molecular and Phenotypic Correlates in 826 Patients

Blood ◽

10.1182/blood.v124.21.403.403 ◽

2014 ◽

Vol 124 (21) ◽

pp. 403-403

Author(s):

Emnet A Wassie ◽

Christy Finke ◽

Naseema Gangat ◽

Terra L Lasho ◽

Animesh Pardanani ◽

...

Keyword(s):

Conflicts Of Interest ◽

International System ◽

Normal Karyotype ◽

Primary Myelofibrosis ◽

World Health ◽

Trisomy 8 ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities ◽

Chromosome 1Q ◽

Favorable Prognosis

Abstract Background : Recent studies have suggested significant associations between karyotype and certain molecular or phenotypic features in primary myelofibrosis (PMF). In the current study of 835 consecutive patients, we examined the spectrum and prevalence of cytogenetic abnormalities in PMF and their molecular and phenotypic correlates. Methods : PMF diagnosis was according to World Health Organization criteria. 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 cytogenetic studies. Spectrum and frequency of cytogenetic abnormalities : Analyzable metaphases were obtained in 826 (99%) of 835 patients studied; 681(82%) had ≥20 metaphases analyzed. 352 (42.6%) patients had abnormal karyotype, including 240 (68.2%) sole, 64 (18.2%) two and 48 (13.6%) complex; comparison of these groups revealed lower platelet count (p<0.01), higher DIPSS-plus score (p=0.03) and higher percentage of younger patients (p=0.04) with complex abnormalities. Monosomal karyotype was noted in 20 (5.7%) patients. Approximately 150 individual abnormalities were identified; most frequent were 20q- (23.3%), 13q- (18.2%), +8 (11.1%), +9 (9.9%), duplication of chromosome 1q (9.7%) and -7/7q- (7.1%). Other notable abnormalities including i(17q) (1.4%), 12p- (1.1%) and inv(3) (0.6%) were much less frequent. Trisomy 8 was the most frequent in the context of complex abnormality (25%). Among the 500 patients seen within one year of initial diagnosis, 179 (35.8%) had abnormal karyotype, which included 121 (67.6%) sole, 31 (17.3%) two and 27 (15.1%) complex abnormalities; the most common abnormalities were 20q- (24.6%), 13q- (15.1%), +8 (14%) and +9 (10%) whereas 11q- (1.7%), i(17q) (1.1%), inv(3) (0.6%), and 12p- (0.6%) were infrequent. Molecular correlates : 476 patients were annotated for JAK2, CALR and MPL mutations; abnormal karyotype frequencies were 43% in JAK2, 42% CALR, 33% MPL mutated and 34% triple-negative cases (p=0.3). 13q- was associated with mutant CALR (p=0.03) and +9 with mutant JAK2 (p=0.02). Subsets of patients were also screened for ASXL1, EZH2, IDH, SRSF2, U2AF1, and SF3B1 mutations; in all instances, mutational frequencies were higher in patients with normal karyotype, reaching significance with ASXL1 (p=0.02) and U2AF1 (p=0.01). Mutant SRSF2 was associated with 20q- (p=0.02). Phenotypic correlates : Phenotypic correlates included abnormal karyotype with anemia (p=0.02), leukopenia (p<0.01) and thrombocytopenia (p<0.01); complex karyotype with younger age (p=0.04) and thrombocytopenia (p<0.01); leukopenia with 20q-, +8 and -7/7q-; and thrombocytopenia with 20q- and -7/7q-. Cytopenias were less likely to occur with 13q- (p<0.01), which was instead associated with thrombocytosis (p<0.01). 20q- was associated with lower incidence of marked leukocytosis (p=0.02). Trisomy 8 was associated with lower incidences of constitutional symptoms (p<0.01) and marked splenomegaly (p<0.01). Conclusions : The association of 13q- with CALR mutations in PMF might underlie its association with both thrombocytosis and favorable prognosis. The association of +9 with JAK2 mutations might reflect selective clonal advantage through JAK2V617F dosage enhancement or mutation-induced chromosomal instability. The association of 20q- with mutant SRSF2 and thrombocytopenia warrant further clarification of its reported association with favorable prognosis. Disclosures No relevant conflicts of interest to declare.

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Very Elderly Patients with Myeloproliferative Neoplasms: Phenotypic Distinctions and Prognostic Determinants of Complications and Mortality

Blood ◽

10.1182/blood-2021-145131 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2572-2572

Author(s):

Judith Jolin ◽

Michael Harnois ◽

Luigina Mollica ◽

Pierre Laneuville ◽

Robert Delage ◽

...

Keyword(s):

Bone Marrow ◽

Overall Survival ◽

Arterial Thrombosis ◽

Smoking Status ◽

Myeloproliferative Neoplasms ◽

Very Elderly ◽

Bone Marrow Biopsies ◽

Free Survival ◽

Younger Patients ◽

History Of

Abstract Background and methods: Increasing life expectancy has had the impact of increasing the proportion of patients with myeloproliferative neoplasms (MPN) aged ≥75 years (very elderly patients; VEP). However, few studies have evaluated the phenotype and prognostic factors specific to this population. This is a retrospective multicenter chart review (11 Quebec centers) of VEP with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) diagnosed between 1978 and 2019, enrolled in the CML-MPN Quebec Research Group registry. All diagnoses were made according to World Health Organization 2016 criteria (Blood. 2016;127:2391), with exemption of bone marrow biopsies in select patients. Standard statistical methods were used for all analyses. Results: Of the 753 patients studied in the registry, 114 patients (15%) were ≥75 years old (VEP) (Table 1). These subjects had a median age of 79 years (range 75-95) with incidence of PV, ET and MF of 38%, 51% and 11% respectively. Compared to patients <75 years old, VEP were less likely to be male (35% vs 45%, p = 0.05), had more frequent and higher levels of leukocytosis (11.4 vs 9.7 x 10 9 / L, p <0.0001), were more frequently "triple negative" and less commonly CALR-mutated (p = 0.0005), and presented significantly higher allelic burdens (45% vs 36%, p = 0.03). VEP also had more cardiovascular comorbidities (p <0.0001) and were more often classified as "high risk" (86% vs. 43%, <0.0001). A history of arterial thrombosis prior to/at diagnosis was more common in VEP vs younger patients (14% vs 7.2%, p = 0.02), as was a global history of arterial and/or venous thrombosis at any time during the follow up (25% vs 18%, p = 0.05). Sites of venous events were specifically skewed towards lower extremity deep vein thrombosis in VEP (75%) vs variously distributed in younger patients (p = 0.05). Bleeding rates were similar among the two groups (16% VEP and 17% non-VEP, p = 0.7) while fewer fibrotic (3% vs 8%, p = 0.03) and leukemic transformations (0 vs 2%, p = 0.04) were recorded in VEP. Significantly fewer bone marrow biopsies were performed in VEP (41% versus 54%, p = 0.01). This cohort was, however, more likely to receive cytoreductive therapy (76% vs 67%, p = 0.05), predominantly hydroxyurea (70% vs 59%, p = 0.02). Multivariate analysis revealed the presence of splenomegaly (HR 4.5; 1.2-17.1, p = 0.03) and smoking status (active/former vs never smokers) (HR 5.2; 1.1-24.9, p = 0.03) as predictors of shortened overall survival for the VEP population (Table 2). It also disclosed higher leukocyte count (p = 0.005) and the presence of diabetes mellitus (p = 0.05) as significant risk factors for shortened hemorrhage-free survival. Platelet count (p = 0.03) and smoking status (p = 0.02) were found to be significant determinants of thrombosis-free survival in univariate analysis but did not maintain their significance in multivariate testing. Kaplan-Meier survival data examining age-stratified outcomes in VEP vs younger patients revealed significantly shorter overall survival in VEP (14.2 years vs not reached, p < 0.0001) (Figure 1). The VEP cohort also displayed significantly reduced arterial thrombosis-free survival (incidence of 6.1% vs 3.9%, p = 0.01). There was no significant difference in event data for venous thrombosis-free (4% in both, p = 0.2) and myelofibrosis-free (2.6% versus 7.8%, p = 0.6) survival. Conclusion: This data addressing VEP with MPN exposes, for the first time: i) a characteristic phenotype (predominantly female, higher leukocyte counts, higher allele burden), ii) distinct adverse outcome patterns, particularly with regard to arterial thrombosis, and iii) unique and independent prognostic factors for survival, suggesting that VEP with MPN constitute a biologically, phenotypically, and prognostically distinct population. Figure 1 Figure 1. Disclosures Busque: Novartis: Consultancy. Szuber: Novartis: Honoraria.

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Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system [see comments]

Blood ◽

10.1182/blood.v88.3.1013.bloodjournal8831013 ◽

1996 ◽

Vol 88 (3) ◽

pp. 1013-1018 ◽

Cited By ~ 4

Author(s):

B Dupriez ◽

P Morel ◽

JL Demory ◽

JL Lai ◽

M Simon ◽

...

Keyword(s):

Prognostic Factors ◽

Median Survival ◽

Scoring System ◽

Leukocyte Count ◽

Normal Karyotype ◽

Hemoglobin Level ◽

Abnormal Karyotype ◽

Myeloid Metaplasia ◽

Agnogenic Myeloid Metaplasia ◽

New Scoring

We studied the survival of 195 patients with agnogenic myeloid metaplasia (AMM) diagnosed between 1962 and 1992 in an attempt to stratify patients into risk groups. Median survival was 42 months. Adverse prognostic factors for survival were age > 60 years, hepatomegaly, weight loss, low hemoglobin level (Hb), low or very high leukocyte count (WBC), high percentage of circulating blasts, male sex, and low platelet count. A new scoring system based on two adverse prognostic factors, namely Hb < 10 g/dL and WBC < 4 or > 30 x 10(3)/L, was able to separate patients in three groups with low (0 factor), intermediate (1 factor), and high (2 factors) risks, associated with a median survival of 93, 26, and 13 months, respectively. An abnormal karyotype (32 cases of 94 tested patients) was associated with a short survival, especially in the low-risk group (median survival of 50 v 112 months in patients with normal karyotype). The prognostic factors for acute conversion were WBC > 30 x 10(3)/L and abnormal karyotype. Thus, hemoglobin level and leukocyte count provide a simple prognostic model for survival in AMM, and the adverse prognostic value of abnormal karyotype may be related to a higher rate of acute conversion.

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