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

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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The Effect of Number of Metaphases Studied and Abnormal Metaphase Percentage On Cytogenetic Risk Stratification in Primary Myelofibrosis

Blood ◽

10.1182/blood.v120.21.1742.1742 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1742-1742

Author(s):

Shaina A Rozell ◽

Biruk Mengistu ◽

Naseema Gangat ◽

Curtis A. Hanson ◽

Ryan A Knudson ◽

...

Keyword(s):

High Risk ◽

Risk Stratification ◽

Conflicts Of Interest ◽

International System ◽

Normal Karyotype ◽

Primary Myelofibrosis ◽

Consecutive Series ◽

Prognostic Impact ◽

Abnormal Karyotype ◽

Very High

Abstract Abstract 1742 Background Karyotype is one of the most potent and reproducible risk factors for both overall (OS) and leukemia-free (LFS) survival in primary myelofibrosis (PMF) (Blood 2011;118:4595). It is currently not clear if the number of metaphases studied or the abnormal metaphase percentage alters this prognostic impact. Methods: An updated Mayo Clinic database of karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify a consecutive series of patients and their cytogenetic information obtained at time of referral was centrally re-reviewed. Cytogenetic results were interpreted and reported according to the International System for Human Cytogenetic Nomenclature; abnormal karyotype was defined by the presence of at least 2 metaphases with structural abnormalities or monosomy or 3 metaphases with polysomy, regardless of number of metaphases examined. For this particular study, the presence of less than 20 evaluable metaphases did not disqualify patients. “Very high risk” karyotype included monosomal karyotype, inv(3) or i(17q) abnormalities (Blood 2011;118:4595). “unfavorable” karyotype included complex or any sole or two abnormalities that included +8, −7/7q-, -5/5q-, inv(3), i(17q), 12p-, or 11q23 rearrangement (Blood 2011;118:4595). All other cytogenetic abnormalities were considered “favorable” Results: A total of 590 patients (median age 65 years; range 19–89 years) including 424 (72%) males. The DIPSS-plus (JCO 2011;29:392) risk distribution was 40% high, 39% intermediate-2, 12% intermediate-1 and 9% low. Cytogenetic findings included 17 (3%) very high risk, 69 (12%) unfavorable, 165 (28%) favorable and 339 (57%) normal karyotypes. The number of bone marrow metaphases studied to report these cytogenetic findings were ≥20 in 468 (79%) patients, 11 to 19 in 71 (12%) patients and ≤10 in 51 (9%) patients; the proportion of cases studied with ≥20 metaphases were 53% for very high risk, 74% for unfavorable, 83% for favorable and 80% for normal karyotype (p=0.006). Among patients with abnormal karyotype, the abnormal metaphase percentage was ≥75% in 148 (59%) patients, 50 to 74% in 36 (15%) patients, 26 to 49% in 27 (11%) patients and ≤25% in 38 (15%) patients; the proportion of patients with ≥75% was 59% for very high risk, 67% for unfavorable and 56% for favorable karyotypes (p=0.70). As expected, OS was significantly different among very high risk, unfavorable, favorable and normal karyotype patients with respective median survivals of 8, 23, 41 and 57 months (p<0.0001). The number of metaphases studied (p=0.62) or the abnormal metaphase percentage (p=0.12), by themselves, did not affect survival. Similarly, the survival difference among the aforementioned cytogenetic risk groups was equally apparent when patients with ≥20 metaphases studied (n=468; P<0.0001) and those with <20 metaphases studied (n=122; p<0.0001) were separately analyzed. Analysis of patients with very high risk or unfavorable karyotype (n=86) revealed no significant effect of abnormal metaphase percentage on survival (Figure; p=0.80). A similar scenario was demonstrated for patients with favorable karyotype (Figure; p=0.24). Conclusions: Neither the number of metaphases examined nor the abnormal metaphase percentage appear to influence the currently recognized cytogenetic risk stratification in PMF. The current study has implications for both clinical practice and clinical research involving cytogenetic prognostication in hematological malignancies. Disclosures: No relevant conflicts of interest to declare.

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Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽

10.1182/blood.v80.11.2873.2873 ◽

1992 ◽

Vol 80 (11) ◽

pp. 2873-2882 ◽

Cited By ~ 75

Author(s):

OI Olopade ◽

M Thangavelu ◽

RA Larson ◽

R Mick ◽

A Kowal-Vern ◽

...

Keyword(s):

Myeloid Leukemia ◽

De Novo ◽

Chromosomal Abnormalities ◽

Normal Karyotype ◽

Intensive Chemotherapy ◽

Trisomy 8 ◽

Cytogenetic Abnormalities ◽

Favorable Prognosis ◽

Multiple Abnormalities ◽

French American British

Abstract We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

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Monosomal Karyotype In Primary Myelofibrosis Is Prognostically Worse Than Otherwise Unfavorable Karyotype

Blood ◽

10.1182/blood.v116.21.3069.3069 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3069-3069

Author(s):

Rakhee Vaidya ◽

Domenica Caramazza ◽

Kebede Begna ◽

Naseema Gangat ◽

Daniel L. Van Dyke ◽

...

Keyword(s):

Clin Oncol ◽

Mayo Clinic ◽

Conflicts Of Interest ◽

Normal Karyotype ◽

Primary Myelofibrosis ◽

Structural Abnormality ◽

Complex Karyotype ◽

Trisomy 8 ◽

First Time ◽

Monosomal Karyotype

Abstract Abstract 3069 Background: Monosomal karyotype (MK) is defined as the presence of two or more distinct autosomal chromosome monosomies or a single autosomal monosomy associated with at least one structural abnormality (Breems DA et al. J Clin Oncol 2008; 26: 4791). In acute myeloid leukemia (AML), MK has been shown to be prognostically worse than complex or other unfavorable karyotype (Breems DA et al. J Clin Oncol 2008; 26: 4791). In primary myelofibrosis (PMF), complex karyotype or isolated trisomy 8 predicts inferior survival (Hussein K et al. Blood 2010; 115: 496). Objective: To determine if MK in PMF is prognostically distinct from previously defined poor cytogenetic risk categories including complex karyotype and isolated trisomy 8. Methods: The Mayo Clinic database for PMF was used to identify consecutive patients with unfavorable karyotype including complex karyotype and sole trisomy 8. WHO criteria were used for PMF diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937). Results: Among 793 PMF patients with cytogenetic information at the time of their first time referral to the Mayo Clinic, 452 displayed a normal karyotype and 341 (43%) an abnormal karyotype. Of the latter, 41 (12%) displayed complex karyotype and 21 (6%) sole trisomy 8. Among the 41 patients with complex karyotype, 17 (42%) met the criteria for MK and 24 (58%) displayed complex karyotype without monosomies. Overall survival was significantly inferior in patients with MK compared to those with either complex karyotype without monosomies (p=0.02; HR 2.3, 95% CI 1.1–4.8) or trisomy 8 (p=0.02; HR 2.4, 95% CI 1.2–5.1) (Fig. 1). Prognosis among all three groups was significantly worse than patients with normal karyotype (Fig. 1). Leukemia-free survival was also significantly inferior in patients with MK compared to those with either complex karyotype without monosomies (p=0.02; HR 6.9, 95% CI 1.3–37.3) or trisomy 8 (p=0.02; HR 14.8, 95% CI 1.7–130.8) (Fig. 2). LFS in patients with normal karyotype was similar to those with either complex karyotype without monosomies (p=0.31) or trisomy 8 (p=0.86) (Figure 2). Conclusions: Monosomal karyotype in PMF is distinctly associated with extremely poor overall and leukemia-free survivals that are significantly worse than those seen in PMF patients with other unfavorable karyotype including complex karyotype without monosomies and sole trisomy 8 abnormalities. Disclosures: No relevant conflicts of interest to declare.

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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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Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia

Blood ◽

10.1182/blood.v80.11.2873.bloodjournal80112873 ◽

1992 ◽

Vol 80 (11) ◽

pp. 2873-2882

Author(s):

OI Olopade ◽

M Thangavelu ◽

RA Larson ◽

R Mick ◽

A Kowal-Vern ◽

...

Keyword(s):

Myeloid Leukemia ◽

De Novo ◽

Chromosomal Abnormalities ◽

Normal Karyotype ◽

Intensive Chemotherapy ◽

Trisomy 8 ◽

Cytogenetic Abnormalities ◽

Favorable Prognosis ◽

Multiple Abnormalities ◽

French American British

We have performed a retrospective analysis of the clinical, morphologic, and cytogenetic findings in 26 patients diagnosed between January 1969 and September 1991 with acute erythroblastic leukemia de novo (EL or AML-M6). Clonal chromosomal abnormalities were found in 20 (77%) patients (95% confidence interval [CI], 61% to 93%). Loss of all or part of the long arm (q) of chromosomes 5 and/or 7 was observed in 17 (65%) patients (95% CI, 47% to 83%). In addition, the karyotypes were often complex, with multiple abnormalities and subclones. Among the remaining nine patients, six had a normal karyotype and one each had trisomy 8, t(3;3), or t(3;5). The overall frequency of abnormalities of chromosomes 5 and/or 7 observed in our M6 patients is similar to that observed in our patients with therapy-related acute myeloid leukemia (t-AML; 99 of 129 patients, 77%), but substantially higher than that noted in our other patients with AML de novo (French- American-British [FAB] subtypes M1-M5: 52 of 334 patients, 16%). Our M6 patients with abnormalities of chromosomes 5 and/or 7 were older and had a shorter median survival (16 v 77 weeks [P = .005]) than did the M6 patients without these abnormalities. We found no correlation between morphologic features and either cytogenetic abnormalities or clinical outcome. Of note was the finding that the percentage of myeloblasts, which may account for only a small fraction of the total marrow elements when the revised FAB criteria are applied, had no bearing on prognosis. We conclude that acute erythroblastic leukemia, when defined by morphologic criteria, consists of two distinctive subgroups: one group tends to be older, has complex cytogenetic abnormalities, especially of chromosomes 5 and/or 7, and shares biologic and clinical features with t-AML; the other group, with simple or no detectable cytogenetic abnormalities, has a more favorable prognosis when treated with intensive chemotherapy.

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Recurrent Amplified Regions on the Long Arm of Chromosome 1 (1q) Are Associated with Disease Progression In Ph-Negative Myeloproliferative Neoplasms (MPN)

Blood ◽

10.1182/blood.v116.21.3087.3087 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3087-3087

Author(s):

Vesna Najfeld ◽

Joseph Tripodi ◽

Timothy Best ◽

Mingjiang Xu ◽

Ronald Hoffman ◽

...

Keyword(s):

High Risk ◽

Disease Progression ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Snp Array ◽

Normal Karyotype ◽

Myelogenous Leukemia ◽

Chromosome 1 ◽

Abnormal Karyotype ◽

Chromosome 1Q

Abstract Abstract 3087 Trisomy of all or part of the long arm of chromosome 1 (1q) is a recurrent abnormality frequently observed at diagnosis in myeloproliferative neoplasms (MPN). Recently, we reported that jumping translocations involving duplications of chromosome 1q (1qJT) represent a clonal marker associated with high risk of transformation to acute myelogenous leukemia (AML) in both MPN and myelodysplastic syndrome (MDS). Breakpoints are often found at either 1q12 or 1q21 (Najfeld et al BJH 2010). Consequently, we hypothesized that these regions are likely to contain a gene or cluster of genes under selection for amplification associated with disease progression. To investigate this, we karyotyped 13 patients (7 males and 6 females) with MPN (primary myelofibrosis [MF]=7, essential thrombocythemia [ET]=2, ET->polycythemia vera- [PV]=1, ET or PV->MF=2, ET->MF->AML=1). Ten of these 13 patients (pts) had an abnormal karyotype, while 3 patients had a normal karyotype. Of pts with an abnormal karyotype, four had trisomy 1q and two had duplication 1q (q12 to q31). The breakpoint 1q12 was observed in 3 pts while the breakpoint 1q21 was identified in 4 pts. One pt had two different populations of cells with a 1q duplication (1q): 36% of cells had a 1q21 breakpoint while 6% cells had a 1q12 breakpoint as identified by FISH using 1q12 and 1q21 specific FISH probes. Additionally, one pt had trisomy for chromosomes 8 and 9, and one had a balanced t(1;9)(p36;p24.1) abnormality. JAK2V617F, an activating mutation implicated in MPN, was present in 6 pts. Of the 13 pts six progressed to AML or had an aggressive disease course that required stem cell transplantation. To map the boundaries of the minimally amplified regions on chromosome 1q associated with disease progression, DNA was isolated from the MPN cells of these 13 patients and genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. Copy number abnormalities were assessed by Genomic Segmentation (Partek Genomic Suite, St Louis, MO). This analysis revealed seven regions that were recurrently amplified (amplified in at least 4 MPN cases but not in normal controls). Of these regions, three were in 1q21.1 and the rest were telomeric to 1q21. We identified six patients with amplifications in 1q21.1, in contrast to the four identified by karyotype analysis. Of these, one pt had a normal karyotype and was JAK2V617F negative. Intriguingly, the region on 1q21 amplified in this patient was also amplified in the relapse sample of another patient at the time of progression to AML. Of note, this region includes PDE4DIP, which had previously shown to be part of a t(1;5)(q23;q33) translocation in MPN associated with eosinophilia. Of the other recurrent amplifications four pts had a gain of 1q32.1 which includes MDM4, a known regulator of the p53 tumor suppressor. Thus, these data suggest that fine mapping of recurrently amplified regions of chromosome 1q may reveal genes under pressure for amplification in high-risk MPN or that may be involved in the high-risk 1qJT found in both MPN and MDS. Disclosures: No relevant conflicts of interest to declare.

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Karyotypic polymorphism in acute myelofibrosis

Blood ◽

10.1182/blood.v60.4.841.841 ◽

1982 ◽

Vol 60 (4) ◽

pp. 841-844 ◽

Cited By ~ 15

Author(s):

I Shah ◽

K Mayeda ◽

F Koppitch ◽

S Mahmood ◽

B Nemitz

Keyword(s):

Bone Marrow ◽

Peripheral Blood ◽

Black Male ◽

Blood Cells ◽

Normal Karyotype ◽

Trisomy 8 ◽

Chronic Granulocytic Leukemia ◽

Cytogenetic Abnormalities ◽

Granulocytic Leukemia

Abstract Acute myelofibrosis (AMF) was diagnosed in a 59-yr-old black male in September 1978, on the basis of pancytopenia, lack of hepatosplenomegaly, fibrosis of the marrow, and paucity of teardrop red blood cells in the peripheral blood. Since then the patient has demonstrated an unusually long survival of 36 mo with a changing cytogenetic course. His initial 46, XY normal karyotype changed in 20 mo to trisomy 8, followed 1 yr later by 1:4 translocation in peripheral blood. Simultaneously with these changes, the fibrosis in the bone marrow progressively decreased, ultimately terminating in chronic granulocytic leukemia-like presentation with reversal to 46, XY karyotype. Fibroblast culture failed to show any evidence of cytogenetic abnormalities. The disappearance of fibrosis confirmed by trichrome and reticulin stains and lack of cytogenetic abnormalities in fibroblasts confirms the secondary role of fibrosis.

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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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Clinical Relevance of Cytogenetics Abnormalities in Adult Patients with Acquired Aplastic Anaemia.

Blood ◽

10.1182/blood.v106.11.3748.3748 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3748-3748

Author(s):

Vikas Gupta ◽

Carol Brooker ◽

Jennifer A. Tooze ◽

Qi-long Yi ◽

Deborah Sage ◽

...

Keyword(s):

Aplastic Anaemia ◽

Clinical Relevance ◽

Cytogenetic Study ◽

Cumulative Risk ◽

Normal Karyotype ◽

Similar Response ◽

Trisomy 8 ◽

Abnormal Karyotype ◽

Monosomy 7 ◽

Poor Prognostic Factor

Abstract The clinical relevance of cytogenetics abnormalities in aplastic anaemia (AA) patients at time of diagnosis is unclear. We evaluated the clinical course of 81 AA patients with successful cytogenetics at diagnosis and treated with immunosuppressive therapy (IST) from January 1993 to March 2004. A cytogenetic study was considered to be successful if there were a minimum of 15 evaluable metaphases in the absence of a clonal abnormality. Response to IST, survival and later clonal complications in patients with an abnormal karyotype (n=10) was compared to those with a normal karyotype (n=71). The cytogenetic abnormalities at diagnosis consisted of trisomy 6 (n=2), trisomy 8 (n=2), trisomy 15 (n=2), monosomy 7 (n=1), add(10) (n=1), t(3;11) (n=1) and t(4;6) (n=1). Four out of five evaluable patients with a trisomy responded to a first or subsequent course of IST. One patient with monosomy 7 achieved a complete response and later developed haemolytic PNH but with no recurrence of the monosomy 7. None of the patients with a non-numerical karyotypic abnormality responded to IST. No significant differences in 4-year event-free survival (EFS) (54% vs. 30%, p=0.15), overall survival (OS) (84% vs. 80%, p=0.33) or later clonal disorders (PNH, MDS and AML) were observed between the patients with a normal karyotype and those with an abnormal karyotype. Advanced age (≥60 years) was the only independent poor prognostic factor for survival in a multivariate analysis. Among the patients with a normal karyotype (n=71), 6 patients later developed a clonal cytogenetic abnormality with a cumulative risk of 10% at 4 years. These abnormalities were trisomy 15 (n=2), trisomy 6(n=1), monosomy 7 (n=2) and t(13;15) (n=1). None of the three patients who acquired trisomies developed any clinically significant problem, while acquisition of monosomy 7 was associated with a transformation to MDS/AML. Our data show that AA patients with a trisomy cytogenetic clone at diagnosis show a similar response to IST, evolution to later clonal abnormalities and survival, compared to those AA patients with a normal karyotype.

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

Blood ◽

10.1182/blood-2021-152549 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3629-3629

Author(s):

Naseema Gangat ◽

Jaya Kittur ◽

Yamna Jadoon ◽

Natasha Szuber ◽

Curtis A. Hanson ◽

...

Keyword(s):

Overall Survival ◽

Arterial Thrombosis ◽

Normal Karyotype ◽

Male Gender ◽

Hemoglobin Level ◽

Leukemic Transformation ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities ◽

Trisomy 9 ◽

History Of

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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