Cytogenetic Clonal Evolution in Myeloproliferative Neoplasms: Contexts and Prognostic Impact Among 650 Patients with Serial Bone Marrow Biopsies

Abstract Background : Cytogenetic abnormalities occur in approximately a third of patients with primary myelofibrosis (PMF) and 5-20% of those with essential thrombocythemia (ET) or polycythemia vera (PV). Abnormal karyotype in PV and specific cytogenetic abnormalities in PMF have been shown to adversely affect survival (Leukemia. 2018;32:1189; Br J Haematol. 2017 Jun 9. doi: 10.1111/bjh.14798). In the current retrospective study, we considered 650 Mayo Clinic patients with myeloproliferative neoplasms (MPN), including ET, PV and PMF, with at least two documented bone marrow (BM) biopsies, in order to examine the incidence and pattern of changes in karyotype and their clinical correlates. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA, based on documentation of at least two serial BM biopsies. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). BM biopsy #1 referred to the baseline karyotype at time of initial diagnosis/referral and BM biopsy #2 to the first repeat BM biopsy after diagnosis. In addition to documenting the presence or absence of changes in karyotype, a notation was made regarding disease phase, at the time of the repeat biopsy, in order to allow accurate interpretation of the data and evaluation of survival impact. Results: 650 patients with MPN, including 153 ET, 105 PV and 392 PMF, were included in the current study and had undergone at least two BM biopsies; 227 patients had three, 108 four, 48 five, 19 six, and 4 seven repeat BM biopsies during their clinical course. Cytogenetic clonal evolution in patients with normal karyotype at baseline : Baseline karyotype was normal in 466 (72%) patients, including 139 (91%) ET, 91 (87%) PV and 236 (60%) PMF. Clonal evolution, which constituted a change from "normal" to "abnormal" karyotype, was documented in 16 (12%) patients with ET, 22 (24%) with PV and 75 (33%) with PMF; the latter included favorable karyotype in 11% of the cases, unfavorable in 12% and very high risk (VHR) in 10%. 11 (69%) of the 16 documented cases of clonal evolution in ET, 10 (45%) of 22 in PV and 11 (15%) of 75 in PMF were accompanied by clinically evident progression to blast or fibrotic phase disease, at the time of the repeat BM biopsy. Cytogenetic clonal evolution in patients with abnormal karyotype at baseline : Baseline karyotype was abnormal in 187 (28%) patients, including 17 (9%) ET, 14 (13%) PV and 156 (40%) PMF. Additional changes in karyotype, during serial BM biopsies, were documented in 6 (35%) ET, 5 (36%) PV and 71 (46%) PMF patients. In PMF, the pattern of changes in karyotype included "favorable" to "favorable" in 7%; "favorable" to "unfavorable" in 13%; "favorable" to "VHR" in 5%; "unfavorable" to "unfavorable" in 13%; "unfavorable" to "VHR" in 3%; and "VHR" to "VHR" in 6%. All 11 (100%) patients with ET or PV who underwent clonal evolution displayed clinically overt disease transformation into leukemic or fibrotic phase disease, at the time of the repeat BM biopsy. Leukemic transformation at the time of the repeat BM biopsy was evident in 13 (18%) of the 71 PMF cases with clonal evolution. Survival impact of cytogenetic clonal evolution without change in disease phase : The survival impact of cytogenetic clonal evolution was examined under the following provisions: i) analysis was limited to events occurring at BM biopsy #2 with survival calculated from the date of BM biopsy #2; ii) patients with leukemic or fibrotic transformation at time of BM biopsy #2 were excluded from analysis; and iii) clonal evolution for the purposes of survival analysis constituted changes from "normal" to "abnormal", for ET and PV, while the type of changes were taken under consideration for PMF. Under these stipulations, clonal evolution appeared to affect survival in general, although statistical significance was apparent for only ET and PMF (Figures 1a, 1b and 1c). Conclusions: Cytogenetic clonal evolution in ET and PV is infrequent, in the absence of clinically overt disease transformation, and is more likely to occur in PMF. Such events, when documented in chronic phase disease, appeared to predict shortened survival in all three MPNs, which was most apparent in ET and with emergence of VHR or unfavorable abnormalities in PMF. These observations warrant prospective studies that account for indication bias. Disclosures No relevant conflicts of interest to declare.

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Cytogenetic Abnormalities in Systemic Mastocytosis: Who Subcategory-Specific Incidence and Prognostic Impact Among 348 Informative Cases

Blood ◽

10.1182/blood-2018-99-112628 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3050-3050

Author(s):

Sahrish Shah ◽

Animesh Pardanani ◽

Yoseph Elala ◽

Terra L. Lasho ◽

Mrinal M. Patnaik ◽

...

Keyword(s):

Bone Marrow ◽

Systemic Mastocytosis ◽

Univariate Analysis ◽

World Health ◽

P Value ◽

Prognostic Impact ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities ◽

Prognostic Effect ◽

Prognostic Relevance

Abstract Background: The World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smouldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM) and mast cell leukemia (MCL) (Blood. 2016;127:2391). Recent studies have highlighted the prognostic importance of mutations in SM, including ASXL1, RUNX1 and SRSF2 (AJH 2016;91:888;Leukemia 2016;30:2342). In the current study, we reviewed the cytogenetic findings in 348 cases of SM, in order to clarify incidence and prognostic impact of cytogenetic abnormalities, stratified by WHO morphologic subcategories. Methods : Study patients were selected, based on availability of cytogenetic information. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with WHO criteria (Blood. 2016;127:2391). Next-generation sequencing was performed in a subset of the study population. Abnormal karyotype was further distinguished into favorable and unfavorable class based on previously published criteria for myelodysplastic syndromes (MDS) (Blood 2012;120:2454) and myeloproliferative neoplasms (MPN) (Leukemia 208;32:1189). Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis at the Mayo Clinic, which coincided with collection of bone marrow for cytogenetic studies. Conventional statistics was used for calculation of overall survival and determination of risk factors. JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 348 SM patients were included in the current study (median age 59 years; range 18-88 years; 53% males); 142 (41%) constituted ISM and 206 (59%) advanced SM; the latter included 155 (45%) SM-AHN, 49 (14%) ASM and 2 MCL cases. The SM-AHN cases included 39 (11%) SM-MPN, 36 (10%) SM-CMML, 22 (6%) SM-MDS, 22 (6%) SM-myeloid unclassified, 14 (4%) SM-MDS/MPN, 12 (3%) SM-lymphoid malignancy and 10 (3%) SM-acute leukemia. Adverse mutations, including ASXL1 (19% mutated), RUNX1 (3% mutated) and NRAS (3% mutated) were detected in 30 (23%) of 129 cases screened. After a median follow-up of 21 months, 139 (40%) deaths and 6 (5%) leukemic transformations were documented. Karyotype was abnormal in 53 (15%) cases and included unfavorable (n=29; 8%) and favorable (n=24; 7%) abnormalities. Abnormal karyotype incidences were 6% for ISM and 22% for advanced SM (p<0.001). Among advanced SM cases, abnormal karyotype incidences were 26% for SM-AHN and 8% for ASM (p<0.001); one of 2 MCL cases displayed abnormal karyotype. Among SM-AHN cases, abnormal karyotype incidences were 0% for SM-AHN-lymphoid, 28% for SM-AHN-myeloid (p<0.001); the latter included 19% for SM-CMML, 21% for SM-MDS/MPN, 23% for SM-MPN, 36% for SM-MDS and 41% of SM-myeloid-unclassified (p<0.001). Clinical correlative studies disclosed significant associations between abnormal karyotype and male sex (p=0.002), age >60 years (p=0.04), thrombocytopenia (p<0.001; 27% vs 10%) and anemia (p<0.001; 25% vs 6%), but not with the presence of adverse mutations (p=0.19). In univariate analysis, abnormal karyotype was associated with inferior survival (HR 3.0, 95% CI 2.0-4.3) and significance was sustained when analysis was adjusted for two-tiered (advanced vs indolent SM; p<0.01) or multi-tiered (ISM vs ASM vs SM-AHN; p<0.01) WHO subcategories. WHO category-specific analysis clarified prognostic relevance of abnormal karyotype in ASM (HR 4.4, 95% CI 1.0-14.4; p=0.05; figure 1a) and SM-AHN-myeloid (HR 1.9, 95% CI 1.2-2.9; p=0.005; figure 1b); however, the near-significance in ASM was fully accounted for by thrombocytopenia (p value corrected to 0.35) and for SM-AHN-myeloid by thrombocytopenia and anemia (p value corrected to 0.06); further stratification of abnormal karyotype into favorable vs unfavorable categories did not affect the results in ASM but revealed an independent prognostic effect for unfavorable karyotype in SM=AHN-myeloid (p=0.009). Conclusions: Abnormal karyotype in SM clusters with SM-AHN-myeloid. We found no correlation between abnormal karyotype and adverse mutations. Anemia and thrombocytopenia were significantly associated with abnormal karyotype and accounted for the apparent prognostic relevance of the latter in ASM. Unfavorable karyotype carries independent prognostic effect in SM-AHN-myeloid. Disclosures No relevant conflicts of interest to declare.

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Cytogenetic clonal evolution in myeloproliferative neoplasms: contexts and prognostic impact among 648 patients with serial bone marrow biopsies

Leukemia ◽

10.1038/s41375-019-0453-5 ◽

2019 ◽

Vol 33 (10) ◽

pp. 2522-2553

Author(s):

Ayalew Tefferi ◽

Maura Nicolosi ◽

Domenico Penna ◽

Rangit Vallapureddy ◽

Curtis A. Hanson ◽

...

Keyword(s):

Bone Marrow ◽

Myeloproliferative Neoplasms ◽

Clonal Evolution ◽

Prognostic Impact ◽

Bone Marrow Biopsies

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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 Significance of Clonal Cytogenetic Heterogeneity (CCH) at Diagnosis in Adult Patients with Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2018-99-118462 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2820-2820

Author(s):

Hiroaki Shimizu ◽

Nahoko Hatsumi ◽

Satoru Takada ◽

Takuma Ishizaki ◽

Akihiko Yokohama ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Research Funding ◽

Clonal Evolution ◽

Statistical Significance ◽

Prognostic Impact ◽

Common Ancestry ◽

Complex Karyotype ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities

Abstract Background:Although cytogenetic abnormalities at diagnosis are recognized as one of the most potent prognostic factors in acute leukemia patients, CCH acquisition at diagnosis, which are considered as a result of clonal evolution of leukemia cells, is not taken into account in prognostic classifications. Recent studies reported that CCH acquisition was observed in 24 - 32% of adult AML patients with abnormal karyotype, was more likely to occur in patients with older age and complex karyotype, and showed adverse prognostic impact. However, the clinical significance of CCH acquisition has not been investigated in adult ALL patients to date. Patients and methods: Of the 238 adult ALL patients diagnosed between 1990 and 2016, 120 patients with abnormal karyotype at diagnosis, who underwent intensive chemotherapy, were included in this study. CCH was defined as presence of two or more cytogenetically abnormal clones. A defined ancestral clonal evolution included either mother-daughter and/or branched patterns. In the mother-daughter pattern, a daughter clone showed all cytogenetic abnormalities of a mother clone plus additional abnormality(s), which define a distinct subclone. In a branch pattern, all subclones possessed common cytogenetic abnormalities suggesting presence of a common ancestry, but each subclone acquires unique additional abnormality(s), which define them as distinctive subclones. Both patterns of cytogenetic clonal evolution were sometimes seen in a patient. Composite karyotypes were applied to patients where a common ancestry could not be clearly determined because of too complicated cytogenetic findings. Fisher's exact test was used to compare binary variables. The logistic regression model was used for multivariate analysis of predisposing factors. Overall survival (OS) was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis of prognostic factors. Values of p < 0.05 were considered to indicate statistical significance. Results:Of the 120 patients included in this study, 64 patients were male, and 56 were female. The median age was 50 years (range, 16-79 years). Karyotypes at diagnosis were Philadelphia chromosome (Ph) in 56 patients, complex in 15, and t(8;14) in seven. According to the definition described above, 47 patients (39%) showed CCH at diagnosis, and two (4%) among them were categorized as composite karyotype. Of the 45 patients harboring a defined ancestral clonal evolution, numbers of subclones were two, three, and four in 32 patients (68%), 11 (24%), and 2 (4%), respectively. Mother-daughter pattern, branched pattern, and both were seen in 34 patients (76%), 5 (11%), and 6 (13%). In univariate analysis for predisposing factors of CCH acquisition, only younger age was significantly associated with CCH acquisition (48% in age <= 50 vs. 29% in age > 50; p = 0.04), but not karyotype. This statistical significance was confirmed with multivariate analysis (odds ratio = 0.44; p = 0.03). When investigating the prognostic impact of CCH acquisition, patients were divided into Ph-negative or Ph-positive ALL groups. In the 64 Ph-negative ALL patients, the CR rates were not significantly different between patients with or without CCH (78% vs. 78%, respectively; p = 1.00). The OS rates were similar between two groups (26% vs. 39% at five years, respectively; p = 0.56). Multivariate analysis for OS revealed that complex karyotype and t(8;14) were independent prognostic factors, but not CCH acquisition. Likewise, in the 56 Ph-positive ALL patients, CCH acquisition was not significantly associated with the CR rates (92% vs. 78%, respectively; p = 0.27), and the OS rates did not significantly differ between the two groups (34% vs. 40% at five years, respectively; p = 0.90). In multivariate analysis for OS, no independent prognostic factor was identified. Conclusion: Adult ALL patients with abnormal karyotype acquired CCH at diagnosis with a frequency comparable to that of AML patients. However, unlike AML patients, CCH acquisition was more frequently observed in younger population and did not show any prognostic impact in ALL patients. These findings suggested that biological backgrounds of CCH acquisition at diagnosis were possibly different between in patients with ALL and AML. So, to confirm these important findings, clinical studies with larger study subjects are warranted. Disclosures Handa: Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Prognostic and therapeutic impact of cytogenetic abnormalities in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.7058 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 7058-7058

Author(s):

Abhishek Avinash Mangaonkar ◽

Hassan Alkhateeb ◽

Aref Al-Kali ◽

Naseema Gangat ◽

Kebede Begna ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Treatment Guidelines ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Prognostic Impact ◽

Trisomy 8 ◽

Abnormal Karyotype ◽

Immature Myeloid Cells

7058 Background: The 2016 WHO classification includes myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), as an MDS/MPN overlap syndrome not meeting criteria for well-defined entities such as CMML. No standard prognostication or treatment guidelines exist for such patients. Methods: We retrospectively identified MDS/MPN-U cases from 1990-2016 through our myeloid malignancies database. All bone marrow reports were reviewed to ensure compliance with 2016 WHO criteria. Clinical & cytogenetic parameters at diagnosis were assessed & compared with treatment outcomes. Results: Eighty nine patients met study criteria, with a median age of 69 years (range: 37-93); 58 (65%) males. Median follow-up was 22.2 months (range: 0-172), with 41 (46%) deaths & 13 (15%) leukemic transformations. Median OS was 24.8 months (range: 0-172). 43 (53%) patients had an abnormal karyotype, with common abnormalities being trisomy 8 (12%), complex karyotype (9%) & del (20q) (6%). Given the fewer types of abnormalities identified, the IPSS cytogenetic stratification was more effective than IPSS-R, with risk categorization including; 45 good (55%), 20 intermediate (25%) & 16 high risk (20%) respectively (8 unavailable). On univariate analysis, increased age (p = 0.05), decreased hemoglobin (p = 0.02), higher ANC (p = 0.03), circulating immature myeloid cells (p = 0.02), higher LDH (p = 0.009), absence of bone marrow ring sideroblasts (p = 0.001) & higher risk (intermediate & high) IPSS cytogenetic categories (p = 0.01) adversely impacted OS. In a multivariate model that included the aforementioned variables, higher risk IPSS cytogenetics retained a negative prognostic impact (p = 0.04). 28 patients received a median of 6 cycles (range: 1-21) of hypomethylating agent therapy (HMA), with an overall response rate of 18% (CR-3, PR-2). All responders had an abnormal karyotype (p = 0.01). However, HMA did not affect either OS or LFS. Conclusions: Intermediate & high risk IPSS cytogenetic categories independently & adversely impact survival in WHO defined MDS/MPN-U patients. HMA use did not impact OS; however, patients with abnormal karyotypes were more likely to respond.

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Cytogenetic Abnormalities May Predict Transformation to Acute Myeloid Leukemia in Polycythemia Vera Patients

Blood ◽

10.1182/blood.v128.22.4258.4258 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4258-4258 ◽

Cited By ~ 1

Author(s):

Juliana E Hidalgo López ◽

Adrián A Carballo-Zarate ◽

L. Jeffrey Medeiros ◽

Carlos E Bueso-Ramos ◽

Guilin Tang

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Clonal Evolution ◽

Chronic Phase ◽

Complex Karyotype ◽

Abnormal Karyotype ◽

Cytogenetic Abnormalities ◽

Group A ◽

Group B

Abstract Introduction: Cytogenetic abnormalities can be detected in about 20% of patients with polycythemia vera (PV) at initial diagnosis. The accumulated risk for acute myeloid leukemia (AML) transformation from PV has been estimated to be 2.3-14.4% at 10 years. Risk factors for AML transformation suggested in other studies include older age, abnormal karyotype and high leukocyte count. The purpose of this study is to evaluate the association of cytogenetic abnormalities with AML transformation in PV. Methods: We searched the database at our institution for patients with a diagnosis of PV during Jan. 1994 to Apr. 2015. Demographic data, clinical presentations and follow-up, and laboratory data including karyotype before and after AML transformation were collected. Bone marrow morphology, especially evidence of myelodysplasia, myelofibrosis and blast percentage were evaluated. Results: A total of 317 patients with a diagnosis of PV were identified. 36 (11%) patients progressed to AML (Group A), including 15 who presented in chronic phase and 21 in blast phase. The median interval from the diagnosis of PV to AML transformation was 97 months (range, 11 - 331 months). For comparison, 50 patients with similar demographic features during the same time interval but no evidence of AML transformation were also included in the study (Group B). The age of patients in both groups was comparable (median age: 57 vs. 54 years, p=0.2791). All patients were positive for JAK2 V617F mutation. The main therapies for patients with chronic phase PV included phlebotomy, hydrea, and tyrosine kinase inhibitors in a small subset of patients. There was no significant difference of treatments among the patients in groups A and B. Karyotype at chronic phase of PV was available in 15 patients in Group A and all 50 patients in Group B. Eleven (73%) patients in Group A showed an abnormal karyotype in chronic phase. The most common chromosomal abnormalities were trisomy 1q (n=6, 40%), including 4 (27%) patients with [+1, der(1;7)(q10;p10)] resulting in trisomy 1q and del(7q); and complex karyotype (n=3, 20%). Del(20q) and +8 was uncommon, only detected in 1 patient each. In Group B, 11 (22%) patients had an abnormal karyotype, which was much less frequent compared with Group A. No patients in Group B showed a complex karyotype or trisomy 1q; instead, del(20q) (n=6, 55%), +9 and/or +8 (n=5, 45%) were the most common chromosomes abnormalities detected. The median follow-up was 10 years in Group A and 14.5 years in Group B. At the time of AML transformation, 35 (97%) patients in Group A showed an abnormal karyotype, including 21 (58%) patients with a complex karyotype, 22 patients with -5/del(5q) and/or -7/del(7q) and 10 (28%) with trisomy 1q [8 with +1, der(1;7)]. Among the 15 patients who had karyotypic information during the chronic phase, 4 (27%) patients showed clonal evolution and 7 (47%) acquired new unrelated abnormal clones when AML transformation occurred. Morphologically, 15 patients in Group A had sequential bone marrow evaluation from chronic phase to blast phase, 14 (93%) patients developed myelofibrosis and 7 (47%) patients showed multilineage dysplasia during the chronic phase. At the time of AML transformation, 35 (97%) patients showed myelodysplasia. In Group B, 5 (10%) patients developed myelodysplasia and 31(62%) developed myelofibrosis in follow-up bone marrow samples. Conclusion: Cytogenetic abnormalities are associated with AML transformation in PV patients. Patients with an abnormal karyotype, especially with abnormalities of trisomy 1q [+1,der(1;7)(q10;p10)] or a complex karyotype, are at highest risk to develop clonal evolution or acquire new myelodysplasia-related clones [like -5/del(5q) and/or -7/del(7q)] or develop myelodysplasia and transform into AML. On the other hand, cytogenetic abnormalities, such as del(20q), +8 and/or +9, although commonly detected in PV, are associated with a low risk for myelodysplasia and AML transformation. Surveillance for cytogenetic abnormalities is helpful in the risk assessment of AML transformation in PV patients. Disclosures No relevant conflicts of interest to declare.

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A review of current knowledge of myeloproliferative disorders in the horse

Acta Veterinaria Scandinavica ◽

10.1186/s13028-021-00573-3 ◽

2021 ◽

Vol 63 (1) ◽

Author(s):

Katy Satué ◽

Juan Carlos Gardon ◽

Ana Muñoz

Keyword(s):

Bone Marrow ◽

Myeloid Leukemia ◽

Current Knowledge ◽

Myeloproliferative Neoplasms ◽

Myeloproliferative Disorders ◽

World Health ◽

Chronic Granulocytic Leukemia ◽

Current State ◽

Multiple Cell ◽

Health Organization

AbstractMyeloid disorders are conditions being characterized by abnormal proliferation and development of myeloid lineage including granulocytes (neutrophils, eosinophils and basophils), monocytes, erythroids, and megakaryocytes precursor cells. Myeloid leukemia, based on clinical presentation and proliferative rate of neoplastic cells, is divided into acute (AML) and myeloproliferative neoplasms (MPN). The most commonly myeloid leukemia reported in horses are AML-M4 (myelomonocytic) and AML-M5 (monocytic). Isolated cases of AML-M6B (acute erythroid leukemia), and chronic granulocytic leukemia have also been reported. Additionally, bone marrow disorders with dysplastic alterations and ineffective hematopoiesis affecting single or multiple cell lineages or myelodysplastic diseases (MDS), have also been reported in horses. MDSs have increased myeloblasts numbers in blood or bone marrow, although less than 20%, which is the minimum level required for diagnosis of AML. This review performed a detailed description of the current state of knowlegde of the myeloproliferative disorders in horses following the criteria established by the World Health Organization.

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BCOR Mutations in Acute Myeloid Leukemia: Clonal Evolution and Prognosis

Blood ◽

10.1182/blood-2020-137127 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-4

Author(s):

Ashley Zhang ◽

Yuntao Liu ◽

Shuning Wei ◽

Benfa Gong ◽

Chunlin Zhou ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Myeloid Leukemia ◽

Statistical Difference ◽

Tp53 Mutation ◽

Clonal Evolution ◽

Normal Karyotype ◽

Abnormal Karyotype ◽

Acute Myeloid

Background BCOR gene is a transcription repressor that may influence normal hematopoiesis and is associated with poor prognosis in acute myeloid leukemia (AML) with normal karyotype. However, due to the rare mutation frequency in AML (3.8%-5%), clinical characteristics and prognosis of AML patients with BCOR mutation including abnormal karyotype are still unknown. In addition, the clonal evolution of AML patients with BCOR mutation has not been fully investigated. Methods By means of next generation of sequencing, we performed sequencing of 114 genes related to hematological diseases including BCOR on 509 newly diagnosed AML patients (except for acute promyelocytic leukemia) from March 2017 to April 2019. The 2017 European Leukemia Net (ELN) genetic risk stratification was used to evaluate prognosis. Overall survival (OS) was defined as the time from diagnosis to death or last follow-up. Relapse-free survival (RFS) was measured from remission to relapse or death. Clonal evolution was investigated through analyzing bone marrow samples at diagnosis, complete remission (CR) and relapse from the same patient. Result Among 509 AML patients, we found BCOR mutations in 23 patients (4.5%). BCOR mutations were enriched in patients with mutations of RUNX1 (p = 0.008) and BCORL1 (p = 0.0003). Patients with BCOR mutation were more at adverse ELN risk category compared to patients without BCOR mutation (p = 0.007). Besides, there was a larger proportion of patients with normal karyotype in BCOR mutation group but it had not reached statistical difference (62.5% vs 45.5%, p = 0.064). The abnormal karyotype in patients with BCOR mutations included trisomy 8, t(9;11), inv(3), -7 and complex karyotype.There were no significant differences in age, sex, white blood cell count, hemoglobin or platelet count between the two groups. More patients died during induction (13.0% vs 3.5%, p = 0.56) and fewer patients achieved CR after 2 cycles of chemotherapy when patients had BCOR mutations (69.6% vs 82.5%, p = 0.115) but the difference had not reached statistical difference . Patients with BCOR mutations had inferior 2-year OS (52.1% vs 70.7%, p = 0.0094) and 2-year RFS (29.8% vs 61.1%, p = 0.0090). After adjustment for ELN risk stratification, BCOR mutation was still remain a poor prognostic factor. However, the adverse prognostic impact of BCOR mutation is overcome by hematopoietic stem cell transplantation (HSCT), in which there was no difference between BCOR mutation group and wild type group (p = 0.474) (Figure 1). Through analysis of paired bone marrow sample at diagnosis, remission and relapse, we revealed the clonal evolution that BCOR mutation was only detected at diagnosis sample as a subclone and diminished at CR and relapse while TP53 mutation was only detected at relapse with a variant allele frequency (VAF) of 25.5%. We also found BCOR mutation at another patient's diagnosis and relapse sample while TP53 mutation was detected at relapse with VAF of 11.8%. Conclusion BCOR is associated with RUNX1 mutation and higher ELN risk. AML patients with BCOR mutation including normal and abnormal karyotype conferred a worse impact on OS that can be overcome by HSCT. BCOR mutation is a subclone at diagnosis or relapse in some patients, in which TP53 mutation clone occurred at relapse. Disclosures No relevant conflicts of interest to declare.

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Tissue microarray technique is applicable to bone marrow biopsies of myeloproliferative neoplasms

Histochemistry and Cell Biology ◽

10.1007/s00418-016-1476-x ◽

2016 ◽

Vol 147 (1) ◽

pp. 75-82 ◽

Cited By ~ 4

Author(s):

Kathrin A. Limberger ◽

Lioudmila Bogatyreva ◽

Rumyana Todorova ◽

Bettina Herde ◽

Dieter Hauschke ◽

...

Keyword(s):

Bone Marrow ◽

Tissue Microarray ◽

Myeloproliferative Neoplasms ◽

Bone Marrow Biopsies ◽

Microarray Technique

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Cytogenetic Studies at Diagnosis in Polycythemia Vera: Clinical and JAK2V617F Allele Burden Correlates.

Blood ◽

10.1182/blood.v110.11.2545.2545 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2545-2545

Author(s):

Naseema Gangat ◽

Jacob J. Strand ◽

Terra L. Lasho ◽

Christy M. Finke ◽

Ryan A. Knudson ◽

...

Keyword(s):

Bone Marrow ◽

Polycythemia Vera ◽

World Health ◽

Chromosome 1 ◽

Leukemic Transformation ◽

Cytogenetic Abnormalities ◽

Allele Burden ◽

Significant Difference ◽

Cytogenetic Studies ◽

Jak2v617f Allele Burden

Abstract Background: Previous cytogenetic studies in polycythemia vera (PV) have included a relatively small number of patients (“n” ranging 10–64). In the current study (n=137), we describe cytogenetic findings at presentation and examine their relationship to clinical and laboratory features, including bone marrow JAK2V617F allele burden. Methods: The study consisted of a consecutive group of patients with PV who fulfilled the World Health Organization (WHO) diagnostic criteria and in whom bone marrow biopsy and cytogenetic studies were performed at diagnosis. Results I: cytogenetic details At diagnosis: A total of 137 patients (median age, 64 years; 49% females) were studied at diagnosis and had adequate metaphases for interpretation. Cytogenetics were normal in 117 patients (85%) and displayed either a sole -Y abnormality in 5 patients (7% of the male patients), and other chromosomal abnormalities in 15 (11%). The latter included trisomy 8 in five patients, trisomy 9 in three patients, two patients each with del(13q), del(20q), and abnormalities of chromosome 1, and one patient each with del(3)(p13p21), dup(13)(q12q14), and del(11)(q21). At follow-up: Repeat cytogenetic studies while still in the chronic phase of the disease were performed in 19 patients at a median of 60 months (range, 8–198) from diagnosis. Of these, 4 had aquired new cytogenetic clones including 3 with normal cytogenetics at time of initial PV diagnosis. The new abnormalities included del(20q), del(5q), del(1p), chromosome 1 abnormality, and inv(3)(q21q26.2). At time of disease transformation: Leukemic transformation was documented in 3 patients of whom cytogenetic information at the time was available in 2 patients; both patients had normal results at time of initial PV diagnosis and complex cytogenetic abnormalities at time of leukemic transformation. In contrast, among 6 patients with available cytogenetic information at time of fibrotic transformation, the results were unchanged from those obtained at time of diagnosis in 5 patients. ii) Correlation between cytogenetics at diagnosis and JAK2V617F allele burden: Allele-specific, quantitative PCR analysis for JAK2V617F was performed in 71 patients using genomic DNA from archived bone marrow obtained at the time of the initial cytogenetic studies. JAK2V617F mutation was detected in 64 of the 71 (90%) patients; median mutant allele burden was 16% (range 3–80%) without significant difference among the different cytogenetic groups: normal vs. –Y vs. other cytogenetic abnormalities (p=0.72). iii) Clinical correlates and prognostic relevance of cytogenetic findings at diagnosis: Among several parameters studied for significant correlations with cytogenetic findings at diagnosis, an association was evident only for age (p=0.02); all –Y abnormalities (n=5) as well as 13 of the 15 (87%) other cytogenetic abnormalities occurred in patients ≥ 60 years of age. Stated another way, the incidence of abnormal cytogenetics (other than -Y) was 4% for patients younger than age 60 years and 15% otherwise. The presence of abnormal cytogenetics at diagnosis had no significant impact on either overall or leukemia-free survival. Conclusions: Abnormal cytogenetic findings at diagnosis are infrequent in PV, especially in patients below age 60 years. Furthermore, their clinical relevance is limited and there is not significant correlation with bone marrow JAK2V617F allele burden.

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