Monosomal Karyotype In Primary Myelofibrosis Is Prognostically Worse Than Otherwise Unfavorable 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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Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival

Blood ◽

10.1182/blood-2010-11-320002 ◽

2011 ◽

Vol 117 (21) ◽

pp. 5612-5615 ◽

Cited By ~ 49

Author(s):

Rakhee Vaidya ◽

Domenica Caramazza ◽

Kebede H. Begna ◽

Naseema Gangat ◽

Daniel L. Van Dyke ◽

...

Keyword(s):

Myeloid Leukemia ◽

Primary Myelofibrosis ◽

International Prognostic Scoring System ◽

Complex Karyotype ◽

Trisomy 8 ◽

Leukemic Transformation ◽

Free Survival ◽

Hazard Ratios ◽

Risk Patients ◽

Monosomal Karyotype

Abstract Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis. Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival.

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Validation of Monosomal Karyotype Based Model In the Risk Stratification of Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v116.21.2745.2745 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2745-2745

Author(s):

Murtadha K. Al-Khabori ◽

Karen Yee ◽

Vikas Gupta ◽

Aaron Schimmer ◽

Andre Schuh ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Risk Stratification ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Structural Abnormality ◽

Complex Karyotype ◽

Poor Risk ◽

Monosomal Karyotype ◽

Acute Myeloid

Abstract Abstract 2745 Background: The influence of cytogenetic abnormalities on the prognosis of acute myeloid leukemia (AML) has been well-documented; however, the relative impact of certain miscellaneous abnormalities remains controversial. Recently, monosomal karyotype-based risk stratification has been shown to further discriminate the prognosis within the poor-risk karyotype group (Breems et al. JCO 2008), but this finding requires further validation. Methods: We retrospectively reviewed 779 consecutive adult AML patients treated with standard induction chemotherapy, consisting of daunorubicin plus cytarabine (3+7), at our institution from 1998–2008. After excluding patients with favourable risk, normal, missing or failed karyotype, 290 patients remained and were included in the analysis. Results: The baseline characteristics of these 290 patients were as follows: median age 59 y (range 18–81), male 181, prior malignancy 110, median white cell count (WBC) 7.6 × 10^9/L (range 0–246). The karyotypic features included single monosomy in 42, 2 or more monosomies in 51, and non-monosomy structural and numerical abnormalities in 197 patients. Of the 290, 116 (40 %) had three or more abnormalities (complex karyotype, CK). A total of 141 patients (49 %) achieved complete remission (CR) with 3+7 induction chemotherapy. Sixty-four patients received allogeneic stem cell transplantation in CR. The median overall survival (OS) for all patients was 12 months (95% CI: 10–14 months). The median OS was 10 (95% CI: 6–18), 7 (95% CI: 6–10) and 14 months (95% CI: 12–16) in the single monosomy, 2+ monosomy and non-monosomy groups, respectively (p < 0.0001 by log-rank test comparing the three groups). Among the patients containing at least one monosomy, the OS was not significantly different between the CK and non-CK groups (p = 0.08 by log rank). Similarly, in the non-monosomy structural abnormality group, the OS was not significantly different between the CK and non-CK groups (p = 0.2). Conclusions: Our results provide validation for the monosomal karyotype-based risk stratification for AML, indicating that patients with at least one monosomy have an inferior OS compared to other poor-risk non-monosomy groups. Within each of the monosomy and non-monosomy groups, the presence of a complex karyotype does not significantly influence the OS. Disclosures: No relevant conflicts of interest to declare.

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Patients with Monosomal Karyotype in Acute Myeloid Leukemia Is Prognostically Worse Than with Complex Karyotype

Blood ◽

10.1182/blood.v118.21.4735.4735 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4735-4735

Author(s):

Liu Xiaoli ◽

Xu Na ◽

DU Qingfeng ◽

Xu Dan ◽

Meng Fanyi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Confidence Interval ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Disease Free Survival ◽

Structural Abnormality ◽

Complex Karyotype ◽

Significant Difference ◽

Monosomal Karyotype ◽

Acute Myeloid

Abstract Abstract 4735 Purpose: Monosomal karyotype (MK) refers to the presence of two or more distinct autosomal monosomies or a single monosomy associated with a structural abnormality. To analyze the prognosis of cytogenetic components of a complex karyotype or Monosomal Karyotype in acute myeloid leukemia (AML) except acute promyelocytic leukemia(APL). Patients and Methods:Cytogenetics and overall survival (OS), Disease free survival(DFS) were analyzed in 551 AML patients age 14 to 60 years in our center.Results: There ware 235 patiets with cytogenetic abnormalities, 25 cases with inv(16)(p13.1q22) or t(16;16)(p13.1;q22),and 63 cases with t(8;21); 31 cases (13.2%)met the criteria for MK and 39 cases (16.6%) had a complex karyotype without monosomies. OS was significantly inferior in patients with MK compared with those with a complex karyotype without monosomies (P<0.01;HR 1.85,95% confidence interval(95%CI),0.95-2.81). There was no difference between MK cases with complex karyotype cases in DFS (P>0.05□GHR 3.42,95% confidence interval(95%CI),2.96-6.70). There was significant difference in regardless of whether OS or DFS between MK+ patients with MK− patients (P<0.01). Conclusion: MK was one of independent risk factor in AML patients. Disclosures: No relevant conflicts of interest to declare.

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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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Prognostic Value of Complex Karyotype and Monosomal Karyotype in Patients with Adult Acute Lymphoblastic Leukemia Treated with Risk-Adapted Protocols

Blood ◽

10.1182/blood.v120.21.4785.4785 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4785-4785

Author(s):

Cristina Motlló ◽

Josep-Maria Ribera ◽

Mireia Morgades ◽

Isabel Granada ◽

Javier Grau ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Prognostic Value ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Normal Karyotype ◽

Complex Karyotype ◽

Cytogenetic Abnormalities ◽

The Impact ◽

Monosomal Karyotype

Abstract Abstract 4785 Background The karyotype is an important predictor of outcome in adults with acute lymphoblastic leukemia (ALL). Some groups have reported the negative prognostic value of complex karyotype (CK, defined as ≥5 unrelated chromosomal abnormalities) in adult ALL (Moorman et al, Blood. 2007:109;3189-97). On the other hand, monosomal karyotype (MK, defined as ≥2 distinct autosomal chromosome monosomies or 1 single monosomy in the presence of structural abnormalities) has been associated with a worse outcome in patients with acute myeloid leukemia. We aimed to assess the prognostic value of cytogenetic abnormalities, especially CK and MK, in adults with ALL treated with protocols of the Spanish PETHEMA Group. Patients and Methods The karyotypes of 783 adult ALL patients from 63 Spanish centers treated according to the protocols of the PETHEMA Group between 1993 and 2011 were reviewed. The several PETHEMA protocols were risk-adapted (standard-risk –SR–, high-risk –HR–) or subtype-oriented (Philadelphia chromosome [Ph+] ALL -with or without imatinib-, and Burkitt's ALL [BL]). The impact of the main cytogenetic abnormalities as well as of the CK and MK on complete remission (CR) rate, CR duration, overall survival (OS) and event-free survival (EFS) was analyzed. Results The median age of the series was 33 years (range 15–82) and 448 patients (57.2%) were male. The karyotypes of 560 out of 783 patients were evaluable after review: normal karyotype 153 patients, t(9;22) 120, t(v;11q23) 30, t(8;14), t(8;22) or t(2;8) 47, high hyperdiploidy (>50 chromosomes) 53, low hyperdiploidy (47–50 chromosomes) 52, hypodiploidy (45–39 chromosomes) 32 and extreme hypodiploidy (<39 chromosomes) 2. Twenty-eight patients (8.3% of the 338 evaluable karyotypes) had CK and 54 (11.2% of the 481 evaluable karyotypes) had MK. The CR rate, probability of CR duration, the OS probability and the EFS probability are described in table 1. In our study the CK and the MK did not have any impact on CR, CR duration, OS and EFS. Analysis of OS probabilities at 4 years of the most important cytogenetic abnormalities showed: normal karyotype: 46±5%, t(9;22): 20±12%, t(v;11q23): 26±17%, hyperdiplody: 54±15%, hypodiploidy: 47±27%, t(1;19): 44±31% and t(8;14)/t(8;22)/t(2;8): 48±16% (p<0.001). Conclusions Our study confirms that cytogenetics is a very important tool for risk assessment in adult ALL. Patients with t(9;22) and t(v;11q23) had the worst prognosis and the t(1;19) did not have prognostic significance. The introduction of imatinib in patients with t(9:22) ALL significantly improved their outcome. The CK and the MK were not associated with a worse prognosis in patients treated with risk-adapted or subtype-oriented protocols of the PETHEMA group. Disclosures: No relevant conflicts of interest to declare.

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Chromosomal Abnormalities in MDS Are Linked to Dysregulation of CDC20 and CEP55 Genes

Blood ◽

10.1182/blood-2020-143249 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Mayara Magna de Lima Melo ◽

Daniela de Paula Borges ◽

Antônio Wesley Araújo Dos Santos ◽

Gabrielle Melo Cavalcante ◽

Leticia Rodrigues Sampaio ◽

...

Keyword(s):

Bone Marrow ◽

Chromosomal Instability ◽

Spindle Assembly Checkpoint ◽

Chromosomal Abnormalities ◽

Bone Marrow Cells ◽

Conflicts Of Interest ◽

Normal Karyotype ◽

Mitotic Arrest ◽

Complex Karyotype ◽

Increased Risk

Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by cytopenias and an increased risk of progression to acute myeloid leukemia (AML). Its pathogenesis is strictly linked to chromosomal instability, which in turn provides a valuable prognostic marker. Malignant cells develop alternative routes to escape mitosis checkpoints, overcoming the mitotic arrest imposed by Spindle Assembly Checkpoint (SAC), a process dependent on CDC20 inactivation. Abnormal levels of CDC20 can inhibit mitotic arrest, promoting premature exit from mitosis. Overexpression of CEP55 also facilitates the mitotic exit, resulting in polyploidy (an event called Mitotic Slippage). Since chromosomal abnormalities are one of the most important prognostic factors for patients with MDS, this study aimed to analyze the possible link between chromosomal abnormalities and CDC20 and CEP55 mRNA expression in MDS. We evaluated the bone marrow cells from 45 patients diagnosed as MDS according to 2016 WHO-classification (1 MDS-SLD, 15 MDS-RS-MLD, 5 MDS-MLD, 1 t-MDS, and 23 MDS-EB) and 5 bone marrow of healthy controls. Conventional Karyotyping was performed by G-banding of 20 metaphases whenever possible. TaqMan expression assays for CDC20 (Hs00426680_mH) and CEP55 (Hs01070181_m1) were performed in duplicate and the expression ratios were calculated using the 2−ΔCq method. Normality was evaluated by Shapiro-Wilk test. Outliers were removed. The Student's t-test or one-way ANOVA with Tukey/Games Howell post-hoc test was used to analyze the influence of relative expression regarding variables. Patients with MDS showed increased expression of CDC20 and CEP55 compared to healthy individuals (p<0.0001 and p<0.0001). Regarding karyotype, there was the overexpression of CDC20 and CEP55 in patients with altered karyotype and aneuploid karyotype when compared to patients with normal karyotype (p <0.0001 and p =0.001; p = 0.013 and p = 0.022, respectively) (Figure 1A-D). CDC20 and CEP55 have fundamental functions in controlling the progression of metaphase to anaphase and both, when upregulated, induce chromosomal instability. Additionally, patients with del(7q) and complex karyotype showed hyperexpression of CEP55 when compared with patients with normal karyotype (p = 0.005 and p = 0.019) (Figure 1E-F), while patients with deletion (5q) had an increased expression of CDC20 when compared with patients with normal karyotype (p <0.0001). Our group previously demonstrate that high CDC20 protein expression is associated with complex karyotype in MDS patients. Thus, we hypothesized that the deregulation of CDC20 and CEP55 expression induces chromosomal changes, each one in its way. Both can cause disturbances in crucial phases of mitosis (anaphase and cytokinesis, respectively). Finally, we detected a strong correlation between CDC20 and CEP55 (r = 0.646; p <0.0001), suggesting both genes may play a synergistic role during chromosomal abnormalities in MDS, creating possible new targets to be evaluated in MDS. Our data suggest CDC20 and CEP55 as possible new therapeutic targets in MDS. There is a need for further studies, validations and urgent in-depth investigations in cell lines/primary samples or murine models. Disclosures No relevant conflicts of interest to declare.

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High Frequency of AML1/RUNX1 Mutations in Specific Cytogenetic Subgroups in De Novo Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v110.11.986.986 ◽

2007 ◽

Vol 110 (11) ◽

pp. 986-986

Author(s):

Frank Dicker ◽

Claudia Haferlach ◽

Wolfgang Kern ◽

Torsten Haferlach ◽

Susanne Schnittger

Keyword(s):

Trisomy 21 ◽

De Novo ◽

Normal Karyotype ◽

Clinical History ◽

Trisomy 13 ◽

Complex Karyotype ◽

Trisomy 8 ◽

Cytogenetic Aberrations ◽

De Novo Aml ◽

Acute Myeloid

Somatic mutations in the DNA-binding domain, the socalled Runt homology domain, of the AML1/RUNX1 gene have been identified to occur in acute myeloid leukaemia (AML) with the highest incidence in AML M0, in therapy-related myelodysplastic syndrome (t-MDS), in therapy-related AML (t-AML) and AML after MDS (s-AML). Cytogenetic aberrations that are associated with RUNX1 mutations (RUNX1mut) have been reported to be trisomy 13 in AML and trisomy 21 in myeloid malignancies, but also loss of chromosome 7q, mainly in t-MDS but rarely in t-AML. So far the majority of RUNX1mut have been described in secondary or therapy-related cases. Thus, we characterized a cohort of 119 patients (pts) with de novo AML and compared these results to 19 MDS and s-AML, 2 t-MDS (n=2) and 8 t-AML. The cohort was selected for specific cytogenetics with high reported frequencies of RUNX1mut: trisomy 13 (n=17), trisomy 21 (n=9), −7/7q- (n=34). In addition pts with normal karyotype (NK) (n=42), inv(3)/t(3;3) (n=12), trisomy 8 (n=11), complex karyotype (n=13) and 10 pts with various other cytogenetic aberrations (other) were analyzed. The incidence of RUNX1mut in the different cytogenetic subgroups was: 94% (16/17) in +13, 56% (5/9) in +21, 29% (10/34) in −7/7q-, 10% (4/42) in NK, 17% (2/12) in inv(3)/t(3;3), 18% (2/11) in +8, 0% (0/13) in complex karyotype and 20% (2/10) in other, respectively. Based on clinical history we observed RUNX1 mutations in: 6/19 (32%) in MDS/s-AML, 1/10 (10%) in t-MDS/t-AML and 34/119 (29%) in de novo AML. Of the 6 RUNXmut cases with MDS/s-AML the karyotypes were heterogeneous NK (n=1), −7 (n=2) +13 (n=1), +21 (n=1), and inv(3) (n=1). The only recurrent cytogenetic aberration in MDS/s-AML was −7, thus the frequency of RUNXmut in the MDS/s-AML group with −7 was 2/8 (25%). Also the only RUNX1mut case with t-AML revealed a −7. These data correspond to those reported in the literature. We further focussed on the analyses of RUNX1 in de novo AML which is rarely reported so far. In the de novo AML group only we detected RUNX1mut with the highest frequency in +13 (16/16; 100%) followed by +21 (4/8; 50%) −7 (7/21; 33%), + 8 (2/10, 20%), inv(3) (1/8; 12.5%), and NK (3/33; 9.1%). In addition, in the group with “other” aberration 2/8 were mutated. Interestingly, these 2 mutated cases displayed a high number of trisomies including +8 and +13. No RUNX1mut were detected in AML with complex karyotype (n=10). These data for the first time show that RUNX1mut are not strongly correlated to MDS, s-AML or t-AML. With almost the same frequency they can be observed in de novo AML if specific cytogenetic groups are considered. Thus the RUNXmut seem to be more related to these cytogenetic subgroups than to the MDS, s-AML or t-AML.

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Influence of Residual Normal Metaphases In Patients with Monosomal Karyotype.

Blood ◽

10.1182/blood.v116.21.1671.1671 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1671-1671 ◽

Cited By ~ 1

Author(s):

Bin Xie ◽

Megan Othus ◽

Bruno C. Medeiros ◽

Min Fang ◽

Frederick R. Appelbaum ◽

...

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Conflicts Of Interest ◽

Standard Dose ◽

Structural Abnormality ◽

Normal Cells ◽

Monosomy 7 ◽

Abnormal Cells ◽

Monosomal Karyotype ◽

Clonal Abnormalities

Abstract Abstract 1671 Breems et al.(J Clin Oncol 2008;26:4791-97) observed that a monosomal karyotype(MK: ≥ 3 cells with ≥2 autosomal monosomies or with 1 autosomal monosomy plus a structural abnormality) conveyed a worse prognosis in untreated AML than a complex karyotype (CC ≥ 4 distinct clonal abnormalities),although there was considerable overlap between MK and CC. The SWOG (Medeiros et al. Blood e pub June, 2010) has confirmed these findings and extended them to patients age 60 or above. Previous data (Estey et al. Haematologica 2000;85:246-49) suggested that the presence of residual normal cells improved prognosis in patients with monosomy 7, prompting us to see if the same was true in patients with MK. Our analysis focused on survival and used the same 176 MK patients identified by Mederios et al. from 1,344 patients enrolled in one of 10 successive SWOG clinical trials. The MK patients had a median age of 61 years and 94% had a CC (≥ 3 distinct clonal abnormalities); 68% received induction with standard dose ara-C, 14% with other ara-C doses, and 18% without ara-C. A univariate proportional hazards model indicated that survival improved as the % of normal cells increased and accordingly as the % of abnormal cells (MK and non MK) decreased. Further investigation indicated that this reflected the number of normal, rather than the number of abnormal, cells. Thus having one or more normal cells was associated with a hazard ratio (HR) of 0.95 (p = 0.02), while the presence of 5 or more normal cells decreased the HR to 0.76. In contrast, there was no association between the number of abnormal MK cells and survival (p=0.15). Accounting for age and treatment (as noted above) did not alter these conclusions (HR for having 1 or more normal cells 0.95, p = 0.03).Despite the p-values these findings have limited medical significance for MK patients; since even the aforementioned decrease in HR to 0.76 would result in a median survival of only 5.3 months vs. the median of 4 months for all 176 MK patients. Nonetheless the results indicate that it might be worthwhile to examine the prognostic effect of residual normal metaphases in patients with better prognosis karyotypes. Disclosures: No relevant conflicts of interest to declare.

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Is Type of Monosomy (Total or Partial) Crucial for Prognostic Value of Monosomal Karyotype in AML Patients? – Preliminary Results of Retrospective Polish Adult Leukemia Group (PALG) Study,

Blood ◽

10.1182/blood.v118.21.3537.3537 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3537-3537

Author(s):

Ewa Wawrzyniak ◽

Agnieszka Wierzbowska ◽

Kotkowsa Aleksandra ◽

Monika Siemieniuk-Rys ◽

Joanna Kosny ◽

...

Keyword(s):

Bone Marrow ◽

Frailty Index ◽

Treatment Strategies ◽

Best Supportive Care ◽

Structural Abnormality ◽

Complex Karyotype ◽

Partial Monosomy ◽

Monosomy 7 ◽

Exact Test ◽

Monosomal Karyotype

Abstract Abstract 3537 Objectives: Cytogenetics is one of the most important prognostic factors in acute myeloid leukemia (AML). Breems et al., based on banding techniques (BT), have identified a monosomal karyotype (MK) to be associated with particularly poor survival. MK is defined by the presence of an autosomal monosomy in conjunction with at least one other autosomal monosomy or structural abnormality. However, classical BT may be not sufficient to confirm the “real” loss of a particular chromosome, especially in patients with complex karyotype (≥ 3 or ≥ 5 separate abnormalities) where parts of „missing” chromosomes could be involved in structural aberrations such as: additions, derivative chromosomes, rings, marker chromosomes and dicentrics. Molecular cytogenetic techniques, such as FISH, could be useful to verify if observed monosomy was “total” (loss of a complete chromosome) or “partial” (loss of only a part of chromosome including centromere). The aim of our study was to assess if the type of monosomy (total or partial), defined using FISH influences the prognosis of AML patients with MK. Materials and methods: Fifty newly diagnosed AML patients with MK, treated between January 2005 and January 2011 with PALG AML1/2004 and AML2/2004 protocols were included into the study. Cytogenetic analysis was performed on metaphases from bone marrow aspirates taken at diagnosis using standard BT. Karyotypes were centrally reviewed by two independent cytogeneticists and reported in accordance with the ISCN. In 41 cases FISH was performed with painting probes and in justified cases additionally with satellite probes and locus-specific probes to assess the type of monosomy. In 9 patients no confirmation by FISH was needed. Results: In 8/50 (16%) patients FISH verification proved the complex, but not monosomal (total or partial) karyotype. These patients were excluded from further study. The median age of 42 evaluable patients was 58 years (range 20–71 years). There were 26 males and 16 females. Twenty three (55%) patients received intensive induction chemotherapy according to PALG protocols (Holowiecki et al. Leukemia 2004), 8 patients - low dose cytarabine and 11 patients with high frailty index received treatment with hydroxyurea (n=9), and best supportive care (n=2). In 38/42 (90.5%) analyzed cases with MK abnormalities were complex. In all but one ≥5 separate aberrations were present. In 27/42 (64.3%) cases a total monosomy was confirmed by FISH (group A) and in 15/42 (35.7%) cases FISH revealed a monosomy to be the partial one (group B). Both groups A and B were comparable in terms of age, sex, immunophenotype and factors associated with tumor mass (leukemic bone marrow infiltration, WBC and peripheral blood blast count, as well as LDH activity). There was also no difference in the proportion of intensive and non-intensive treatment strategies between both groups. Six (26,1%) of intensively treated patients achieved complete remission (CR). The CR rate in patients with partial monosomy (40%) was higher than in total monosomy group (15,4%), however the difference was not significant (p=0.19; Fisher's exact test). The median overall survival (OS) for all evaluable patients was 66 days (range 1–659 days) and the probability of OS at 1 yr was 14% (95% CI 4–23%). Total monosomy was the only factor associated with decreased probability of OS both in univariate (p=0.036) (Fig. 1) and multivariate (p=0.037) analyses in AML patients with MK. Additionally, in patients with total monosomy the frequency of distinct monosomies was analyzed. The most frequent monosomies were monosomy 7 (n=13; 48%) and monosomy 18 (n=10; 37%). Other total monosomies included: monosomy 17 (n=3; 11%), monosomy 16 (n=2; 7%) and others (n=4). We did not observe any total monosomy 5. Conclusions: Our results indicate for the first time that partial monosomy is associated with significantly better OS than total monosomy in high risk AML with MK and provide further evidence for the heterogeneity of this defined cytogenetic group. These data also clearly demonstrate an important role of FISH method for precise evaluation of complex karyotype, which results in correct classification within MK group, as well as in adequate description of monosomy type. Disclosures: Wierzbowska: Genzyme: Membership on an entity's Board of Directors or advisory committees. Dmoszynska:Roche: Honoraria; Mundipharma:.

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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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