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

Blood ◽  
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.

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

Blood ◽  
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.

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

Blood ◽  
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.

Revised-IPSS (IPSS-R) Is a Powerful Tool to Evaluate the Outcome of MDS Patient Treated with Azacitidine (AZA): The Groupe Francophone Des Myelodysplasies (GFM) Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 422-422 ◽  
Author(s):  
Lionel Ades ◽  
Mathilde Lamarque ◽  
Sophie Raynaud ◽  
Raphael Itzykson ◽  
Sylvain Thepot ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Scoring System ◽  
Prognostic Value ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Risk Groups ◽  
Predictive Score ◽  
Prognostic Impact ◽  
Very High

Abstract Abstract 422 Background: The IPSS published in 1997, based on cytogenetics, marrow blast % and the number of cytopenias, has played a major role in prognosis assessment in MDS. A provisional revised IPSS had been presented in 2011, which in our experience brought limited additional prognostic value for outcome of AZA treatment (Lamarque, ASH 2011). A final IPSS-R has now been published (Greenberg, Blood 2012), using the same parameters but 5 rather than 3 cytogenetic subgroups (Schanz et al, JCO, 2011), new cut off values for cytopenias and bone marrow blast % and different weighing of parameters. It appears to refine IPSS prognostic value but, like the original IPSS, was established in pts who had received no disease modifying drugs. We assessed the prognostic value of IPSS-R in 264 higher risk MDS treated with AZA, a drug with a survival impact in those pts. Methods: Between Sept 2004 and Jan 2009, before drug approval in EU, we enrolled 282 IPSS high and int 2 (higher) risk MDS in a compassionate patient named program of AZA and established in this cohort a prognostic scoring system (“AZA predictive score” based on Performance status (PS), cytogenetics, presence of circulating blasts, and RBC transfusion dependency) (Itzykson, Blood, 2011). We took advantage of this cohort to evaluate the prognostic impact of IPSS-R in higher risk MDS treated with AZA. Results: Median age was 71 years. WHO diagnosis: 4% RA, RARS or RCMD, 20% RAEB-1, 54%RAEB-2, 22% RAEB-t/AML. Cytogenetics could be reclassified using IPSS-R cytogenetic groups (Shanz, JCO 2011) in 265 pts, in: 1% very good, 37% good, 18% int, 12% poor and 32% very poor. 18%, 48% and 34% pts had Hb<8g/dl, between 8 and 10 and >10 g/dl, respectively. 43%, 32% and 25% had baseline platelet count <50 G/l between 50–100 and >100 G/L, respectively. ANC was <0.8 G/l in 45% pts. Marrow blast % was <=2%, 3–5%, 5–10%, >10 % in 2%, 3%, 18% and 77% pts. Overall IPSS-R could be calculated in 259 patients and was low (1 pt), Intermediate (28 pts, 11%), high (87 pt, 34%) and very high (143 pt, 55% pts). The only pt in the low group was excluded from further analysis. Using the “classical” IPSS, high and Int-2 patients treated with AZA had significantly different Response (37% vs 49%, p=0.05) and OS (median 9.4 vs 16 mo, respectively, p=0.004). Using the IPSS-R, 46%, 47% and 39% responded (CR, PR, or Hematological improvement- HI) to AZA in the int, poor and very poor groups, respectively (p=0.463). Individual IPSS-R parameters, including IPSS-R cytogenetic classification (p= 0.646), Hb level (p= 0.948), platelet count (p=0.10), ANC (p= 0.465) and marrow blast % stratified according to R-IPSS (p=0.287) had no significant impact on AZA response. According to IPSS-R cytogenetic classification, median OS was 21.8 mo, 12.3 mo, 15.1 mo and 7.1 mo in the good, int, poor and very poor risk groups respectively (overall p <10−4). Finally, According to IPSS-R, median OS was 30.7 mo, 17.6 mo, and 10 mo in the Intermediate, High and Very High risk groups, respectively (p <10−4, figure 1). I. The 55% patients with very high risk according to IPSS-R could be further subdivided by our AZA scoring system (Itzykson et al, Blood, 2011) in 3%, 67% and 30% low, int or high risk with a significant different OS across those groups (median not reached (NR), 12.7 and 5.9 mo, p <10−4). Similarly, The 34% patients with high risk according to IPSS-R could be further subdivided by the same AZA scoring system in 6%, 80% and 14% low, int or high risk with a significant different OS across those groups (median NR, 17.3 and 6.1 mo, p <10−4). Conclusion: Contrary to the provisional IPSS-R presented in 2011, the final IPSS-R (Greenberg, Blood 2012) has strong prognostic value for survival in MDS pts treated with AZA.Its prognosic value can be further improved by specific scoring systems established for AZA treatment, like the one published by our group (Itzykson, Blood, 2011). Disclosures: No relevant conflicts of interest to declare.

Impact Of Revised-International Prognostic Scoring System (R-IPSS) Cytogenetic-Risk Stratification In Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5234-5234
Author(s):  
Maria Otazo ◽  
Sarvari Venkata Yellapragada ◽  
Matthew Zheng ◽  
Ang Li ◽  
Ruben Hernandez Perez ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Stratification ◽  
Median Survival ◽  
Predictive Power ◽  
Conflicts Of Interest ◽  
Biological Behavior ◽  
The Impact ◽  
Very High ◽  
Risk Categories

Abstract Background MDS encompasses a heterogeneous group of clonal marrow disorders resulting in various degree of ineffective hematopoiesis and risk of Acute Myelogenous (AML) transformation. Intuitively, the original IPSS (4-categories) lacked predictive power to dissect subgroups with more aggressive biological behavior suitable for MDS disease modifying strategies. The new coalesced R-IPPS discriminates biological subgroups and enhances predictive power based on redefined cytogenetic [5-categories-very good: -Y, del(11q); Good: e.g., normal karyotype, del(5q), del (20q); intermediate: e.g., +8,+19, del(7q); poor: e.g., -7 inv 3/del(3q), complex 3 abnormalities (abn); very poor: complex > 3 abn], depth of cytopenias and revised blast count subcategories at disease initiation, therefore allows more precise risk adapted intervention. Here, we aimed at validating the impact of cytogenetic subcategories on survival and initiated exploration of applicability of R-IPSS in our cohort of veterans diagnosed with MDS. This strategy allowed gaining insight into intrinsic disease characteristics and survival of our population. Methods From 2000-2012, 124 patients (pts) with confirmed diagnosis MDS were identified from the Michael E. Medical Center Cancer Registry. Long rank test was used to compare median Overall Survival (OS) in all generated cytogenetic and R-IPSS subgroups. Given the known effect of patient age on survival, all scored pts had survival age- adjusted using previously described formula (Greenberg. Blood. 2012). Results  Among pts studied, median age was 72 years (range, 53-91). With a median survival for the all cohort of MDS pts of 17.6 months (mo), the 3-years overall survival (OS) was 55%. In our cohort, cytogenetic classification revealed discriminative parameter from variables contained in R-IPSS with OS for very good of 32 mo (N= 10 [9.4%]), good of 26.2 mo (N=64 [59.8 %]), intermediate of 16.8 mo  (N=10 [12.8%]), poor of 12.1 mo (N=14 [16.7%]) and very poor of 4.2 mo (N=9 [7%])  (P=0.5; P=0.11; P= 0.13,P =0.08; P=0.02, respectively) (Fig.1). R-IPSS was calculated as reported. Median OS for patients in low, very low, intermediate, high and very high-risk categories were 34, 35.5, 14.5, 15, 7.8 mo, respectively (Fig.2). Age adjusted median survival estimation allowed more robust discrimination of survival with median survival of 35.5 months (mo) (P=0.8; HR=1), 18.2 mo (P=0.49; HR=1.9), 15 mo (P=0.008; HR=2.1) and 8.5mo (P=0.00; HR=4.1) for low, intermediate, high and very high-risk subgroups (Fig.3). No statistical significance difference in survival was observed between very low and low risk categories. Conclusions Our results validate the predictive value of the newly developed cytogenetic risk stratification groups contained in R-IPSS. For cytogenetic risks, clinical trends were observed across very low, low, intermediate and poor risk with significant different survival seen between poor and very poor cytogenetic groups. When taking in consideration all variables included in R-IPSS, a more precise discrimination of biological subgroups was observed after cohort age-adjustment. Larger pts samples are needed to refine difference in survival between very low and low categories. Disclosures: No relevant conflicts of interest to declare.

scholarly journals FLT3-ITD As a Target for Minimal Residual Disease Monitoring in Early T-Cell Precursor (ETP) Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1073-1073 ◽  
Author(s):  
Nellina Andriano ◽  
Barbara Buldini ◽  
Daniela Silvestri ◽  
Tiziana Villa ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Induction Therapy ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
False Negative ◽  
Consecutive Series ◽  
Prognostic Impact ◽  
Cell Precursor

Abstract Background. The ‘early T-cell precursor’ (ETP) subtype of T-ALL comprises up to 15% of T-ALL and has been reported to be associated with high risk of relapse. In addition to properties of T cell development, gene expression profile and immunophenotype of ETP-ALL show stem cell and early myeloid features. Consistently, this leukemia subgroup shows lower frequencies of prototypical T-ALL lesions and a higher prevalence of mutations typically associated with AML, including RAS and FLT3 mutations. In particular, FLT3-ITD was identified in up to 35% of adult ETP-ALL but data on its prevalence in pediatric ETP-ALL are lacking. In agreement with its stem-cell signature, ETPs frequently lack Immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements, the most used and sensitive targets for MRD monitoring. As a consequence, alternative markers are required to extend the application of molecular MRD to most ETP-ALL patients. Aim. We explored the prevalence of FLT3-ITD mutation in a large series of pediatric ETP-ALL enrolled in two consecutive protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP), and we evaluated the potential use of FLT3-ITD as an alternative DNA marker for MRD monitoring. Methods. Out of 439 T-ALL patients enrolled in Italy into the AIEOP-BFM ALL2000 and AIEOP ALLR2006 consecutive protocols, 145/168 Early-T ALL (TI/II) patients were screened for FLT3-ITD occurrence. Among Early-T patients, 34 were defined as ETP according to immunophenotype, and 31 of them were screened for FLT3-ITD. Twenty-two ETP patients enrolled in Italy into the ongoing AIEOP-BFM ALL2009 were also screened, together with T-ALL cases without IG/TR molecular markers only for the technical validation of the method. PCR screening and RQ-PCR for FLT3-ITD were performed as previously reported (Nakao, Leukemia 1996;10:1911; Beretta, Leukemia 2004;18:1441). Parallel MRD analysis for IG/TR on the same samples, and flow cytometry-MRD were performed by standard procedures. EuroMRD guidelines were applied for performance and interpretation of RQ-PCR. Results. Among ALL2000/R2006 and ALL2009 ETP cases, 4/31 (12.9%) and 3/22 (13.6%) were FLT3-ITD positive, respectively; 5/7 were PPR, and all 7 were stratified as high risk. For ALL2000/R2006 patients, IG/TR MRD monitoring was feasible in 2 cases, and both were MRD-HR; 3/4 cases are alive in CCR, and one died after HSCT. Overall, the FLT3-ITD marker was detected in 12 T-ALL cases; only 4 of them had valuable IG/TR markers, while 8/12 (66%) did not present a suitable IG/TR MRD marker. FLT3-ITD MRD monitoring was performed on 11/12 FLT3-ITD positive T-ALL cases. Mean length of the ITD was 44 nucleotides (nts) (range 24-71), with a mean of 7 randomly inserted nts (range 1-26). Standard curves performed by 10-fold dilutions in DNA from PB Healthy Donor, showed a quantitative range of at least 5.0E-04 in all cases and 1.0E-04 in 5/11. Sensitivity of the assay was at least 1.0E-04 in all tested cases, and 1.0E-05 in 7/11. A comparison between IG/TR and FLT3-ITD was feasible in 3 out of 4 cases (1 is ongoing); all 3 cases were monitored by 2 IG/TR markers. At day15 and day33 of the Induction therapy, when MRD was very high (10-1 to 10-3 range), the IG/TR and FLT3-ITD were fully comparable, with less than 2 times difference. At day78 (after IB Induction block) 1 case was fully negative for both markers, 1 was slightly positive by FLT3-ITD (although not quantifiable and at the limit of the sensitivity) and negative for both IG/TR. The latter case was highly positive for both IG/TR (5.0E-03) but low positive (<1.0E-04) by FLT3-ITD. In this case, the IG/TR and FLT3-ITD were concordant and finally both were negative at subsequent time points. Conclusions. This is the first report on FLT3-ITD prevalence in a consecutive series of children with ETP-ALL, which resulted to be 14.8% (4/31), a value lower than that reported in adult ETP-ALL. The limited number of cases does not allow to draw conclusions on the prognostic impact of FLT3-ITD in ETP-ALL, although 3 out of 4 patients are alive in CCR. Although available in a limited subset, FLT3-ITD can be used as a marker for sensitive molecular MRD monitoring in ETP-ALL, when IG/TR markers are not available (about 2/3 of cases). The results of MRD monitoring in a limited set of cases suggests that ETP patients might respond well to IB Induction therapy. As already known for AML, caution for false negative results is required when only FLT3-ITD is monitored. Disclosures No relevant conflicts of interest to declare.

Validation of Updated Cytogenetic Risk Classification in Patients with Myelodysplastic Syndrome: Retrospective Study at Single Institution.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4837-4837
Author(s):  
Jina Yun ◽  
Jee Hyun Kong ◽  
Jung A. Kim ◽  
Dong Hwan Dennis Kim ◽  
Jun Ho Jang ◽  
...  
Keyword(s):  
High Risk ◽  
Scoring System ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Medical Center ◽  
High Risk Group ◽  
Risk Classification ◽  
International Prognostic Scoring System ◽  
Prognostic Impact ◽  
Very High

Abstract Abstract 4837 Introduction The International Prognostic Scoring System (IPSS) or the WHO Classification-Based Prognostic Scoring System (WPSS) are considered as gold standard to evaluate the patients with MDS in terms of their clinical courses. Recently, a new prognostic cytogenetic risk classification, defined as favorable (5q-, 12p-, 20q-, +21, -Y, 11q-, t(11)(q23), normal, 2 abnormalities including 5q-), intermediate-1 (+1q, 3q21/q26-abnormalities, +8, t(7q), +19, -21, any other single, any other double), intermediate-2 (-X, -7/7q-, 2 abnormalities incl. -7/7q-, complex = 3 abnormalities) or unfavorable risk group (Complex >3 abnormalities), has been reported through 3 large, well-characterized international investigations (German-Austrian (GA), Spanish MDS-registry, IMRAW). This new cytogenetic classification system showed better discrimination of patients according to their prognosis with respect to overall survival and leukemic transformation. The current study attempted to evaluate the new prognostic cytogenetic risk classification in patients with MDS, retrospectively. Patients and methods Between 1996 and 2007, 180 patients with MDS, who were diagnosed and treated at the Samsung medical center, Seoul, Korea, were enrolled into the study. One hundred seventy one patients were analyzed, 115 patients receiving best supportive care were included in the present analysis. Clinical characteristics were as follows; age 59 years (median, range 16-83), male 72%; 3 patients (pts) has 5q-; 1 patient (pt), 12p-; 3 pts, 20q-; 5 pts, -Y; 1 pt, 11q-; 1 pt, t(11)(q23); 80 pts, normal; 2 pts, 2 abnormalities including 5q-; 1 pt, +1q; 1 pt, 3q21/q26-abnormalities; 18 pt, +8; 16 pts, any other single; 19 pts, any other double; 2 pts, -7/7q-; 6 pts, complex = 3 abnormalities; 12 pts, complex >3 abnormalities. Results According to IPSS, 10 patients (9%) were at low risk, 77 patients (67%) at intermediate-1 (Int-1) risk, 22 patients (19%) at intermediate-2 (Int-2) risk and 6 patients (5%) at high risk. According to WPSS, 10 patients (9%) were at very low, 25 patients (22%) at low, 36 patients (31%) at intermediate, 31 patients(27%) at high and 13 patients(11%) at very high risk group. According to new cytogenetic risk classification, 66 patients (57%) were at favorable, 34 patients (30%) at intermediate-1 (Int-1), 9 patients (8%) at intermediate-2 (Int-2) and 6 patients (5%) at unfavorable subgroup. The median OS in overall population was 23.2 months. According to the IPSS, median OS in the Low, Int-1, Int-2 and High subgroup was 37.8, 27.5, 14.8 and 11.6 months, respectively (p<0.001). According to the WPSS, median OS in the subgroup of Very low, Low, Intermediate, High and Very high risk was 54.6, 43.1, 27.5, 16.5 and 11.9 months, respectively (p<0.001). By the new cytogenetic risk classification, median OS in the Favorable, Int-1, Int-2 and Unfavorable subgroup was 23.8, 24.1, 13.0 and 9.1 months (p=0.035). Sixteen cases (13.9%) showed documented leukemic evolutions with median 9.2 months of onset. It was difficult to analyze of leukemic evolution risk due to small number of sample size. Discussion In the present study, the new cytogenetic risk classification does not seem to be validated retrospective series of patients, we couldn't validate that the new cytogenetic subgroups are powerful predictor of prognosis as good as IPSS or WPSS. To warrant availability of the new cytogenetic risk classification, large data sets should be necessary. Also, we should be consider review about the prognostic impact of the karyotype in MDS. Disclosures No relevant conflicts of interest to declare.

Revised Cytogenetic Risk Stratification in Primary Myelofibrosis: A Mayo Clinic Study of 903 Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 631-631 ◽  
Author(s):  
Ayalew Tefferi ◽  
Emnet A Wassie ◽  
Kebede Begna ◽  
Christy Finke ◽  
Alem A Belachew ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Risk Model ◽  
Normal Karyotype ◽  
World Health ◽  
Complex Karyotype ◽  
Mutational Status ◽  
Number Of Patients ◽  
Very High ◽  
Risk Categories

Abstract Background : Cytogenetic abnormalities in PMF have been broadly classified into “favorable” and “unfavorable” risk categories. The latter include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, 11q rearrangements and complex karyotype (Leukemia. 2011;25:82). In a more recent study, we had demonstrated an even worse prognosis for patients with monosomal karyotype (MK), inv(3) and i(17q) abnormalities (Blood. 2011;118:4595). In the current study, we revisited the topic using a larger database. Methods: PMF diagnosis was according to World Health Organization criteria (Blood. 2009;114:937). Cytogenetic analysis and reporting was done according to the International System for Human Cytogenetic Nomenclature (Cytogenetic and genome research. 2013. Prepublished on 2013/07/03 as DOI 10.1159/000353118). Assignment to “normal” karyotype required a minimum of 10 metaphases analyzed. A complex karyotype was defined as the presence of 3 or more distinct structural or numeric abnormalities. MK was defined as 2 or more distinct autosomal monosomies or single autosomal monosomy associated with at least one structural abnormality (JCO. 2008;26:4791). Results : A total of 903 patients (median age 65 years; range 19-92; 63% males) met the above stipulations for study eligibility. Dynamic International Prognostic Scoring System (DIPSS)-plus risk distribution (JCO. 2011;29:392) was high in 344 (38%) patients, intermediate-2 in 334 (37%), intermediate-1 in 128 (14%) and low in 97 (11%). 472 patients were annotated for JAK2/CALR/MPL mutations; 276 (58%) harbored JAK2, 117 (25%) CALR and 33 (7%) MPL mutations. Abnormal karyotype was documented in 437 (48%) patients and included sole abnormalities of 20q- (n=71; 16%), 13q- (n=57; 13%), +8 (n=25; 5%), -7/7q- (n=17; 4%) and +9 (n=16; 3%). 22 (5%) patients displayed MK and 31 (7%) complex karyotype without MK. At a median follow-up time of 3 years, 634 (70%) deaths and 65 blast transformations (BT; 7%) were recorded. A step-wise survival analysis, using “normal karyotype” and “MK/inv(3)/i(17q)” as comparators for “low” and “very high risk” categories, respectively, resulted in four distinct cytogenetic risk designations: very high (MK, inv(3), i(17q), -7/7q-, 11q or 12p abnormalities; n=67), high (complex without MK, two abnormalities not included in very high risk category, 5q-, +8, other autosomal trisomies except +9, and other sole abnormalities not included in other risk categories; n=164), intermediate (sole abnormalities of 20q-, 1q duplication or any other translocation, and -Y or other sex chromosome abnormality; n=133) and low (normal or sole abnormalities of 13q- or +9; n=539); the corresponding median survivals were 0.9, 2.6, 3.8 and 4.6 years, with respective HR (95% CI) of 4.4 (3.3-5.8), 2.0 (1.6-2.4) and 1.3 (1.03-1.6). Very high (HR 6.1, 95% CI 2.9-13.2) and high (HR 2.2, 95% CI 1.1-4.1) risk categories were also associated with higher risk of BT. There was no significant correlation between the revised cytogenetic risk stratification and JAK2/CALR/MPL mutational categories (p=0.22), but none of the triple-negative or MPL-mutated patients displayed “very high risk” karyotype. The revised cytogenetic model was also effective in risk-stratification of JAK2 or CALR mutated patients, when analyzed separately, and its prognostic relevance for survival was generally independent of JAK2/CALR/MPL mutational status (p<0.01), DIPSS (p<0.01) or DIPSS-plus (p<0.01). Comparison of the currently used “favorable” vs “unfavorable” with the revised cytogenetic risk model showed a significant number of patients with “favorable” karyotype (n=213 of total 753) being re-assigned to high (n=82) or intermediate (n=131) risk categories. Conclusions : The currently used cytogenetic risk stratification in PMF is too broad and underestimates prognosis in a significant number of patients with “favorable” karyotype. We have developed a revised four-tier risk model that is independent of conventional risk models and JAK2/CALR/MPL mutational status and is expected to facilitate the development of genetics-based prognostic scoring systems in PMF. Disclosures No relevant conflicts of interest to declare.

Investigation of a 22-gene genomic classifier (GC) for risk stratification and molecular subtyping in an Asian prostate cancer (PCa) cohort.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 249-249
Author(s):  
Wei Loong Sherman Yee ◽  
Wai Yee Woo ◽  
Adelene Sim ◽  
Kar Perng Low ◽  
Alice Meng ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Racial Differences ◽  
White Men ◽  
Risk Groups ◽  
Molecular Subtyping ◽  
Basal Subtype ◽  
Grid Database ◽  
Risk Patients ◽  
Very High

249 Background: A 22-gene GC has been proposed to refine risk stratification of localized PCa by conventional NCCN criteria, and this may potentially influence treatment recommendations. Nonetheless, majority of studies looking at the utility of GC were conducted in White and non-White men from Western cohorts. We therefore investigated the association of GC with NCCN risk groups (RG) in an Asian PCa cohort. Additionally, we examined for inter-racial differences in molecular subtyping between Asian and White/non-White PCa. Methods: GC (Decipher Biosciences Inc., CA) was performed on diagnostic biopsies of men who were treated with radiotherapy +/- hormonal therapy at a single institution (N = 75). ISUP Gleason’s grade (GG) and tumor cellularity were reviewed by an expert GU pathologist. RNA was extracted from 2 x 2.0-mm tumor cores using Qiagen AllPrep DNA/RNA FFPE Kit (Qiagen, Germany) and gene expression was performed on Affymetrix Human Exon 1.0 ST Array (ThermoFischer, CA). PAM50 molecular subtyping was derived using the DecipherGRID database. Results: We profiled 80 tumors from 75 patients, comprising of 18 (24.0%), 9 (12.0%), 21 (28.0%), and 19 (25.3%) NCCN low-/favorable intermediate-, unfavorable intermediate-, high- and very high-RG, respectively; of note, 8 (10.7%) patients had regional/metastatic disease at diagnosis. Using the GC, 27 (33.8%), 14 (17.5%) and 39 (48.8%) were classified as low- (<0.45), intermediate- (0.45-0.6) and high-RG, respectively (>0.6). When stratified using a three-tier clinico-genomic (CG) classification system (Spratt et al. 2017), 6 of 21 (28.6%) NCCN-defined high-risk and 4 of 19 (21.1%) very high-risk patients were downgraded to CG-defined intermediate-/low-risk, while 2 of 27 (7.4%) NCCN low-/intermediate-risk patients were in fact upgraded to CG high-risk. Next, we interrogated the PAM50 basal-luminal signature in our cohort. Interestingly, when matched to White (N = 5762) and non-White (N = 155) for NCCN RG, ISUP GG and age, we observed a high proportion of basal subtype (62.7%) in Asians, which contrasted the prevalence observed in White (16.7%) and non-White (15.9%) North American patients (Chi-sq P <0.001). Conclusions: Here, we demonstrated the utility of the 22-gene GC for refining the NCCN risk stratification in a largest Asian PCa dataset to-date. An unexpectedly high proportion of PAM50 basal-subtype was observed, suggesting race-specific differences of the tumor transcriptome.

Abstract P019: A Single Model For Predicting Major Adverse Cardiovascular Events In Individuals With And Without History Of Atherosclerotic Cardiovascular Disease: The Atherosclerosis Risk In Communities (aric) Study

Circulation ◽  
2021 ◽  
Vol 143 (Suppl_1) ◽  
Author(s):  
Yejin Mok ◽  
Lena Mathews ◽  
Ron C Hoogeveen ◽  
Michael J Blaha ◽  
Christie M Ballantyne ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
High Risk ◽  
Risk Stratification ◽  
Cardiovascular Events ◽  
Major Adverse Cardiovascular Events ◽  
Atherosclerotic Cardiovascular Disease ◽  
Single Model ◽  
History Of ◽  
Very High

Background: In the 2018 AHA/ACC Cholesterol guideline, risk stratification is an essential element. The use of a Pooled Cohort Equation (PCE) is recommended for individuals without atherosclerotic cardiovascular disease (ASCVD), and the new dichotomous classification of very high-risk vs. high-risk has been introduced for patients with ASCVD. These distinct risk stratification systems mainly rely on traditional risk factors, raising the possibility that a single model can predict major adverse cardiovascular events (MACEs) in persons with and without ASCVD. Methods: We studied 11,335 ARIC participants with (n=885) and without (n=10,450) a history of ASCVD (myocardial infarction, ischemic stroke, and symptomatic peripheral artery disease) at baseline (1996-98). We modeled factors in the PCE and the new classification for ASCVD patients (Figure legend) in a single CVD prediction model. We examined their associations with MACEs (myocardial infarction, stroke, and heart failure) using Cox models and evaluated the discrimination and calibration for a single model including those factors. Results: During a median follow-up of 18.4 years, there were 3,658 MACEs (3,105 in participants without ASCVD). In general, the factors in the PCE and the risk classification system for ASCVD patients were associated similarly with MACEs regardless of baseline ASCVD status, although age and systolic blood pressure showed significant interactions. A single model with these predictors and the relevant interaction terms showed good calibration and discrimination for those with and without ASCVD (c-statistic=0.729 and 0.704, respectively) (Figure). Conclusion: A single CVD prediction model performed well in persons with and without ASCVD. This approach will provide a specific predicted risk to ASCVD patients (instead of dichotomy of very high vs. high risk) and eliminate a practice gap between primary vs. secondary prevention due to different risk prediction tools.

Identification of Molecular Biomarkers and Pathways for Risk Stratification in Human Papilloma Virus-Associated Cancers

2021 ◽  
Author(s):  
Eun Jung Kwon ◽  
Hye Ran Lee ◽  
Ju Ho Lee ◽  
Mihyang Ha ◽  
Yun Hak Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Expression Patterns ◽  
Risk Groups ◽  
Molecular Biomarkers ◽  
Low Risk ◽  
Receptor Interaction ◽  
Prognostic Impact ◽  
Tumor Microenvironments ◽  
Cell Immunity

Abstract Background: Human papillomavirus (HPV) is the major cause of cervical cancer (CC) etiology; its contribution to head and neck cancer (HNC) incidence is steadily increasing. As individual patients’ response to the treatment of HPV-associated cancer is variable, there is a pressing need for the identification of biomarkers for risk stratification that can help determine the intensity of treatment. Methods: We have previously reported a novel prognostic and predictive indicator (HPPI) scoring system in HPV-associated cancers regardless of the anatomical locations by analyzing the TCGA and GEO databases. In this study, we comprehensively investigated the association of group-specific expression patterns of common differentially expressed genes (DEGs) between high-risk and low-risk groups in HPV-associated CC and HNC, identifying a molecular biomarkers and pathways for the risk stratification. Results: Among the identified 174 DEGs, expression of the genes associated with extracellular matrix (ECM)-receptor interaction pathway (ITGA5, ITGB1, LAMB1, LAMC1) were increased in high-risk groups in both HPV-associated CC and HNC while expression of the genes associated with the T-cell immunity (CD3D, CD3E, CD8B, LCK, and ZAP70) were decreased vise versa. The individual genes showed statistically significant prognostic impact on HPV-associated cancers but not on HPV-negative cancers. The expression levels of identified genes were similar between HPV-negative and HPV-associated high-risk groups with distinct expression patterns only in HPV-associated low-risk groups. Each group of genes showed negative correlations, and distinct patterns of immune cell infiltration in tumor microenvironments. Conclusion: These results identify molecular biomarkers and pathways for risk stratification in HPV-associated cancers regardless of anatomical locations. The identified targets are selectively working in only HPV-associated cancers, but not in HPV-negative cancers indicating possibility of the selective targets governing HPV-infective tumor microenvironments.

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