Search

• Effect of acute myeloid leukemia karyotype on the outcomes of allogeneic stem cell transplantation was tested. • Cytogenetic evolution affects prognosis after allogeneic stem cell transplantation. Recent progress in genetic analysis technology has helped researchers understand the pathogenesis of acute myeloid leukemia (AML). Considering this progress, AML karyotype is still one of the most significant prognostic factors that provides risk-adapted treatment approaches. Karyotype changes during treatment have been observed at times, but their prognostic impact is sparse, especially on allogeneic stem cell transplantation (allo-SCT). Here, we retrospectively investigated the effect of chromosomal changes between diagnosis and pretransplantation on the prognosis of allo-SCT by analyzing the outcomes of 212 consecutive patients who underwent allo-SCT for the first time at Toranomon Hospital, Tokyo, Japan, between 2008 and 2018. Cytogenetic abnormalities at diagnosis and pretransplantation were categorized based on the 2017 European Leukemia Net risk stratification. Genetic abnormalities such as FLT3-ITD and NPM1 were not considered in this study due to lack of genetic information in most patients. We defined cytogenetic evolution as chromosomal changes classified from lower category to higher category. Seventeen patients (8%) had cytogenetic evolution between diagnosis and pretransplantation, and they showed a significantly worse relapse rate than those who were categorized in the intermediate group based on the karyotype at diagnosis (3-year confidence interval [CI] of relapse, 57.4% versus 24.9%; P <.01). In multivariate analysis, cytogenetic evolution before allo-SCT had a significant impact on the CI of relapse (hazard ratio [HR], 3.89; CI, 1.75 to 8.67; P <.01), as well as the high score of the hematopoietic cell transplantation-specific comorbidity index (HR, 0.54; CI, 0.31 to 0.94; P =.03), but had no significant impact on overall survival or nonrelapse mortality. These results indicate that cytogenetic evolution has a significant impact after allo-SCT and should be considered during AML treatment. [ABSTRACT FROM AUTHOR]

This study aimed to validate the capability of the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic scoring system to predict outcomes of patients with myelodysplastic syndromes (MDS) who had undergone HLA-haploidentical related donor hematopoietic stem cell transplantation (haplo-HSCT). We also propose and validate a more suitable prognostic scoring system. A total of 157 patients with MDS who underwent haplo-HSCT were enrolled. The CIBMTR prognostic scoring system could predict the 2-year clinical outcomes, but failed to predict the 100-day clinical outcomes after haplo-HSCT. Our multivariable model identified 2 independent predictors of overall survival: age and monosomal karyotype (MK). Weighted scores of 5, 3, and 2 were assigned to age ≥50 years, age 30 to 49 years, and MK, respectively, and a 2-category system was created: low (score ≤3) and high (score >3). Our refined prognostic scoring system can predict both the 100-day and 2-year clinical outcomes after haplo-HSCT. Our findings indicate that the CIBMTR prognostic scoring system is predictive of the outcomes of patients with MDS following haplo-HSCT, and that older patients with MDS and/or patients with MK should be closely monitored after haplo-HSCT. [ABSTRACT FROM AUTHOR]

The presence of a monosomal karyotype (MK+) and/or a complex karyotype (CK+) identifies subcategories of AML with poor prognosis. The prognostic significance of the most common monosomies (monosomy 5, monosomy 7, and monosomy 17) within MK+/CK+ AML is not well defined. We analyzed data from 1,592 AML patients age 17–93 years enrolled on ECOG-ACRIN therapeutic trials. The majority of MK+ patients (182/195; 93%) were MK+/CK+ with 87% (158/182) having ≥5 clonal abnormalities (CK≥ 5). MK+ patients with karyotype complexity ≤4 had a median overall survival (OS) of 0.4y compared to 1.0y for MK- with complexity ≤4 (p < 0.001), whereas no OS difference was seen in MK+ vs. MK- patients with CK≥ 5 (p = 0.82). Monosomy 5 (93%; 50/54) typically occurred within a highly complex karyotype and had no impact on OS (0.4y; p = 0.95). Monosomy 7 demonstrated no impact on OS in patients with CK≥ 5 (p = 0.39) or CK ≤ 4 (p = 0.44). Monosomy 17 appeared in 43% (68/158) of CK≥ 5 patients and demonstrated statistically significant worse OS (0.4y) compared to CK≥ 5 patients without monosomy 17 (0.5y; p = 0.012). Our data suggest that the prognostic impact of MK+ is limited to those with less complex karyotypes and that monosomy 17 may independently predict for worse survival in patients with AML. [ABSTRACT FROM AUTHOR]

Monosomal karyotype (MK) is known as a far end of the unfavorable cytogenetics in adult acute myeloid leukemia (AML), while available data in childhood AML is scarce. In this study, we investigated the prevalence and prognostic value of MK with retrospectively analyzed 119 patients newly diagnosed with childhood de novo AML. Ten patients (8.4%) revealed to have MK. All MK-positive (MK(+)) AML were associated with complex cytogenetic abnormalities and belonged to the cytogenetic adverse-risk group. Nine of MK(+) patients (90%) achieved complete remission. The event-free survival (EFS) and overall survival (OS) of MK(+) adverse group were comparable to the ESF and OS of MK-negative non-adverse group (EFS 60.0 ± 15.5% vs 59.0 ± 5.1%, P = 0.925; OS 70.0 ± 14.5% vs 58.1 ± 5.3%, P = 0.696). In multivariate analysis, MK was not an independent adverse prognostic factor for EFS (hazard ratio 0.45, 95% C.I. 0.13–1.50, P = 0.194). In addition, 7 of 9 MK(+) patients who received allogeneic hematopoietic stem cell transplantation (HSCT) survived event-free, with a median follow-up of 64 months. In conclusion, MK did not act as an adverse prognostic factor in childhood de novo AML. Allogeneic HSCT might have contributed to the excellent outcome of MK(+) childhood de novo AML. [ABSTRACT FROM AUTHOR]

The plethora of knowledge gained on myelodysplastic syndromes (MDS), a heterogeneous pre-malignant disorder of hematopoietic stem cells, through sequencing of several pathway genes has unveiled molecular pathogenesis and its progression to AML. Evolution of phenotypic classification and risk-stratification based on peripheral cytopenias and blast count has moved to five-tier risk-groups solely concerning chromosomal aberrations. Increased frequency of complex abnormalities, which is associated with genetic instability, defines the subgroup of worst prognosis in MDS. However, the independent effect of monosomal karyotype remains controversial. Recent discoveries on mutations in RNA-splicing machinery ( SF3B1, SRSF2, ZRSR2, U2AF1, U2AF2) ; DNA methylation ( TET2, DNMT3A, IDH1/2 ); chromatin modification ( ASXL1, EZH2 ); transcription factor ( TP53, RUNX1 ); signal transduction/kinases ( FLT3, JAK2 ); RAS pathway ( KRAS, NRAS, CBL, NF1, PTPN11 ); cohesin complex ( STAG2, CTCF, SMC1A, RAD21 ); DNA repair ( ATM, BRCC3, DLRE1C, FANCL ); and other pathway genes have given insights into the independent effects and interaction of co-occurrence of mutations on disease-phenotype. RNA-splicing and DNA methylation mutations appeared to occur early and are reported as ‘founder’ mutations in over 50% MDS patients. TET2 mutation, through altered DNA methylation, has been found to have independent prognostic response to hypomethylating agents. Moreover, presence of DNMT3A, TET 2 and ASXL1 mutations in normal elderly individuals forms the basis of understanding that accumulation of somatic mutations may not cause direct disease-development; however, cooperation with other mutations in the genes that are frequently mutated in myeloid and other hematopoietic cancers might result in clonal expansion through self-renewal and/or proliferation of hematopoietic stem cells. Identification of small molecules as inhibitors of epigenetic mutations has opened avenues for tailoring targeted drug development. The recommendations of a Clinical Advisory Committee is being considered by WHO for a revised classification of risk-groups of MDS, which is likely to be published in mid 2016, based on the new developments and discoveries of gene mutations. [ABSTRACT FROM AUTHOR]

The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed. [ABSTRACT FROM AUTHOR]

Various cytogenetic risk scoring systems may determine prognosis for patients with myelodysplastic syndromes (MDS). We evaluated 4 different risk scoring systems in predicting outcome after allogeneic hematopoietic cell transplantation (alloHCT). We classified 124 patients with MDS using the International Prognostic Scoring System (IPSS), the revised International Prognostic Scoring System (R-IPSS), Armand's transplantation-specific cytogenetic grouping, and monosomal karyotype (MK) both at the time of diagnosis and at alloHCT. After adjusting for other important factors, MK at diagnosis (compared with no MK) was associated with poor 3-year disease-free survival (DFS) (27% [95% confidence interval, 12% to 42%] versus 39% [95% confidence interval, 28% to 50%], P = .02) and overall survival (OS) (29% [95% confidence interval, 14% to 44%] versus 47% [95% confidence interval, 36% to 59%], P = .02). OS but not DFS was affected by MK at alloHCT. MK frequency was uncommon in low-score R-IPPS and IPSS. Although IPSS and R-IPSS discriminated good/very good groups from poor/very poor groups, patients with intermediate-risk scores had the worst outcomes and, therefore, these scores did not show a progressive linear discriminating trend. Cytogenetic risk score change between diagnosis and alloHCT was uncommon and did not influence OS. MK cytogenetics in MDS are associated with poor survival, suggesting the need for alternative or intensified approaches to their treatment. [ABSTRACT FROM AUTHOR]

We investigated the impact of patient and disease characteristics, including cytogenetics, previous therapy, and depth of response, on the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for patients with myelodysplastic syndrome (MDS). We analyzed 256 MDS patients who underwent transplantation from a matched related (n = 133) or matched unrelated (n = 123) donor after 2001. Of the 256, 78 (30.5%) did not receive cytoreductive therapy before HSCT; 40 (15.6%) received chemotherapy, 122 (47.7%) received hypomethylating agents (HMA), and 16 (6.2%) received both (chemo+HMA). Disease status at HSCT defined by International Working Criteria was complete remission in 46 (18%) patients. There were significant differences between therapy groups: there were more therapy-related MDS and higher use of matched related donor in the untreated group. The chemotherapy group had higher serum ferritin levels at HSCT. Patients were older and had more high-risk disease by revised International Prognostic Scoring in the HMA group. Despite those differences, transplantation outcomes were similar in patients who were untreated and who received cytoreductive therapy before HSCT. Three-year event-free survival (EFS) was 44.2%, 30.6%, 34.2%, and 32.8% for untreated, chemotherapy, HMA, and chemo+HMA groups, respectively ( P = .50). Multivariate analyses revealed that older age (hazard ratio [HR], 1.3; P = .001); high-risk histologic subtypes, including refractory anemia with excess blasts (HR, 1.5; P = .05) and chronic myelomonocytic leukemia (HR, 2.1; P = .03), high-risk cytogenetics with monosomal karyotype (MK) (HR, 4.0; P < .0001) and high serum ferritin level at HSCT (HR, 1.8; P = .002) were poor prognostic factors for EFS. Bone marrow blast count 5% or higher at HSCT (HR, 1.6; P = .01) and MK (HR, 4.2; P < .0001) were the only prognostic factors for increased relapse incidence after HSCT. Patients with MK represented a poor prognostic group, with 3-year EFS of 11.4% and relapse incidence of 60.9%. In this analysis, various therapy approaches before HSCT did not lead to different transplantation outcomes. Cytogenetics defined by MK was able to identify a very poor prognostic groups that innovative transplantation approaches to improve outcomes are urgently needed. [ABSTRACT FROM AUTHOR]

Abstract: Monosomal karyotype (MK) and complex karyotype (CK) are well known to be associated with a very poor clinical outcome in patients with acute myeloid leukemia (AML). However, whether or not the prognostic impact of MK and CK remains relevant for patients who have undergone allogeneic hematopoietic cell transplantation (allo-HCT) is still unclear. We retrospectively analyzed the status of MK and CK, as well as other clinical laboratory features, in 148 allo-HCT AML patients at our institution and correlated with their event-free survival (EFS) and overall survival (OS) after transplantation. MK and CK were identified in 14 (9%) and 19 (13%) cases, respectively. On univariate analysis, only age (≥60 years) and WBC count (≥15 × 109/L) were significant adverse predictors for EFS (P < .001 and P = .017, respectively) and OS (P = .002 and P = .021, respectively). MK, CK, and other relevant parameters analyzed did not affect the clinical outcome. Multivariable analysis confirmed that both older age and high WBC count were independent prognostic factors for a shorter OS (P = .001 and P = .003, respectively) and a shorter EFS (P < .001 and P = .001, respectively). Our results indicate that neither MK nor CK are high-risk factors in AML patients undergoing allo-HCT. [Copyright &y& Elsevier]

Abstract: Karyotype is a powerful prognostic factor for complete remission (CR) and overall survival (OS) in acute myelogenous leukemia (AML). Adverse-risk karyotype AML is now treated with intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) to overcome relapse. We attempted to stratify patients with this disease using a combination of known factors. We evaluated clinical correlates in 211 adults with AML and adverse-risk karyotypes. We divided the patients into several subgroups based on the number of chromosomal aberrations (NCAs), normal karyotype (NK) mosaicism, and monosomal karyotype (MK) status. CR rates and survival outcomes were compared among the subgroups, and the relapse rate was calculated in the allo-HSCT subgroup. The cutoff of NCA ≥5 showed the worst OS (P < .001) compared with NCA ≥3 or NCA ≥4 even after allo-HSCT. NK mosaicism significantly improved OS in both the NCA <5 (P = .024) and NCA ≥5 (P = .030) subgroups, but after allo-HSCT, it showed a favorable effect only in the NCA <5 subgroup. MK showed worse OS (P = .041), but there was no significantly worse effect after allo-HSCT compared with non-MK. Finally, we stratified patients into 4 subgroups, NCA ≥5 and NCA <5 with and without NK mosaicism. The most favorable OS and lower relapse rate after allo-HSCT were achieved by the NCA <5 with NK mosaicism subgroup, and the NCA ≥5 without NK mosaicism subgroup showed the worst prognosis in both entire group and allo-HSCT subgroup analysis. This study reveals that the combination of NCA and NK mosaicism may predict survival outcomes accurately, and suggests that novel treatment strategies for highly adverse-risk group AML should be tailored in the future. [Copyright &y& Elsevier]

Abstract: A monosomal karyotype (MK) was identified by banding techniques (BT) in acute myeloid leukemia (AML). However, BT may be insufficient to determine the actual loss of a complete chromosome, especially in complex karyotypes. We have investigated the effect of monosomy type, total (MK-t) and partial (MK-p), reevaluated by FISH, on prognosis. We have found that complete remission rate and probability of overall survival at 1 year was higher in MK-p (n =27) than MK-t (n =15) group (40% vs. 15.4%, P =0.19 and 30% vs. 9%, P =0.046, respectively). Our results indicate for the first time that monosomy type influences the prognosis of MK-AML. [Copyright &y& Elsevier]

Abstract: Several cytogenetic features, including monosomal karyotype (MK), have been associated with unfavorable prognosis in acute myeloid leukemia (AML). However, little is known about the prognostic significance of immunophenotypes in AML patients with unfavorable-risk cytogenetics. We evaluated immunophenotypes, cytogenetics, clinical features and survival outcomes in 233 uniformly treated AML patients who harbored unfavorable cytogenetics. CD11b expression was observed in 145 (70%) of 208 patients and emerged as an independent prognostic factor for inferior overall survival in multivariate analysis (p =0.024). MK and age≥60 years were predictors for lower complete remission rate (p =0.017, p <0.0001, respectively) and shorter overall survival (p =0.024, p <0.0001), while complex karyotype (CK) predicted a shorter overall survival (p =0.013). CD11b expression was strongly correlated with MK and identified a subset of patients with MK who had extremely poor overall survival. We proposed a prognostic scoring model using CD11b positivity, age≥60 years, the presence of MK and the presence of CK to classify the patients into distinct risk groups. We identified the poor prognosis of CD11b expression and validated the adverse influence of MK, CK and age≥60 years in cytogenetically unfavorable AML patients. Our proposed scoring model may be adapted in clinical practice to further the stratification of this high-risk population. [Copyright &y& Elsevier]

Monosomal karyotype (MK) has recently been reported to identify a distinct subset of acute myeloid leukemia (AML) with adverse prognosis. We retrospectively evaluated the frequency of MK in a large cohort of 549 unselected AML cases diagnosed in our department over a period of 13 years and explored potential associations with clinicobiological features and outcome. MK was found in 62 of 549 cases (11.3%), with all but one assigned to the unfavorable cytogenetic risk category; 57 of these 62 MK cases had a complex karyotype. Comparison with a subgroup of AML cases, who had unfavorable karyotypic profiles yet without MK (non-MK) and who were treated uniformly with similar, “3+7”-based regimens, revealed significant (P < 0.05) associations between MK and advanced age, low white blood cell count at diagnosis, and inferior overall survival (6.5 vs. 15 months for non-MK cases). In conclusion, MK defines a sizeable subset of patients with unfavorable cytogenetics who exhibit a distinct clinical profile, even in direct comparison with other unfavorable karyotypes. [ABSTRACT FROM AUTHOR]

We studied cytogenetic risk grouping schemes to stratify patients with acute myelogenous leukemia (AML) (n = 212) into prognostically distinct subgroups for relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (HSCT). Patients were divided according to cytogenetic abnormalities based on the Medical Research Council, Southwest Oncology Group, Cancer and Leukemia Group B (CALGB), Dana-Farber, and recently described monosomal karyotype (MK) classification schemes and analyzed separately for first complete remission (CR1; n = 134) and beyond (CR2+; n = 78). Multivariate analysis was performed after adjusting for age, conditioning intensity, donor type, and cytomegalovirus serology status. Although none of the covariates was associated with OS in CR1, the presence of MK (MK+) was associated with worse RI and PFS (hazard ratio [HR], 3.3, P = .01 and HR, 2.0, P = .05, respectively). No other classification scheme was predictive of outcomes in CR1. In CR2+, for RI, only MK+ was predictive of poor outcome (HR, 3.7; P = .03). For PFS, all 5 classification schemes were predictive, and for OS, both the MK+ and CALGB adverse karyotypes were predictive. In addition to cytogenetics, nonmyeloablative conditioning was associated with decreased PFS and OS in patients in CR2+ in all models. Our results indicate that among all classification schemes, MK classification can identify a subgroup with very poor prognosis in patients with AML after allogeneic HSCT. [Copyright &y& Elsevier]