Total Tumor ADC Histogram Analysis: A New Tool for Predicting High-Risk Cytogenetic Abnormalities in Multiple Myeloma Patients.

RATIONALE AND OBJECTIVES: We explored the feasibility of using total tumor apparent diffusion coefficient (ttADC) histogram parameters to predict high-risk cytogenetic abnormalities (HRCA) in patients with multiple myeloma (MM) and compared the performance of an image prediction model based on these parameters with that of a combined prediction model based on these parameters and clinical indicators. METHODS: We retrospectively analyzed the parameters of the ttADC histogram based on whole-body diffusion-weighted images(WB-DWI) and clinical indicators in 92 patients with MM. The patients were divided into HRCA and non-HRCA groups according to the results of the fluorescence in situ hybridization. Logistic regression analysis was used to construct the image prediction and combined prediction models. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to evaluate the performance of the models to identify HRCA. The DeLong test was used to compare the AUC differences of each prediction model. RESULTS: Logistic regression analysis results revealed that the ttADC histogram parameter, ttADC entropy < 7.959 (OR: 39.167; 95% confidence interval [CI]: 3.891-394.208; P < 0.05), was an independent risk factor for HRCA. The image prediction model consisted of ttADC entropy and ttADC SD. The combined prediction model included ttADC entropy along with patient clinical indicators such as biological sex and M protein percentage. The AUCs of the image prediction and combined prediction models were 0.739 and 0.811, respectively (P < .05). The image prediction model showed a sensitivity of 73.9% and a specificity of 68.1%. The combined prediction model showed 82.6% sensitivity and 72.5% specificity. CONCLUSIONS: Using ttADC histogram parameters based on WB-DWI images to predict HRCA in patients with MM is feasible, and combining ttADC parameters with clinical indicators can achieve better predictive performance.

Exploring the Impact of Cytogenetic Abnormalities on Treatment Responses and Survival Outcomes in Multiple Myeloma: A Single-Centre Experience of 13 Years of Follow-Up.

(1) Background: The introduction of novel therapies has led to a considerable evolution in the management of Multiple Myeloma, and chromosomal abnormalities predict the success of treatment. We aimed to characterize cytogenetic abnormalities for risk stratification in the patient population and to evaluate the predictive and prognostic value of the specified abnormalities in distinct treatment modalities. (2) Methods: This study included patients with Multiple Myeloma who applied to the Internal Medicine Clinic of the Cukurova University Faculty of Medicine. Between 2010 and 2023, 98 cases with cytogenetic abnormality data were identified. We analysed the effects of cytogenetic abnormalities on survival and response rates to first chemotherapies. (3) Results: P53 del was the most prevalent abnormality, and t(11;14) was the most common translocation. There was no significant difference in the mean survival and treatment response rates for specific cytogenetic abnormalities. When chemotherapies based on lenalidomide were initiated, patients' life-death statuses differed significantly from those of treatments without lenalidomide. Regardless of the type of chromosomal aberration, lenalidomide-based treatments independently enhanced average survival 14-fold, while there was no significant difference in overall survival among treatments. (4) Conclusions: In individuals with cytogenetic abnormalities, lenalidomide-based treatments should be started regardless of the chemotherapy to be used for the condition.

Prognostic impact of genetic abnormalities in 536 first-line chronic lymphocytic leukaemia patients without 17p deletion treated with chemoimmunotherapy in two prospective trials: Focus on IGHV-mutated subgroups (a FILO study).

The potential prognostic influence of genetic aberrations on chronic lymphocytic leukaemia (CLL) can vary based on various factors, such as the immunoglobulin heavy variable (IGHV) status. We conducted an integrative analysis on genetic abnormalities identified through cytogenetics and targeted next-generation sequencing in 536 CLL patients receiving first-line chemo(immuno)therapies (CIT) as part of two prospective trials. We evaluated the prognostic implications of the main abnormalities, with specific attention to their relative impact according to IGHV status. In the entire cohort, unmutated (UM)-IGHV, complex karyotype, del(11q) and ATM mutations correlated significantly with shorter progression-free survival (PFS). Focusing on the subset of mutated IGHV (M-IGHV) patients, univariate analysis showed that complex karyotype, del(11q), SF3B1 and SAMHD1 mutations were associated with significant lower PFS. The prognostic influence varied based on the patient's IGHV status, as these abnormalities did not affect outcomes in the UM-IGHV subgroup. TP53 mutations had no significant impact on outcomes in the M-IGHV subgroup. Our findings highlight the diverse prognostic influence of genetic aberrations depending on the IGHV status in symptomatic CLL patients receiving first-line CIT. The prognosis of gene mutations and cytogenetic abnormalities needs to be investigated with a compartmentalized methodology, taking into account the IGVH status of patients receiving first-line BTK and/or BCL2 inhibitors.

Tri-ing to decipher trisomy AML.

Lam et al. compared trisomy acute myeloid leukaemia (AML) patients (inclusive of single trisomy, double trisomy or tetrasomy cases) with cytogenetically normal AML to uncover distinguishing molecular and prognostic features of trisomy AML. The study contributes to our understanding of trisomy AML, but the heterogeneity of trisomy subtypes remains a barrier to its study. Commentary on: Lam et al. Distinct karyotypic and mutational landscape in trisomy AML. Br J Haematol 2024;204:939-944.

Cytogenetics in the management of acute myeloid leukemia and histiocytic/dendritic cell neoplasms: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

Genetic data are becoming increasingly essential in the management of hematological neoplasms as shown by two classifications published in 2022: the 5th edition of the World Health Organization Classification of Hematolymphoid Tumours and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Genetic data are particularly important for acute myeloid leukemias (AMLs) because their boundaries with myelodysplastic neoplasms seem to be gradually blurring. The first objective of this review is to present the latest updates on the most common cytogenetic abnormalities in AMLs while highlighting the pitfalls and difficulties that can be encountered in the event of cryptic or difficult-to-detect karyotype abnormalities. The second objective is to enhance the role of cytogenetics among all the new technologies available in 2023 for the diagnosis and management of AML.

Cytogenetics in the management of hematologic neoplasms with germline predisposition: guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

The number of predisposing genes is continuously growing with the widespread availability of DNA sequencing, increasing the prevalence of hematologic malignancies with germline predisposition. Cytogenetic analyses provide an effective approach for the recognition of these malignancies with germline predisposition, which is critical for proper diagnosis, optimal treatment and genetic counseling. Based on the World Health Organization and the international consensus classifications as well as the European LeukemiaNet recommendations, this review first presents an advanced classification of neoplasms with germline predisposition focused on the acquired cytogenetic alterations during leukemogenesis. The various genetic rescue mechanisms and the progression to transformation are then explained. The review also outlines the specific constitutional and somatic cytogenetic aberrations indicative of germline predisposition disorders in B-acute lymphoblastic leukemia (ALL), T-ALL, bone marrow failure syndrome and myeloid neoplasms. An emphasis is made on monosomy 7 in the predisposition field, its frequency and diagnosis impact as well as its various circumstances of occurrence. Lastly, we propose cytogenetic technical recommendations and guidelines for clinical reporting of these specific aberrations.

Additional cytogenetic abnormalities in patients with newly diagnosed acute promyelocytic leukemia predict inferior event-free survival.

BACKGROUND: The innovative combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has established a new chapter of curative approach in acute promyelocytic leukemia (APL). The disease characteristics and prognostic influence of additional cytogenetic abnormalities (ACA) in APL with modern therapeutic strategy need to be elucidated. METHODS: In the present study, we retrospectively investigated disease features and prognostic power of ACA in 171 APL patients treated with ATRA-ATO-containing regimens. RESULTS: Patients with ACA had markedly decreased hemoglobin levels than that without ACA (p = 0.021). Risk stratification in the ACA group was significantly worse than that in the non-ACA group (p = 0.032). With a median follow-up period of 62.0 months, worse event-free survival (EFS) was demonstrated in patients harboring ACA. Multivariate analysis showed that ACA was an independent adverse factor for EFS (p = 0.033). By further subgroup analysis, in CD34 and CD56 negative APL, patients harboring ACA had inferior EFS (p = 0.017; p = 0.037). CONCLUSIONS: To sum up, ACA remains the independent prognostic value for EFS, we should build risk-adapted therapeutic strategies in the long-term management of APL when such abnormalities are detected.

Smoking status in acute myeloid leukemia is associated with worse overall survival and independent of prior nonhematopoietic malignancies, cytogenetic abnormalities, and WHO category.

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with several patient- and disease-associated variables known to impact prognosis. Tobacco smoking is an environmental factor associated with a greater incidence of AML, but there have been limited studies that evaluated smoking toward overall survival. We retrospectively searched for AML cases and collected clinical and diagnostic data for each case. We also used an independent next-generation sequencing (NGS) data set to assess for a distinct mutational signature associated with smoking. When stratified by smoking status, there was a greater number of males, patients aged ≥60 years, and patients with ≥2 comorbidities within the smoking category (P < .05). Survival analysis demonstrated decreased survival probability in the smokers, male smokers, smokers with 1 other comorbidity, and smokers without a prior history of nonhematopoietic malignancy (P < .05) as compared to nonsmokers. Smoking was associated with a decrease in survival within the World Health Organization categories of AML, not otherwise specified (AML NOS; P = .035) and AML with recurrent genetic abnormalities (AML RGA; P = .002). Multivariate analysis showed that patients who were smokers had a greater hazard ratio than nonsmokers after adjusting for the other covariates. Our findings demonstrated that smoking was independently associated with decreased overall survival after adjusting for other potentially confounding factors. In addition, our results suggest that a mutational signature can be recognized using NGS data in a subset of AML patients who smoke.

Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development.

BACKGROUND: Forty-six ,XY Differences/Disorders of Sex Development (DSD) are characterized by a broad phenotypic spectrum ranging from typical female to male with undervirilized external genitalia, or more rarely testicular regression with a typical male phenotype. Despite progress in the genetic diagnosis of DSD, most 46,XY DSD cases remain idiopathic. METHODS: To determine the genetic causes of 46,XY DSD, we studied 165 patients of Tunisian ancestry, who presented a wide range of DSD phenotypes. Karyotyping, candidate gene sequencing, and whole-exome sequencing (WES) were performed. RESULTS: Cytogenetic abnormalities, including a high frequency of sex chromosomal anomalies (85.4%), explained the phenotype in 30.9% (51/165) of the cohort. Sanger sequencing of candidate genes identified a novel pathogenic variant in the SRY gene in a patient with 46,XY gonadal dysgenesis. An exome screen of a sub-group of 44 patients with 46,XY DSD revealed pathogenic or likely pathogenic variants in 38.6% (17/44) of patients. CONCLUSION: Rare or novel pathogenic variants were identified in the AR, SRD5A2, ZNRF3, SOX8, SOX9 and HHAT genes. Overall our data indicate a genetic diagnosis rate of 41.2% (68/165) in the group of 46,XY DSD.

Clinical relevance of high-risk cytogenetic abnormalities and the second revision of the International Staging System (R2-ISS) in patients with multiple myeloma in clinical practice.

High-risk cytogenetic abnormalities (HRCAs) are the most critical factor affecting prognosis in multiple myeloma (MM). However, the clinical significance of HRCAs in routine practice has not been fully elucidated. We retrospectively analyzed clinical features and outcome in 60 newly diagnosed MM patients with or without HRCAs including t(4;14), t(14;16), del(17p), and 1q gain/amplification. The median age was 71 years (range, 35-90). Abnormalities with t(4;14), t(14;16), del(17p), and 1q gain/amplification were found in 10, 1, 6, and 21/14 patients, respectively, and 10 patients had ≥ 2 HRCAs. Patients with HRCAs exhibited progressive clinical features such as anemia, high ß2-microglobulin, and high LDH. Symptomatic relapse was more common in patients with HRCAs. The median progression-free survival (PFS) by number of HRCAs (0, 1, and ≥ 2) was 51.7, 21.4, and 26.1 months (p = 0.011), and the median overall survival (OS) was not reached, 60.7, and 46.8 months (p = 0.045), respectively. Multivariate analysis revealed that HRCAs were an independent factor for PFS. Accordingly, the second revision of International Staging System (R2-ISS), which incorporates HRCA scores, was more useful for prognostic stratification (p = 0.0023). These results suggest that presence of multiple HRCAs including 1q gain/amplification is associated with advanced stage and poor prognosis in clinical practice as well.

Long-term outcomes of aplastic anemia with cytogenetic abnormalities at diagnosis.

OBJECTIVES: To elucidate the clinical characteristics of AA patients with cytogenetic abnormalities. METHODS: We retrospectively screened 30 patients (30/1206, 2.5%) with cytogenetic abnormalities from 1206 patients with severe and very severe AA who received immunosuppressive therapy (IST) during the years 2012-2019. RESULTS: The most common abnormalities were trisomy 8 (+8, 10/30, 33.3%) and loss of Y (-Y, 8/30, 26.7%). The abnormal clones disappeared 6 months after IST in 14 patients and sustained in 12 patients. Patients with sustained abnormal clones had a lower hematologic response at 6 months after IST than the disappeared (33.3% vs. 64.3%, p = .116). The hematologic response after IST, 5-year overall survival, 5-year event-free survival, myelodysplastic syndrome or acute myeloid leukemia transformation in AA patients with cytogenetic abnormalities were not statistically different from those in normal cytogenetic patients. CONCLUSION: For AA patients with chromosome abnormalities but ineligible for hematopoietic stem cell transplant, IST is effective and appropriate as first-line treatment.

A Retrospective Cytogenetic Abnormality in Pediatric Acute Lymphoblastic Leukemia: Report of 11 Years.

Background: Acute lymphoid leukemia (ALL) is the largest subset of hematologic malignancies, accounting for approximately 70%-80% of childhood leukemia, and is most common at age 4 years. The aim of this study was to define the frequency of chromosomal abnormalities in pediatric ALL. Materials and Methods: In this 11-year retrospective study, we investigated 99 patients which referred to our department due to ALL from 2010 to 2020. The age group of the patients ranged from 6 months to 14 years with a mean of 6.71 ± 4.09 years. Clinical and diagnostic findings were extracted from patients' medical records. Results: We showed cytogenetic abnormalities of 99 pediatric ALL patients, including 78 pre-B-ALL, 9 common B-ALL, and 12 T-ALL cases. The 5-year overall survival rate (OSR) and event-free survival (EFS) of all cytogenetic abnormalities (n = 99) were 48% and 43%, respectively. There was a significant relationship between the two cytogenetic abnormalities, hypodiploidy and t(9;22), with death (P < 0.05). On comparing the subjects with normal cytogenetics to the other cytogenetic abnormalities, EFS was significantly low for hypodiploidy (P = 0.0163, hazard ratio = 0.5308) and t(9;22) (P = 0.0131, hazard ratio = 0.4908), while other cytogenetic abnormalities did not have a statistically significant difference in EFS. Conclusions: Our results emphasized the importance of the cytogenetic findings in evaluating the survival outcomes, which allows identifying a variety of OSR and EFS, because some of the cytogenetic abnormalities may interfere with the death and prognosis.

[Treatment strategies for multiple myeloma based on molecular pathogenesis].

It is well documented that multiple myeloma (MM) originates in a single plasma cell transformed by chromosome 14q translocations or chromosomal hyperdiploidy and evolves with the accumulation of point mutations of driver genes and/or cytogenetic abnormalities. Furthermore, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at premalignant stages and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes, including drug sensitivities. Generally, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs although could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to the microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ∼20% of MM evolve neutrally in the context of strong oncogenic drivers, including high-risk IgH translocations, and are relatively resistant to IMiDs. Treatment strategies considering the genomic landscape and the pattern of clonal evolution may further improve the treatment outcome of MM.

[Influence of the number of high-risk cytogenetic abnormalities on the clinical characteristics and prognosis in 360 patients with newly diagnosed multiple myeloma].

Objective: To investigate the influence of the number of high-risk cytogenetic abnormalities (HRCA) on the clinical characteristics and prognosis of patients with newly diagnosed multiple myeloma (MM) . Methods: A total of 360 patients with newly diagnosed MM admitted to Jiangsu Province Hospital between November 2013 and September 2020 were included in this study. Cytoplasmic light chain immunofluorescence with fluorescence in situ hybridization (cIg-FISH) was used to detect HRCA. Cytogenetic abnormalities were combined with clinical characteristics and outcomes for further analysis. Results: Among the 360 patients, 120 patients (33.3%) presented with no HRCAs, and 175 (48.6%) , 61 (16.9%) , and four (1.1%) patients had one, two, and three HRCA (s) , respectively. Patients were divided into three groups, including the no-HRCA group, one-HRCA group, and ≥two-HRCA group, according to the number of HRCAs. There were significant differences in the R-ISS stage, hemoglobin level, albumin level, and the proportion of bone marrow plasma cells among the three groups (P<0.05) . The COX proportional-hazards model identified extramedullary disease (P=0.018) , HRCA ≥ 2 (P=0.001) , and absence of autologous hematopoietic stem cell transplantation (P<0.001) as independent risk factors for progression free survival (PFS) and identified lactate dehydrogenase (LDH) level ≥ 220 U/L (P<0.001) , HRCA ≥2 (P=0.001) , and absence of autologous hematopoietic stem cell transplantation (P=0.005) as independent risk factors for overall survival (OS) . The median PFS was 28 months, 22 months, and 14 months (P=0.005) for the three cohorts, and their OS was not reached,60 months, and 30 months (P=0.001) , respectively. Conclusions: HRCA ≥ 2 is an independent risk factor for decreased survival in patients with newly diagnosed MM. More HRCAs result in heavier tumor burden, as well as a higher risk of disease progression and death.

Chromosomal Instability in Chronic Myeloid Leukemia: Mechanistic Insights and Effects.

The most recent two decades have seen tremendous progress in the understanding and treatment of chronic myeloid leukemia, a disease defined by the characteristic Philadelphia chromosome and the ensuing BCR::ABL fusion protein. However, the biology of the disease extends beyond the Philadelphia chromosome into a nebulous arena of chromosomal and genetic instability, which makes it a genetically heterogeneous disease. The BCR::ABL oncoprotein creates a fertile backdrop for oxidative damage to the DNA, along with impairment of genetic surveillance and the favoring of imprecise error-prone DNA repair pathways. These factors lead to growing chromosomal instability, manifested as additional chromosomal abnormalities along with other genetic aberrations. This worsens with disease progression to accelerated and blast phase, and modulates responses to tyrosine kinase inhibitors. Treatment options that target the genetic aberrations that mitigate chromosome instability might be a potential area for research in patients with advanced phase CML.

The favorable prognostic value of the loss of sex chromosomes in patients with t(8;21) acute myeloid leukemia: an exploratory study.

BACKGROUND: Acute myeloid leukemia (AML) with t(8;21) is generally associated with a favorable clinical course. Loss of sex chromosome (LOS) are frequently observed in t (8;21) AML, but the prognostic value of LOS remains uncertain. METHODS: A total of 73 patients with AML with t(8;21) were studied and divided into t(8;21) with LOS group (n = 36) and t(8;21) alone group (n = 37). The patients with t(8;21) AML with ACAs other than LOS were excluded. The clinical characteristics of these two groups were compared, and the prognostic value of LOS was evaluated based on disease-free survival (DFS) and overall survival (OS). RESULTS: The clinical characteristics (except for gender) were found to have no significant difference between these two groups, and the male patients tended to account for a larger proportion in the former group (P = .001). The OS of the t(8;21) AML with LOS group was significantly longer than that of the t(8;21) AML alone group (P = .005). While not obvious, the patients with LOS seemed to have longer DFS (P = .061). The multivariable analysis also showed LOS to be an independent favorable prognostic factor of t(8;21) AML (P = .022). CONCLUSIONS: Our results suggested that LOS could be associated with a favorable prognosis in t(8;21) AML patients without other ACAs, and for this subtype of AML, longer DFS and a satisfactory and stable survival can be achieved with high-dose cytarabine (HDAC) consolidation treatment.

Cytogenetic abnormalities in NPM1-mutated acute myeloid leukemia.

NPM1mut acute myeloid leukemia (AML) has been identified as a distinct entity of myeloid neoplasms according to the 2017 European LeukemiaNet (ELN) guidelines. It confers a favorable prognosis regardless of cytogenetic abnormalities. We evaluated 418 newly diagnosed AML patients to test the validity of this hypothesis. Seventy-four patients with NPM1mut AML showed a good response to induction and a relatively favorable prognosis. Abnormal karyotypes were observed in 15 patients. Chromosomal abnormalities were significantly associated with a worse prognosis in NPM1mut AML patients (5-year overall survival (OS): 38.9 ± 12.9%, p = .037; event-free survival (EFS): 33.3 ± 12.2%, p = .043, respectively). Four patients with abnormal karyotypes who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) during CR1 had longer survival than those who received chemotherapy only. Multivariable analysis revealed abnormal karyotypes independently predicted OS and EFS among NPM1mut AML patients. In summary, cytogenetic abnormalities are strong prognostic indicators in NPM1mut AML. Therefore, they should be classified accordingly, and alloHSCT should be performed on selected patients during CR1.

Influence of the number of high-risk cytogenetic abnormalities on the clinical characteristics and prognosis in 360 patients with newly diagnosed multiple myeloma / 中华血液学杂志

Objective: To investigate the influence of the number of high-risk cytogenetic abnormalities (HRCA) on the clinical characteristics and prognosis of patients with newly diagnosed multiple myeloma (MM) . Methods: A total of 360 patients with newly diagnosed MM admitted to Jiangsu Province Hospital between November 2013 and September 2020 were included in this study. Cytoplasmic light chain immunofluorescence with fluorescence in situ hybridization (cIg-FISH) was used to detect HRCA. Cytogenetic abnormalities were combined with clinical characteristics and outcomes for further analysis. Results: Among the 360 patients, 120 patients (33.3%) presented with no HRCAs, and 175 (48.6%) , 61 (16.9%) , and four (1.1%) patients had one, two, and three HRCA (s) , respectively. Patients were divided into three groups, including the no-HRCA group, one-HRCA group, and ≥two-HRCA group, according to the number of HRCAs. There were significant differences in the R-ISS stage, hemoglobin level, albumin level, and the proportion of bone marrow plasma cells among the three groups (P<0.05) . The COX proportional-hazards model identified extramedullary disease (P=0.018) , HRCA ≥ 2 (P=0.001) , and absence of autologous hematopoietic stem cell transplantation (P<0.001) as independent risk factors for progression free survival (PFS) and identified lactate dehydrogenase (LDH) level ≥ 220 U/L (P<0.001) , HRCA ≥2 (P=0.001) , and absence of autologous hematopoietic stem cell transplantation (P=0.005) as independent risk factors for overall survival (OS) . The median PFS was 28 months, 22 months, and 14 months (P=0.005) for the three cohorts, and their OS was not reached,60 months, and 30 months (P=0.001) , respectively. Conclusions: HRCA ≥ 2 is an independent risk factor for decreased survival in patients with newly diagnosed MM. More HRCAs result in heavier tumor burden, as well as a higher risk of disease progression and death.

Predictive value of 1q21 gain in multiple myeloma is strongly dependent on concurrent cytogenetic abnormalities and first-line treatment.

Improved therapies in multiple myeloma (MM) have forced a constant risk stratification update, first Durie-Salmon, then international scoring systems (ISS), next revised-ISS (RISS) including high-risk cytogenetic abnormalities (HRCAs) such as del(17p) and t(4;14), and now R2-ISS including 1q21 gain has been proposed. Predictive value of 1q21 gain by itself or in concurrence with other cytogenetic abnormalities is evaluated in 737 real-world plasma cell neoplasm (PCN) patients under current therapies. Ten-year progression-free survival (10y-PFS) rates for patients with 2, 3 and >3 copies of 1q21 were 72.2%, 42.5% and 43.4% (P<1.1×10-17). Cox regression analysis confirmed that 1q21 gain was an independent prognostic factor for PFS (HR=1.804, P<0.0001, Harrell C-statistic =0.7779±0.01495) but not for OS (P=0.131). Gain of 1q21 was strongly associated with hypodiploidy (38.8% vs. 7.0%, P=1.3×10-22), hyperdiploidy (44.1% vs. 16.4%, P=1.6×10-13), HRCAs (12.6% vs. 3.5%, 1.8×10-5), IGH breaks (12.3% vs. 2.1%, P=2.1×10-7) and del(13q) (8.0% vs. 4.0%, P=0.031). In our series, 1q21 gain by itself did not improve RISS predictive capacity in patients either eligible or ineligible for autologous stem cell transplantation (ASCT). However, compared with patients with other 1q21 gains: concurrence with hyperdiploidy improved the prognosis of ASCT-eligible patients from 62.5% to 96.0% 10-year overall-survival (10y-OS, P<0.002); concurrence with hypodiploidy improved the prognosis of ASCT-ineligible patients from 35.7% to 71.0% (P=0.013); and concurrence with del(13q) worsened the prognosis of ASCT-ineligible patients from 12.5% to 53.4% (P=0.035). Gain of 1q21 should be patient-wisely evaluated, irrespective of the RISS, considering its concurrence with other cytogenetic abnormalities and eligibility for ASCT.

Coexistence of myelodysplastic syndrome and acute megakaryoblastic leukemia: An aggressive disease.

Coexistent myelodysplastic syndrome and acute megakaryoblastic leukemia is an aggressive disease which often do not respond to standard chemotherapy due to the various molecular and cytogenetic abnormalities. Understanding of the molecular pathogenesis may lead to better therapeutic modalities as current conventional therapies are largely ineffective.