Complex Karyotype Research Articles

Efficacy and safety of venetoclax plus hypomethylating agents in relapsed/refractory acute myeloid leukemia: a multicenter real-life experience.

Venetoclax (VEN) has been shown to play a synergistic effect in combination with hypomethylating agents (HMAs) in the frontline treatment of acute myeloid leukemia (AML). However, the potential role of this therapy in the relapsed/refractory (R/R) AML setting, still needs to be further unveiled. The aim of the current study was to retrospectively outline the safety profile, response and survival outcomes of R/R AML patients treated with VEN in association with HMAs. Clinical, biological, and molecular data were collected from 57 patients with R/R AML treated with VEN combined with azacitidine or decitabine between 2018 and 2023. The median age of patients was 63 years, 38 (66.7%) received treatment for relapsed disease while 19 (33.3%) for refractory disease, 5 (8.7%) were treated for molecular relapse. A consistent proportion of the cohort was represented by patients with unfavorable prognostic factors such as complex karyotype (36.8%), secondary AML (29.8%), previous exposure to HMAs (38.6%), and relapse after allogeneic stem cell transplant (22.8%). A total of 14 patients achieved CR (24.6%), 3 (5.3%) CRi, 3 (5.3%) MLFS, and 3 (5.3%) PR, accounting for an ORR of 40.4%. The CR/CRi rate was higher in the group treated with azacitidine than in the group treated with decitabine (37.8% vs. 15%). The median OS was 8.2 months, reaching 20.1 months among responding patients. VEN-HMAs treatment allowed to bridge to allogeneic stem cell transplantation 11 (23.9%) of eligible patients, for which a median OS of 19.8 months was shown. On multivariate analysis, ECOG performance status ≥2, complex karyotype and not proceeding to allogeneic stem cell transplantation after therapy with VEN-HMAs were the factors independently associated with shorter OS. Patients treated with the azacitidine rather than the decitabine containing regimen generally displayed a trend toward superior outcomes. The major toxicities were prolonged neutropenia and infections. In conclusion, this study showed how VEN-HMAs could represent an effective salvage therapy in patients with R/R AML, even among some of those patients harboring dismal prognostic features, with a good toxicity profile. Further prospective studies are thus warranted.

Establishment of a human ovarian clear cell carcinoma cell line mutant in PIK3CB but not PIK3CA

A human ovarian clear cell carcinoma cell line was established from a 46-year-old Japanese woman. That line, designated MTC-22, has proliferated continuously for over 6 months in conventional RPMI 1640 medium supplemented with 10% foetal bovine serum and has been passaged over 50 times. MTC-22 doubling-time is ~ 18 h, which is much shorter than most ovarian clear cell carcinoma lines reported to date. Morphologically, MTC-22 cells exhibit polygonal shapes and proliferate to form a monolayer in a jigsaw puzzle-like arrangement without contact inhibition. Ultrastructurally, cells exhibit numerous intracytoplasmic glycogen granules and well-developed mitochondria. G-band karyotype analysis indicated that cells have a complex karyotype close to tetraploid. We observed that the expression pattern of a series of ovarian carcinoma-related molecules in MTC-22 cells was identical to that seen in the patient’s tumour tissue. Notably, MTC-22 cells, and the patient’s carcinoma tissue, expressed low-sulphated keratan sulphate recognised by R-10G and 294-1B1 monoclonal antibodies, a hallmark of non-mucinous ovarian carcinoma, and particularly of clear cell ovarian carcinoma. Moreover, characteristic point mutations—one in ARID1A, which encodes the AT-rich interaction domain containing protein 1A, and the other in PIK3CB, which encodes the catalytic subunit of phosphoinositide 3-kinase—were seen in the patient’s tumour tissue and retained in MTC-22 cells. Collectively, these findings indicate that MTC-22 cells could serve as a valuable tool for investigating the pathophysiology of ovarian clear cell carcinoma, particularly that harbouring PIK3CB mutations, and for developing and validating new diagnostic and therapeutic approaches to this life-threatening malignancy.

Kinome expression profiling improves risk stratification and therapeutic targeting in myelodysplastic syndromes

AbstractThe human kinome, which comprises >500 kinases, plays a critical role in regulating numerous essential cellular functions. Although the dysregulation of kinases has been observed in various human cancers, the characterization and clinical implications of kinase expressions in myelodysplastic syndromes (MDS) have not been systematically investigated. In this study, we evaluated the kinome expression profiles of 341 adult patients with primary MDS and identified 7 kinases (PTK7, KIT, MAST4, NTRK1, PAK6, CAMK1D, and PRKCZ) whose expression levels were highly predictive of compromised patient survival. We then constructed the kinase stratification score (KISS) by combining the weighted expressions of the 7 kinases and validated its prognostic significance in 2 external MDS cohorts. A higher KISS was associated with older age, higher peripheral blood and marrow blast percentages, higher Revised International Prognostic Scoring System (IPSS-R) risks, complex karyotype, and mutations in several adverse-risk genes in MDS, such as ASXL1, EZH2, NPM1, RUNX1, STAG2, and TP53. Multivariate analysis confirmed that a higher KISS was an independent unfavorable risk factor in MDS. Mechanistically, the KISS-high patients were enriched for gene sets associated with hematopoietic and leukemic stem cell signatures. By investigating the Genomics of Drug Sensitivity in Cancer database, we identified axitinib and taselisib as candidate compounds that could potentially target the KISS-high myeloblasts. Altogether, our findings suggest that KISS holds the potential to improve the current prognostic scheme of MDS and inform novel therapeutic opportunities.

Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm

AbstractTherapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome-7 abnormalities (4% vs 13%; P = .005) but not complex karyotype (3% vs 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs 12%; P = .04) and lower NRAS (6% vs 22%, P = .007) and CBL (4% vs 12%, P = .04) mutation frequency. Prior therapy with antimetabolites (odd ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.42; P = .01) and mitotic inhibitors (OR, 1.24; 95% CI, 1.06-1.44; P = .009) was associated with NF1 and SETBP1 mutations whereas prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71; 95% CI, 0.55-0.92; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (hazard ratio, 1.76; 95% CI, 1.07-2.89; P = .026). Compared with a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P < .001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.

Abstract 3179: Spindle assembly checkpoint as a therapeutic target for TP53-mutated myeloid neoplasms

Abstract Introduction TP53-mutated (TP53mut) myeloid neoplasms (MN) are a distinct entity of myeloid neoplasms with no effective therapies and poor survival (Grob et al, Blood 2022). The TP53-deficient state facilitates the downstream dysfunction of the spindle assembly checkpoint (SAC), predisposing to genomic instability. Recently, a SAC protein, threonine tyrosine kinase (TTK), has emerged as an attractive therapeutic target. Upregulation of TTK has been described in various solid tumors. It is stipulated that targeting SAC proteins might result in extreme level of genomic instability that even cancer cells could not tolerate. We hypothesized that inhibition of TTK with a small molecular inhibitor—TTKi may offer a promising therapeutic strategy for TP53mut MN. Method We evaluated relative TTK mRNA expression and its association with TP53mut and complex karyotypes (CK) in the BEAT AML cohort (Tyner et al., 2018). We used myeloid cell lines, OCI-AML-3, THP-1, and U937 cell lines that harbor-near diploid, moderately aneuploid, and highly aneuploid karyotype, respectively. The efficacy of TTKi CFI-402257 (AbMole) was tested using cell viability, apoptosis, and colony-forming unit (CFU) assays using the standard protocol. Finally, we tested the efficacy of CFI-402257 using the diagnostic bone marrow mononuclear cell (BMMC) cells from TP53mut MN patients. Results Among 591 AML patients in the BEAT AML cohort (41.6% diploid, 35.9% non-CK, 22.7% CK), TTK mRNA expression was progressively higher with increasing chromosomal abnormality burden. TTK expression was 1.96-fold higher in TP53mut AML compared to TP53wt AML (P=0.0008). Further stratified by TP53mut VAF, there was a trend towards higher expression of TTK in TP53mut VAF≥50 compared to the cases with VAF&amp;lt;50 (P=0.06). Next, the treatment with TTKi (CFI-402257) led to a dose-dependent reduction in cell viability across all cell lines, with TP53mut cells (U937 and THP-1) being more sensitive than TP53-wildtype (TP53wt) OCI_AML-3 cells. Similarly, TTKi inhibited the CFU potential of THP-1, U937, and OCI-AML-3 cells. Finally, TTKi induced dose-dependent apoptosis in TP53mut MN patient BMMC but not in healthy donors, resulting in a significant reduction in colony-forming potential. Conclusion Overexpression of TTK was strongly associated with TP53mut and CK in AML. Inhibition of TTK-induced dose-dependent apoptosis in all myeloid cell lines tested with TP53mut highly aneuploid cell line (U937)—traditionally the most chemorefractory phenotype—being the most sensitive. TTKi induced preferential and dose-dependent inhibition of viability and cell proliferation potential in TP53mut MN compared to healthy donor cells, implying a therapeutic window. Further pre-clinical and clinical studies are indicated to evaluate SAC inhibition as a therapeutic strategy for TP53mut MN. Citation Format: Arini Arsana, Huixing Huang, Arief Al-Kali, Mithun Shah. Spindle assembly checkpoint as a therapeutic target for TP53-mutated myeloid neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3179.

Abstract 1764: Long read sequencing allows comprehensive molecular profiling of complex karyotype acute myeloid leukemia (CKAML) with 5q deletions

Abstract Background Acute myeloid leukemia with complex karyotype (CKAML) does frequently show del(5q), deletion of chromosome 5q. Previous work in MDS and AML showed that CKAML form clusters distinguishing del(5q) cases with commonly retained regions (CRRs) in the telomeric (≥5q34) and centromeric (≤5q14.2) ends from cases with loss of the telomeric and/or centromeric regions. Interestingly, del(5q) patients with CRRs were shown to have less genomic lesions and were associated with a better prognosis than other 5q-deleted CKAML cases. Aim: Combining the advantages of two different long read sequencing technologies, Pacific Biosciences (PacBio) and Oxford Nanopore Technologies (ONT), we aimed to more comprehensively characterize the molecular landscape of CKAML with del(5q). Our integrative workflow enabled an in-depth characterization of copy number variations (CNV), genomic rearrangements, transcriptomic and epigenomic changes. Methods: Low coverage whole genome sequencing (WGS) using ONT was performed on 209 patients with CKAML to identify del(5q) cases for further in-depth analysis. For 10 selected cases with known CRR status, genomic deep sequencing using PacBio Revio and ONT PromethION was performed, as well as PacBio Revio MAS-seq for fusion transcript detection. Results: A mean sequencing depth of 3-fold (range 0.4-17.3-fold) was obtained by low coverage WGS of the 209 CKAML cases. With a resolution of 0.1 Mbp n=134 del(5q) cases were identified in our CKAML cohort (64%) and commonly deleted regions on 5q could be resolved at 5q21.2 to 5q23.3 and 5q33.3 to 5q35 (Fisher test, FDR Benjamini-Hochberg, p&amp;lt;10−30). These regions separated del(5q) in n=52 cases showing CRR retention and n=82 showing partially no CRR, (either the centromeric or telomeric regions, n=74, or of both regions, n=8 involved). Subsequent co-occurrence analysis provided evidence of an association between the loss of telomeric 5q region with a 3p12-25 deletion. In-depth analysis (30-50 fold) of ten distinct del(5q) cases by PacBio and ONT revealed additional insights into the complex clonal composition of del(5q) cases. For example, one case showed two distinct subclones with 5q14.2-5q35.1 deletion and with translocation t(3;5)(p14;q14) respectively. Moreover, we could demonstrate that 5q-aberrations are far more complex than initially thought showing, e.g. inverted terminal duplications that resulted in fusion transcripts involving PDE4D and leading to its deregulated expression. Conclusion: Using our long read deep sequencing approach we could further delineate the structural complexity of del(5q) CKAML. While gene expression profiling, methylation analysis and correlation of findings with clinical outcome are ongoing and will be presented at the meeting, our results help to further pinpoint the biology underlying del(5q) and to further refine this heterogeneous CKAML subgroup. Citation Format: Felix Schick, Ekaterina Slonova, Eric Straeng, Sarah Huet, Maurizio Raso, Marlon Tilgner, Frederik Damm, Pierre Sujobert, Olga Blau, Lars Bullinger, Anna Dolnik. Long read sequencing allows comprehensive molecular profiling of complex karyotype acute myeloid leukemia (CKAML) with 5q deletions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1764.

Transplant versus no transplant in myelodysplastic syndrome and acute myeloid leukemia with TP53 mutation; a referral center experience.

A remarkably high rate of post-transplant relapse in patients with TP53-mutated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) calls to question the utility of allogeneic stem cell transplant (HSCT). We, therefore, performed a retrospective analysis to compare the outcomes between HSCT (N = 38) versus non-HSCT (N = 45) approaches. Patients in the HSCT cohort were younger (median age 63 vs. 72) while patients in the non-HSCT cohort more commonly had complex karyotype with chromosome 17 aberrancy and 5q deletion (p < .01). A total of 69 TP53 variants including 64 pathogenic variants, and 5 variants of undetermined significance were detected. Nine patients (4 in HSCT and 5 in non-HSCT) had multi-hit TP53 variants. After induction: 57.9% versus 56.6% in the HSCT versus non-HSCT cohort achieved morphologic complete remission. Median time to HSCT was 6 months and median follow-up was 15.1 months for HSCT and 5.7 months for non-HSCT. Median disease-free survival (DFS) and overall survival (OS) were 11.7 and 15.9 months for HSCT, and 4.1 and 5.7 months for non-HSCT cohorts, respectively. Non-relapse mortality at 12 months was 22% versus 44% for HSCT versus non-HSCT. In the HSCT cohort, the rate of grade II-IV acute and chronic graft-versus-host disease (GVHD) was 55% and 18%, respectively. None of the patients from the non-HSCT cohort were alive while four patients from the HSCT cohort were alive, in remission, and without GVHD (GRFS) at the time of abstraction. Better treatment strategies for patients with TP53-mutated MDS/AML remain an area of unmet clinical need.

Childhood and Adolescent Relapsed/Refractory Aggressive B-Cell Lymphomas With t(8;14) and BCL2 Expression, Burkitt Lymphoma Versus Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge.

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA).

Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis: A retrospective analysis of the DRST and GREM registries

We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999–2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2–0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1–0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2–6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8–10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.

Strain background of Candida albicans interacts with SIR2 to alter phenotypic switching.

The genetic background between strains of a single species and within a single strain lineage can significantly impact the expression of biological traits. This genetic variation may also reshape epigenetic mechanisms of cell identity and environmental responses that are controlled by interconnected transcriptional networks and chromatin-modifying enzymes. Histone deacetylases, including sirtuins, are critical regulators of chromatin state and have been directly implicated in governing the phenotypic transition between the 'sterile' white state and the mating-competent opaque state in Candida albicans, a common fungal commensal and pathogen of humans. Here, we found that a previously ambiguous role for the sirtuin SIR2 in C. albicans phenotypic switching is likely linked to the genetic background of mutant strains produced in the RM lineage of SC5314. SIR2 mutants in a specific lineage of BWP17 displayed increased frequencies of switching to the opaque state compared to the wild-type. Loss of SIR2 in other SC5314-derived backgrounds, including newly constructed BWP17 sir2Δ/Δ mutants, failed to recapitulate the increased white-opaque switching frequencies observed in the original BWP17 sir2Δ/Δ mutant background. Whole-genome sequencing revealed the presence of multiple imbalanced chromosomes and large loss of heterozygosity tracts that likely interact with SIR2 to increase phenotypic switching in this BWP17 sir2Δ/Δ mutant lineage. These genomic changes are not found in other SC5314-derived sir2Δ/Δ mutants that do not display increased opaque cell formation. Thus, complex karyotypes can emerge during strain construction that modify mutant phenotypes and highlight the importance of validating strain background when interpreting phenotypes.

Blast Phase of Myeloproliferative Neoplasm Resembles Acute Myeloid Leukemia, Myelodysplasia-Related, in Clinical Presentation, Cytogenetic Pattern, and Genomic Profile, and Often Undergoes Reversion to Second Chronic Phase Status After Induction Chemotherapy.

BCR::ABL-negative myeloproliferative neoplasm (MPN) has a prolonged clinical course, and some cases eventually undergo transformation to blast phase; its pathogenesis remains to be elucidated. To evaluate the clinicopathologic characteristics of MPN in blast phase. The study aimed to retrospectively analyze the clinical and laboratory data of 24 cases. Median latency to blast phase was 48 months (range, 7-384 months). Complex karyotypes were seen in 12 of the 24 cases (50%). Overall, 16 cases (66.7%) exhibited high allele burdens of MPN driver mutations along with increased blasts, consistent with linear clonal evolution, whereas the remainder (8; 33.3%) showed loss or partial loss of the driver mutation suggestive of a parallel evolution. Additional mutations were noted in 23 cases (100%), including TP53 mutations in 10 of 24 cases (41.7%). Following chemotherapy, 15 of the 24 patients (62.5%) reverted to a second chronic phase while retaining or regaining MPN driver mutations and losing blast-related mutations, although 9 of the 15 patients (60%) later died of disease progression. Median overall survival was 10 months (CI, 4.6-15.4), with those harboring complex karyotypes demonstrating decreased survival (6 versus 29 months; P = .004). MPN-blast phase resembles acute myeloid leukemia, myelodysplasia-related, in cytogenetic pattern, mutation profile, and clinical outcome. Two patterns of clonal evolution are inferred by dynamic analysis of mutation profiles: linear and parallel evolutions. Although overall survival was dismal, 62.5% of our cases achieved second chronic phase, and they showed better survival than those without second chronic phase.

Myelodysplasia-related gene mutations are associated with favorable prognosis in patients with TP53-mutant acute myeloid leukemia.

This study aimed to examine the characteristics and treatment outcomes of patients with TP53-mutant acute myeloid leukaemia (AML) and to explore potential prognostic factors. This retrospective analysis included 130 patients diagnosed with TP53-mutant AML at the Fujian Medical University Union Hospital between January 2016 and June 2023. Patients' ages ranged from 17 to 80 years, with a median age of 59 years. The proportions of de novo, therapy-related, and secondary AML cases were 71.5%, 7.7%, and 20.8%, respectively. Complex karyotypes were observed in 60.6% of patients, and the proportions of -5 or del(5q), -7 or del(7q), and - 17 or del(17p) were 41.7%, 27.9% and 14.4%, respectively. DNA methylation- and myelodysplasia-related (MR) gene mutations were observed in 36.9% and 25.4% of patients, respectively. These patients showed poor survival, with a median overall survival (OS) of 4.5 months, a 1-year OS rate of 32.5%, a 3-year OS rate of 18.8%, and a 5-year OS rate of 11.3%. The complete response rates for intensive chemotherapy (IC), hypomethylating agent (HMAs)-based therapies, and azacitidine plus venetoclax were 35.7%, 22.2%, and 37.5%, respectively. Patients who did or did not receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) had similar prognoses (median OS: 6.0 vs. 3.9 months; P = 0.6415). Multivariate analysis indicated that MR gene mutations is an independent favorable prognostic factor of OS (HR = 0.366, 95% CI: 0.181-0.738, P = 0.005). In conclusion, patients with TP53-mutant AML have poor prognoses under current treatment strategies and MR gene mutations are associated with a more favorable survival. Therefore, further studies are needed to improve the survival rates in this population.

Risk Factors for Fragility Fractures in Chronic Lymphocytic Leukemia.

Abnormal bone health and fragility fractures (FF) are more common in patients with chronic lymphocytic leukemia (CLL). We hypothesize that there may be risk factors in CLL patients with osteoporosis that increasethe risk of FFs. We conducted a cohort study encompassing all patients diagnosed with CLL from January 1, 2000, to July 31, 2020, utilizing International Classification of Diseases (ICD) codes related to abnormal bone health (osteopenia, osteoporosis, and/or presence of FF) within a single tertiary care institution.Of the 89 patients included, 55 (62%) were female with a mean age of 68 ± 11 years at cohort entry. Fifty-nine (66%) had at least one FF present (pFF) and 30 (34%) did not have an FF (nFF). There were no differences in IGHV (Immunoglobulin heavy chain variable region gene) mutation status, chromosomal abnormalities, or the presence of a complex karyotype. The spine accounted for 81% of identified FF. T-score <-2.5 was more common in those without FF (pFF 38% vs. nFF 71%, P= 0.02). DXA evaluation was not conducted for 36 (40%)individuals within the cohort. Risk factors for fragility fractures included male sex (relative risk [RR] 8.1, 95% confidence interval [CI] 2.1-31.7), diabetes mellitus (RR 1.4, 95% CI 1.04-1.8), smoking (RR 1.3, 95% CI 1.02-1.8), Rai stage >0 (RR 1.4, 95% CI 1.04-1.9), and T-score >-2.5 (RR 1.8, 95% CI 1.1-3.1).There is a high frequency of vertebral FFs in people with CLL despite T-scores not being in the osteoporotic range. Increased awareness to screen and treat vertebral FFs in people with CLL is needed.

Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes.

Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.

Risk factors and remaining challenges in the treatment of acute promyelocytic leukemia.

The treatment of acute promyelocytic leukemia (APL) has evolved with the introduction of all-trans retinoic acid (ATRA) and subsequent arsenic trioxide (ATO), particularly in standard-risk APL with an initial white blood cell count (WBC) < 10,000/μL, where a high cure rate can now be achieved. However, for some patients with risk factors, early death or relapse remains a concern. Insights from the analysis of patients treated with ATRA and chemotherapy have identified risk factors such as WBC, surface antigens, complex karyotypes, FLT3 and other genetic mutations, p73 isoforms, variant rearrangements, and drug resistance mutations. However, in the ATRA + ATO era, the significance of these risk factors is changing. This article provides a comprehensive review of APL risk factors, taking into account the treatment approach, and explores the challenges associated with APL treatments.

Clinical outcomes of patients with acute myeloid leukemia and cardiovascular disease

Incidence of both acute myeloid leukemia (AML) and cardiovascular disease (CVD) increases with age. We evaluated whether pre-existing CVD impacts clinical outcomes in AML. We retrospectively evaluated 291 consecutive adult AML patients treated at our institution, 2014–2020. Pretreatment comorbidities were identified by chart review. Outcomes included complete remission (CR) and CR with incomplete count recovery (CRi) rates, disease-free survival (DFS), overall survival (OS) and incidence of cardiovascular adverse events. CVD was present in 34% of patients at AML diagnosis. CVD patients had worse performance status (p=0.03) and more commonly had secondary AML (p=0.03) and received hypomethylating (HMA) agent-based therapy (72% vs 38%, p< 0.001). CVD (0.45 vs 0.71, p<0.001) and diabetes mellitus (HR= 0.24, 95% CI: 0.08 – 0.8, p= 0.01) were associated with lower probability of achieving CR/CRi. Accounting for age, performance status (PS), complex karyotype, secondary disease and treatment, CVD patients had shorter OS (HR=1.5, 95% CI: 1.1–2.2, p=0.002), with 1- and 3-year OS 44% vs 67% and 25% vs 40%, respectively, but there was no difference in cumulative incidence of relapse between patients with vs without CVD. Thus, CVD is an independent risk factor for lower response rate and shorter survival in AML patients.

Successful treatment of a B/T MPAL patient by chemo-free treatment with venetoclax, azacitidine, and blinatumomab

B/T mixed phenotype acute leukemia (MPAL), which represents only 2–3% of all MPAL cases, is classified as a high-risk leukemia subtype. Adults diagnosed with B/T MPAL have a notably low 3-year survival rate, estimated at 20–40%. The rarity and undercharacterization of B/T MPAL present substantial challenges in identifying an optimal treatment protocol. This report aims to shed light on this issue by presenting a case in which a patient with a complex karyotype was treated using a combination of venetoclax, azacitidine, and blinatumomab. This novel, chemo-free regimen resulted in the patient achieving both hematologic and molecular complete remission, with no severe organ or hematological toxicity observed. Notably, the patient continued to maintain molecular remission for 1 year following the transplantation. Based on these findings, the combination of venetoclax, azacitidine, and blinatumomab could be considered a potential therapeutic approach for B/T MPAL patients, meriting further investigation.

Acute Myeloid Leukemia Post Cytotoxic Therapy in Breast Cancer Survivors-Over 23 Years of Single Center Analysis.

Background: Acute myeloid leukemia post cytotoxic therapy (AML-pCT) among breast cancer (BC) survivors represents a life-threatening complication. This study aims to assess the clinical outcomes of AML-pCT post BC. Methods: An analysis of all AML patients treated at a single hematology center (2000-2023) was performed to select patients with AML-pCT post BC. We applied the 2022 ELN criteria to define the genetic risk. Results: Among 847 AML patients, 28 were diagnosed with AML-pCT following BC. Complex karyotype (CK) occurred in 23.8% of patients. The median overall survival (OS) was 40 months. The survival outcomes were better after allogenic hematopoietic stem cell transplantation (alloHCT) treatment compared to chemotherapy alone (median OS: 47 versus 7 months, p = 0.008). Patients demonstrating CK showed lower survival compared to those without CK (2-year OS: 25.0% versus 66.2%, p = 0.0048). The multivariable Cox proportional hazards regression model indicated that treatment with alloHCT emerged as a significant factor associated with improved OS. The treatment was associated with superior OS (HR = 0.07, 95% CI = 0.01-0.86, p = 0.04). Conclusions: Patients with AML-pCT following BC were characterized with the highest frequency of adverse genetic risk profiles and demonstrated worse survival rates. AlloHCT should be performed as early as possible in such patients. The growing need for studies on inherited cancer susceptibility underscores the importance of close AML-pCT development monitoring in BC survivors.

Genetic landscape and clinical outcomes of patients with BCOR mutated myeloid neoplasms.

The BCL6-corepressor (BCOR) is a tumor-suppressor gene located on the short arm of chromosome X. Data are limited regarding factors predicting survival in BCOR-mutated (mBCOR) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We evaluated 138 patients with mBCOR myeloid disorders, of which 36 (26.1%) had AML and 63 (45.6%) had MDS. Sixty-six (47.8%) patients had a normal karyotype while 18 (13%) patients had complex karyotype. BCOR-mutated MDS/AML were highly associated with RUNX1 and U2AF1 co-mutations. In contrast, TP53 mutation was infrequently seen with mBCOR MDS. Patients with an isolated BCOR mutation had similar survival compared to those with high-risk co-mutations by European LeukemiaNet (ELN) 2022 criteria (median OS 1.16 vs. 1.27 years, P=0.46). Complex karyotype adversely impacted survival among mBCOR AML/MDS (HR 4.12, P<0.001), while allogeneic stem cell transplant (alloSCT) improved survival (HR 0.38, P=0.04). However, RUNX1 co-mutation was associated with an increased risk of post-alloSCT relapse (HR 88.0, P=0.02), whereas melphalan-based conditioning was associated with a decreased relapse risk (HR 0.02, P=0.01). We conclude that mBCOR is a high-risk feature across MDS/AML, and that alloSCT improves survival in this population.

A real-world analysis of clinical outcomes in AML with myelodysplasia-related changes: a comparison of ICC and WHO-HAEM5 criteria

AbstractThe proposed fifth edition of the World Health Organization classification of hematolymphoid tumors (WHO-HAEM5) and International Consensus Classification (ICC) provide different definitions of acute myeloid leukemia with myelodysplasia-related genetics (AML-MR). We conducted a retrospective study which included a cohort of 432 patients, with 354 patients fulfilling WHO-HAEM5 criteria for WHO-AML-MR or 276 patients fulfilling ICC criteria for ICC-AML-MR by gene mutation or cytogenetics (ICC-AML-MR-M/CG). The clinicopathological features were largely similar, irrespective of the classification used, except for higher rates of complex karyotype, monosomy 17, TP53 mutations, and fewer RUNX1 mutations in the WHO-AML-MR group. TP53 mutations were associated with distinct clinicopathological features and dismal outcomes (hazard ratio [HR], 2.98; P < .001). ICC-AML-MR-M/CG group had superior outcome compared with the WHO-AML-MR group (HR, 0.80, P = .032), largely in part due to defining TP53 mutated AML as a standalone entity. In the intensively-treated group, WHO-AML-MR had significantly worse outcomes than AML by differentiation (HR, 1.97; P = .024). Based on ICC criteria, ICC-AML-MR-M/CG had more inferior outcomes compared to AML not otherwise specified (HR, 2.11; P = .048 and HR, 2.55; P = .028; respectively). Furthermore, changing the order of genetic abnormalities defining AML-MR (ie, by gene mutations or cytogenetics) did not significantly affect clinical outcomes. ICC-AML-MR-M/CG showed similar outcomes regardless of the order of assignment. We propose to harmonize the 2 classifications by excluding TP53 mutations from WHO-HAEM5 defined AML-MR group and combining AML-MR defined by gene mutations and cytogenetics to form a unified group.