Common Cytogenetic Abnormalities Research Articles

Prognostic Implications of Circulating Plasma Cell Percentage in Multiple Myeloma and Primary Plasma Cell Leukemia Defined by New Criteria

Introduction: The definition of primary plasma cell leukemia (pPCL) has been revised from ≥20% to ≥5% circulating plasma cells (CPC). However, the precise prognosis associated with CPC remains controversial. This study aimed to investigate prognostic biomarkers for myeloma patients based on CPC presence. Methods: A comprehensive analysis was conducted on 309 consecutive patients diagnosed with either multiple myeloma or pPCL, utilizing peripheral blood smears stained with Wright-Giemsa. Results: Patients were grouped by CPC percentage: 0% (221, 71.5%), 1–4% (49, 15.9%), 5–19% (16, 5.2%), ≥20% (23, 7.4%). CPC >5% correlated with unfavorable characteristics, including anemia, renal dysfunction, and advanced International Staging System. Common cytogenetic abnormalities such as 1q21 amplification, 17p deletion, and Myc rearrangement were prevalent among CPC-positive patients. Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with CPC ≥5% (29.47 vs. 10.03 months; 64.10 vs. 12.30 months). Additionally, PFS and OS were shorter in CPC-positive patients without autologous hematopoietic stem cell transplantation (ASCT) and those with response < partial remission to the first-line regimen. Furthermore, an association emerged between soft tissue-related extramedullary disease and inferior PFS, while Myc rearrangement correlated with abbreviated OS. Conclusion: Biological characteristics displayed greater aggressiveness in patients with positive CPC, leading to significantly shorter PFS and OS. The presence of CPC, ASCT, and overall response rate were independent prognostic factors. While no new threshold for pPCL with CPCs is proposed, Myc rearrangements and CPC positivity could serve as ultra-high-risk factors for multiple myeloma.

Abstract 5053: Clinicopathologic and molecular genetic features of STAT3-mutated myeloid neoplasms

Abstract STAT3 is a key transcription factor that can mediate cancer progression through phosphorylation or gain-of-function mutations. STAT3 mutations have been mainly associated with large granular lymphocytic T-cell leukemia. Whereas STAT3 activation is common in myeloid neoplasms, it is primarily mediated through STAT3 phosphorylation. STAT3 mutation has only rarely been reported in myeloid neoplasms. We assessed the clinicopathologic and molecular genetic features of 32 STAT3-mutated myeloid neoplasms. Twenty (62.5%) cases were classified as acute myeloid leukemia (AML), 7 (21.9%) as myelodysplastic syndrome (MDS), and 5 (15.6%) as chronic myelomonocytic leukemia (CMML). It is of note that STAT3 mutation was not detected in myeloproliferative neoplasms (MPN). STAT3 mutations were detected at the initial diagnosis in 22 of 25 (88%) cases, suggesting STAT3 mutation is an early event in pathogenesis. However, STAT3 mutations represented the dominant clone in only 6 (18.8%) cases, all classified as AML. Most are missense mutations, located at the SH2 domain. The median variant allele frequencies were 6.8%, 4.6% and 3.1% for AML, MDS and CMML, respectively, and in a case of CMML, the VAF increased from 2.4% to 34.8% upon leukemic transformation. STAT3 mutation was accompanied by co-existing mutations in all cases, with SRSF2 (40.6%), TET2 (40.6%), ASXL1 (37.5%), and SETBP1 (34.4%) being most common. Cases with STAT3 mutations were usually associated with morphologic dysplasia and increased blasts. Monosomy 7/del7q was the most common cytogenetic abnormality, seen in 11 (34.4%) cases. With a median follow-up of 24.5 months, 21 patients died, 6 had persistent disease, and 5 achieved complete remission. We summarize that STAT3 mutation is present in a variety of myeloid neoplasms, but not seen in MPN. It is often an early events and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by activating JAK-STAT pathway, and may serve as a potential therapeutic target. Citation Format: Matthew T. Ye, Zhuang Zuo, Steliana Calin, Fengxi Ye, Hua He, Wataru Kamata, M. James You. Clinicopathologic and molecular genetic features of STAT3-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 5053.

Efficacy Analysis of Bortezomib Combined with Lenalidomide in Newly Diagnosed Multiple Myeloma with 1q21 Gain/Amp.

1q21 gain/Amp is one of the most common cytogenetic abnormalities. There are controversies about its effects on prognosis and may be associated with inferior outcomes in patients with newly diagnosed multiple myeloma (NDMM). To explore the optimal induction treatment, we analyzed and compared the efficacy of combinations of bortezomib-lenalidomide-dexamethasone (VRD) and only bortezomib-based triplet regimens without lenalidomide (only bortezomib-based) as induction therapy in patients with NDMM with 1q21 gain/Amp. Seventy-six NDMM patients with 1q21 gain/Amp who were admitted to our center from 2016 to 2022 were retrospectively analyzed in this study. The progression and efficacy of the patients were observed. Within our study group, the overall survival rate stood at 75.0%, and the progression-free survival (PFS) rate reached 40.8% in NDMM patients with 1q21 gain/Amp. The best outcome assessment was that 17.1% achieved complete response (CR) and 44.7% achieved very good partial response (VGPR). Patients in the VRD group had a deeper response (VGPR: 63.6% vs 37.0%, P = 0.034), lower disease progression rate (31.8% vs 70.3%, P = 0.002), longer sustained remission (median 49.7 months vs 18.3 months, P = 0.030), and longer PFS (median 61.9 months vs 22.9 months, P = 0.032) than those treated with only bortezomib-based induction therapy. No significant differences were found among patients with partial response or better (86.4% vs 77.8%, P = 0.532) or CR (27.3% vs 13.0%, P = 0.180). Multivariate analysis showed that only bortezomib-based induction therapy (P = 0.003, HR 0.246, 95% CI 0.097-0.620), International Staging System stage III (P = 0.003, HR 3.844, 95% CI 1.588-9.308) and LMR <3.6 (P = 0.032, HR 0.491, 95% CI 0.257-0.940) were significantly associated with adverse PFS. When compared with the sequential administration of bortezomib and lenalidomide or only bortezomib-based protocols, NDMM patients with 1q21 gain/Amp may benefit more from VRD as initial treatments.

ALL induction outcome: Real-world data from a pediatric oncology center in an LMIC setup with rural predominance.

Acute lymphoblastic leukemia (ALL) has survival rates of greater than 90% in developed nations. However, various sociodemographic factors adversely affect outcome rates in low- and middle-income countries (LMICs). To study induction outcome of ALL and various factors affecting it. This was a prospective cohort study which enrolled 86 children up to the age of 18 years with newly diagnosed ALL registered in newly established pediatric hematology and oncology division over the duration of 3 years. Sociodemographic and clinical data was collected. Outcome was assessed using morphological remission, minimal residual disease (MRD) and mortality rate. Of the 170 children with malignancies registered, 86 were ALL. Mean age was 7.09 ± 4.07 years and the M: F ratio of 1.32:1. Sixteen (38.09%) of them had severe acute malnutrition and another 16 (38.09%) had moderate acute malnutrition. Thirty (68.18%) children over 5 years were undernourished. Seventy-four (86.05%) were B-ALL and 12 (13.95%) T-ALL. In total, 28.77% had WBC counts greater than 50 × 109/L. t (12;21) was the most common cytogenetic abnormality. Majority (60.46%) of the patients belonged to lower socioeconomic status. Seventy-one (93.42%) patients completed induction of which 100% attained morphological remission and 64 (90.14%) were MRD negative. There were five mortalities, three (60%) due to sepsis and 2 (40%) due to hemophagocytic lymphohistiocytosis. Fifty (65.78%) children had morbidities during induction, febrile neutropenia being the commonest. Successful induction outcome rates at par with high-income countries can be achieved even in resource-limited settings of LMIC with support from government and NGOs. Decentralized cancer care centers can effectively pave the way in reducing cancer mortality in children of lower socioeconomic status residing in rural areas.

1q21+ is associated with poor prognosis in newly diagnosed multiple myeloma patients with extramedullary disease: a retrospective study.

1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered an independent predictor of poor prognosis; however, its impact on extramedullary disease (EMD) remains unknown. Our study reviewed the clinical relevance and prognostic value of 1q21+ status in 92 patients with NDMM and EMD. 1q21+ was detected in 23.9% (22/92) of patients. Patients with 1q21+ presented with advanced International Staging System stages (P = 0.006), lower level of hemoglobin (P = 0.004), higher percentage of plasma cells in the bone marrow (P < 0.001), higher level of serum β2-microglobulin (7.24g/L vs. 3.85g/L, P = 0.003), and higher levels of lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P = 0.019). The prevalence of soft tissue-related EMD (EMD-S) (54.5% vs. 18.6%, P < 0.001), renal dysfunction (50.5% vs. 17.7%, P = 0.002), and hypercalcemia (27.3% vs. 7.1%, P = 0.011) was also higher. 1q21+ was strongly associated with other high-risk cytogenetic abnormalities, including IgH/FGFR3 (22.7% vs. 4.3%, P = 0.007) and IgH/MAF translocations (22.7% vs. 1.4%, P < 0.001). 1q21+ patients had significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24months vs. 47months, P = 0.002; PFS: 14months vs. 38months, P < 0.001); the poor survival outcomes could not be reversed by autologous hematopoietic stem cell transplantation. Multivariate analysis suggested that 1q21+ , EMD-S, elevated lactate dehydrogenase (LDH) levels, and P53 deletion were independent risk factors for poor prognosis in patients with EMD. In patients with 1q21+ EMD, hypercalcemia, elevated LDH levels, and P53 deletion were independent adverse risk prognostic factors.

The der(1;7)(q10;p10) defining a distinct profile from -7/del(7q) in myelodysplastic syndromes: Asystematic review and meta-analysis.

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by ineffective hematopoiesis due to stem cell abnormalities. Monosomy 7q aberrations are a common cytogenetic abnormality in MDS. Specifically, an unbalanced translocation der(1;7)(q10;p10) [der(1;7)] has been identified in MDS patients, which is a monosomy 7q aberration variant like -7/del(7q). However, knowledge of der(1;7)'s features remains limited. Existing studies have compared the clinical and genetic characteristics of der(1;7) to those of -7/del(7q) but yielded inconsistent findings. Accordingly, we conducted meta-analyses comparing der(1;7) to -7/del(7q). Publications were searched from the following databases up to January 10, 2023: Pubmed, Web of Science, Embase, Cochrane, and ClinicalTrials.gov. Eligible studies were assessed for risks of bias. Relevant data were extracted from included studies and analyzed using random-effects models. Publication bias was evaluated and sensitivity analyses were performed. The comparative meta-analyses included 405 MDS patients with der(1;7) from nine studies. The analysis revealed that der(1;7) was associated with a greater male preponderance (86.1% vs. 68.3%, Odds Ratios (ORs) 2.007, p < 0.01) than -7/del(7q), lower platelets counts compared to del(7q), higher hemoglobin levels than -7, lower absolute neutrophil counts, and higher percentage of patients with non-excess blasts (66.9% vs. 41.3%, ORs 2.374, p = 0.01) in comparison with -7/del(7q). The der(1;7) existed more as a sole karyotype aberration (55.6% vs. 37.0%, ORs 2.902, p = 0.02), co-occurred more often with +8 (22.7% vs. 4.2%, ORs 5.714, p = 0.04) whereas less -5/del(5q) (1.5% vs. 41.3%, ORs 0.040, p < 0.01) and complex karyotype (7.3% vs. 54.8%, OR 0.085, p < 0.01). The der(1;7) was associated with higher frequencies of RUNX1 (40.8% vs. 12.3%, ORs 4.764, p < 0.01), ETNK1 (28.1% vs. 2.5%, ORs 42.106, p < 0.01) and EZH2 (24.8% vs. 6.9%, ORs 3.767, p = 0.02) mutations, but less TP53 mutation (2.4% vs. 45.3%, ORs 0.043, p < 0.01). Moreover, der(1;7) patients had longer time to progression (Hazard Ratios (HRs) 0.331, p = 0.02), better overall survival (OS) than -7 patients (HRs 0.557, p < 0.01), but similar OS with del(7q) patients (HRs 0.837, p = 0.37). The findings revealed distinct clinical, cytogenetic, and molecular characteristics distinguishing der(1;7) from -7/del(7q), indicating der(1;7) defines a unique subtype within MDS with monosomy 7q. These findings support classifying der(1;7) as a separate MDS entity in future.

The Efficacy and Prognosis of Advanced Myelodysplastic Syndrome in Children

Pediatric myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell neoplasm with an annual incidence of 1-4 cases/million. The low incidence of advanced MDS in children and poor prognosis attract our attention. However, there are limited reports on the scheme and efficacy of pediatric advanced MDS. In this study, we retrospectively analyzed the efficacy of chemotherapy in pediatric advanced MDS and assessed the prognosis of patients. According to 2016 World Health Organization (WHO) classification of haematolymphoid tumours, 30 newly diagnosed pediatric advanced MDS patients during Dec 2007 to Apr 2022 from our single center were selected as the research object. The clinical data and prognosis were analyzed. The median age of patients is 8 years (range: 1-15years). The median bone marrow blast is 15.75% (range: 5-29.5%), while the median peripheral blood blast is 4% (range: 0-29%). Cytogenetic analysis was available for 29 patients, 69% (20/29) cases had abnormal karyotype. Monosomy 7 (37.9%) was the most common cytogenetic abnormality. Out of the total, 7 patients were treated with CAG/HAG regimen (C: aclarubicin 6mg d1-14, H: homoharringtonine 1mg/m 2d1-14, A: cytarabine 10mg/m 2 q12h d1-14, and G: Granulocyte Colony-stimulating Factor 200mg/m 2 d1-14 ), 8 patients with decitabine (20mg/m 2 d1-5), 11 patients with decitabine and CAG/HAG, 4 patients with AML-like chemotherapy (Daunorubicin+cytarabine+etoposide ) or other. The evaluation of response of therapy was available in 25 patients, 5 cases (20%) in partial remission (PR), 11 cases (44%) in complete remission (CR), 9 cases in(36%)non-remission (NR). The total response rate of chemotherapy is 60%, with CAG/HAG therapy 33%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 78%, AML-like chemotherapy 100%. The total complete remission rate of chemotherapy is 44%, with CAG/HAG therapy 17%, decitabine therapy 43%, combined CAG/HAG and decitabine therapy 56%, AML-like chemotherapy 67%. Patients receiving CAG/HAG in combination with decitabine had higher response rates compared to CAG/HAG or decitabine alone (OR=17.5, 95% CI 1.2-250.3, P=0.035). With a median follow-up of 20 months (range: 1-158months), 23 patients received HSCT after chemotherapy, and they had a higher 2-year overall survival rate compared to those who did not undergo transplantation (86% vs 0%, p&amp;lt;0.001). Decitabine combined with CAG/HAG improve the response rate of advanced pediatric MDS. Chemotherapy bridged hematopoietic stem cell transplantation significantly improves the prognosis of advanced pediatric MDS.

1q21+ Is Associated with Poor Prognosis in Newly Diagnosed Multiple Myeloma Patients with Extramedullary Disease: A Retrospective Study

Abstract: Background: 1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered as an independent factor for poor prognosis, but its impact on extramedullary disease (EMD) remains unknown. Method: In our retrospective analysis, patients who met the diagnostic criteria of IMWG and first diagnosed with EMD from January 2011 to May 2022 were enrolled in the study. EMD patients were divided into 2 subgroups: 1q21+ and 1q21- according to the FISH analysis. 1q21+ abnormality was regarded as gain of 1q21 (gain [1q21], 3 copies) and amplification of 1q21 (amp [1q21], ≥4 copies). Continuous variables were analyzed by independent-sample t test or Mann-Whitney U test and categorical variables were compared using chi-square test or Fisher's exact test. Kaplan-Meier method was applied for PFS and OS curve made and differences were evaluated by Log-rank test. Cox proportional hazard models were constructed for prognostic factors analyze. Result: Patients with 1q21+ presented with advanced International Staging System stages (stage III percentage: 68.2% vs. 30.0%, P=0.006), lower level of hemoglobin (91g/dL vs. 113.5g/dL, P=0.004), higher tumor burden (BMPC infiltration≥50% : 45.0% vs. 11.9%, P＜0.001), higher level of serum β2-microglobulin (7.24 g/L vs. 3.85 g/L, P=0.003) and lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P=0.019). Higher incidence of soft tissue related EMD (54.5% vs. 18.6%, P＜0.001), renal dysfunction (50.5% vs. 17.7%, P=0.002) and hypercalcemia (27.3% vs. 7.1%, P=0.011) was also observed in 1q21+ subgroup. 1q21+ was found to be strongly associated with other high risk cytogenetic abnormalities including IgH/FGFR3 translocation (22.7% vs. 4.3%, P=0.007) and IgH/MAF translocation (22.7% vs. 1.4%, P＜0.001). Patients with 1q21+ had a significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24 months vs. 47 months, P=0.002; PFS: 14months vs. 38months, P＜0.001), and the poor survival outcome couldn't be reversed by autologous hematopoietic stem cell transplantation (auto-HSCT). Further investigation estimated the impact of cooccurrence of 1q21+ and del17p on survival outcome. For median OS, 1q21- patients without del17p was 47 months, 1q21+ patients without del17p were 28 months, 1q21- patients with del17p was 22 months, and patients presented with both 1q21+ and del17p was 18 months (p=0.02). The median PFS for 1q21- without del17p, 1q21+ without del17p, 1q21+ with del17p was 38 months, 20 months and 6.5 months respectively, while not reached for 1q21- patients (P＜0.001). Multivariate analysis suggested 1q21+ along with EMD-S, elevated LDH level and P53 deletion were independent risk factors for poor prognosis in EMD patients. For 1q21+ EMD patients, hypercalcemia, elevated LDH level and P53 deletion were defined as independent adverse risk prognostic factors. Conclusion: Taken together, our findings emphasized that 1q21+ increased the possibility of disease progression and predicted poor survival in EMD patients. 1q21+ EMD tends to be associated with other high risk disease factors. ASCT may not overcome the adverse effect of 1q21+ in EMD patients. We suggested 1q21+ should be considered as a high-risk factor and added into routine assessment of risk stratification in EMD patients.

Relapsed and Refractory Multiple Myeloma with Pleural Involvement: A Case Series

Introduction. Development of novel treatments and immunotherapeutics continue to improve outcomes in patients with multiple myeloma (MM), especially in those patients with standard and intermediate risk disease; patients with high-risk disease continue to have dismal outcomes. Secondary extramedullary disease (sEMD) is a high-risk disease feature associated with an expected survival less than one year (Zanwar, AJH, 2023). Detailed description of patients presenting with sEMD involving the pleural has not been previously published. In the present project, we aimed to identify and characterize this patient population. Methods. This study was approved by the University of Utah (UU) IRB (#00156207). Inclusion was determined by search of the UU Department of Radiology database for all imaging including PET, CT, and MRI; search terms included pleura, pleural, lung, extramedullary, plasmacytoma, and multiple myeloma. Descriptive analysis was completed and included patient demographics, treatment, and outcomes. Survival was described with Kaplan-Meier analysis. Results. Fourteen patients treated at the UU between 2004 and 2023 were identified as having sEMD and pleural involvement. Demographics are highlighted in Table 1. The median age was 59 (range 34-79), 50% of patients were male, 86% were Caucasian, and 8% were Hispanic. Patients were treated with a median of 2.5 (range 1-9) lines of therapy prior to sEMD development and 6 (range 2-13) in total. 50% of the patients were penta-class refractory. The median follow-up after MM diagnosis was 34.5 months (range 13.0-162.0), median follow-up after pleural EMD diagnosis was 9.0 months (range 0.4-92.0), and the median time to development of pleural EMD following diagnosis was 18.2 months (range 3.8-142.8). At initial diagnosis, half of the patients had &amp;gt; 50% bone marrow clonal plasma cells, 29% had R-ISS stage 3 disease and 36% had R2-ISS stage III/IV. Of the 11 patients with available cytogenetic information at the time of sEMD diagnosis, 73% had high-risk cytogenetics (defined as presence of del(17p), t(4;14), t(14;16) and/or +1q). The most common cytogenetic abnormalities were +1q in 73%, including 36% with 3 copies and 36% with &amp;gt; 4 copies, amp(1q), and del(17p) in 36% . Of these patients, 18% had double hit and 18% had triple hit disease. The most frequent concomitant cytogenetic abnormalities were +1q and del(17p) seen in 36% of the patients. On imaging, 79% had additional sites of EMD other than the pleura. The most frequent other sites of sEMD were skin/soft tissue, intrabdominal extrahepatic, and hepatic. Pleural effusion was present in only one patient. Following diagnosis of sEMD with pleural involvement, the overall response rate (ORR) was 93% and the ORR was 88% in patients with 1q21 abnormalities. In this population, the median OS from diagnosis was 2.5 years (range 1.1-14) and mOS from diagnosis of pleural EMD was 0.64 years (range 0.03-7.7). Conclusion. To the best of our knowledge, this is the largest case series focused on the characterization of patients with sEMD and pleural involvement. The survival results align with those recently presented by Zanwar et al., suggesting that pleural involvement does not portend worse prognosis than EMD in general. We highlight that the majority of patients have 1q21 abnormalities and additional sites of EMD. Ultimately, patients with sEMD and pleural involvement have extremely high-risk disease, are responsive to treatments but have a drastically shortened survival.

Identification and Validation of High-Risk Genes Contributing to Poor Prognosis in Multiple Myeloma Patients with chr1q Gain/Amplification

The gain/amplification of 1q21 (1q gain/amp) is a common cytogenetic abnormality (CA) in multiple myeloma (MM) and implies poor outcome. Despite the dysregulation of numerous genes located in chromosome 1q due to gain/amplification, the pivotal genes influencing the prognosis of multiple myeloma remain undefined. Gene expression matrices and clinical data of multiple myeloma (MM) patients were acquired from publicly available databases, including the Gene Expression Omnibus (GEO) and CoMMpass. A comparative analysis was performed between MM patients with and without 1q gain/amplification to identify genes that exhibited differential expression due to this genetic alteration. The Least Absolute Shrinkage and Selection Operator (LASSO) technique and multivariate Cox regression analysis were employed to select potential candidate genes strongly associated with an unfavorable prognosis in MM patients. The overall survival of MM patients was assessed using the Kaplan-Meier method, and survival curves were compared using the log-rank test. In the training set comprising 413 MM patients from the GSE4581 database, 93 individuals (22.5%) displayed 1q gain/amplification. Differential gene expression analysis identified 541 upregulated genes in patients with 1q gain/amp, with 187 of these genes located on chromosome 1q. Subsequently, the 187 upregulated genes on chromosome 1q underwent LASSO and multivariate Cox regression analysis. As a result, ten genes (ANP32E, ARPC5, CDC42BPA, CDKN2C, CHD1L, COAS, ISG20L2, NUF2, TAGLN2, UBE2T) were identified as significant contributors to poor overall survival in MM patients. Additional analysis utilizing single-cell RNA sequencing (scRNAseq) was conducted on plasma cells from 12 MM patients and ten healthy donors from the GSE117156 dataset. The findings unveiled elevated expression levels of CDKN2C, ISG20L2, NUF2 and UBE2T in malignant plasma cells compared to those from healthy donors. The prognostic significance of the four high-risk genes (CDKN2C, ISG20L2, NUF2 and UBE2T) was further confirmed in the CoMMpass database, which comprises 858 MM patients. Although patients with 1q gain/amp showed more inferior survival ( P=0.012), without the four high-risk genes overexpression in patients with 1q gain/amp showed the similar survival with patients without 1q abnormal( P=0.74). Furthermore, in the CoMMpass database, we observed a notable pattern wherein patients with higher expression levels of the four high-risk genes (N=27) were more prevalent in the late stage, with 51% of them classified at stage III. Conversely, only 27% of patients with low expression levels of the four high-risk genes were at stage III. Notably, no significant differences were observed in terms of age, sex, or race between the two groups. In summary, our findings demonstrate that overexpression of CDKN2C, ISG20L2, NUF2 and UBE2T contribute to the poor outcome in multiple myeloma patients with 1q gain/ amplification.

Clinical Features of Myeloid Neoplasms with Germline GATA2 Mutations–a Systematic Review of Clinical Studies Retrieved through Extensive Searching

Aims: Recent findings increasingly find individuals are being recognized as having germline predisposition to myeloid malignancies. GATA2 mutation is one of the most extensively studied germline mutations. However, until recently most of studies have focused on the mechanism of how GATA2 as one of the driver mutations causes malignancies. As regards the clinical features, such as the treatment and prognosis of myeloid neoplasms associated with germline GATA2 mutations, only small studies published, based on which they were insufficiently studied. Therefore, we did the systematic review to summarize the diagnosis, therapeutic methods and prognosis of myeloid malignant diseases associated with germline GATA2 mutations. Methods: Two reviewers independently comprehensively searched Pubmed and hand searched the professional journals and the reference lists of related and included articles from Jan 1 st, 1990 until May 1 st, 2023. They also independently screened and evaluated the retrieved records and then extracted data of included studies. Studies reported clinical materials on the diagnosis, treatment and prognosis of myeloid malignant patients with germline GATA2 mutations will be included and the clinical data will be summarized. Searching strategies were as follows: #1 germline or predispo* or somat* or famil* or germ line or congenit* or altera* or non-tumor; #2 gene* or genom* or sequenc* or muta* or SNP or abnormal* or translocat* or chromosom* or frameshift* or exom* or GATA; #3 “acute myeloid leukemia” “Leukemia, Myeloid, Acute” “Myelodysplastic Syndromes” “refractory anemia” “myeloid or myeloblast*” or AML or MDS; #4 #1 and #2 and #3 Results: 2457 records were retrieved and 23 studies with 396 patients were included. Screening process was shown in Figure 1. Studies included were all small sample sized. The diagnosis age was from three to 78 years old, most of the median ages of included studies were less than 30 years indicated carriers would have symptoms in young age, on the other hand, there were also patients who began having symptoms in old age (the oldest 78 years) or remained asymptomatic carriers without getting sick in the whole life. There was no sex difference. Emberger syndrome which caused lymphedema and MonoMAC and/or DCML (dendritic cell, monocyte, B-lymphocyte and NK-lymphocyte) deficiency syndromes that caused cytopenia and infections were generally appeared earlier before myeloid malignancies. Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) are common malignant diseases for patients with germline GATA2 mutations predisposition. The morbidity was not able to be calculated based on the data available. MDS was the most common myeloid neoplasm compared with AML and CMML which were always transformed from MDS. Other hematologic malignancies were rare. The disease transformation was shown from refractory cytopenia to malignant clonal hematopoiesis that caused MDS, and then transformed into leukemia. In total, 311/396 (78.5%) patients developed malignant myeloid diseases. Nine studies had done the family pedigree analysis and there were 162 family members who had the germline GATA2 mutations predisposition, in which there were 32 asymptomatic carriers (19.7%). 128 patients were reported to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT), 81 (63.3%) were alive and 44 (34.4%) died of relapse or transplantation related complications. Three patients' outcome was unknown. In study Michael A. Spinner et al, survival rate was 54% by 4 years after allo-HSCT (21 patients included). Nearly all patients (15/18) with myeloid malignancies who did not receive transplantation had died. The most common cytogenetic abnormalities were monosomy 7 and trisomy 8, and other abnormalities were also common. Conclusions: Most of germline GATA2 mutation carriers will have symptoms in young age and many of them will progress into malignant myeloid diseases. Allo-HSCT was effective to treat symptomatic patients, especially for patients with malignant hematologic diseases, and furthermore that is the only curative treatment. Asymptomatic carriers are not rare and for them regular tests are essential. More clinical studies on germline GATA2 mutations for myeloid neoplasms are needed to clarify the clinical features in this setting and improve its treatment and prognosis.

NAMPT Haploinsufficiency Is a Therapeutic Vulnerability in High-Risk Myeloid Malignancies

Monosomy 7 (−7) and del7q are the most common high-risk cytogenetic abnormalities and occur across the spectrum of myeloid disorders. -7/del(7q) also co-occur with other high-risk factors such as mutations or deletion of TP53. Standard, non-specific chemotherapy drugs are less effective in these high-risk patients, resulting in a median survival rate of approximately one year. To identify novel, targeted agents for these neoplasms, we sought “collateral lethal” genes, i.e. essential, druggable genes encoded on chromosome 7 that are haploinsufficient upon their loss of heterozygosity. To this end, we first identified essential genes located on chromosome 7. We mined genome-wide CRISPR/Cas9 screen data from 27 human acute myeloid leukemia (AML) cell lines within the DepMap database and identified 65 chromosome 7-encoded, candidate essential genes in AML. To determine those essential genes with known inhibitors, we intersected these 65 candidates with the Drug-Gene Interaction and canSAR.ai databases. We found that nicotinamide phosphoribosyltransferase ( NAMPT), the rate-limiting enzyme that catalyzes the first step of NAD + biosynthesis from nicotinamide, was one of four essential and druggable targets on chromosome 7. Notably, NAMPT was the only essential gene on chromosome 7 with a first-in-class orally bioavailable inhibitor, KPT 9274, currently in clinical trials (NCT04914845). Moreover, NAMPT DNA copy number, mRNA, and protein levels all negatively correlated with cell line sensitivity to NAMPT loss, implicating NAMPT as a collateral lethal candidate gene. We confirmed that isogenic human AML cell lines CRISPR-engineered to partially reduce NAMPT DNA copy led to reduced NAMPT protein levels, indicating NAMPT is a haploinsufficient gene. Cells with ~50% NAMPT levels were significantly more sensitive to the KPT 9274 treatment, and became less viable and more apoptotic, compared to control locus edited cells. To determine whether TP53 status could alter this vulnerability, we generated cell lines with both TP53 loss and 50% NAMPT loss. We found TP53 mutational status did not attenuate the observed effects of NAMPT inhibition on cell survival. Viability assays with primary patient AML samples confirmed that -7/del(7q) status imparts significantly elevated sensitivity to KPT 9274 treatment than samples with diploid chromosome 7 alleles. In summary, our findings reveal NAMPT heterozygosity as a therapeutic vulnerability in high-risk myeloid neoplasms that warrants clinical follow-up. Further, we provide a framework centered on data-mining for uncovering collateral lethal genes in other cancers with recurrent chromosomal arm level deletions.

The Molecular Landscape of Acute Myeloid Leukemia with Trisomy 8: A Comprehensive Cancer Center Analysis of 627 Patients

1. Introduction Trisomy 8 is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). Trisomy 8 frequently occurs with additional aberrant or complex karyotypes; it can also occur as the sole cytogenetic abnormality. While prior studies have shown that trisomy 8 cooperates with other somatic genetic mutations (e.g., RUNX1), there is persistent controversy about the prognostic impact of AML with trisomy 8. We analyzed the relationship between trisomy 8 and additional molecular lesions, the ELN 2022 revision, and the prognostic impact of trisomy 8 across modern treatment strategies. 2. Methods We analyzed 627 patients from the Project ERIS database with newly diagnosed AML treated from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. We identified 86 patients with trisomy 8 independent of the presence of complex cytogenetics and a cohort of 541 historical controls without trisomy 8. We recorded baseline patient-related and disease characteristics, including age, ECOG, Charlson comorbidity index (CCI) scores, molecular profiling and ELN 2022 cytogenetic risk, dates of regimen initiation, and survival. We used the D'Agostino &amp; Pearson method for normality testing and the t-test or Mann-Whitney (as applicable) tests for between-group comparisons. Categorical comparisons used Fischer's exact test. We applied the Bonferroni correction if multiple comparisons were made. The Wilson-Brown method was used for 95% confidence intervals. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results The most common cytogenetic abnormalities associated with trisomy 8 were the presence of a complex karyotype (45.2%, 95% CI: 35.0-55.9), loss of 5 (15.5%, 95% CI, 9.3-24.7%), loss of 7 (8.3%, 95% CI, 4.1-16.2), and -17p (13.1%, 95% CI, 7.5-21.9). ASXL1 mutations tended to occur significantly more frequently in trisomy 8 compared to those without (27.5% vs 13.0%, p = 0.029, Table A). Similarly, TP53 mutations occurred significantly more frequently in trisomy 8 than those without (27.5% vs 13.0%, p = 0.029). Conversely, DNMT3A mutations were less likely to be associated with trisomy 8, which approached statistical significance (10.0% vs 23.47%, p = 0.063). NPM1 mutations were significantly less likely to be associated with trisomy 8 compared to those without (7.5% vs 30.3%, p = 0.002). Consequently, trisomy 8 was significantly more likely to be associated with ELN 2022 adverse risk disease (odds ratio: 2.754, p &amp;lt; 0.0001). Next, we compared response and survival with intensive chemotherapy using conventional 7+3 in those with and without trisomy 8. In 51 patients with trisomy 8, the composite complete response rate (CRc; CR + CRi + CRh) was 34.1% (95% CI, 21.9-48.9), significantly worse compared to 330 patients without trisomy 8 (55.1%, 95% CI, 49.4-60.6, p = 0.010). The median overall survival was significantly worse in patients with trisomy 8 treated with 7+3 compared to those without trisomy 8 (7.1 m. vs 19.2 m., p = 0.009, Figure B). In 13 patients treated with venetoclax and a hypomethylating agent (HMA), the CRc was 25.0% (95% CI, 8.9-53.2), which was nonsignificantly worse compared with 87 patients without trisomy 8 that demonstrated a CRc of 48.4% (95% CI, 36.4-60.6, p = 0.206). The overall survival of patients treated with venetoclax + HMA nonsignificantly favored patients without trisomy 8 (8.2 m. vs 5.0 m., p = 0.268). 4. Discussion AML with trisomy 8 is significantly enriched in ASXL1 and TP53 mutations; conversely, trisomy 8 is significantly less likely to harbor NPM1 mutations. Patients with trisomy 8 are significantly more likely to have ELN 2022 adverse-risk disease. The CRc rate and median overall survival are significantly worse in patients with trisomy 8 treated with intensive chemotherapy. We observed no significant difference in response or survival in patients with or without trisomy 8 treated with venetoclax + HMA.

AML1-ETO and CCND2 Overexpression Cooperate to Drive AML Initiation and Progression

Objectives: The translocation between chromosome 8 and 21, resulting in the AML1-ETO fusion gene, is one of the most common cytogenetic abnormalities observed in acute myeloid leukemia (AML). However, AML1-ETO alone is insufficient to cause leukemia, additional secondary events are required for leukemogenesis. CCND2 gene, a key member of the CyclinD2-CDK4/6 complex, plays a crucial role as a cell cycle regulator. In hematopoietic malignancies, CCND2 mutations (particularly with a conserved mutated hotspot on Thr280) have been found in AML, particularly in core binding factor leukemias. The mutated CCND2 protein exhibits greater stability and resistance to proteasomal degradation. Previous research had shown that CCND2 was a transcriptional target of AML1-ETO, indicating that AML1-ETO can promote CCND2 expression. However, it remains unclear whether mutated CCND2 can cooperate with the AML1-ETO to drive leukemia initiation and progression. Methods: In our previous study, a conditional AML1-ETO knock-in mouse model was developed, in which the AML1-ETO fusion gene was tagged with m-Cherry. To investigate the role of CCND2 in this model, the coding sequences of both CCND2 wt (wild-type) and CCND2 mut (mutant with Thr280Ala substitution) were cloned into the retroviral vector MSCV-IRES-EGFP. Subsequently, the fetal liver cells (embryonic day=12.5) from AML1-ETO mice were infected with the corresponding retroviruses. Results: Four months post AML1-ETO induction, the percentage of m-Cherry + GFP + cells of the mice in CCND2 wt and CCND2 mut groups began to increase. The results revealed a substantial upregulation of CCND2 mRNA and protein expression in these groups compared to that of the Vec group. Additionally, the CCND2 mut group exhibited even higher CCND2 protein expression due to impaired protein degradation. Moreover, the shortened survival time and pathological findings in mice from the CCND2 wt and CCND2 mut groups confirmed that they were succumbed to leukemia infiltration. To assess the stemness of leukemia stem cells (LSCs), extreme limiting dilution analysis (ELDA) was conducted, and it showed a significant increase in LSC frequency in the CCND2 wt and CCND2 mut groups compared to that of the Vec group. Notably, transplanting AML1-ETO cells alone didn't confer any competitive advantage in sublethally irradiated mice, while the overexpression of CCND2 provided them with the ability to survive. Transcriptome analysis indicated that compared to the Vec group, CCND2 wt and CCND2 mut groups exhibited notable enrichment in OXPHOS, E2F, and G2M gene sets. Interestingly, the mTORC1 signaling pathway was particularly enriched in the CCND2 mut group compared to the other two groups. To verify this speculation, phosphorylated S6 and total S6 protein levels were assessed through Western blotting. The results showed that compared to Vec group, the p-S6/total S6 ratio show a gradual increase in the CCND2 wt and CCND2 mut groups, indicating activation of the mTOR pathway by CCND2 protein. Everolimus, a selective inhibitor of mTOR, was administered to CCND2 wt and CCND2 mut mice at a dose of 5mg/kg via oral gavage (three times a week) for three consecutive weeks. The Everolimus-treated mice exhibited reduced leukemic burden and fewer number of LSCs compared to that of the vehicle-treated group. Additionally, Everolimus restored the non-leukemic cells and extended their survival time in CCND2 wt and CCND2 mut group mice. Conclusion: In our study, a leukemia mouse model with co-expression of AML1-ETO and CCND2 mutation was successfully established, which demonstrated that the introduction of the CCND2 gene into the existing AML1-ETO model can trigger the development of leukemia. It was also confirmed that CCND2 overexpression results in the upregulation of the mTOR pathway, which drove the progression of leukemia. Everolimus effectively improved the outcome of mice with CCND2 wt or CCND2 mut, suggesting its potential as a therapeutic agent for this subtype of leukemia.

Crebbp Mutations Are Associated with Slow Minimal Residual Response to Upfront Induction Chemotherapy in Pediatric High-Hyperdiploid B-Cell Precursor Acute Lymphoblastic Leukemia Treated in the AIEOP-BFM ALL 2009 Protocol

Introduction High-hyperdiploidy (HHD) represents the most common cytogenetic abnormality found in B-cell precursor acute lymphoblastic leukemia (B-ALL). Despite the overall good outcome of this entity, up to 15% of patients suffer from disease relapse. Genome-wide ALL studies with next-generation sequencing (NGS) approaches identified a distinct pattern of somatic mutations in HHD ALL, enriched in mutations occurring in genes activating the RAS pathway and in CREBBP gene, especially in relapsed patients. Although several studies have attempted to explore the prognostic significance of these mutations that are potentially susceptible of targeted therapies, their impact in uniformly treated patients with newly diagnosed B-ALL is not well characterized, and there is no consensus on their clinical significance. In this study, we aimed to investigate the frequency of recurrent mutations and to define their prognostic role in the setting of newly diagnosed HHD B-ALL, by using end of induction minimal residual disease (MRD) and event-free survival (EFS). Methods We included 101 consecutive patients, aged between 1-17 years, with newly diagnosed HHD B-ALL and enrolled in the AIEOP-BFM ALL 2009 protocol (NCT01117441). HHD was defined by the presence of a DNA index ≥1.16 and lack of ETV6::RUNX1, BCR::ABL1, KMT2A::AFF1 translocations. Diagnostic leukemia samples of 89 patients were sequenced using a validated clinical NGS panel profiling 39 genes involved in leukemia pathogenesis. Mutations affecting RAS pathway ( NRAS, KRAS, PTPN11, NF1, BRAF) and mutations affecting CREBBP gene were included. In addition, digital multiplex ligation-dependent probe amplification (digital MLPA) analysis for the identification of IKZF1 deletion and IKZF1plus phenotype was evaluable for 67 patients. A Fisher exact test and Wilcoxon rank sum test were used for categorical and continuous variables. MRD was assessed by an IG/TR PCR assay at day +33 of induction (timepoint 1, TP1) and at day +78 (timepoint 2, TP2). EFS was estimated by using Kaplan and Meier method and differences between groups were tested using the log-rank test. Resistance to treatment, relapse, death or second malignant neoplasm were considered as events, whichever occurred first. Results Patients' characteristics according to the presence of studied mutations are shown in Table 1. Mutations affecting RAS pathway and CREBBP occurred in 57.3% and 12.3% of HHD B-ALL patients, respectively. Clonal RAS pathway mutations, defined by variant allele frequency (VAF) ≥25%, were found in 16.8% of cases. Among the 11 patients with mutations of CREBBP, 7 had also a mutation affecting KRAS and the association was significant (p=0.03). Seven patients (10.4%) had deletion of IKZF1, of whom 5 (7.4%) were IKZF1plus. There was no association between any mutations or IKZF1 status and patient presenting characteristics, as including sex, age and WBC counts. MRD was evaluable in 84 patients at the end of induction (TP1). MRD level ≥5x10 -4 was found in 36.4% of patients with CREBBP mutations and in 9.6% of those without, and this association was statistically significant (p=0.02). Additionally, MRD negativity was found in 9.1% and 38.4%, respectively. At TP2, MRD was still detectable in 45.5% of patients with CREBBP mutations compared to 20.6% of those with CREBBP wildtype (p=0.08). Similarly, we observed an association between RAS pathway mutations and MRD at TP1 (p=0.01) with a marked difference in MRD negative patients (21.3% vs 51.4% in patients with and without mutations). No association was observed between MRD level and clonal RAS pathway mutations or IKZF1 status. Despite the association between CREBBP mutations and high MRD at TP1, no significant difference in final high-risk group was found (27.3% vs 11.5%, p=0.17). A total of 8 events were observed, of which 6 were relapses. No impact of any mutations or IKZF1 status in term of 5-years EFS was found in our cohort. Conclusion Our study shows that CREBBP mutations in HHD B-ALL are associated with inferior early response to treatment in terms of MRD level at the end of induction (TP1) but not with worse EFS with our whole current chemotherapy backbone. Therefore, the inclusion of CREBBP mutated patients in very low risk protocols should be carefully evaluated. The validation of these findings is ongoing through the analysis of patients treated by other international study groups adopting different chemotherapy backbones.

Common genetic abnormalities and phenotypic scoring in Saudi patients with acute B-lymphoblastic leukemia

&lt;b&gt;Introduction: &lt;/b&gt;B-acute lymphoblastic leukemia (B-ALL) is a malignant neoplasm of hematopoietic stem cells originating in bone marrow and characterized by proliferation of blast cells of lymphoid series. The aim of this study was to predictive scoring system (SS) using a fully standardized EuroFlow eight-color panel.&lt;br /&gt; &lt;b&gt;Methods:&lt;/b&gt; The expression of the different cluster of differentiation (CD) markers involved in the B-ALL EuroFlow panel was investigated by measuring their positivity, percentage, and median fluorescence intensity.&lt;br /&gt; &lt;b&gt;Results:&lt;/b&gt; CD9, CD123, and TdT were used to predict &lt;i&gt;TCF3PBX1&lt;/i&gt; with 80.0% sensitivity (SN) and 100% specificity (SP). CD20 and CD66 were used to predict hypoploidy with 63.0% SN and 100% SP. As a result, no useful discriminative SS was developed.&lt;br /&gt; &lt;b&gt;Conclusions:&lt;/b&gt; Four SSs were proposed for the prediction of the most common cytogenetic abnormalities of Saudi B-ALL.

Cytogenetic studies in reproductive function disorders: a retrospective analysis

Aim. Fertility disorders are one of the most common problems of reproductive medicine. Chromosomal abnormalities play a crucial role in reproductive failure. The main purpose of our study was to determine the types and frequency of chromosomal aberrations in couples with history of infertility. Methods. Karyotyping was performed in 652 couples with reproductive failure between 2004 and 2022, including 203 couples with primary infertility (PI), 240 couples with recurrent pregnancy loss (RPL) and 209 – with sporadic pregnancy loss (SPL). Results. Numerical and structural karyotype abnormalities were detected in 37 (2.84 %) of 1304 individuals with infertility, most frequently in group with PI – 3.4 % and RPL – 3.3 %. Chromosomal abnormalities were detected in 3.1 % woman and 2.6 % men. The most common cytogenetic abnormalities (26 cases of 37; 2 %) are translocations, reciprocal – 18 cases (1.4 %) and Robertsonian – 8 cases (0.6 %). Numerical and structural gonosomal abnormalities were detected in 9 individuals (0.7 %), supernumerary marker chromosome – in 2 (0.14 %). Conclusions. Karyotype abnormalities are most common in individuals with PI and RPL and a occur with the same frequency among women and men. Numerical gonosomal abnormalities were detected only as mosaic form.

Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome.

Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).

Analysis 33 patients of non-DS-AMKL with or without acquired trisomy 21 from multiple centers and compared to 118 AML patients

ABSTRACTBackgroundAcute megakaryoblastic leukemia (AMKL) without Down syndrome (non-DS-AMKL) usually a worse outcome than DS-AMKL. Acquired trisomy 21(+21) was one of the most common cytogenetic abnormalities in non-DS-AMKL. Knowledge of the difference in the clinical characteristics and prognosis between non-DS-AMKL with +21 and those without +21 is limited.ObjectiveVerify the clinical characteristics and prognosis of non-DS-AMKL with +21.MethodWe retrospectively analyzed 33 non-DS-AMKL pediatric patients and 118 other types of AML, along with their clinical manifestations, laboratory data, and treatment response.ResultsCompared with AMKL without +21, AMKL with +21 has a lower platelet count (44.04 ± 5.01G/L) at onset (P > 0.05). Differences in remission rates between AMKL and other types of AML were not significant. Acquired trisomy 8 in AMKL was negatively correlated with the long-term OS rate (P < 0.05), while +21 may not be an impact factor. Compared with the other types of AML, AMKL has a younger onset age (P < 0.05), with a mean of 22.27 months. Anemia, hemorrhage, lymph node enlargement, lower white blood cell, and complex karyotype were more common in AMKL (P < 0.05). AMKL has a longer time interval between onset to diagnosis (53.61 ± 71.15 days) (P < 0.05), and patients with a diagnosis delay ≥3 months always presented as thrombocytopenia or pancytopenia initially.ConclusionsDue to high heterogeneity, high misdiagnosis rate, and myelofibrosis, parts of AMKL may take a long time to be diagnosed, requiring repeated bone marrow punctures. Complex karyotype was common in AMKL. +21 may not be a promising indicator of a poor prognosis.

A novel t (5; 17) (q35; q21) associated with t (8; 21) (q22; q22) in a patient with acute myeloid leukemia: case report and review of literature.

The t (8; 21) (q22; q22) with the resulting RUNX1- RUNX1T1 rearrangement is one of the most common cytogenetic abnormalities in acute myeloid leukemia (AML). It is associated with favorable prognosis. The t (5; 17) (q35; q21) is an uncommon translocation, fuses the gene for the nucleophosmin (NPM) to the retinoic acid receptor α(RARA) and was described essentially in acute promyelocytic leukemia (APL) variant. We present the case of a 19-year-old male patient who developed an AML with t (8; 21) (q22; q22) associated to t (5; 17) (q35; 21). Morphology and immunophenotype of the leukemic cells were compatible with AML. The patient received chemotherapy based on cytarabine and anthracycline without all-trans retinoic acid (ATRA) followed by allogenic stem cell transplantation in first remission. To the best of our knowledge, this is the first report of an association between a rare translocation t (5; 17) and t (8; 21) in AML. In this report, we will discuss the prognosis of this association as well as the treatment.