PUBLICATIONS

Abstract Potential synergism between Bruton’s tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142) https://www.nature.com/articles/s41467-024-47198-4

Objective: The effect of clonal hematopoiesis of indeterminate potential (CHIP) on the manifestation and clinical outcomes of acute ischemic stroke (AIS) has not been fully elucidated. Methods: Patients with AIS were included from a prospective registry coupled with a DNA repository. Targeted next-generation sequencing on 25 genes that are frequently mutated in hematologic neoplasms was performed. The prevalence of CHIP was compared between patients with AIS and age-matched healthy individuals. A multivariate linear or logistic regression model was used to assess the association among CHIP and stroke severity, hemorrhagic transformation, and functional outcome at 90 days. Results: In total, 380 patients with AIS (mean age = 67.2 ± 12.7 years; 41.3% women) and 446 age-matched controls (mean age = 67.2 ± 8.7 years; 31.4% women) were analyzed. The prevalence of CHIP was significantly higher in patients with AIS than in the healthy controls (29.0 vs 22.0%, with variant allele frequencies of 1.5%, p = 0.024). PPM1D was found to be most significantly associated with incident AIS (adjusted odds ratio [aOR] = 7.85, 95% confidence interval [CI] = 1.83-33.63, p = 0.006). The presence of CHIP was significantly associated with the initial National Institutes of Health Stroke Scale (NIHSS) score (β = 1.67, p = 0.022). Furthermore, CHIP was independently associated with the occurrence of hemorrhagic transformation (65/110 clonal hematopoiesis positive [CH+] vs 56/270 CH negative [CH-], aOR = 5.63, 95% CI = 3.24-9.77, p < 0.001) and 90-day functional disability (72/110 [CH+] vs 99/270 [CH-], aOR = 2.15, 95% CI = 1.20-3.88, p = 0.011). Interpretation: CH was significantly associated with incident AIS. Moreover, particularly, sequence variations in PPM1D, TET2, and DNMT3A represent a new prognostic factor for AIS. ANN NEUROL 2023;94:836-847.

Aims Clonal haematopoiesis of indeterminate potential (CHIP), defined as a clonal expansion of age-related recurrent somatic mutations, has recently emerged as a novel cardiovascular risk factor. However, the precise role of CHIP in the development of atherosclerotic cardiovascular disease (ASCVD) remains unclear. Methods Among 4,300 asymptomatic Korean participants aged 40–79 years, we investigated the risk of ASCVD by CHIP and the interplay between CHIP and conventional risk factors in ASCVD development. Additionally, we assessed changes in coronary arteries based on the presence of CHIP using coronary computed tomography angiography (CCTA). Results CHIP was present in 363 participants (8.4%), and its prevalence increased with age. Commonly mutated genes were DNMT3A, TET2 and ASXL1, in order. During follow-up (median, 4.7 years), 18 ASCVD cases (5.0%) were observed in CHIP carriers vs. 62 (1.6%) in non-carriers (p < 0.001), indicating an elevated risk of ASCVD associated with CHIP (adjusted HR 2.49, 95% CI 1.45–4.29, p < 0.001). Notably, with high levels of low-density lipoprotein (LDL) cholesterol, CHIP enhanced the risk of ASCVD (adjusted HR 6.20, 95% CI 3.14–12.23, p < 0.001), demonstrating synergism between CHIP and LDL cholesterol levels (S-index, 4.94; 95% CI 1.08–22.53, p = 0.039). Serial CCTAs confirmed that CHIP, in conjunction with high LDL cholesterol levels, had significant early impact on coronary arteries, revealing new measurable coronary atherosclerosis, mainly with unstable plaque, in proximal lesions. Conclusions The presence of CHIP was significantly associated with the risk of ASCVD, promoting the early stage of atherosclerosis through synergy with high LDL cholesterol in the general population.

Background and Aims Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF. Methods Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The asso- ciation between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes—the composite of heart failure, ischaemic stroke, or death—according to the presence of CHIP muta- tions in AF was investigated from the UK Biobank cohort. Results The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respect- ively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multi- variable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10–1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14–1.99, P = .004) followed by per- sistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation pre- sented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05–2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E′, and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death). Conclusions CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes

Background Clonal hematopoiesis (CH) frequently progresses after chemotherapy or radiotherapy. We evaluated the clinical impact of preoperative CH on the survival outcomes of patients with non-small cell lung cancer (NSCLC) who underwent surgical resection followed by adjuvant therapy. Methods A total of 415 consecutive patients with NSCLC who underwent surgery followed by adjuvant therapy from 2011 to 2017 were analyzed. CH status was evaluated using targeted deep sequencing of blood samples collected before surgery. To minimize the possible selection bias between the two groups according to CH status, a propensity score matching (PSM) was adopted. Early-stage patients were further analyzed with additional matched cohort of patients who did not receive adjuvant therapy. Results CH was detected in 21% (86/415) of patients with NSCLC before adjuvant therapy. Patients with CH mutations had worse overall survival (OS) than those without (hazard ratio [95% confidence interval] = 1.56 [1.07–2.28], p = 0.020), which remained significant after the multivariable analysis (1.58 [1.08–2.32], p = 0.019). Of note, the presence of CH was associated with non–cancer mortality (p = 0.042) and mortality of unknown origin (p = 0.018). In patients with stage IIB NSCLC, there was a significant interaction on OS between CH and adjuvant therapy after the adjustment with several cofactors through the multivariable analysis (HR 1.19, 95% CI 1.00–1.1.41, p = 0.041). Conclusions In resected NSCLC, existence of preoperative CH might amplify CH-related adverse outcomes through adjuvant treatments, resulting in poor survival results.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with atherosclerosis and cardiovascular disease. It has been suggested that CHIP may be related to diabetes, so we investigated the association between CHIP and new-onset type 2 diabetes. Methods: This study included 4,047 subjects aged >=40 years without diabetes. To detect CHIP, targeted gene sequencing of genomic DNA from peripheral blood cells was performed. The incidence of new-onset type 2 diabetes during the follow-up period was evaluated. Results: Of the total subjects, 635 (15.7%) had CHIP. During the median follow-up of 5.1 years, the incidence of new-onset diabetes was significantly higher in CHIP carriers than in subjects without CHIP (11.8% vs. 9.1%, p = 0.039). In a univariate analysis, CHIP significantly increased the risk of new-onset diabetes (HR 1.32, 95% CI 1.02–1.70, p = 0.034), but in a multivariate analysis, it was not significant. The CHIP-related risk of new onset diabetes differed according to LDL cholesterol level. In the hyper-LDL cholesterolemia group, CHIP significantly increased the risk of diabetes (HR 1.64, 95% CI 1.09–2.47, p = 0.018), but it did not increase the risk in the non-hyper-LDL cholesterolemia group. The subjects with CHIP and hyper-LDL-cholesterolemia had approximately twice the risk of diabetes than subjects without CHIP and with low LDL cholesterol (HR 2.05, 95% CI 1.40–3.00, p < 0.001). Conclusion: The presence of CHIP was a significant risk factor for new-onset type 2 diabetes, especially in subjects with high LDL cholesterol. These results show the synergism between CHIP and high LDL cholesterol as a high-risk factor for diabetes.

Clonal hematopoiesis of indeterminate potential (CHIP) refers to a population of myeloid stem cells with acquired gene mutations, but does not fulfill the diagnostic criteria for hematologic malignancy.1 There is growing evidence supporting the role of CHIP mutations in altered immune function through effector cells such as monocytes/macrophages and their dysregulated cytokine/chemokine expression.2,3 Since the immunopathogenesis of such an adverse outcome of CHIP largely shares that of severe COVID-19,4 such as high levels of circulating pronflammatory cytokines or dysregulated monocytes and macrophages,5,6 several previous studies have examined whether CHIP might contribute to the progression of COVID-19.7- 9 However, due to the weak significance of association or lack of stratified analysis, it is still unknown whether the presence of CHIP in previously healthy COVID-19 patients has a clinical impact on the disease severity. In this study, we aimed to verify the clinical implications of CHIP in COVID-19 severity, especially in patients without canonical clinical risk factors for severe COVID-19 by analyzing clinical and laboratory characteristics using clustering and statistical examinations including interaction term.

Abstract Background Clonal haematopoiesis of indeterminate potential (CHIP) is a predisposition to haematological malignancy whose relationship with chronic inflammatory diseases, such as cardiovascular diseases, has been highlighted. Here, we aimed to investigate the CHIP emergence rate and its association with inflammatory markers in Behçet’s disease (BD). Methods We performed targeted next-generation sequencing to detect the presence of CHIP using peripheral blood cells from 117 BD patients and 5004 healthy controls between March 2009 and September 2021 and analysed the association between CHIP and inflammatory markers. Results CHIP was detected in 13.9% of patients in the control group and 11.1% of patients in the BD group, indicating no significant intergroup difference. Among the BD patients of our cohort, five variants (DNMT3A, TET2, ASXL1, STAG2, and IDH2) were detected. DNMT3A mutations were the most common, followed by TET2 mutations. CHIP carriers with BD had a higher serum platelet count, erythrocyte sedimentation rate, and C-reactive protein level; older age; and lower serum albumin level at diagnosis than non-CHIP carriers with BD. However, the significant association between inflammatory markers and CHIP disappeared after the adjustment for various variables, including age. Moreover, CHIP was not an independent risk factor for poor clinical outcomes in patients with BD. Conclusions Although BD patients did not have higher CHIP emergence rates than the general population, older age and degree of inflammation in BD were associated with CHIP emergence.

Background Clonal hematopoiesis of indeterminate potential (CHIP) increases the risk of cerebrovascular events, while its association with cerebral white matter hyperintensity (WMH) is undemonstrated. We evaluated the effect of CHIP and its major driving mutations on cerebral WMH severity. Methods From an institutional cohort of a routine health check-up program with a DNA repository database, subjects who were ≥50 years of age, with one or more cardiovascular risk factors but no central nervous system disorder, and performed brain MRI were included. Along with the presence of CHIP and its major driving mutations, clinical and laboratory data were obtained. WMH volume was measured in total, periventricular, and subcortical regions. Results Among the total 964 subjects, 160 subjects were classified as CHIP positive group. CHIP was most frequently associated with DNMT3A mutation (48.8%), followed by TET2 (11.9%) and ASXL1 (8.1%) mutations. Linear regression analysis adjusting for age, sex, and conventional cerebrovascular risk factors suggested that CHIP with DNMT3A mutation was associated with the lower log-transformed total WMH volume, unlike other CHIP mutations. When classified according to variant allele fraction (VAF) value of DNMT3A mutation, higher VAF classes were associated with the lower log-transformed total WMH and the lower log-transformed periventricular WMH volume, but not with the log-transformed subcortical WMH volumes. Conclusions Clonal hematopoiesis with DNMT3A mutation is quantitatively associated with a lower volume of cerebral WMH, especially in the periventricular region. CHIP with DNMT3A mutation might have a protective role in the endothelial pathomechanism of WMH.

Abstract Background and aims: Studies have demonstrated that the risk of atherosclerotic cardiovascular disease (ASCVD) can be assessed by polygenic risk score (PRS) using common genetic variants. Because metabolic syndrome is a well-known, robust risk factor of ASCVD, we established PRS of metabolic disease and analyzed whether this PRS could predict incident ASCVD. Methods: We constructed PRSs for eight quantifiable metabolic phenotypes-systolic/diastolic blood pressure, body mass index (BMI), four blood lipid components, and fasting blood glucose-by genome-wide association studies of two prospective Korean cohorts (n = 37,285). We conducted a grid search of combinations of metabolic PRSs to identify the most optimal weighted score for incident ASCVD (PRSMetS-ASCVD). The utility of PRSMetS-ASCVD was validated in an independent prospective cohort (n = 4333). Results: The individuals in the highest PRS quintile demonstrated a 1.4-2.0-fold increased risk of incident hypertension, obesity, hyperlipidemia, and diabetes. Using the PRSMetS-ASCVD, we identified 6.7% of the population as a high risk group demonstrating a 3.3-fold (95% confidence interval 1.7-6.1, p < 0.001) higher risk for incident ASCVD. The model combining the PRSMetS-ASCVD demonstrated a better performance for predicting ASCVD than that consisting of only conventional risk factors, such as age, sex, BMI, smoking, hypertension, diabetes and hyperlipidemia. The population with high PRSMetS-ASCVD minimally overlapped with that of high Framingham risk score, thus suggesting the additive independent benefits beyond the Framingham risk score, especially in younger individuals. Conclusions: The polygenic risk of metabolic disease independently predicts those at an increased risk of ASCVD, identifying those at a genetically high risk of incident ASCVD.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been reported to be associated with increased cardiovascular disease, aging and insulin resistance. Despite the debate of causal contribution of CHIP on metabolic diseases, we want to explore whether CHIP is related to diabetic peripheral neuropathy (DPN).Methods: This study analyzed the prevalence of CHIP in patients with type 2 diabetes classified according to DPN status. Logistic regression analysis was used to evaluate the association between CHIP and DPN. Results: CHIP was more prevalent in subjects without DPN than those with DPN (19.9% vs. 8.8%, respectively; P=0.013). Individuals having any CHIP, or DNA methyltransferase 3A (DNMT3A) CHIP were less likely to have any abnormality shown in DPN test; the adjusted odds ratio were 0.85 (95% confidence interval [CI], 0.73 to 1.00) and 0.70 (95% CI, 0.56 to 0.89), respectively. Interestingly, DNMT3A CHIP showed the negative association, but Tet methylcytosine dioxygenase 2 (TET2) CHIP showed the positive association with abnormal feet electrochemical skin conductance level. Conclusion: On the contrary to expectations, CHIP was negatively associated with DPN. Functional linking between the mutation in hematopoietic cells and DPN, and the opposite role of DNMT3A and TET2 should be investigated.

Direct haplotyping enables noninvasive prenatal testing (NIPT) without analyzing proband, which is a promising strategy for pregnancies at risk of an inherited single-gene disorder. Here, we aimed to expand the scope of single-gene disorders that NIPT using linked-read direct haplotyping would be applicable to. Three families at risk of myotonic dystrophy type 1, lipoid congenital adrenal hyperplasia, and Fukuyama congenital muscular dystrophy were recruited. All cases exhibited distinct characteristics that are often encountered as hurdles (i.e., repeat expansion, identical variants in both parents, and novel variants with retrotransposon insertion) in the universal clinical application of NIPT. Direct haplotyping of parental genomes was performed by linked-read sequencing, combined with allele-specific PCR, if necessary. Target DMPK, STAR, and FKTN genes in the maternal plasma DNA were sequenced. Posterior risk calculations and an Anderson–Darling test were performed to deduce the maternal and paternal inheritance, respectively. In all cases, we could predict the inheritance of maternal mutant allele with > 99.9% confidence, while paternal mutant alleles were not predicted to be inherited. Our study indicates that direct haplotyping and posterior risk calculation can be applied with subtle modifications to NIPT for the detection of an expanded range of diseases.

Considering difficulties in on-site ADAMTS13 testing and the performance instability of PLASMIC score according to ethnicity, we developed a prediction tool, MED-TMA (machine learning (ML) method for differential diagnosis (DDx) of thrombotic microangiopathy (TMA)) to support clinical decision. Data from 319 patients visiting 31 hospitals in Korea clinically diagnosed with primary TMA was randomly separated by 2:1 into two groups – the development dataset (D-set, n = 212), the validation dataset (V-set, n = 107). Feature elimination was conducted to select optimal clinical predictors. We developed the model with the selected features using ML methods, verifying using V-set. After the feature elimination using 19 clinical variables, five variables were selected with high importance value. Among nine ML methods, four ML methods were chosen considering the Area Under the Curves (AUC) and the correlation between the methods using D-set. We developed MED-TMA based on an optimized ensemble model with the selected four ML methods resulting in AUC values of 0.945 and 0.924 in D-set and V-set, respectively. In addition to the binary outcome, MED-TMA was capable of providing a probability for DDx of TMA. The ensemble approach driven MED-TMA showed comparable accurate and intuitive decision support for DDx of TMA to that of the existing models based on a single ML method. We provide a web-based nomogram for the appropriate use of effective but costly therapeutics to treat TMA patients (http://hematology.snu.ac.kr/medtma/).

Background: Trichilemmal carcinoma (TC) is an extremely rare hair follicle tumor. We aimed to explore the genetic abnormalities involved in TC to gain insight into its molecular pathogenesis.Methods: Data from patients diagnosed with TC within a 12-year period were retrospectively reviewed. Genomic DNA isolated from a formalin-fixed paraffin-embedded (FFPE) tumor tissue block was sequenced and explored for a panel of cancer genes. Results: DNA was extracted from the FFPE tissue of four patients (50% female; mean age, 51.5 years) diagnosed with TC for analysis. The tumor was located in the head and neck of three patients and in the shoulder of one patient. TP53 mutations (p.Arg213, p.Arg249Trp, and p.Arg248Gln) were found in three patients. Fusions previously identified in melanoma were detected in two patients (TACC3-FGFR3 and ROS1-GOPC fusions). Other mutations found included NF1-truncating mutation (Arg1362), NRAS mutation (p.Gln61Lys), TOP1 amplification, and PTEN deletion. Overall, genetic changes found in TC resemble that of other skin cancers, suggesting similar pathogenesis. All patients with TP53 mutations had aggressive clinical course, two who died (OS 93 and 36 months), and one who experienced recurrent relapse. Conclusions: We reported the genomic variations found in TC, which may give insight into the molecular pathogenesis. Overall, genetic changes found in TC resembled that of other skin cancers, suggesting similar pathogenesis. TP53 mutations was were identified in patients who had an aggressive clinical course. Genetic alterations identified may further suggest the potential treatment options of TC. Keywords: Trichilemmal carcinoma, DNA sequencing, Molecular pathogenesis

Reconstruction of parental haplotypes is a major step in noninvasive prenatal testing (NIPT) for singlegene disorders (1). Indirect haplotyping, based on genotypes of the mother, father, and proband, is challenging when the genotype of the proband is unavailable (2). A 2017 study by Hui et al. made a progress in NIPT for single-gene disorders through direct haplotyping using linked-read sequencing (10 X genomics), thereby resolving the drawback of indirect haplotyping (3). This method has been applied successfully to several monogenic disorders such as congenital adrenal hyperplasia and hemophilia (3). However, this approach warrants further examination to establish its clinical applicability to a range of single-gene disorders.

Background: Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant brain tumors with inactivation of the SMARCB1 gene, which play a critical role in genomic transcriptional control. In this study, we analyzed the genomic and transcriptomic profiles of human AT/RTs to discover new druggable targets. Methods: Multiplanar sequencing analyses, including whole exome sequencing (WES), single nucleotide polymorphism (SNP) arrays, array comparative genomic hybridization (aCGH), and whole transcriptome sequencing (RNA-Seq), were performed on 4 AT/RT tissues. Validation of a druggable target was conducted using AT/RT cell lines. Results: WES revealed that the AT/RT genome is extremely stable except for the inactivation of SMARCB1. However, we identified 897 significantly upregulated genes and 523 significantly downregulated genes identified using RNASeq, indicating that the transcriptional profiles of the AT/RT tissues changed substantially. Gene set enrichment assays revealed genes related to the canonical pathways of cancers, and nucleophosmin (NPM1) was the most significantly upregulated gene in the AT/RT samples. An NPM1 inhibitor (NSC348884) effectively suppressed the viability of 7 AT/RT cell lines. Network analyses showed that genes associated with NPM1 are mainly involved in cell cycle regulation. Upon treatment with an NPM1 inhibitor, cell cycle arrest at G1 phase was observed in AT/RT cells. Conclusions: We propose that NPM1 is a novel therapeutic target for AT/RTs. Keywords: Atypical teratoid/rhabdoid tumor, NPM1, Nucleophosmin

Myeloid sarcoma (MS), or granulocytic sarcoma, is a rare extramedullary tumor of immature myeloid cells. MS may present simultaneously with or during the course of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or any forms of myeloproliferative neoplasms (MPN). Less commonly, it is detected as an isolated form without bone marrow (BM) involvement. Although the prognosis of MS has not been well examined due to the rarity of this disorder, it is known to be refractory to standard therapies of AML and is generally associated with a poor outcome1. Furthermore, it has been noted that patients with myeloid sarcoma have a predisposition to extramedullary relapses.