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Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort (P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation.

Background: ETNK1 mutation has been suggested as a useful tool to support the diagnosis of atypical chronic myeloid leukemia. ETNK1 mutations, however, occur in other myeloid neoplasms. Methods: The authors assessed the clinicopathologic and molecular genetic features of 80 ETNK1‐mutated myeloid neoplasms. Results: Thirty‐seven neoplasms (46%) were classified as myelodysplastic syndrome, 17 (21%) were classified as myelodysplastic/myeloproliferative neoplasm, 14 (18%) were classified as acute myeloid leukemia, and 12 (15%) were classified as myeloproliferative neoplasm. ETNK1 mutations were detected at the first test in 96% of patients, suggesting that ETNK1 mutation is an early event in pathogenesis. ETNK1 mutations represented the dominant clone in 63% of patients and was persistently dominant in 93%. The variant allele frequencies were usually higher in acute myeloid leukemia and increased upon leukemic transformation. ETNK1 mutation was accompanied by coexisting mutations in all patients, with ASXL1 (50%), TET2 (25%), EZH2 (24%), RUNX1 (24%), and SRSF2 (24%) mutations being the most common. Neoplasms with ETNK1 mutations were associated with morphologic dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. With a median follow‐up of 16.5 months, 30 patients died, 44 had persistent disease, and four achieved complete remission after stem cell transplantation. Conclusions: ETNK1 mutation is present in various myeloid neoplasms, often as an early event and a dominant clone and always with concurrent mutations. It may play an important role in the pathogenesis and progression of myeloid neoplasms by causing DNA damage and inducing other mutations and genomic instability, and it may serve as a potential therapeutic target. ETNK1 mutation is not disease‐specific and should be interpreted with caution to classify myeloid neoplasms. ETNK1 mutation is not disease‐specific and is associated with dysplasia, increased blasts, myelofibrosis, and noncomplex karyotypes. ETNK1 mutation often represents an early event and a dominant clone, and it has a probable role in leukemogenesis and targeted therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The advent of next-generation sequencing has elucidated the understanding of the genetic landscape of myeloid neoplasms. Most myeloid neoplasms carry more than one gene mutation at their initial presentation or develop them during the disease course. The patterns of and interactions between these mutated genes are of great research interest and may improve our ability to diagnose and prognosticate patients. It is known that certain gene mutations have a cooperative effect in the pathogenesis of myeloid neoplasms, whereas other gene mutations are mutually exclusive. A commonly cited example of mutually exclusive mutations is SF3B1 and PHF6. This observation, however, has never been rigorously assessed. Since SF3B1 and PHF6 mutations can both serve as drivers of mutations and play key roles in the development of myeloid neoplasms, it is of clinical importance to clarify this issue. We report the clinicopathologic and molecular features of 21 myeloid neoplasms with double SF3B1 and PHF6 mutations. We summarize that concurrent mutations in SF3B1 and PHF6 are rare, but they do exist in a variety of myeloid neoplasms. SF3B1 mutations usually occur as early initiating events whereas PHF6 mutations occur late, with a role in disease progression. The presence of a larger number of other co-mutated genes suggests that the neoplastic cells have gone through active clonal evolution. It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the patients. PHF6 mutations occurred either concurrently with SF3B1 mutations or in subsequent follow-up samples and are associated with disease progression and impending death in most cases. Most cases had co-mutations, the most common being ASXL1, RUNX1, TET2, and NRAS. With a median follow-up of 39 months (range, 3-155), 17 (81%) patients died, 3 were in complete remission, and 1 had persistent myelodysplastic syndrome. The median overall survival was 51 months. In summary, concurrent mutations in SF3B1 and PHF6 are rare, but they do exist in a variety of myeloid neoplasms, with roles as early initiating events and in disease progression, respectively. [ABSTRACT FROM AUTHOR]

In a subset of acute myeloid leukemia (AML) cases, the core binding factor beta subunit gene (CBFB) was rearranged via inv(16)(p13.1q22) or t(16;16)(p13.1;q22), in which the smooth muscle myosin heavy chain 11 gene (MYH11) was the partner (CBFB::MYH11). Rare variants of CBFB rearrangement occurring via non-classic chromosomal aberrations have been reported, such as t(1;16), t(2;16), t(3;16), t(5;16), and t(16;19), but the partners of CBFB have not been characterized. We report a case of AML with a complex karyotype, including t(2;16)(q37;q22), in which the protein phosphatase 1 regulatory subunit 7 gene (PPP1R7) at chromosome 2q37 was rearranged with CBFB (CBFB::PPP1R7). This abnormality was inconspicuous by conventional karyotype and interphase fluorescence in situ hybridization (FISH), thus leading to an initial interpretation of inv(16)(p13.1q22); however, metaphase FISH showed that the CBFB rearrangement involved chromosome 2. Using whole genome and Sanger sequencing, the breakpoints were identified as being located in intron 5 of CBFB and intron 7 of PPP1R7. A microhomology of CAG was found in the break and reconnection sites of CBFB and PPP1R7, thus supporting the formation of CBFB::PPP1R7 by microhomology-mediated end joining. [ABSTRACT FROM AUTHOR]

The CML patient developed myeloid blast crisis 18 months after the initial diagnosis of CML; the MPN-U patient developed accelerated phase of disease 24.1 months after initial diagnosis (Figure B S2 b ). Of the four patients alive at last follow-up, one patient had AML transforming from MDS with a follow-up time of 20.6 months and three were in complete remission including two patients who received allo-SCT. Keywords: acute myeloid leukaemia; EVI1; MECOM; MYC; myelodysplastic syndrome EN acute myeloid leukaemia EVI1 MECOM MYC myelodysplastic syndrome 604 608 5 07/27/22 20220801 NES 220801 I MYC i rearrangement can occur in various B-cell lymphomas, plasma cell neoplasm, rarely B or T cell lymphoblastic leukaemia, and blastic plasmacytoid dendritic cell neoplasm.1-6 However, the occurrence and significance of I MYC i rearrangement in other myeloid neoplasms have not been thoroughly investigated.7-13 Here, we assessed a cohort of 40 patients with 8q24/ I MYC i -rearranged myeloid neoplasms diagnosed from January 2009 through December 2020. [Extracted from the article]

Simple Summary: Acute myeloid leukemia with plasmacytoid dendritic cell differentiation (pDC-AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are two leukemias characterized by neoplastic pDC proliferation. In this study, we aimed to explore the immunophenotypic and molecular profiles of pDC-AML and compare them with BPDCN. We found that pDCs in pDC-AML and BPDCN possessed different immunophenotype. The mutation profiles of these two were also different. These findings demonstrate that pDC-AML and BPDCN are two distinct entities and pDCs in these two entities derive from different subsets of pDC precursors. Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number of pDCs in pDC-AML was 6.6% (range, 2% to 26.3%) and their immunophenotype reminiscent of pDCs in early or intermediate stages of differentiation. The immunophenotype of pDCs in pDC-AML was different from BPDCN (n = 39), with major disparities in CD34 (96% vs. 0%), CD56 (8% vs. 97%) and TCL1 (12% vs. 98%) and significant differences in frequency of CD4, CD13, CD22, CD25, CD36, CD38, CD117 and CD303 expression. At the molecular level, the genetic landscapes of pDC-AML and BPDCN also differ, with RUNX1 mutations detected in 64% of pDC-AML versus 2% of BPDCN. Disparities in TET2 (21% vs. 56%), FLT3 (23% vs. 0%), DNMT3A (32% vs. 10%) and ZRSR2 (2% vs. 16%) (all p < 0.05) were also detected. The distinct immunophenotypic and mutation profiles of pDC-AML and BPDCN indicate that the neoplastic pDCs in pDC-AML and BPDCN derived from different subsets of pDC precursors. [ABSTRACT FROM AUTHOR]

Fluorescence in situ hybridization analysis (FISH) using a CBFB breakapart probe is widely used to detect CBFB rearrangement (CBFBr) in cases of acute myeloid leukemia (AML). However, detection of 3′CBFB deletion (3′CBFBdel) often poses a challenge for interpretation, and the clinical importance of 3′CBFBdel associated CBFBr remains largely unknown. We identified 16 AML patients with 3′CBFBdel, 11 (69%) of which were confirmed to have CBFB::MYH11 fusion. These 11 patients presented with de novo AML; 10 showed myelomonocytic differentiation, 8 had a prominent eosinophilic component, and 7 showed characteristic eosinophils with basophilic granules. Next generation sequencing showed mutations in 7/8 patients, 5 with KRAS/NRAS, 3 with FLT3-TKD, but none with KIT mutations. Except for one patient who died 5 days after diagnosis of AML, all 10 patients received chemotherapy and achieved remission initially. However, within 3 years, 5 (50%) patients had relapsed, of whom, 1 died and 4 received hematopoietic stem cell transplant. After a median follow-up of 76 months, 3 patients died and 8 were alive in complete remission. Our study shows that detection of 3′CBFBdel is not equivalent to unbalanced CBFB rearrangement, and therefore, an alternative confirmatory test is warranted. AML with 3′CBFBdel/CBFBr often shows similar pathological features to AML with inv(16), but appears to have different mutation profiles and a higher risk of relapse requiring hematopoietic stem cell transplant. [ABSTRACT FROM AUTHOR]

A 52-yr-old woman presented with therapy-related acute myeloid leukemia. A bone marrow biopsy showed 21% blasts with a myeloid phenotype and no other notable features such as abnormal eosinophils. Routine nanofluidics-based reverse transcriptase polymerase chain reaction (PCR) leukemia translocation panel designed to screen for recurrent genetic abnormalities in acute leukemia detected an inversion 16 transcript variant E. This prompted rereview of karyotype and fluorescence in situ hybridization studies, which confirmed inv(16), leading to appropriate prognostication and modification of treatment. This case underscores the utility of a powerful molecular screening method for the routine detection of recurrent genetic abnormalities of acute myeloid leukemia. It was especially useful in this case because of the lack of characteristic morphologic findings seen in inversion 16 and the difficulty in its detection by conventional karyotype analysis. [ABSTRACT FROM AUTHOR]

Summary: Clonal haematopoiesis (CH) in patients with acute myeloid leukaemia (AML) may persist beyond attaining complete remission. From a consecutive cohort of 67 patients with nucleophosmin 1‐mutated (NPM1mut) AML, we identified 50 who achieved NPM1mut clearance and had parallel multicolour flow cytometry (MFC) and next generation sequencing (NGS). In total, 13 (26%) cleared all mutations, 37 (74%) had persistent CH frequently involving DNA methyltransferase 3α (DNMT3A,70%), tet methylcytosine dioxygenase 2 (TET2, 27%), isocitrate dehydrogenase 2 (IDH2, 19%) and IDH1 (11%). A small number (<1%) of aberrant CD34+ myeloblasts, but immunophenotypically different from original AML blasts [herein referred to as a pre‐leukaemic (PL) phenotype], was detected in 17 (49%) patients with CH, but not in any patients with complete clearance of all mutations (P = 0·0037). A PL phenotype was associated with higher mutation burden (P = 0·005). Persistent IDH2 and serine and arginine‐rich splicing factor 2 (SRSF2) mutations were exclusively observed in PL+ CH+ cases (P = 0·016). Persistent dysplasia was seen exclusively in cases with a PL+ phenotype (29% vs. none; P = 0·04). The PL+ phenotype did not correlate with age, intensity of induction therapy or relapse‐free survival. Post‐remission CH in the setting of NPM1mut clearance is common and may result in immunophenotypic changes in myeloid progenitors. It is important to not misinterpret these cells as AML measurable residual disease (MRD). [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a molecularly heterogeneous neoplasm that poses a substantial therapeutic challenge. Despite therapy, the patient's disease progressed and bone marrow evaluation in September 2019 showed persistent AML with 50% blasts and persistent FLT3 I - i ITD mutation. In the current case, I BCR-ABL1 i was not seen by karyotype in relapsed bone marrow specimen showing AML in May of 2019, but was seen in September of 2019 after the patient had been on single agent gilteritinib therapy for ~3 months. Less commonly, other mechanisms for I FLT3 i resistance such as secondary FLT3-F691L gatekeeper mutations or rarely I BCR-ABL1 i fusion can be seen at the time of progression on I FLT3 i inhibitor therapy [[3], [22]]. [Extracted from the article]

Objectives: It has been believed that immunoglobulins can only be produced by B lymphocytes and plasma cells. We have previously reported that IgG can be expressed in myeloblasts from patients with acute myeloid leukemia (AML) and plays a role in the proliferation and apoptosis of leukemic cells. However, its clinical impact has not been assessed. Methods: We assessed the expression of different classes of immunoglobulin in peripheral blood and bone marrow samples from 132 AML patients and correlated the levels of expression with clinicopathologic and molecular genetic features, as well as clinical outcome. Results: We found that, in addition to IgG, all classes of immunoglobulin are expressed in myeloblasts, including IgG, IgM, IgA, IgD, IgE, Igκ, and Igλ. The levels of IgG expression (coupled with Igκ or Igλ) are higher than those of IgM, IgA, IgD, and IgE. Using receiver operating characteristic (ROC) curve analysis, we identified two distinct groups of AML patients with differential expression of immunoglobulin and different clinical outcomes. Conclusions: High levels of immunoglobulin expression are associated with monocytic differentiation, multilineage dysplasia, TET2 and KRAS mutations, and poor overall survival. Assessment of immunoglobulin may serve as a useful marker for prognostic stratification and target therapy. [ABSTRACT FROM AUTHOR]

As new drugs targeting MYC show clinical activity in acute myeloid leukemia (AML), understanding MYC expression in AML is of critical importance. We assessed MYC protein expression by immunohistochemistry in bone marrow of patients with untreated AML (n = 265). Overall, 90% of patients demonstrated MYC overexpression and MYC immunopositivity ≤6% was associated with superior complete remission (CR) duration of 23 months versus 12 months for MYC immunopositivity >6% (p = .028). Among 241 patients at higher risk for relapse, including those ≥55 years of age and patients with intermediate- and high-risk AML, MYC immunopositivity ≤6% conferred significantly superior median overall survival (OS) (24 versus 13 months; p = .042), event-free survival (EFS) (14 versus 6 months; p = .048), and relapse-free survival (RFS) (25 versus 12 months; p = .024). The prognostic impact of MYC-immunopositivity was retained on multivariate analysis of OS, EFS, and RFS. We conclude that MYC immunopositivity is an important prognostic factor in patients with untreated AML, particularly those at higher risk for relapse. [ABSTRACT FROM AUTHOR]

Approximately 10% of patients with polycythemia vera (PV) transform to acute leukemia (blast phase) at 10 years after initial diagnosis of PV. The bone marrow pathologic, cytogenetic, and molecular features of blast phase have not been well characterized. In this study, we reviewed 422 PV patients over a period of 11 years and identified 58 patients who developed acute myeloid leukemia (blast phase) during the course of disease. We found that blast phase of PV was characterized by overt myelodysplasia (n = 51, 88%); moderate to severe myelofibrosis (33 of 45, 73%); an abnormal karyotype (n = 51, 88%) that was often complex karyotype (n = 42, 72%); and gene mutations involving TP53 (55%), TET2 (27%), and DNMT3A (25%). Patients with blast phase of PV had an aggressive clinical course, with a median overall survival of 4 months after onset of blast phase. Eleven patients had close follow-up from polycythemic phase to blast phase: Four patients showed dysplastic changes in the polycythemic phase, and three of them transformed to blast phase without a "middle phase" of post-PV myelofibrosis.We conclude that blast phase of PV is characterized by myelodysplasia, moderate to severe fibrosis, a high frequency of an abnormal and often complex karyotype, and frequentTP53mutation. [ABSTRACT FROM AUTHOR]

Objectives: To report aberrant myeloblasts detected by flow cytometry immunophenotypic studies in an asymptomatic patient with familial platelet disorder with propensity to myeloid malignancy, a rare autosomal dominant disease caused by germline heterozygous mutations in Runt-related transcription factor 1.Methods: Morphologic evaluation, flow cytometry immunophenotypic studies, nanofluidics-based qualitative multiplex reverse transcriptase polymerase chain reaction, Sanger sequencing, and next-generation sequencing-based mutational hotspot analysis of 53 genes were performed on bone marrow biopsy and aspirate samples.Results: Flow cytometry immunophenotypic analysis showed 0.6% CD34+ blasts with an abnormal immunophenotype: CD13 increased, CD33+, CD38 decreased, CD117 increased, and CD123 increased.Conclusions: The acquisition of new phenotypic aberrancies in myeloblasts as detected by flow cytometry immunophenotypic studies might be a harbinger of impending myelodysplastic syndrome or acute myeloid leukemia in a patient with familial platelet disorder with propensity to myeloid malignancy. [ABSTRACT FROM AUTHOR]

Nucleophosmin (NPM1) mutations in chronic myelomonocytic leukemia (CMML) are extremely uncommon, and the clinicopathologic features of these neoplasms are poorly characterized. Over a 10-yr interval, NPM1 mutation analysis was performed in 152 CMML at our institution. NPM1 mutations were identified in 8 (5.3%) patients, five men and three women, with a median age of 72 yr (range, 27-87). In all patients, the bone marrow was hypercellular with multilineage dysplasia, monocytosis, and retained maturation supporting a diagnosis of CMML. NPM1 mutation allele burden was <5% in two patients and >10% in six patients. Four (50%) patients, all with >10% NPM1, progressed AML with a median interval of 11 months (range, 1-21). Compared with 144 CMML without NPM1 mutations, CMML patients with NPM1 mutation presented with more severe anemia (P = 0.053), higher BM monocyte percentage (P = 0.033), and an increased tendency for AML progression (P = 0.088) and an inferior overall survival (P = 0.076). Mutations involving NRAS/KRAS (2/7), TET2(2/5), ASXL1(1/5,) and FLT3(0/8) were not significantly different between these two groups. In summary, CMML with NPM1 mutation shows histopathological features of CMML, but patients appear to have a high probability for AML progression and may require aggressive clinical intervention, especially in patients with a high mutation burden. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a distinct clinicopathologic entity with a poor prognosis. However, double inv(3)(q21q26.2) is extremely rare in AML. We report here 3 cases analyzed by oligonucleotide microarray comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP). Clinicopathologic, cytogenetic and molecular findings were correlated with clinical outcome to better understand the entity. Results: The study group included one man and two women at 56-74 years of age. The AML arose from myelodysplastic syndrome in one patient and from chronic myelomonocytic leukemia in another patient. Monosomy 7 was found as additional cytogenetic finding in one patient. One patient had a single inv(3) in the initial clone and acquired double inv(3) as part of clonal evolution. EVI1 (MECOM) rearrangement was confirmed using metaphase/interphase fluorescence in situ hybridization (FISH). Microarray (aCGH + SNP) data analysis revealed that the double inv(3) was a result of acquiring copy neutral loss of heterozygosity of chromosome 3q: arr[hg19] 3q13.21q29(10,344,387-197,802,470)x2 hmz, spanning ~ 94.3 Mb in size. Mutational profiling showed a PTPN11 mutation at a low level (~10 %) in one patient and wild type FLT3 and RAS in all patients. No patients achieved cytogenetic remission and all died with an overall survival (OS) of 23, 12 and 5 months, respectively. Conclusions: Double inv(3) is a result of acquired copy neutral loss of heterozygosity, a somatic repair event occurring as a part of mitotic recombination of the partial chromosome 3q. The double inv(3) in AML patients is highly associated with a rapid disease progression. [ABSTRACT FROM AUTHOR]

Background: TP53 mutation is more prevalent in therapy-related myeloid neoplasms (t-MN) than their de novo counterparts; however, the pattern of mutations involving TP53 gene in t-MN versus de novo diseases is largely unknown. Methods: We collected 108 consecutive patients with therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML). Clinical, hematological, and cytogenetic data were collected by searching the electronic medical record. TP53 sequencing was performed in all patients using a clinically validated next-generation sequencing-based gene panel assay. A previously published patient cohort consisting of 428 patients with de novo MDS/AML was included for comparison. Results: We assessed 108 patients with t-MN, in which 40 patients (37%) had TP53 mutations. The mutation frequency was similar between t-MDS and t-AML; but significantly higher than de novo MDS/AML (62/428 patients, 14.5%) (p < 0.0001). TP53 mutations in t-MN were mainly clustered in DNA-binding domains, with an allelic frequency of 37.0% (range, 7.1 to 98.8). Most mutations involved single nucleotide changes, of which, transitions (65.9%) were more common than transversions (34.1%). Missense mutations were the most frequent, followed by frameshift and nonsense mutations. This TP53 mutation pattern was strikingly similar to that observed in de novo MDS/AML. TP53 mutations in t-MN were associated with a complex karyotype (p < 0.0001), a higher number of chromosomal abnormalities (p < 0.0001), and an inferior overall survival in affected patients (6.1 vs 14.1 months) by univariate (p < 0.0001) and multivariate analyses (p = 0.0020). Conclusions: Our findings support the recent notion that heterozygous TP53 mutation may be a function of normal aging and that mutated cells are subject to selection upon exposure to cytotoxic therapy. t-MN carrying TP53 mutation have an aggressive clinical course independent of other confounding factors. [ABSTRACT FROM AUTHOR]

Array-based comparative genomic hybridization (aCGH) chromosomal analysis facilitates rapid detection of cytogenetic abnormalities previously undetectable by conventional cytogenetics. In this study, we analyzed 48 uniformly treated patients with acute myeloid leukemia (AML) by 44K aCGH and correlated the findings with clinical outcome. aCGH identified previously undetected aberrations, as small as 5 kb, of currently unknown significance. The 36.7 Mb minimally deleted region on chromosome 5 lies between 5q14.3 and 5q33.3 and contains 634 genes and 15 microRNAs, whereas loss of chromosome 17 spans 3194 kb and involves 342 genes and 12 microRNAs. Loss of a 155 kb region on 5q33.3 ( p < 0.05) was associated with achievement of complete remission (CR). In contrast, loss of 17p11.2-q11.1 was associated with a lower CR rate and poorer overall survival (Kaplan-Meier analysis, p < 0.0096). aCGH detected loss of 17p in 12/48 patients as compared to 9/48 by conventional karyotyping. In conclusion, aCGH analysis adds to the prognostic stratification of patients with AML. [ABSTRACT FROM AUTHOR]

Objectives: To assess CD105 (endoglin) expression in 119 acute myeloid leukemia (AML) and 13 control cases using immunohistochemistry. Methods: CD105 expression was assessed retrospectively by using immunohistochemistry in bone marrow specimens. Results: CD105 was strongly and diffusely positive in all 9 (100%) AMLs with t(15;17)(q24.1;q21.2), 2 (100%) AMLs with t(8;21)(q22;q22), 1 (100%) AML with t(6;9)(p23;q34), 7 (28%) of 25 AMLs with myelodysplasia-related changes, 1 (33%) of 3 therapy-related AMLs, 3 (16%) of 19 AMLs unclassifiable, 1 (14%) of 7 AMLs with inv(16)(p13.1q22), and 5 (11%) of 45 AMLs not otherwise specified. Uninvolved bone marrow in these cases showed no CD105 expression by erythroid precursors, megakaryocytes, or endothelial or stromal cells. Two of 13 control bone marrow specimens showed partial CD105 positivity in myeloid cells. In 21 strongly CD105+ AML cases tested for the IDH2 mutation, 9 (42%) were mutated (P = .004). Conclusions: These data suggest that CD105 could be a therapeutic target in a subset of patients with AML. [ABSTRACT FROM AUTHOR]

Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-Ketoglutarate (α-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of α-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alter-ations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential mol-ecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics. [ABSTRACT FROM AUTHOR]

Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) is a controversial diagnosis, as others propose that it represents chronic myelogenous leukemia in blast phase (CML-BP). NPM1 mutations occur in 25-35% of patients with AML but are absent in patients with CML. Conversely, ABL1 mutations occur in 25% of imatinib-naive patients with CML-BP but are not described in patients with AML. We analyzed for NPM1 and ABL1 mutations in nine Ph+ patients with AML and five patients with CML-BP initially presenting in BP. In six cases of Ph+ AML, we screened for a panel of gene mutations using Sequenome®-based methods including AKT1, AKT2, AKT3, BRAF, EGFR, GNAQ, GNAS, IDH1, IDH2, KRAS, MET, NRAS, PIK3CA and RET. Two of nine (22%) patients with Ph+ AML had NPM1 mutations and were alive 36 and 71 months after diagnosis. All cases of Ph+ AML were negative for ABL1 and other gene mutations. One (20%) patient with CML-BP had ABL1 mutation; no patients had NPM1 mutations. These data suggest that Ph+ AML is distinct from CML-BP. [ABSTRACT FROM AUTHOR]

Summary: Acute myeloid leukemia is a heterogeneous group of diseases. Mutations of the isocitrate dehydrogenase (IDH) genes represent a novel class of point mutations in acute myeloid leukemia. These mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate and confer novel enzymatic activity, facilitating the reduction of α-ketoglutarate to d-2-hydroxyglutarate, a putative oncometabolite. IDH1/IDH2 mutations are heterozygous, and their combined frequency is approximately 17% in unselected acute myeloid leukemia cases, 27% in cytogenetically normal acute myeloid leukemia cases, and up to 67% in acute myeloid leukemia cases with cuplike nuclei. These mutations are largely mutually exclusive. Despite many similarities of IDH1 and IDH2 mutations, it is possible that they represent distinct molecular or clinical subgroups of acute myeloid leukemia. All known mutations involve arginine (R), in codon 132 of IDH1 or codon 140 or 172 of IDH2. IDH1 R132 and IDH2 R140 mutations are frequently accompanied by normal cytogenetics and NPM1 mutation, whereas IDH2 R172 is frequently the only mutation detected in acute myeloid leukemia. There is increasing evidence that the prognostic impact of IDH1/2 mutations varies according to the specific mutation and also depends on the context of concurrent mutations of other genes. IDH1 R132 mutation may predict poor outcome in a subset of patients with molecular low-risk acute myeloid leukemia, whereas IDH2 R172 mutations confer a poor prognosis in patients with acute myeloid leukemia. Expression of IDH1/2 mutants induces an increase in global DNA hypermethylation and inhibits TET2-induced cytosine 5-hydroxymethylation, DNA demethylation. These data suggest that IDH1/2 mutations constitute a distinct mutational class in acute myeloid leukemia, which affects the epigenetic state, an important consideration for the development of therapeutic agents. [Copyright &y& Elsevier]

The clinical importance of erythroid predominance in bone marrow of patients with acute myeloid leukemia (AML) is controversial. These cases represent a heterogeneous group of diseases that historically have been classified into different categories. We studied 313 AML patients and specifically compared the clinical, cytogenetic, and molecular features of cases of AML with erythroid predominance, arbitrarily defined as ⩾50% erythroid precursors, to AML cases without erythroid predominance. We also assessed 51 patients with a high-grade myelodysplastic syndrome (MDS), refractory anemia with excess blasts (RAEB). All neoplasms were classified according to the World Health Organization classification. With the exception of therapy-related AML/MDS, the presence of erythroid predominance in variously classified categories of AML was associated with a survival advantage. In addition, AML with erythroid predominance had a lower frequency of cytogenetic abnormalities as well as a lower frequency of mutations involving NPM1, NRAS and FLT3 as compared with AML without erythroid predominance. We conclude that the clinical, cytogenetic, and molecular features of AML with erythroid predominance in the non-therapy-related setting are much closer to those of a high-grade myelodysplastic syndrome than they are to other types of AML. [ABSTRACT FROM AUTHOR]

The t(3;21)(q26.2;q22) translocation is rare in cases of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). We studied 17 patients with MDS/AML associated with t(3;21) and compared them with 17 patients with MDS associated with inv(3) (q21q26.2)/t(3;3)(q21;q26.2), because these entities share 3q26 locus abnormalities. The t(3;21) group included 9 men and 8 women, with a median age of 62 years (range, 13-81 years). One case was de novo AML and 16 cases were therapy-related, including 12 MDS (blasts, <15%) and 4 AML (blasts, 33%-50%). All patients had multilineage dysplasia, whereas none had thrombocytosis. Additional cytogenetic aberrations were identified in 12 cases, including --7/7q (n = 9) and a complex karyotype (n = 7). All patients died, with 1- and 2-year survival rates of 35% and 6%, respectively. Although multilineage dysplasia and frequent association with --7/7q were similar in both groups, MDS/AML cases associated with t(3;21) have a higher frequency of therapy-related disease and shorter survival times, suggesting that they are distinct from MDS/AML cases associated with inv(3)/t(3;3). [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) with isolated trisomy 4 is rare. Associations with KIT mutations on chromosome 4q12 have been documented. The clinicopathologic features and mutational status of KIT, FLT3, NPM1, CEBPA, and RAS were assessed in 13 AML cases with isolated trisomy 4. There were 9 men and 4 women with a median age of 54 years. Median blast count was 84% (range, 24%-93%). Morphologic features varied across five 2008 World Health Organization categories. FLT3 (5/10) and NPM1 (4/10) mutations were observed at a frequency similar to normal-karyotype AML cases. KIT D816V (1/10), RAS (1/11; NRAS), and CEBPA (0/9) mutations were rare or absent. In 11 of 13 cases, complete remission was achieved. In 8 cases, relapse occurred, with median relapse-free survival of 11 months. Median overall survival was 28 months. AML with isolated trisomy 4 is rare and associated with high bone marrow blast counts and an intermediate to poor prognosis. KIT mutations are uncommon. [ABSTRACT FROM AUTHOR]

BACKGROUND: Acute myeloid leukemia (AML) infrequently involves the central nervous system (CNS). This study was undertaken in patients with AML to determine whether cytogenetic findings predict CNS involvement. METHODS: The medical records of 1354 patients with AML who were treated at The University of Texas MD Anderson Cancer Center between January 2000 and December 2008 were reviewed. Forty patients (3%) had CNS involvement at time of presentation or disease recurrence, of whom 37 had conventional cytogenetics performed on bone marrow aspirate material. Demographics, treatment, and status at last follow-up were collected. RESULTS: Eleven patients (30%) had a diploid karyotype, and 14 patients (38%) had complex cytogenetics. Only 5 of the 40 patients had CNS disease at diagnosis, and the remaining patients had CNS disease at relapse. Patients who developed CNS disease were younger ( P = .019), had a higher white blood cell (WBC) count at diagnosis ( P = .001), had higher lactate dehydrogenase level (LDH) levels ( P < .0001), and had higher percentages peripheral blast cells ( P = .024) at diagnosis compared with the rest of the population. In addition, patients with CNS disease had higher rates of chromosome 16 inversion ( P < .001), chromosome 11 abnormality ( P = .005), and trisomy 8 ( P = .02) and had a tendency toward complex cytogenetics ( P = .2) compared with the control group (patients who had AML with no CNS involvement). CONCLUSIONS: Patients with AML and CNS disease often had higher LDH levels and WBC counts at diagnosis, and they often presented with chromosome 16 inversion and chromosome 11 abnormalities. The current study indicated that the overall survival of patients with AML who had CNS involvement is poor. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: CXC chemokine receptor 4 (CXCR4) is activated by phosphorylation (pCXCR4) and is essential for the migration of hematopoietic precursors to bone marrow. CXCR4 overexpression predicts a poor prognosis in patients with acute myeloid leukemia. Data regarding the prognostic impact of CXCR4 in patients with B-acute lymphoblastic leukemia (B-ALL) are sparse and limited to the pediatric population. METHODS: The authors analyzed CXCR4 and pCXCR4 expression in 54 adults with newly diagnosed B-ALL. CXCR4 was assessed by flow cytometry (FC) and immunohistochemistry (IHC) using an anti-CXCR4 antibody. pCXCR4 expression was assessed using an anti-pCXCR4 antibody. RESULTS: The study group included 30 men and 24 women with a median age of 42 years (range, 17-84 years). Philadelphia chromosome was present in 19 patients. The median follow-up was 16 months (range, 17-84 months). Forty-nine patients had a complete response, and 12 patients relapsed with a median relapse free survival >120 weeks. Fifteen patients (28%) died with a median survival >125 weeks. CXCR4 detected by FC and IHC was highly correlated ( P < .001). CXCR4 was not associated with clinical or laboratory findings or survival. In contrast, pCXCR4 was associated with higher leukocyte count ( P = .006) and serum bilirubin level ( P = .03). In multivariate analysis, pCXCR4 expression ( P = .027), high serum creatinine level ( P < .01), presence of the Philadelphia chromosome ( P = .017), and late clinical response ( P < .001) were associated with worse overall survival. CONCLUSIONS: The current results indicated that detection of the activated form of CXCR4, pCXCR4, provides independent prognostic information in adult patients with B-ALL. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) with inv(3) (q21q26.2) or t(3;3)(q21;q26.2) is a distinct subtype in the World Health Organization classification. The natural history of myelodysplastic syndrome (MDS) associated with these cytogenetic aberrations is poorly understood. We studied 17 MDS (11 de novo and 6 therapy related) and 3 chronic myelomonocytic leukemia (CMML) cases associated with inv(3) (q21q26.2) or t(3;3)(q21;q26.2). The de novo cases were further classified as refractory cytopenia with multilineage dysplasia (n = 8) and refractory anemia with excess blasts (n = 3). Isolated inv(3)/t(3;3) was identified in 4 cases, whereas -7/7q (n = 13) and -5/5q (n = 6) were common additional aberrations. Nineteen patients died, including 13 in whom the disease progressed to AML after a median of 7 months. Median survival for patients with de novo disease was similar to that for patients with therapy-related MDS (13 vs 17.5 months). MDS or CMML with inv(3)/t(3;3) are aggressive diseases with a high risk of progression to AML. [ABSTRACT FROM AUTHOR]

We reviewed FLT3 and NPM1 mutation data in a large cohort of patients with myelodysplastic syndrome (MDS). The frequencies of FLT3 and NPM1 mutation were 2.0% and 4.4%, respectively, and mutations were restricted to cases of intermediate- and high-risk MDS. Cytogenetic abnormalities were identified in 46.9% of cases. FLT3 mutations were associated with a complex karyotype (P = .009), whereas NPM1 mutations were associated with a diploid karyotype (P < .001). FLT3 mutation (P < .001) was associated with progression to acute myeloid leukemia (AML), as were a higher bone marrow (BM) blast count (P < .001) and complex cytogenetics (P = .039). No patient with an NPM1 mutation alone had disease that progressed to AML. Cox proportional regression multivariate analysis indicated that FLT3 mutation, NPM1 mutation, complex cytogenetics, BM blast count, pancytopenia, and age were independent factors that correlated with progression-free survival. We conclude that FLT3 and NPM1 mutations are rare in MDS, but assessment of mutation status is potentially useful for predicting progression to AML. [ABSTRACT FROM AUTHOR]

Mutations in the isocitrate dehydrogenase 1 (IDH1) and IDH2 genes are reported in acute myeloid leukemia (AML). We studied the frequency and the clinicopathologic features of IDH1 and IDH2 mutations in AML. Mutations in IDH1 (IDH1(R)¹³²) and IDH2 (IDH2(R)¹⁷²) were assessed by Sanger sequencing in 199 AML cases. Point mutations in IDH1(R)¹³² were detected in 12 (6.0%) of 199 cases and in IDH2(R)¹⁷² in 4 (2.0%) of 196 cases. Of the 16 mutated cases, 15 (94%) were cytogenetically normal, for an overall frequency in this group of 11.8%. IDH1(R)¹³² and IDH2(R)¹⁷² mutations were mutually exclusive. Concurrent mutations in NPM1, FLT3, CEBPA, and NRAS were detected only in AML with the IDH1(R)¹³² mutation. The clinical and laboratory variables of patients with AML with IDH mutations showed no significant differences compared with patients with wild-type IDH. We conclude that IDH1(R)¹³² and IDH2(R)¹⁷² mutations occur most often in cytogenetically normal AML cases with an overall frequency of approximately 11.8%. [ABSTRACT FROM AUTHOR]

Summary: The 3q21q26 syndrome is recognized as a distinct clinicopathologic entity. Patients have a myeloid neoplasm associated with 3q21q26 cytogenetic abnormalities and present with anemia, leukopenia, and either thrombocytosis or a normal platelet count associated with dysplasia. To determine if JAK2 V617F mutation is implicated in the abnormal thrombopoiesis of the 3q21q26 syndrome, we analyzed bone marrow samples of 12 patients, including 10 patients with acute myeloid leukemia and 2 patients with a myelodysplastic syndrome, associated with either inv(3)(q21;q26) or t(3;3)(q21;q26). The platelet count ranged from 142 to 597 × 103/μL. Using polymerase chain reaction and pyrosequencing assays, no evidence of JAK2 V617F was identified in 11 of 12 cases. A JAK2 V617F mutation was identified in one patient who had acute myeloid leukemia with concurrent mast cell disease. Separate DNA analysis of myeloblasts and mast cells after laser capture microdissection confirmed that JAK2 V617F was present in both components. We conclude that JAK2 V617F mutation is uncommon in the 3q21q26 syndrome and that its presence may indicate an unusual coexistence of a myeloproliferative neoplasm. [Copyright &y& Elsevier]

The article discusses a study which found that cuplike nuclei or prominent nuclear invaginations in acute myeloid leukemia (AML) are linked with the presence of FMS-like tyrosine kinase-3 gene (FLT3) internal tandem duplication and nucleophosmin (NPM1) mutation. The study were conducted among patients with AML without maturation and with cuplike nuclei. The results of the study revealed that morphologic features of AML with cuplike nuclei may help in determining the workup of neoplasms.

The article informs that nucleophosmin (NPM1) gene mutations can be used to predict a favorable prognosis in patients suffering from acute myeloid leukemia. It is stated that cytoplasmic localization of nucleophosmin (NPM) protein is considered a surrogate for NPM1 gene mutation. It is mentioned that DNA sequencing cannot be replaced by immunohistochemical analysis.

Background: It is unknown whether patients with nonleukemic myeloid sarcoma (MS) and those with acute myeloid leukemia (AML) have similar responses to anti-AML treatment. In the current study, the authors addressed this question by matching MS patients with analogous AML patients and comparing their clinical outcomes.Methods: Twenty-three consecutive patients with MS and 1720 consecutive patients with AML were identified who presented at The University of Texas M. D. Anderson Cancer Center from 1990 to 2004. All AML patients and 16 MS patients received cytarabine plus idarubicin or fludarabine as induction remission therapy. Treated MS patients and AML patients were matched according to cytogenetics, age, Zubrod performance status, and time of treatment. Event-free survival (EFS) and overall survival (OS) were compared using Kaplan-Meier analyses.Results: Complete response rates were 69% in patients with MS and 57% in patients with AML (P = .45). The respective 2-year EFS and OS rates were 32% and 18% (P = .08) and 43% and 29% (P = .11). Matches were identified for 14 MS patients who were paired repeatedly with 91 AML patients to produce 94 matches (3 AML patients were matched twice). EFS was longer in 56 MS pair mates, shorter in 26 pair mates, and similar in 12 pair mates (P = .01; Fisher exact test). OS analyses yielded similar results.Conclusions: Anti-AML therapy was highly effective in patients with nonleukemic MS. The results from this study emphasize the need to treat patients who have nonleukemic MS with AML-type therapy. [ABSTRACT FROM AUTHOR]

Abstract: We identified a reciprocal translocation between chromosomes 3 and 8, with breakpoints at bands 3q26 and 8q24, in five patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The t(3;8)(q26;q24) was the sole cytogenetic aberration in two patients, was associated with trisomy 13 in one patient, and occurred with monosomy 7 in two patients. In three patients, the AML or MDS developed 36, 52, and 57 months following chemotherapy for soft tissue sarcoma, mantle cell lymphoma, and diffuse large B-cell lymphoma, respectively; in these three patients, the neoplasms were considered to be therapy-related. All five patients displayed marked trilineage dysplasia and variable degrees of cytopenias, with marked thrombocytosis noted in one patient and a normal platelet count in another patient. All patients were treated with combination chemotherapy; at writing, four were still alive and one had died during a follow-up period ranging from 1 to 16 months. We conclude that the t(3;8)(q26;q24) is a recurrent translocation associated with therapy-related MDS/AML or de novo AML, and is frequently associated with monosomy 7. [Copyright &y& Elsevier]

The article discusses the highlights of the 2013 Workshop of the Society for Hematopathology/European Association for Haematopathology titled "Progress in Acute Myeloid Leukemia (AML), Myelodysplastic Syndromes and Acute Lymphoblastic Leukemia" held in Houston, Texas on October 24 to 26, 2013. Topics discussed include the World Health Organization (WHO) category of AML and cases of cytogenetically normal AML.

Abstract: EVI is a proto-oncogene that is activated in acute myeloid leukemia with chromosomal rearrangements that map to chromosome 3q26. We previously reported the clinicopathologic features of five cases of acute myeloid leukemia carrying t(3;8)(q26;q24). Using fluorescence in situ hybridization analysis, we demonstrate in the current study that the breakpoint on chromosome 3 is at EVI1/MDS1, and the breakpoint on chromosome 8 is just distal to the PVT1 oncogene homolog, a C-MYC activator in mice. The breakpoint on chromosome 8 was detected between the components of the LSI MYC dual-color break-apart rearrangement probe. Reverse-transcriptase polymerase chain reaction assay showed expression of EVI1 in all four cases analyzed, and DNA sequence analysis confirmed the findings. Reverse transcriptase polymerase chain reaction assay also demonstrated the expression of PVT1 and C-MYC in all four cases assessed. Western blot analysis detected EVI1 in one case analyzed. We conclude that the t(3;8)(q26;q24) results in deregulated EVI1 expression, similar to other balanced or unbalanced chromosomal translocations involving chromosome 3q26. [Copyright &y& Elsevier]

Context.—Heterozygous mutation of the nucleophosmin gene (NPM1) has recently been described as one of the most frequent genetic lesions in acute myeloid leukemia (AML). Objective.—(1) To discuss the clinical, morphologic, immunophenotypic, and genetic features of AML with NPM1 gene mutations, along with various detection methods, (2) To explore the mechanisms by which NPM1 gene mutations contribute to leukemogenesis. Data sources/extraction.-Data were analyzed from 7 recently published papers. Results.—NPM1 gene mutations tend to occur more frequently in women, and also tend to be associated with a higher white blood cell count. There is no significant age difference. NPM1-mutated AML is preferentially associated with AML with monocytic differentiation (in particular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations, and a trend toward favorable clinical outcome, especially in patients without FLT3 gene mutation. NPM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM. Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies. These mutations may contribute to leukemogenesis, at least in part, through disruption of the p14ARF (alternative reading frame) MDM2-p53 pathway and centrosomal duplication. Conclusions.—Detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups. Exploring the mechanisms may lead to a better understanding of how mutant NPM protein becomes leukemogenic, thereby providing insights for the development of new chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

• Clonal cytogenetic abnormalities (CCA) in donor cells after stem cell transplant (SCT) can be seen in donor-derived cells. • CCA may reflect a constitutional abnormality in a donor or may be present in a recipient with or without overt neoplasia. • In our cohort, ~1% of the patients had CCA in donor-derived cells. • Loss of 7q is the most common somatic CCA, in donor derived cells. • Presence of del(7q) in cases without an overt neoplasia appears to be an adverse prognostic factor. Clonal cytogenetic abnormalities (CCA) in donor-derived cells after stem cell transplant (SCT) are typically reported in donor-derived cell neoplasms, but CCA also may reflect a constitutional abnormality in the donor or may be present in a recipient without overt hematological malignancy. We reviewed 8515 tests on 2035 patients, who had allogenic sex mismatched SCT and underwent serial cytogenetic analysis between 2006 and 2020 in our institution. A constitutional CCA was observed in 3 patients: inv(10), t (1;5), and t (13;14). A somatic CCA without overt neoplasia was detected in 12 patients: del(7q) (n = 6), del(20q) (n = 3), der(11) t (11;11) (n = 1), t (1;9) (n = 1), dup(6p)(n = 1). In this group, four patients with cytopenia had del(7q), and an association between del(7q) and an adverse overall survival (OS) was observed [HR:5.99; 95%CI 1.23–29.92). Four patients had a donor-derived cell neoplasm: myelodysplastic syndrome (n = 3) and acute myeloid leukemia (n = 1), and all four neoplasms had loss of 7q. In our cohort, ∼1% of the patients (19/2,035) had CCA in donor-derived cells. Balanced constitutional CCA can pose a reproductive risk to donor. Loss of 7q is the most common somatic CCA, in donor-derived cells. [ABSTRACT FROM AUTHOR]