Progression of chronic myelogenous leukemia (CML) to accelerated (AP) and blast phase (BP) is because of secondary molecular events, as well as additional cytogenetic abnormalities. On the basis of the detection of JAK2, CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations in myelodysplastic/myeloproliferative neoplasms, we hypothesized that they may also contribute to progression in CML. We screened these genes for mutations in 54 cases with CML (14 with chronic phase, 14 with AP, 20 with myeloid, and 6 with nonmyeloid BP). We identified 1 CBLB and 2 TET2 mutations in AP, and 1 CBL, 1 CBLB, 4 TET2, 2 ASXL1, and 2 IDH family mutations in myeloid BP. However, none of these mutations were found in chronic phase. No cases with JAK2V617F mutations were found. In 2 cases, TET2 mutations were found concomitant with CBLB mutations. By single nucleotide polymorphism arrays, uniparental disomy on chromosome 5q, 8q, 11p, and 17p was found in AP and BP but not involving 4q24 (TET2) or 11q23 (CBL
In aplastic anemia (AA), contraction of the stem cell pool may result in oligoclonality, while in myelodysplastic syndromes (MDS) a single hematopoietic clone often characterized by chromosomal aberrations expands and outcompetes normal stem cells. We analyzed patients with AA (N ؍ 93) and hypocellular MDS (hMDS, N ؍ 24) using single nucleotide polymorphism arrays (SNP-A) complementing routine cytogenetics. We hypothesized that clinically important cryptic clonal aberrations may exist in some patients with BM failure. Combined metaphase and SNP-A karyotyping improved detection of chromosomal lesions: 19% and 54% of AA and hMDS cases harbored clonal abnormalities including copy-neutral loss of heterozygosity (UPD, 7%). Remarkably, lesions involving the HLA locus suggestive of clonal immune escape were found in 3 of 93 patients with AA. In hMDS, additional clonal lesions were detected in 5 (36%) of 14 patients with normal/noninformative routine cytogenetics. In a subset of AA patients studied at presentation, persistent chromosomal genomic lesions were found in 10 of 33, suggesting that the initial diagnosis may have been hMDS. Similarly, using SNP-A, earlier clonal evolution was found in 4 of 7 AA patients followed serially. In sum, our results indicate that SNP-A identify cryptic clonal genomic aberrations in AA and hMDS leading to improved distinction of these disease entities. IntroductionApproximately 10% of patients with myelodysplastic syndromes (MDS) present with a hypocellular BM and distinction of these patients from those with aplastic anemia (AA) is often a diagnostic challenge. [1][2][3][4] The morphologic diagnosis of MDS relies on the presence of dysplastic features and detection of clonal chromosomal abnormalities. In particular, detection of recurrent genomic lesions supports the diagnosis of a neoplastic clonal process. However, low cellularity of the aspirates in AA and hypocellular MDS (hMDS) often hampers precise morphologic assessment and leads to unsuccessful cytogenetic testing, resulting in misdiagnosis.Around 50% of patients with MDS, including hypocellular cases, show a normal karyotype by metaphase cytogenetics (MC), making the distinction from AA more difficult. Similarly, MDS can also develop as a late clonal complication of AA; the evolution rate of clonal chromosomal defects may be as high as 20% in 10 years, but the risk factors for evolution have not been identified. [5][6][7][8] Karyotype abnormalities encountered in this setting often include loss of chromosomes 6 and 7, and trisomy 8. 5 Identification of clonal progression is an important diagnostic task, as the prognosis of patients with AA-derived MDS is less favorable and treatment choices differ, in particular when high-risk chromosomal abnormalities are involved.Many investigators believe that the presence of chromosomal abnormalities is not compatible with the diagnosis of AA. 9,10 However, some diagnostic guidelines do not preclude a diagnosis of AA even if abnormal cytogenetics is present in otherwise hypocellular ...
BackgroundA combination of horse anti-thymocyte globulin and cyclosporine produces responses in 60-70% of patients with severe aplastic anemia. We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe aplastic anemia. Design and MethodsTwenty patients with severe aplastic anemia treated with rabbit anti-thymocyte globulin were compared to 67 historical control cases with matched clinical characteristics treated with horse anti-thymocyte globulin. ResultsResponse rates at 3, 6 and 12 months were similar for patients treated with rabbit anti-thymocyte globulin or horse anti-thymocyte globulin: 40% versus 55% (P=0.43), 45% versus 58% (P=0.44) and 50% versus 58% (P=0.61), respectively. No differences in early mortality rates or overall survival were observed. We then performed multivariable analyses of response at 6 months and overall survival and identified the presence of a paroxysmal nocturnal hemoglobinuria clone (P=0.01) and a pretreatment absolute reticulocyte count greater than 30¥10 9 /L (P=0.007) as independent predictors of response and younger age (P=0.003), higher pretreatment absolute neutrophil (P=0.02) and absolute lymphocyte counts (P=0.03) as independent predictors of overall survival. None of the immunogenetic polymorphisms studied was predictive of response to immunosupressive therapy. ConclusionsDespite reports suggesting differences in biological activity of different anti-thymocyte globulin preparations, rabbit and horse anti-thymocyte globulin appear to have a similar efficacy for upfront treatment of severe aplastic anemia. (Clinicaltrial.gov: NCT01231841)
Hospitalized patients frequently have considerable volumes of blood removed for diagnostic testing which could lead to the development of hospital-acquired anemia. Low hemoglobin levels during hospitalization may result in significant morbidity for patients with underlying cardiorespiratory and other illnesses. We performed a retrospective study and data was collected using a chart review facilitated through an electronic medical record. A total of 479 patients who were not anemic during admission were included in analysis. In our study, we investigated the incidence of HAA and found that, between admission and discharge, 65% of patients dropped their hemoglobin by 1.0 g/dL or more, and 49% of patients developed anemia. We also found that the decrease in hemoglobin between admission and discharge did not differ significantly with smaller phlebotomy tubes. In multivariate analysis, we found that patients with longer hospitalization and those with lower BMI are at higher risk of developing HAA. In conclusion, our study confirms that hospital-acquired anemia is common. More aggressive strategies such as reducing the frequency of blood draws and expanding the use of smaller volume tubes for other laboratory panels may be helpful in reducing the incidence of HAA during hospitalization.
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