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Kao, Jelena M.; McMillan, Alex; Greenberg, Peter L.
doi: 10.1002/ajh.21249pmid: 18645988
The International Prognostic Scoring System (IPSS) was created for evaluating clinical outcomes of patients with myelodysplastic syndromes (MDS). We evaluated the depth of cytopenias to determine whether this parameter could further refine the prognostic ability of the IPSS. Correlation was determined between the depth of cytopenias in 816 patients from the International MDS Risk Analysis Workshop database and patients' clinical features. Univariate analyses of hemoglobin (Hb), absolute neutrophil count, and platelet depth levels were assessed relative to the IPSS risk groups, refined French‐American‐British categories, cytogenetic groups, bone marrow blast percentage (%), age groups, overall survival (OS), and time to evolution of acute myeloid leukemia (AML). Multivariate analysis of different cytopenic levels was performed to determine whether depth of cytopenias was prognostically additive to the IPSS. All cytopenic categories had statistically significant rank correlations with IPSS, bone marrow blast %, and refined French‐American‐British categories. In multivariate analysis, Hb levels had additive prognostic value to the IPSS for evaluation of OS, but not time to AML, with greatest prognostic value in Intermediate‐1 and Intermediate‐2 categories. In contrast, platelet or absolute neutrophil count levels alone or in combination lacked additive prognostic value to the IPSS regarding OS or time to AML evolution. The depth of Hb level per se at the time of diagnosis has additive predictive value to the IPSS for OS in the intermediate‐risk groups. This information should prove useful for aiding therapeutic decision‐making, prognostic classification, and designing clinical trials for patients with MDS. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Stone, Richard M.; DeAngelo, Daniel J.; Janosova, Anna; Galinsky, Ilene; Canning, Christine; Ritz, Jerome; Soiffer, Robert J.
doi: 10.1002/ajh.21253pmid: 18756547
The most important problem in the therapy of patients with acute myeloid leukemia (AML) is relapse after intensive therapy. We sought to determine if interleukin‐2 (low‐dose with intermittent boluses) administration could be feasibly administered after standard therapy to potentiate anti‐tumor immunity in a fashion analogous to the post‐allogeneic stem cell transplant “graft‐vs‐leukemic” effect. Adults with de novo AML received daunorubicin and cytosine arabinoside induction therapy. Patients achieving complete remission received high dose ara‐C (HIDAC) for three courses followed by low dose rIL‐2 (Amgen), administered by continuous infusion (450,000 U/m2/day) for 10 weeks with intermittent boluses (500,000/U/m2 over 2 hr) given in weekly intervals starting on Week 4. Of the 32 enrolled patients, 27 achieved CR; 8/11 who received rIL‐2 completed therapy. 6/11 are long term survivors (median follow‐up, 139 months). rIL‐2 was well tolerated and associated with a 5‐fold increase in circulating NK‐lymphocytes and a 3‐fold increase in circulating T‐cells. Mononuclear cells from patients receiving rIL‐2 exhibited enhanced cytolytic activity in vitro against cryopreserved autologous leukemia cells. This study supports further investigation of immunotherapy in the post‐intensive chemotherapy setting in the management of patients with AML. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Bennett, Carolyn M.; Boye, Eileen; Neufeld, Ellis J.
doi: 10.1002/ajh.21219pmid: 18645989
We describe monozygotic female twins discordant for hemophilia A, born to a carrier mother and normal father. Affected twin A presented at age 1 year with excessive bruising and factor VIII procoagulant activity (FVIII:C) of less than 1% of normal. Twin B is an asymptomatic carrier with FVIII:C level of 42%. Peripheral blood DNA was tested for X‐chromosome inactivation (methylation) patterns of the X‐linked human androgen receptor gene, comparing the twins' patterns to parental. Twin A showed nonrandom inactivation skewed toward the paternal X, whereas twin B showed random X‐inactivation. This is the first reported case of discordance for hemophilia A between female monozygotic twins. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Deborah Chirnomas, Sarah; Geukes‐Foppen, Marnix; Barry, Kristen; Braunstein, Jennifer; Kalish, Leslie A.; Neufeld, Ellis J.; Powell, Andrew J.
doi: 10.1002/ajh.21221pmid: 18661491
This study examined the relationship between hepatic and myocardial iron concentration, assessed by T2*‐MRI in 66 patients (3–82 years) with transfusion‐dependent anemias and thalassemia intermedia, to determine whether hepatic iron levels alone suffice for chelation adjustments. We found a poor correlation between hepatic and myocardial iron (r = 0.10, P = 0.43) and identified a subgroup (14%) with increased myocardial iron without a matched degree of hepatic hemosiderosis. Left ventricular ejection fraction was insensitive for detecting elevated myocardial iron. These findings were present in both adult and pediatric patients. We recommend therapeutic monitoring of iron burden by evaluation of both liver and myocardial iron with T2*‐MRI. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Kim, Sung‐Yong; Lee, Dong‐Gun; Kim, Myung‐Shin; Kim, Hee‐Je; Lee, Seok; Min, Chang‐Ki
doi: 10.1002/ajh.21227pmid: 18661492
An infection after allogeneic stem cell transplantation (SCT) can affect the activity of immune cells and increase the level of proinflammatory cytokines. Further, a post‐SCT infection may influence the milieu of the graft‐versus‐leukemia (GVL) effect and graft‐versus‐host disease (GVHD). We performed a retrospective study of patients with acute leukemia who had undergone allogeneic SCT using the same preparative regimens and bone marrow as the stem cell source to determine if early post‐transplant infection was associated with the risk of leukemic relapse and GVHD. The analysis revealed that patients who had a febrile infection (FI) before post‐transplant day 21 (FI group) had a lower actuarial probability of leukemic relapse (P < 0.001) and a higher relapse‐free survival rate (P = 0.012) than those patients who did not have a FI before post‐transplant day 21 (non‐FI group). The experience of early post‐transplant FI (HR = 0.316; 95% CI = 0.174–0.575; P < 0.001), together with the presence of chronic GVHD and high risk cytogenetics, were independent predictive factors for post‐transplant leukemic relapse. The FI group had a trend towards a higher lymphocyte count on post‐transplant day 21 than the non‐FI group (P = 0.063), despite the delayed recovery of the platelet count and a trend towards delayed recovery of the neutrophil count. These findings suggest that a change in the immunologic network by infectious diseases in the early post‐transplant period favors the milieu of the GVL effect. The specific immunologic change during FI, which can potentiate the GVL effect, remains to be determined. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Sangerman, Jose; Maksimova, Yelena; Edelman, E. Jennifer; Morrow, Jon S.; Forget, Bernard G.; Gallagher, Patrick G.
doi: 10.1002/ajh.21254pmid: 18704959
Mutations of ankyrin‐1 are the most frequent cause of the inherited hemolytic anemia, hereditary spherocytosis (HS), in people of European ancestry. Ankyrin‐1, which provides the primary linkage between the erythrocyte membrane skeleton and the plasma membrane, has numerous isoforms generated by alternative splicing, alternate polyadenylation, use of tissue‐specific promoters, and alternate NH2 or COOH‐termini. Mutation detection in erythrocyte membrane protein genes, including ankyrin, has been a challenge, primarily due to the large size of these genes, and the apparent frequent occurrence of HS‐associated null alleles. Using denaturing high‐performance liquid chromatography (DHPLC), we screened the ankyrin gene of the proband of a large, three generation African–American kindred with ankyrin‐deficient HS. DHPLC yielded an abnormal chromatogram for exon 1. Examination of the corresponding exon 1 sequence in genomic DNA from the proband revealed heterozygosity for a mutation of the initiator methionine (ATG to ATA Met 1 Ile). Coupled in vitrotranscription/translation studies with rabbit reticulocyte lysates demonstrated that the wild‐type ankyrin erythroid cDNA initiates only from the known initiator methionine, indicating that the use of alternate initiator methionine is not a mechanism of isoform diversity in erythroid cells. The mutant ankyrin allele, unlike some initiator methionine mutations that utilize downstream codons for translation initiation, was associated with a null allele. This is the first report describing ankyrin‐linked HS in an African–American kindred. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Wang, Biyun; Li, Xiao‐Qiu; Ma, Xuejun; Hong, Xiaonan; Lu, Hongfen; Guo, Ye
doi: 10.1002/ajh.21256pmid: 18756548
Overexpression of P‐glycoprotein (P‐gp) has been identified by a variety of methods in NK cells and NK malignancies. The aim of this study was to determine the clinical significance of P‐gp in previously untreated extranodal NK/T‐cell lymphoma, nasal type. Tumor specimens from 30 patients initially treated with CHOP or CHOP‐based chemotherapy were examined by immunohistochemistry using JSB‐1, a monoclonal antibody recognizing the intracellular epitope of P‐gp molecule. Twenty cases (67%) were positive for P‐gp expression. The complete response rate achieved in P‐gp positive patients was significantly lower than in P‐gp negative ones (20% vs. 60%, P = 0.045). With a median follow‐up of 25 months, the 2‐year progression‐free survival (PFS) and overall survival (OS) rates for all patients were 66 and 69%, respectively. Compared with both PFS and OS rates of P‐gp positive patients, those of P‐gp negative patients showed a trend of benefit that did not reach statistical significance for borderline P values (PFS: 90% vs. 54%, P = 0.1057; OS: 90% vs. 61%, P = 0.2028). Our results suggest that P‐gp expression is related with poor treatment outcomes of extranodal NK/T‐cell lymphoma, nasal type. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
Carpenter, Shannon L.; Lieff, Susan; Howard, Thad A.; Eggleston, Barry; Ware, Russell E.
doi: 10.1002/ajh.21264pmid: 18756540
Genetic modifiers contribute to phenotypic variability in patients with sickle cell anemia (SCA). The influence of the bilirubin UDP‐glucuronosyltransferase (UGT) 1A1 (TA)nTAA promoter polymorphism on bilirubin levels and gallbladder disease in SCA was examined using prospectively collected data from the Cooperative Study of Sickle Cell Disease. A total of 324 children with HbSS (median age 6.9 years) had UGT1A1 genotyping; 243 (75%) had common (TA)6 or (TA)7 alleles, whereas 81 (25.0%) had variant (TA)5 or (TA)8 alleles. The UGT1A1 genotype significantly influenced average bilirubin levels for the common alleles: 6/6 genotype = 2.36 ± 1.13 mg/dL, 6/7 genotype = 2.90 ± 1.54 mg/dL, and 7/7 genotype = 4.24 ± 2.11 mg/dL (P < 0.0001). Thirty‐nine percent of children with the 7/7 genotype had documented gallbladder disease, compared with 18.2% with the 6/7 genotype and only 9.9% with the wildtype 6/6 UGT1A1 genotype (P = 0.001). To analyze the (TA)5 and (TA)8 variant alleles, three groups were generated, showing increasing bilirubin levels with increasing TA repeats and age. Group 3 (genotypes 6/8, 7/7, and 7/8) had a significantly greater rate of bilirubin change than Groups 1 (genotypes 5/6, 5/7, and 6/6) or 2 (genotype 6/7). These results validate previous smaller studies and confirm that the UGT1A1 promoter polymorphism exerts a powerful influence on bilirubin levels and the development of gallbladder disease in children with SCA. UGT1A1 genotyping should be considered as a screening tool for predicting children most likely to develop gallbladder disease at a young age. Am. J. Hematol., 2008. © 2008 Wiley‐Liss, Inc.
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