|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Hematology Branch, National Heart, Lung and
Blood Institute, National Institutes of Health, Bethesda, MD.
A serious complication of aplastic anemia (AA) is its evolution to
clonal hematologic diseases such as myelodysplasia (MDS) and leukemia,
which is usually associated with the appearance of a cytogenetic
abnormality in bone marrow cells. We present here an analysis of a
cohort of 30 patients with otherwise typical AA in whom clonal
karyotypic evolution was observed during frequent periodic marrow
examinations. The actuarial risk for this complication has been
estimated in other studies at around 15% at 5 years. Conversion from
normal to abnormal karyotype occurred at a constant rate after initial
diagnosis, with about 50% of cases developing within the first 30 months. Transient chromosomal abnormalities were infrequent.
Clinically, AA patients with clonal cytogenetic patterns were
heterogenous; a variety of karyotypic defects with numerical and
structural abnormalities of chromosome 7 accounted for 40% of all
cases followed by trisomy 8, structural and numerical abnormalities of
chromosome 13, deletion of Y chromosome, and complex cytogenetic
abnormalities. Unlike in primary MDS, aberrancies of chromosome 5 and
20 were infrequent. The clinical course depended on the specific
abnormal cytogenetic pattern. Most deaths related to leukemic
transformation occurred in patients with abnormalities of chromosome 7 or complex cytogenetic alterations or both. Evolution of
chromosome 7 abnormalities was seen most often in refractory patients who had failed to respond to therapy. In contrast, trisomy 8 developed in patients with good hematologic responses who often required chronic immunosuppression with cyclosporine A (CsA), and
survival was excellent. Although AA patients with monosomy 7 showed a
similar prognosis to those with primary MDS, trisomy 8 in AA appears to
have a more favorable prognosis than in MDS.
(Blood. 2002;99:3129-3135) With the introduction of immunosuppressive therapy
(IST) for aplastic anemia (AA), the survival of patients who
are not treated with bone marrow (BM) transplantation has improved
significantly.1 However, with long-term systematic
observation, evolution of AA to other hematologic diseases has been
frequently recognized as a serious late sequelae of this disease.
Historically, paroxysmal nocturnal hemoglobinuria (PNH) was considered
the most common clonal complication, but its incidence is now
appreciated to be high at initial presentation of AA.2,3
The second most common clonal disease occurring in the context of AA is
myelodysplasia (MDS). Aberrant maturation, increased numbers of
myeloblasts, and marrow hypercellularity are all characteristic of MDS,
but persistent marrow hypocellularity in AA may preclude reliable morphologic analysis. The finding of a cytogenetic abnormality therefore is the most objective evidence of clonal evolution.
The acquisition of an abnormal karyotype in the setting of diagnosed AA
is not infrequent, but estimates have been variable among published
studies, due to differences in diagnostic criteria, patient
populations, treatment protocols, and the frequency of follow-up BM
examinations.4-15 In an early study from Seattle, an
abnormal karyotype acquired in the course of the disease was reported
in 3 of 183 AA patients.9 In a recent European analysis, abnormalities occurred in 23 of 170 patients, but in 4 cases, chromosomal changes were present at first diagnosis.6 In
another report of 69 Italian AA patients, an abnormal karyotype was
found in 18, but the findings were transient in 8 patients and in
only 7 cases was the karyotypic abnormality known not to be present initially.8 Similarly, in a recent series of 13 patients
with AA and abnormal cytogenetics, only 2 developed the abnormality later in the course of the disease.7 Of 40 Japanese
children treated with granulocyte colony-stimulating factor (G-CSF) and cyclosporine A (CsA), cytogenetic evolution was found in
11.11 At our institution, abnormal cytogenetics excludes a
diagnosis of AA, regardless of marrow morphology; in our National
Institutes of Health (NIH) series of 122 patients treated with
intensive immunosuppression, 14 have developed karyotypic
abnormalities, with a risk of about 21% at 10 years.6 In
a preliminary combined analysis of 189 patients treated with various
immunosuppressive regimens on consecutive protocols, the actuarial risk
of karyotypic conversion was estimated at 14% at 5 years and 20% at
10 years (J.M., unpublished observation).
Based on our stringent initial diagnostic criteria, the new appearance
of a karyotypically abnormal clone has warranted a change of diagnosis
from AA to MDS. To avoid observer bias, we purposely selected karyotype
rather then morphologic criteria in our case definition. Using this
approach, we could determine the clinical features and prognosis of
patients who developed abnormal cytogenetics in the course of their AA.
Patients
Case definitions and diagnostic criteria
The diagnosis of AA was established by BM biopsy and peripheral blood counts according to the International Study of Aplastic Anemia and Agranulocytosis criteria; severity was classified by the criteria by Camitta et al.16 For the diagnosis of severe AA (sAA), in addition to a hypocellular BM without evidence of karyotypic abnormalities or morphologic dysplasia, patients fulfilled 2 of 3 blood criteria as previously described.16,19 Patients with AA, whose pancytopenia did not qualify as severe but with 2 of 3 blood parameters (absolute neutrophil count [ANC] < 1200, platelet count < 60 000/µL, and hemoglobin of < 8 g/dL), were classified as having moderate AA (mAA). When present, MDS was subclassified according to French-American-British (FAB) nomenclature and International Prognostic Scoring System (IPSS)17,18; hypocellular MDS was diagnosed if the overall biopsy cellularity was less than 25%. In general, the diagnosis of AA required exclusion of other pathologic conditions that can mimic its presentation. All bone marrow biopsies and aspirates were evaluated for morphology by an independent hematopathologist not associated with this study. For the period between January 1989 and August 2001, we identified a
total of 30 patients fulfilling the case definition criteria (Tables
1 and
2).
Other studies performed The presence of a PNH clone was determined historically by a Ham test or more recently using flow cytometry; the latter test was considered positive when more than 1% of glycosyl-phosphatidylinositol-anchored protein (GPI-AP)-deficient cells in blood were found as defined by negativity for surface staining for CD66b and CD16 in a distinctive population of cells.3 Patients with the presence of PNH clone and otherwise fulfilling criteria of sAA or mAA were classified as having AA/PNH.Therapy and response criteria All but 2 patients received therapy with horse antithymocyte globulin (ATG; 40 mg/kg/d for 4 days) followed by 6 months of CsA adjusted to blood levels between 200 and 300 µg/L. One patient received 50 mg/kg cyclophosphamide for 4 days followed by CsA as initial therapy and one patient was treated only with a combination of growth factors (erythropoietin [EPO] and G-CSF). Six patients received 2 cycles of ATG. Several patients were also treated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF; Table 1). The response to immunosuppression was determined 6 months after treatment and defined as transfusion independence for red cells and platelets and improvement in blood counts such that they no longer fulfilled severity criteria.19Statistical analysis Means or medians (for nonnormal sample distribution) ± SD were calculated when appropriate. The unpaired Student t test was applied to compare the means. For not normally distributed samples, an unpaired Wilcoxon test was used. Proportions were compared using 2 test.
Demographic and clinical features of AA patients who developed abnormal karyotype Patients who develop cytogenetic abnormalities in the course of AA have appeared to have heterogenous clinical characteristics and outcomes. To accurately address possible differences, we identified a large cohort of AA patients who had developed cytogenetic abnormalities. Loss of Y chromosome was observed in 2 patients and was included in this analysis but may be associated with aging, and its pathologic significance is not clear.29 Abnormalities involving chromosomes 7, 8, and 13 were most frequent among the group of 30 patients fulfilling case definition criteria (Tables 2 and 3). All but 2 patients had presented with blood counts warranting a diagnosis of sAA; the remaining had mAA at presentation, which progressed to sAA. The average time from the initial diagnosis to cytogenic evolution was 39 ± 33 months (range, 5-126 months; Figure 1).
The mean age of AA patients who developed karyotypic abnormalities was 42 years (range, 8-77 years) with a male-to-female ratio of 16:14. At presentation of AA, the mean platelet count was 13 900/µL (range, 2000-39 000/µL); ANC was 488/µL (range, 48-1400/µL); and the mean reticulocyte count (ARC) and hemoglobin concentration were 23 000/µL (range, 3000-65 000/µL) and 7.3 g/dL (range, 6-10 g/dL), respectively (Table 1). Clinically, of 29 patients treated with IST, 28 had received ATG/CsA and 1 had received cyclophosphamide and CsA in combination. Thirteen patients did not respond to immunosuppression and 16 did respond (54%). In addition, prior to cytogenetic evolution, 6 patients received therapy with SCF combined with G-CSF, 1 patient received EPO and G-CSF as long-term primary therapy, 2 patients received GM-CSF, and another 3 received G-CSF as a supportive therapy prior to and after IST (Table 1). After transformation to MDS, therapies included androgens, G-CSF, and some patients (see below) continued CsA. All patients were tested for the presence of a PNH clone. In 21 cases assessed by flow cytometry, 12 had detectable GPI-AP-deficient granulocytes (57%), and in another 2 patients in whom flow cytometry was not performed, the presence of PNH was established by the Ham test. The prevalence of PNH in this group of patients was at least 50% and not statistically different from an historical cohort of AA (38% at presentation, 35% 1-4 years, and 50% in patients with > 4 years disease duration). There were no additional conversions to PNH within this group observed after cytogenetic evolution. Clinical features and outcomes of clonal evolution in AA In total, in comparison to initial presentation, there was a trend to higher blood counts at the time of diagnosis of clonal evolution (mean ANC of 1263/µL; range, 160-3300/µL), mean platelet count of 54 000/µL (range, 5000-155 000/µL), and mean hemoglobin concentration and ARC of 9.9 g/dL (range, 7-15 g/dL) and 52 000/µL (range, 7 000-13 800/µL), respectively; however, the individual blood counts depended on the response status to initial immunosuppression (see below). Marrow morphology was characterized by predominance of hypercellularity (41%) and patchy biopsy cellularity (27%), although continued hypocellularity was found in 1 of 3 of the patients. Frank dysplasia, including changes in megakaryocyte morphology, were found in 15 of 30 patients, and a left shift in myeloid differentiation was observed in 12. However, in 9 of 30 patients, there were no morphologic changes suggestive of MDS.AA patients who developed secondary chromosomal abnormalities showed a mortality rate of about 27% with mean follow-up after evolution of 29 months (from the initial diagnosis, the total observation interval was 70 months; Figure 1). All but 2 deaths were related to complications of leukemia. In total, 13 patients (45%) developed either refractory anemia with excess blasts in transformation (RAEBt) or acute myeloid leukemia (AML; Table 2). Of these patients, 5 underwent unrelated matched BM transplantation. Of the 30 patients, totally clonal hematopoiesis (100% of affected metaphases) was present at initial cytogenetic diagnosis in 13 patients. In all but 2 patients who initially presented with a mosaic of normal and abnormal karyotype, there was a steady increase in percentages of karyotypically abnormal metaphases during the observation interval. Disappearance of an abnormal clone was observed only in 2 patients, in both of whom, at evolution, only 20% to 25% cytogenetically abnormal metaphases were counted. Abnormal karyotypes  and another with Y). When compared with patients with numerical or structural defects of chromosome 7 at diagnosis of abnormal karyotype, those with trisomy 8 showed significantly higher mean ANC, hemoglobin concentration, and
mean reticulocyte and platelet counts at the time of chromosomal evolution (Table 4).
The prognosis of patients with abnormalities of chromosome 7 appear much worse in comparison to those with trisomy 8 (Figure 1); although all patients with trisomy 8 remain alive and had not progressed to leukemia over a mean observation interval of 44 months (range, 5-84 months), those patients who developed numerical or structural chromosome 7 aberrancy showed high rates of mortality (50%) and transformation (RAEBt and AML in 6 of 11). Two patients who developed complex karyotypic abnormality also progressed to RAEBt or AML.
Our report differs from previously published summaries in the large numbers of patients examined and the exclusion of cases in whom cytogenetics were abnormal at presentation of marrow failure. AA patients with true evolution of karyotypic changes were clinically diverse, and their prognosis was strongly linked to the type of cytogenetic defect. In agreement with other published data,5,8,14,15 the most common cytogenetic abnormalities were aberrations of chromosome 7 and trisomy 8; in a study from Seattle, monosomy 7 was found in 3 and trisomy 8 in 2 of 7 patients with karyotypic abnormalities,5 in a Dutch series, in 3 of 5 patients who evolved to MDS from AA,14 whereas among Italian patients,8 trisomy 8 was most frequent, present in 8 of 18 cases, followed by monosomy 7 in 2 of 18 patients (only a minority of these patients had initially normal cytogenetics at the time of presentation). In contrast to these results and to our own data, a recent meta-analysis showed trisomy 6 as most common in AA,20 but in all of the patients included in this study, the abnormal karyotype was present at initial diagnosis. The appearance of a cytogenetic abnormality in a patient with AA provides strong evidence of clonal evolution to MDS. However, a high proportion of transient chromosomal changes, as reported in some studies, would diminish the diagnostic and prognostic implications of new cytogenetic defects. The low incidence of this finding in our study may be due to the stringent exclusion of patients who showed abnormal cytogenetics at presentation. Myelodysplasia evolving from AA and primary MDS differ in the
distribution of specific cytogenetic abnormalities. In primary MDS,
abnormalities of chromosome 5 are most frequent (10%-37% of
patients),21-28 but this chromosome is only occasionally
affected in AA. 20q Cytogenetic abnormalities are strong predictors of clinical behavior and survival in acute and chronic leukemias,30,31 multiple myeloma,32 and primary MDS.18 In our series, in agreement with the IPSS classification for primary MDS,18 there was a major difference in prognosis of patients who developed defects of chromosome 7 or who had complex karyotypic abnormalities; these lesions were present in all of our patients who died or developed leukemia. In retrospect, these patients usually had had treatment-refractory and persistent pancytopenia. In contrast, trisomy 8 and other prognostically more benign abnormalities were frequent in the context of a good hematologic response to immunosuppression, and even after evolution to trisomy 8, improved blood counts were often dependent on continued CsA administration. Blood counts of patients at the time of cytogenetic evolution to trisomy 8 were significantly higher than those of patients with monosomy 7. The prognosis of trisomy 8 in primary MDS is not entirely favorable, with survival comparable to that of monosomy 7.25-28 Trisomy 8 is found in more advanced FAB subtypes, often included in the intermediate-risk group with average survival of 2.4 years (17.2 months in an analysis of 115 patients with trisomy)8,26 and time to evolution of AML of 1.6 years.18 The sharp contrast of this observation with the clinical course and prognosis of trisomy 8 evolving from AA suggests a different biology for an apparently identical cytogenetic abnormality in late AA and in primary MDS. Patients with abnormalities of chromosome 7 in AA fared as poorly as in primary MDS, with a high rate of conversion to acute leukemia.18,27 Fundamental questions in the evolution of clonal disease in AA are whether its pathophysiology is intrinsic to the natural history of AA, and now only observed as patients survive longer due to effective therapy, or secondary as a complication of, for example, immunosuppression,13 or chronic growth factor administration. However, MDS has occurred in AA treated with androgens only9,33 and though prolonged G-CSF treatment was linked by Japanese investigators to evolution of monosomy 7,11,34,35 there was no increased risk observed in a randomized study of ATG and CsA with and without G-CSF36 or in an analysis of data from the European Group for Blood and Marrow Transplantation.37 Many of our patients received hematopoietic growth factors, mainly as support or salvage therapy, and refractory disease itself may be the underlying risk factor for clonal evolution. Most AA patients who did not undergo BM transplantation will be treated with immunosuppression and hematopoietic growth factors, and in the absence of appropriate control groups, it is difficult to rigorously establish or exclude a pathophysiologic relationship between clonal evolution and therapy. The relationship between AA, a disease dominated by an immune pathophysiology, and MDS, usually viewed as a premalignant process, remains unclear both clinically and pathophysiologically. In historical studies of abnormal karyotypes in AA, patients with abnormal cytogenetics and hypoplastic marrows at presentation were often included,6-10 and in some institutions, abnormal cytogenetics are compatible with a primary diagnosis of AA.7-9,20 In our series, our case definition was more stringent; cytogenetics were normal at first presentation, and most abnormal cytogenetic findings occurred after multiple normal studies. Whether more sensitive methods, such as fluorescent in situ hybridization, would have disclosed small populations of aberrant cells at earlier time points remains a moot question but a subject of current research. Were underdiagnosis due to inadequate techniques for the detection of chromosomal changes important, a more rapid evolution to MDS might be anticipated, but in our experience, chromosomal changes emerged gradually over time, more consistent with stochastic kinetics than a determinative process. Clinically, karyotypic abnormalities appear to concur with other features of typical AA such as the high incidence of HLA-DR238,39 and coexistence of an expanded PNH clone3; patients who show cytogenetic evolution do not obviously belong to a distinct nosologic subtype, as might be expected with primary misdiagnosis of MDS. Nevertheless, some of the same laboratory features have been reported in primary MDS.40 For clinicians, the distinction between AA and hypocellular MDS ultimately may depend on empiric observations of the behavior associated with specific cytogenetic patterns. Monosomy 7 should continue to be regarded as itself a dire event, but for trisomy 8, the cytogenetic abnormality does not alter the desirability of an aggressive immunologic approach to improve the function of an empty BM.
Submitted June 12, 2001; accepted November 19, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jaroslaw P. Maciejewski, Hematopoiesis and Experimental Hematology Section, Cleveland Clinic Taussig Cancer Center, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: maciejj{at}cc.ccf.org.
1. Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995;95:3367-3377.
2.
Dunn DE, Tannawattanacharoen P, Boccuni P, et al.
Paroxysmal nocturnal hemoglobinuria cells in patients with bone marrow failure syndromes.
Ann Intern Med.
1999;131:401-408 3. Maciejewski JP, Rivera C, Dunn D, Young NS. Clinical features of the relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria. Br J. Hematol. 2001;115:1015-1022[CrossRef][Medline] [Order article via Infotrieve]. 4. Tichelli A, Gratwohl A, Wursch A, et al. Late hematologic complications in severe aplastic anemia. Br J Haematol. 1988;69:413-418[Medline] [Order article via Infotrieve].
5.
Doney K, Leisenring W, Storb R, Appelbaum FR.
Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy.
Ann Intern Med.
1997;126:107-115 6. Socie G, Rosenfeld S, Frickhofen N, Gluckman E. Tichelli A. Late clonal complications of aplastic anemia. Semin Hematol. 2000;37:91-101[CrossRef][Medline] [Order article via Infotrieve]. 7. Geary CG, Harrison CJ, Philpott NJ, Hows JM, Gordon-Smith EC, Marsh CW. Abnormal cytogenetic clone in patients with aplastic anemia: response to immunosuppressive therapy. Br J Hematol. 1999;104:271-274[CrossRef][Medline] [Order article via Infotrieve].
8.
Mikhailova N, Sesserego M, Fugazza G, et al.
Cytogenetic abnormalities in patients with severe aplastic anemia.
Haematologica.
1996;81:418-422 9. Appelbaum F, Barrall J, Storb R, et al. Clonal cytogenetic abnormalities in patients with otherwise typical aplastic anemia. Exp Hematol. 1987;5:1134-1139. 10. De Planque MM, Baciagalupo A, Wursch A, et al. Long-term follow up of severe aplastic anemia patients treated with antithymocyte globulin. Br J Hematol. 1989;73:121-126[Medline] [Order article via Infotrieve]. 11. Yamazaki E, Kanamori H, Taguchi J, Harano H, Mohri H, Okubo T. The evidence for clonal evolution with monosomy 7 in aplastic anemia following granulocyte colony-stimulating factor using the polymerase chain reaction. Blood Cells Mol Dis. 1997;23:213-218[CrossRef][Medline] [Order article via Infotrieve].
12.
Plaquette RL, Tebyani N, Frane M, et al.
Long-term outcome of aplastic anemia in adults treated with anti-thymocyte globulin: comparison with bone marrow transplantation.
Blood.
1996;85:283-290
13.
Socie G, Henryamar M, Bacigalupo A.
Malignant tumors occurring after treatment of aplastic anemia.
N Engl J Med.
1993;329:1152-1157 14. De Planque MM, Kluin-Nelemans HC, van Kierken HJ, et al. Evolution of acquired severe aplastic anemia to myelodysplasia and subsequent leukemia in adults. Br J Haematol. 1988;70:55-62[Medline] [Order article via Infotrieve]. 15. Jameel T, Anwar M, Abdi SI, Saleem M, Ahmad PA, Khattak MF. Aplastic anemia or aplastic preluekemic syndrome? Ann Hematol. 1997;75:189-193[CrossRef][Medline] [Order article via Infotrieve].
16.
Camitta BM, Thomas ED, Nathan DG, et al.
Severe aplastic anemia: a prospective study of the effect of early bone marrow transplantation on acute mortality.
Blood.
1976;48:63-70 17. Bennett JM, Catovsky D, Daniel MT, et al. Proposal for the classification of the myelodysplastic syndromes. Br J Hematol. 1986;51:181-199.
18.
Greenberg P, Cox Ch, LeBeau M, et al.
International scoring system for evaluating prognosis in myelodysplastic syndromes.
Blood.
1997;89:2079-2088
19.
Rosenfeld SJ, Kimball J, Vining D, Young NS.
Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia.
Blood.
1995;85:3058-3065 20. Yi-Kong Keung, Pettenati MJ, Cruz JM, Powell BL, Woodruff RD, Buss DH. Bone marrow cytogenetic abnormalities of aplastic anemia. Am J Hematol. 2001;66:167-171[CrossRef][Medline] [Order article via Infotrieve]. 21. Michalova K, Musilova J, Zemanova Z. Cytogenetic abnormalities in 532 patients with myeloid leukemias and myelodysplastic syndrome. The Czechoslovak MDS Cooperative Group. Czech Med. 1999;13:133-144. 22. Vila L, Charrin C, Archimbaud E, Treille-Ritouet D, et al. Correlations between cytogenetics and morphology in myelodysplastic syndromes. Blut 1990;60:223-227[CrossRef][Medline] [Order article via Infotrieve]. 23. Bernasconi P, Alessandrino EP, Boni M, et al. Karyotype in myelodysplastic syndrome: relations to morphology, clinical evolution and survival. Am J Hematol. 1994;46:270-277[Medline] [Order article via Infotrieve]. 24. Knapp RH, Dewald GW, Pierre RV. Cytogenetic studies in 174 consecutive patients with preleukemic or myelodysplastic syndromes. Mayo Clin Proc. 1985;60:507-516[Medline] [Order article via Infotrieve]. 25. Succiu S, Kuse R, Weh HJ, Hossfeld DK. Results of chromosome studies and their relation to morphology, course and prognosis in 120 patients with de novo myelodysplastic syndrome. Cancer Genet Cytogenet. 1990;44:15-26[CrossRef][Medline] [Order article via Infotrieve]. 26. Pedersen B. MDS and AML with trisomy 8 as a sole chromosome aberration show different sex ratios and prognostic profiles: a study of 115 published cases. Am J Hematol. 1997;56:224-229[CrossRef][Medline] [Order article via Infotrieve]. 27. Sole F, Espinet B, Sanz GF, et al. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Br J Hematol. 2000;108:346-356[CrossRef][Medline] [Order article via Infotrieve]. 28. Sousa de Feranadez T, Ornellas MH, Otero de Carvalho L, Tabak D, Abdelhay E. Chromosomal alterations associated with evolution from myelodysplastic syndrome to acute myeloid leukemia. Leuk Res. 2000;24:839-848[CrossRef][Medline] [Order article via Infotrieve]. 29. Wiktor A, Rybicki BA, Piao ZS, et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer. 2000;27:11-16[CrossRef][Medline] [Order article via Infotrieve].
30.
Grimwalde D, Walker H, Oliver F, et al.
The importance of diagnostic cytogenetics on outcome in AML: analysis of 1612 patients entered into the MRC AML 10 trial.
Blood.
1998;92:2322-2333
31.
Slovak ML, Kopecky KJ, Cassileth PA, et al.
Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study.
Blood.
2000;96:4075-4083 32. Fonseca R, Coignet LJ, Dewald GW. Cytogenetic abnormalities in multiple myeloma. Hematol Oncol Clin North Am. 1999;13:1169-1180[CrossRef][Medline] [Order article via Infotrieve]. 33. Varma N, Varma S, Movafagh A, Gareval G. Unusual clonal cytogenetic abnormalities in aplastic anemia [letter]. Am J Hematol. 1995;49:256-257[Medline] [Order article via Infotrieve].
34.
Ohara A, Kojima S, Hamajima N.
Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia.
Blood.
1997;90:1009-1013 35. Kaito K, Kobayashi M, Katayama T, et al. Long-term administration of G-CSF for aplastic anemia is closely related to the early evolution of monosomy 7 MDS in adults. Br J Hematol. 1998;103:297-303[CrossRef][Medline] [Order article via Infotrieve].
36.
Kojima S, Hibi S, Kosaka Y, et al.
Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia.
Blood.
2000;96:2049-2054 37. Bacigalupo A, Brand R, Oneto R, et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy. The European Group for Blood and Marrow Transplantation experience. Semin Hematol. 2000;37:69-80[CrossRef][Medline] [Order article via Infotrieve].
38.
Nimer SD, Ireland P, Meshkinpour A, Frane M.
An increased HLA DR2 frequency is seen in aplastic anemia patients.
Blood.
1994;84:923-927
39.
Maciejewski JP, Follmann D, Rivera CE, Simonis T, Young NS.
Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and PNH/aplastic anemia syndrome.
Blood.
2001;98:3513-3519 40. Young NS, Barrett AJ. Immune modulation of myelodysplasia: rationale and therapy. In: Bennett JM, ed. The Myelodysplastic Syndromes: Pathobiology and Clinical Management. New York, NY: Marcel Dekker. In press.
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  J. K. Ahn, H.-S. Cha, E.-M. Koh, S.-H. Kim, Y. G. Kim, C.-K. Lee, and B. Yoo Behcet's disease associated with bone marrow failure in Korean patients: clinical characteristics and the association of intestinal ulceration and trisomy 8 Rheumatology, August 1, 2008; 47(8): 1228 - 1230. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. T. Calado and N. S. Young Telomere maintenance and human bone marrow failure Blood, May 1, 2008; 111(9): 4446 - 4455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Link, G. Kunter, Y. Kasai, Y. Zhao, T. Miner, M. D. McLellan, R. E. Ries, D. Kapur, R. Nagarajan, D. C. Dale, et al. Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia Blood, September 1, 2007; 110(5): 1648 - 1655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Calado, S. A. Graf, K. L. Wilkerson, S. Kajigaya, P. J. Ancliff, Y. Dror, S. J. Chanock, P. M. Lansdorp, and N. S. Young Mutations in the SBDS gene in acquired aplastic anemia Blood, August 15, 2007; 110(4): 1141 - 1146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Sloand, L. Pfannes, G. Chen, S. Shah, E. E. Solomou, J. Barrett, and N. S. Young CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins Blood, March 15, 2007; 109(6): 2399 - 2405. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Bagby and G. Meyers Bone Marrow Failure as a Risk Factor for Clonal Evolution: Prospects for Leukemia Prevention Hematology, January 1, 2007; 2007(1): 40 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. S. Young, R. T. Calado, and P. Scheinberg Current concepts in the pathophysiology and treatment of aplastic anemia Blood, October 15, 2006; 108(8): 2509 - 2519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Sloand, A. S. M. Yong, S. Ramkissoon, E. Solomou, T. C. Bruno, S. Kim, M. Fuhrer, S. Kajigaya, A. J. Barrett, and N. S. Young Granulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor PNAS, September 26, 2006; 103(39): 14483 - 14488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. S. Young Pathophysiologic Mechanisms in Acquired Aplastic Anemia Hematology, January 1, 2006; 2006(1): 72 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zeng, A. Miyazato, G. Chen, S. Kajigaya, N. S. Young, and J. P. Maciejewski Interferon-{gamma}-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles Blood, January 1, 2006; 107(1): 167 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Sloand, L. Mainwaring, M. Fuhrer, S. Ramkissoon, A. M. Risitano, K. Keyvanafar, J. Lu, A. Basu, A. J. Barrett, and N. S. Young Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome Blood, August 1, 2005; 106(3): 841 - 851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Maciejewski and A. M. Risitano Aplastic Anemia: Management of Adult Patients Hematology, January 1, 2005; 2005(1): 110 - 117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Chen, W. Zeng, A. Miyazato, E. Billings, J. P. Maciejewski, S. Kajigaya, E. M. Sloand, and N. S. Young Distinctive gene expression profiles of CD34 cells from patients with myelodysplastic syndrome characterized by specific chromosomal abnormalities Blood, December 15, 2004; 104(13): 4210 - 4218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. C. Bagby, J. M. Lipton, E. M. Sloand, and C. A. Schiffer Marrow Failure Hematology, January 1, 2004; 2004(1): 318 - 336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rosenfeld, D. Follmann, O. Nunez, and N. S. Young Antithymocyte Globulin and Cyclosporine for Severe Aplastic Anemia: Association Between Hematologic Response and Long-term Outcome JAMA, March 5, 2003; 289(9): 1130 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Sloand, S. Kim, M. Fuhrer, A. M. Risitano, R. Nakamura, J. P. Maciejewski, A. J. Barrett, and N. S. Young Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities Blood, December 15, 2002; 100(13): 4427 - 4432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Tisdale, J. P. Maciejewski, O. Nunez, S. J. Rosenfeld, and N. S. Young Late complications following treatment for severe aplastic anemia (SAA) with high-dose cyclophosphamide (Cy): follow-up of a randomized trial Blood, December 15, 2002; 100(13): 4668 - 4670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Greenberg, N. S. Young, and N. Gattermann Myelodysplastic Syndromes Hematology, January 1, 2002; 2002(1): 136 - 161. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
clinical comparisons