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MeSH Review:

Anemia, Refractory, with Excess of Blasts

Denzlinger, C. et al., Maeck, L. et al., Jensen, I.M. et al., Lyons, J. et al., Zagonel, V. et al., et al.

Hellström-Lindberg, Ahlgren, Beguin, Carlsson, Carneskog, Dahl, Dybedal, Grimfors, Kanter-Lewensohn, Linder, Luthman, Löfvenberg, Nilsson-Ehle, Samuelsson, Tangen, Winqvist, Oberg, Osterborg, Ost, Hofmann, Ganser, Seipelt, Ottmann, Zander, Geissler, Hoffmann, Höffken, Fischer, Isele, Hoelzer, Yagasaki, Jinnai, Yoshida, Yokoyama, Matsuda, Kusumoto, Kobayashi, Terasaki, Ohyashiki, Asou, Murohashi, Bessho, Hirashima, Mihara, Chowdhury, Nakaju, Hidani, Ihara, Hyodo, Yasunaga, Takihara, Kimura, Estey, Thall, Pierce, Cortes, Beran, Kantarjian, Keating, Andreeff, Freireich,

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Disease relevance of Anemia, Refractory, with Excess of Blasts

We treated 23 patients with myelodysplastic syndromes (MDS); 2 refractory anemia (RA) with prior therapy, 11 RA with excess of blasts (RAEB), and 10 RAEB in transformation (RAEB-T), with daily oral 45 mg/m2 all-trans retinoic acid (ATRA) in a multiinstitutional prospective study [1].
These included patients from different morphologic subtypes: four with refractory anemia (RA), two with RA and ring sideroblasts (RARS), one patient with RA with excess of blasts (RAEB), and one with chronic myelomonocytic leukemia (CMML) [2].
Patients with RA and RARS with a higher percentage of Bmi-1+ cells showed disease progression to RAEB [3].
The WT1 expression levels were examined for 57 patients with myelodysplastic syndromes (MDS) (refractory anemia (RA), 35; RA with excess of blasts (RAEB) 14; RAEB in transformation (RAEB-t), six; and MDS with fibrosis, two) and 12 patients with acute myeloid leukemia (AML) evolved from MDS [4].
Morphological subtypes were RA in 53 (20%), RARS in 32 (12%), pure sideroblastic anemia (PSA) in 41 (16%), RAEB in 60 (23%), RAEB/T in 34 (13%), and CMML in 43 cases (16%) [5].

High impact information on Anemia, Refractory, with Excess of Blasts

Accordingly, we randomized 215 patients with newly diagnosed AML (153 patients) or high-risk myelodysplastic syndrome (MDS) (refractory anemia with excess blasts [RAEB] or RAEB-t, 62 patients) to receive fludarabine + ara-C + idarubicin (FAI) alone, FAI + ATRA, FAI + G-CSF, or FAI + ATRA + G-CSF [6].
Fifty evaluable patients (10 refractory anemia [RA], 13 refractory anemia with ring sideroblasts [RARS], and 27 refractory anemia with excess blasts [RAEB]) were included in the study, three were evaluable only for epo as monotherapy and 47 for the combined treatment [7].
In contrast, granulocytic differentiation of marrow cells was induced in liquid culture by G-CSF in 15 of 32 (47% patients), while GM-CSF did so in only 4 of 18 (22%) patients (P less than .025) including, for RAEB/RAEB-T patients: 9 of 18 versus 0 of 9, respectively (P less than .025) [8].
Mutations at codon 12 of Ki-ras or N-ras were detected in three cases (9%): one of six cases of refractory anemia with excess blasts (RAEB) and two of nine cases of chronic myelomonocytic leukemia (CMML) [9].
A sustained hematologic remission was achieved after low-dose cytarabine therapy in the case of RAEB [9].

Chemical compound and disease context of Anemia, Refractory, with Excess of Blasts

Polymorphonuclear cells from the two patients with 7-monosomy revealed reduced mitochondrial malate dehydrogenase activity, but those from the patient with RAEB "in transformation" without chromosome aberrations did not [10].
ATG, cyclosporine, and methylprednisone induced complete (N=4) or partial (N=1) remission in five patients (16% of total; RA, two patients; RARS, two patients; and RAEB, one patient) [11].
Two patients affected by refractory anemia with excess of blasts (RAEB) and eight with RAEB in transformation (RAEB-T) were treated with Decitabine at a daily dose of 45 mg/m2, divided into three 4 h infusions for 3 days (six patients) or as continuous infusion of 50 mg/m2 for 3 days (four patients) [12].
We examined the efficacy of thalidomide in 34 patients with myelodysplastic syndromes (MDS): five RAEB-T, four RAEB, three CMML, six RARS, and 16 RA [13].
INTERPRETATION AND CONCLUSIONS: Our results show that in de novo RAEB and RAEB-t, treatment with IDA and Ara-C is associated with satisfactory frequency of response with acceptable toxicity [14].

Biological context of Anemia, Refractory, with Excess of Blasts

This correlation was not detected in RAEB and RAEBt patients and no detectable TPO serum concentrations were found in six CMML patients whether they showed decreased or normal platelet count [15].
When the patients were subdivided according to the revised FAB classification, a reduction in PHA-ICC from the RAEB group and a progressive impairment of ADCC from RA to RAEB-t patients was observed [16].
Apoptosis was significantly increased in FAB subtypes RA, RARS and RAEB (<10% blasts) (56.5% (15.1-86.5%)) compared to normal controls (18.5% (3.4-33.4%), P<0.0001) and RAEB-t/MDS-AML (16% (2.1-43.2%), P<0.0001) [17].
By analysing 39 patients (15 RA/RAS, 14 RAEB and 10 RAEB-t) and eight normal controls, we found significant differences in both the percentage of cells positive for these immature myeloid antigens between the FAB groups as well as in the fractions of CD13 and CD33 positive cells in S or S-G2M phase of the cell cycle [18].
Asynchronous antigen expression (CD19+/CD79a- cells) was found in 7/11 cases of RA/RARS and 6/18 cases of RAEB in which this phenotype was examined [19].

Anatomical context of Anemia, Refractory, with Excess of Blasts

In the cytopenic patients the increase in leukotriene production was correlated to an expansion of peripheral blood leukocytes; RAEB patients responded to GM-CSF with enhanced leukotriene biosynthesis even if the peripheral leukocytes decreased, possibly due to an abnormal number and/or irritability of leukotriene-producing cells [20].
Moreover, in RAEB and RAEBt, a significant correlation was observed between c-mpl, CD34, megakaryocyte glycoprotein IIb (GPIIb) expression, and the presence of dysmegakaryopoiesis [21].
FACS and morphology analysis after 7 days of suspension culture demonstrated partial differentiation along the erythroid lineage in cases with RA/RARS (75%) and RAEB/RAEB-T (66%) reflected by the presence of erythroblasts and normoblasts with variable expression of CD34, CD36 and Glycophorin A [22].
Here, we examine cellular hMSH2 expression in bone marrow samples from 10 haematopoietically normal individuals in comparison with nine patients with myelodysplastic syndrome (MDS) [one refractory anaemia (RA), two RA with ringed sideroblasts (RARS), four RA with excess blasts (RAEB) and two RAEB in transformation (RAEB-T)] [23].
The effect on hemoglobin (Hb), platelets, and absolute neutrophil count (ANC), as well as on transfusion frequency, was examined in 25 patients with MDS (11 RA, four RARS, eight RAEB, two CMML) [24].

Gene context of Anemia, Refractory, with Excess of Blasts

PGP positivity was rare in 'low risk' MDS (RA and RARS: 2/12 cases) as opposed to 'high risk' MDS (RAEB, RAEB-T, CMML: 25/60 cases) and MDS-AML (7/10 cases) (p = 0.04) [25].
None of the resulting chimeric transcripts except for the ACS2/ETV6 transcript in the RAEB case led to a fusion protein [26].
AML1/RUNX1 mutations have been reported frequently in myelodysplastic syndrome (MDS) patients, especially those diagnosed with refractory anemia with excess blast (RAEB), RAEB in transformation (RAEBt), or AML following MDS (these categories are defined as MDS/AML) [27].
The range of CD34 expression of blasts in RAEB samples was 1-14% (mean 6.2%) and in RAEB-T samples 29-48% (mean 35.5%) [28].
However, results were dependent upon disease category: TNF-alpha levels were significantly higher in patients with refractory anaemia (RA) than in patients with RA with excess blasts (RAEB) or RAEB in transformation (RAEB-T) (P=0.043) [29].

Analytical, diagnostic and therapeutic context of Anemia, Refractory, with Excess of Blasts

We conducted a phase II trial of CPT-11 in 26 patients with high-risk MDS (RAEB 1: n = 4; RAEB 2: n = 9; MDS having progressed to AML: n = 10; CMML: n = 3) who could not receive anthracycline/cytarabine intensive chemotherapy [30].
Refractory cytopenia with multilineage dysplasia and RAEB II seemed to have different prognoses from RA or RARS and RAEB I, respectively [31].
Fractionated total body irradiation (FTBI) and CY was used in six patients with refractory anaemia with excess of blasts (RAEB) and RAEB in leukaemic transformation (RAEB-T) [32].
In the present study, we analyzed the expression of platelet glycoprotein (GP) Ia/IIa, IIb/IIIa, Ib/IX, and IV in 21 MDS patients (12 RA, 2 RARS, 4 RAEB, 1 RAEB-T, 2 CMML) and healthy controls by flowcytometric analysis and quantitation of platelet GP RNA using fluorescence-based PCR [33].
In this prospective study, patients with "high risk' primary MDS, namely RAEB or RAEBt, were treated with combination chemotherapy (CT) supported by GM-CSF [34].

References

Treatment of myelodysplastic syndromes with all-trans retinoic acid. Leukemia Study Group of the Ministry of Health and Welfare. Ohno, R., Naoe, T., Hirano, M., Kobayashi, M., Hirai, H., Tubaki, K., Oh, H. Blood (1993) [Pubmed]
Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin. Janssen, J.W., Buschle, M., Layton, M., Drexler, H.G., Lyons, J., van den Berghe, H., Heimpel, H., Kubanek, B., Kleihauer, E., Mufti, G.J. Blood (1989) [Pubmed]
Bmi-1 is useful as a novel molecular marker for predicting progression of myelodysplastic syndrome and patient prognosis. Mihara, K., Chowdhury, M., Nakaju, N., Hidani, S., Ihara, A., Hyodo, H., Yasunaga, S., Takihara, Y., Kimura, A. Blood (2006) [Pubmed]
The Wilms' tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Tamaki, H., Ogawa, H., Ohyashiki, K., Ohyashiki, J.H., Iwama, H., Inoue, K., Soma, T., Oka, Y., Tatekawa, T., Oji, Y., Tsuboi, A., Kim, E.H., Kawakami, M., Fuchigami, K., Tomonaga, M., Toyama, K., Aozasa, K., Kishimoto, T., Sugiyama, H. Leukemia (1999) [Pubmed]
Risk assessment in primary myelodysplastic syndromes: validation of the Düsseldorf score. Aul, C., Gattermann, N., Germing, U., Runde, V., Heyll, A., Schneider, W. Leukemia (1994) [Pubmed]
Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/- all-trans retinoic acid +/- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Estey, E.H., Thall, P.F., Pierce, S., Cortes, J., Beran, M., Kantarjian, H., Keating, M.J., Andreeff, M., Freireich, E. Blood (1999) [Pubmed]
Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin: results from a randomized phase II study and long-term follow-up of 71 patients. Hellström-Lindberg, E., Ahlgren, T., Beguin, Y., Carlsson, M., Carneskog, J., Dahl, I.M., Dybedal, I., Grimfors, G., Kanter-Lewensohn, L., Linder, O., Luthman, M., Löfvenberg, E., Nilsson-Ehle, H., Samuelsson, J., Tangen, J.M., Winqvist, I., Oberg, G., Osterborg, A., Ost, A. Blood (1998) [Pubmed]
Impact of marrow cytogenetics and morphology on in vitro hematopoiesis in the myelodysplastic syndromes: comparison between recombinant human granulocyte colony-stimulating factor (CSF) and granulocyte-monocyte CSF. Nagler, A., Binet, C., Mackichan, M.L., Negrin, R., Bangs, C., Donlon, T., Greenberg, P. Blood (1990) [Pubmed]
Mutation of Ki-ras and N-ras oncogenes in myelodysplastic syndromes. Lyons, J., Janssen, J.W., Bartram, C., Layton, M., Mufti, G.J. Blood (1988) [Pubmed]
Studies on mitochondrial and cytoplasmic malate dehydrogenase in childhood myelodysplastic syndrome. Muchi, H., Yamamoto, Y. Blood (1983) [Pubmed]
Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes. Yazji, S., Giles, F.J., Tsimberidou, A.M., Estey, E.H., Kantarjian, H.M., O'Brien, S.A., Kurzrock, R. Leukemia (2003) [Pubmed]
5-Aza-2'-deoxycytidine (Decitabine) induces trilineage response in unfavourable myelodysplastic syndromes. Zagonel, V., Lo Re, G., Marotta, G., Babare, R., Sardeo, G., Gattei, V., De Angelis, V., Monfardini, S., Pinto, A. Leukemia (1993) [Pubmed]
Thalidomide for the treatment of patients with myelodysplastic syndromes. Strupp, C., Germing, U., Aivado, M., Misgeld, E., Haas, R., Gattermann, N. Leukemia (2002) [Pubmed]
Idarubicin and cytosine arabinoside in the induction and maintenance therapy of high-risk myelodysplastic syndromes. Invernizzi, R., Pecci, A., Rossi, G., Pelizzari, A.M., Giusto, M., Tinelli, C., Ascari, E. Haematologica (1997) [Pubmed]
Endogenous serum thrombopoietin concentrations in patients with myelodysplastic syndromes. Zwierzina, H., Rollinger-Holzinger, I., Nuessler, V., Herold, M., Meng, Y.G. Leukemia (1998) [Pubmed]
Defective antibody-dependent and lectin-induced polymorphonuclear cytotoxicity in patients with myelodysplastic syndromes. Fontana, L., De Sanctis, G., Bottari, V., Petti, M.C., Mandelli, F. Haematologica (1990) [Pubmed]
'Low-risk' myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. Parker, J.E., Fishlock, K.L., Mijovic, A., Czepulkowski, B., Pagliuca, A., Mufti, G.J. Br. J. Haematol. (1998) [Pubmed]
The proliferative activity of myelopoiesis in myelodysplasia evaluated by multiparameter flow cytometry. Jensen, I.M., Hokland, P. Br. J. Haematol. (1994) [Pubmed]
Maturation-associated immunophenotypic abnormalities in bone marrow B-lymphocytes in myelodysplastic syndromes. Ribeiro, E., Sudón, S.M., de Santiago, M., Lima, C.S., Metze, K., Giralt, M., Saad, S.T., de Matos, A.O., Lorand-Metze, I. Leuk. Res. (2006) [Pubmed]
Enhanced endogenous leukotriene biosynthesis in patients treated with granulocyte-macrophage colony-stimulating factor. Denzlinger, C., Kapp, A., Grimberg, M., Gerhartz, H.H., Wilmanns, W. Blood (1990) [Pubmed]
Prognostic value of c-mpl expression in myelodysplastic syndromes. Bouscary, D., Preudhomme, C., Ribrag, V., Melle, J., Viguié, F., Picard, F., Guesnu, M., Fenaux, P., Gisselbrecht, S., Dreyfus, F. Leukemia (1995) [Pubmed]
CD34+/CD36- cells from myelodysplasia patients have a limited capacity to proliferate but can differentiate in response to Epo and MGF stimulation. Brada, S.J., de Wolf, J.T., Hendriks, D.W., Smit, J.W., Vellenga, E. Leukemia (1998) [Pubmed]
Differential cellular expression of the human MSH2 protein in normal and myelodysplastic haematopoiesis. Maeck, L., Kohaus, P., Haase, D., Hiddemann, W., Alves, F. Br. J. Haematol. (2000) [Pubmed]
Treatment of patients with low-risk myelodysplastic syndromes using a combination of all-trans retinoic acid, interferon alpha, and granulocyte colony-stimulating factor. Hofmann, W.K., Ganser, A., Seipelt, G., Ottmann, O.G., Zander, C., Geissler, G., Hoffmann, K., Höffken, K., Fischer, J.T., Isele, G., Hoelzer, D. Ann. Hematol. (1999) [Pubmed]
Expression of the multidrug resistance P-glycoprotein and its relationship to hematological characteristics and response to treatment in myelodysplastic syndromes. Lepelley, P., Soenen, V., Preudhomme, C., Lai, J.L., Cosson, A., Fenaux, P. Leukemia (1994) [Pubmed]
Fusion of TEL/ETV6 to a novel ACS2 in myelodysplastic syndrome and acute myelogenous leukemia with t(5;12)(q31;p13). Yagasaki, F., Jinnai, I., Yoshida, S., Yokoyama, Y., Matsuda, A., Kusumoto, S., Kobayashi, H., Terasaki, H., Ohyashiki, K., Asou, N., Murohashi, I., Bessho, M., Hirashima, K. Genes Chromosomes Cancer (1999) [Pubmed]
Hyperactivation of the RAS signaling pathway in myelodysplastic syndrome with AML1/RUNX1 point mutations. Niimi, H., Harada, H., Harada, Y., Ding, Y., Imagawa, J., Inaba, T., Kyo, T., Kimura, A. Leukemia (2006) [Pubmed]
Immunotyping of blasts in refractory anaemia with excess of blasts. Oertel, J., Kleiner, S., Huhn, D. Br. J. Haematol. (1993) [Pubmed]
A role for tumour necrosis factor-alpha, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Gersuk, G.M., Beckham, C., Loken, M.R., Kiener, P., Anderson, J.E., Farrand, A., Troutt, A.B., Ledbetter, J.A., Deeg, H.J. Br. J. Haematol. (1998) [Pubmed]
Phase II trial of CPT-11 in myelodysplastic syndromes with excess of marrow blasts. Ribrag, V., Suzan, F., Ravoet, C., Feremans, W., Guerci, A., Dreyfus, F., Damaj, G., Vantelon, J.M., Bourhis, J.H., Fenaux, P. Leukemia (2003) [Pubmed]
Application of different prognostic scoring systems and comparison of the FAB and WHO classifications in Korean patients with myelodysplastic syndrome. Lee, J.H., Lee, J.H., Shin, Y.R., Lee, J.S., Kim, W.K., Chi, H.S., Park, C.J., Seo, E.J., Lee, K.H. Leukemia (2003) [Pubmed]
Myeloablative conditioning for marrow transplantation in myelodysplastic syndromes and paroxysmal nocturnal haemoglobinuria. Kolb, H.J., Holler, E., Bender-Götze, C., Walther, U., Mittermüller, J., Clemm, C., Bauchinger, M., Gerhartz, H.H., Brehm, G., Ledderose, G. Bone Marrow Transplant. (1989) [Pubmed]
Platelet glycoprotein expression in patients with myelodysplastic syndrome. Seidl, C., Siehl, J., Ganser, A., Hofmann, W.K., Fischer, M., Kirchmaier, C.M., Hoelzer, D., Seifried, E. Thromb. Res. (2000) [Pubmed]
Treatment of high risk myelodysplastic syndromes with idarubicin and cytosine arabinoside supported by granulocyte-macrophage colony-stimulating factor. (GM-CSF). Economopoulos, T., Papageorgiou, E., Stathakis, N., Constantinidou, M., Parharidou, A., Kostourou, A., Dervenoulas, J., Raptis, S. Leuk. Res. (1996) [Pubmed]

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