Refractory Anemia With An Excess Of Blasts Research Articles

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n=331) or single-unit unrelated cord blood (UCB) (n=668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P=0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P=0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P=0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P=0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P<0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P<0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P<0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P<0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Acute erythroid leukaemias

Note Criteria for diagnosis of acute erythroid leukaemia. Erythroleukaemia Historically, AML with erythroid features has been designated M6 by the French-American-British (FAB) group. The FAB criteria for M6 diagnosis are: bone marrow erythroblasts equal to or greater than 50% and blasts equal to or greater than 30% of the non-erythroid cells. The World Health Organization (WHO) have recently recommended that the requisite blast percentage for a diagnosis of AML be 20% or greater, and this includes erythroid leukaemia. AML M6 would equate to the new WHO definition of erythroleukaemia (erythroid/ myeloid). If there are less than 20% blasts, the diagnosis is refractory anaemia with an excess of blasts (RAEB). Trilineage dysplasia is common but is not a prerequisite for diagnosis. Erythroid dysplasia may manifest as binuclearity, nucleo-cytoplasmic asynchrony and vacuolation. The morphological appearance of the myeloblasts is not characteristic and they may contain Auer rods. Myeloperoxidase and Sudan black B stains may be positive in the myeloblasts. The iron stain may show ringed sideroblasts and PAS may be positive in the erythroid precursors in a block or diffuse pattern. Pure erythoid leukaemia In addition to the typical AML M6 (erythroleukaemia), there is a second subtype of acute erythoid leukaemia where there is a neoplastic proliferation of immature cells entirely committed to the erythroid series (>80% of marrow cells) without evidence of a myeloid component. This is termed pure erythroid leukaemia by the WHO. Morphology is characterised by medium sized erythroblasts with fine nuclear chromatin, distinct nucleoli and deeply basophilic cytoplasm that often have vacuoles. Occasionally the blasts can resemble acute lymphoblastic leukaemia, distinction can be made by immunophenotyping. The erythroid nature of the blasts can be shown by electron microscopy demonstrating free ferritin particles. The blasts are negative for Sudan black B and myeloperoxidase (MPO), but positive for PAS in a block pattern.

Prevalence and Survival of Myelodysplastic Syndrome of the Refractory Anemia Type in Hospitalized Cognitively Different Geriatric Patients

Background: Myelodysplastic syndrome (MDS) is predominantly a disease of old age. The number of MDS cases diagnosed over the last 20 years has risen substantially due to increased awareness and improved geriatric care. Although MDS is increasingly diagnosed, the prevalence and prognosis of early-stage affected elderly are not completely known. Objective: To evaluate the prevalence, characteristics and prognosis of newly diagnosed MDS patients hospitalized in an acute and subacute geriatric department. Methods: Between 1993 and 1996, 3,275 patients hospitalized in the geriatric department of a teaching hospital for acute care or short-term rehabilitation were investigated for unexplained hematological abnormalities. Demographic, chronic comorbidities, cause of hospitalization, functional and cognitive status, hematological and other laboratory parameters were collected. Results: Two hundred and forty-five (7.5%) patients had unexplained cytopenia, macrocytosis or monocytosis, of whom 37 (15%) were diagnosed as having MDS. Only 9 patients were hospitalized for evaluation of anemia, 28 for infections, cardiac, cerebrovascular events and other causes. Thirty-four patients had refractory anemia (RA), two had RA with ringed sideroblasts and 1 had RA with an excess of blasts (RAEB). The follow-up period was up to 70 months. No differences were found between demented and cognitively normal patients in age, sex, comorbidities or laboratory parameters. Comparison of survival curves (excluding the RAEB case) according to demographic, clinical and hematological parameters has shown that only dementia adversely affects survival, compared to cognitively normal patients (p = 0.024). Conclusions: MDS of the RA type is a common and incidental finding in older hospitalized patients. It is a frequent cause of anemia and other hematological abnormalities but has less significance on survival rates than dementia, although its full impact remains to be determined.

Study of p53 in Elderly Patients with Myelodysplastic Syndromes by Immunohistochemistry and DNA Analysis

We analyzed the tumor suppressor gene product, p53, in elderly patients with myelodysplastic syndromes (MDS) and in overt leukemia patients after transformation from MDS using immunohistochemical techniques. We examined 52 MDS patients (mean age 79 years, range 68 to 96) from the time of initial diagnosis to death or development of overt leukemia. p53 protein was detected by immunohistochemistry (IHC) in 8/52 patients (15%) at initial diagnosis: 1/26 with refractory anemia (RA), 0/4 with RA with ringed sideroblasts, 3/11 with RA with an excess of blasts (RAEB), 3/8 with RAEB in transformation, and 1/3 with chronic myelomonocytic leukemia. We also analyzed gene mutations in patients with positive IHC. p53 mutations were detected in 3/8 (38%) patients. IHC-positive patients had a significantly higher incidence of leukemic transformation and the presence of a complex karyotype with monosomy 17. IHC-positive cells included blasts as well as mature myeloid cells, erythroblasts, and megakaryocytes. Scrutiny of our data in combination with previous data revealed that patients with positive IHC in multilineage cells were older than those in whom positivity was noted mostly in myeloblasts. This suggests that p53 IHC positivity with a multilineage pattern may be a characteristic of MDS in older patients.

Spontaneous and cytokine-induced thrombocytopenia in myelodysplastic syndromes: serum thrombopoietin levels and bone marrow morphology. Scandinavian MDS Group, Sweden and Norway.

Thrombocytopenia is a substantial clinical problem for patients with myelodysplastic syndromes (MDS). Cytokine treatment for granulocytopenia and anaemia may further reduce the platelet counts. We studied serum thrombopoietin levels (S-TPO) in 52 patients with MDS and 96 healthy controls and related the results to clinical and morphological variables. S-TPO was also assessed after treatment with granulocyte-CSF (G-CSF) and erythropoietin (EPO) in 30 of these patients. S-TPO in MDS was not a normally distributed variable; mean value was 394 pg/ml, SD +/-831 and median value 123 (12-5000 pg/ml). The controls showed lower S-TPO levels than the patients (median 78 pg/ml, P = 0.003) whereas no differences between the MDS subgroups were observed (P = 0.86). Patients with ringed sideroblastic anaemia (RARS) showed the highest platelet counts and higher S-TPO levels than the controls (P = 0.005). No association between platelet counts and S-TPO levels was found in the patients (P = 0.67). TPO levels were generally low in patients with refractory anaemia with an excess of blasts (RAEB), but very high levels were found in five patients. Patients with a high transfusion need had higher S-TPO levels, whereas bone marrow blast counts, cellularity or megakaryocytes showed no correlation with S-TPO. Patients with 5q- showed lower TPO levels than the other patients, indicating that thrombopoietin is not a mediator of thrombocytosis in these cases. Treatment with G-CSF + EPO significantly reduced the platelet counts (P = 0.0002), but this change was not related to significant changes in S-TPO levels or morphology. Patients with RARS and thrombocytosis who normalized their platelet counts showed a concomitant reduction in S-TPO. This may suggest that the increased platelet counts observed in RARS may be caused by increased S-TPO levels. In conclusion, our study shows that platelet, megakaryocyte and thrombopoietin regulation is rather complex in myelodysplastic syndromes and that spontaneous or induced thrombocytopenia are not usually mirrored by increased S-TPO levels.

Transplantation II

The characteristics of Japanese (JPN) patients with myelodysplastic syndromes (MDS) were investigated in 838 retrospectively collected cases. The median age of the JPN patients was 60 years, about 10 years younger than that in most of the reports based on Western patients. Median survivals were 65 months for refractory anemia (RA), 58 months for RA with ring sideroblasts (RARS), 16 months for RA with an excess of blasts (RAEB), 10 months for RAEB in transformation (RAEBT), and 20 months for chronic myelomonocytic leukemia (CMML). Cumulative leukemia-free rates at final observation were 73% for RA, 79% for RARS, 24% for RAEB, 20% for RAEBT, and 53% for CMML. When low-risk (RA and RARS) patients were divided into two groups, those 40 years of age and older, and those under 40, the cumulative leukemia-free rate was 94% for the younger patients (n = 101), compared with 66% for the older patients (n = 318). The prognostic factors for survival were different from those in Western reports, i.e., variables representing quantitative abnormalities (hemoglobin levels, granulocyte, and platelet counts) were not major prognostic factors, while variables representing qualitative abnormalities (morphological abnormalities in granulocytic and megakaryocytic series cells) were highly significant. Two scoring systems for overall survival and for leukemic transformation were developed, based on multivariate prognostic factor analysis. Neither system included variables representing the degree of cytopenia. Whatever the reason for the different prognostic factors in JPN and Western MDS patients, the use of a scoring system based on Western patients for clinical decision-making in a JPN patient could be misleading, and vice versa.

Acute myelogenous leukemia with t(6;9)(p23;q34): Report of three patients

Acute myelogenous leukemia (AML) with the translocation t(6;9)(p23;q34) is a rare disease entity with a poor prognosis. We report three patients; two were diagnosed with AML of French-American-British (FAB) Cooperative Group type M2 and one with refractory anemia with an excess of blasts (RAEB) followed by AML type M2. The first patient, a 22-year-old man, achieved complete remission (CR) after three courses of chemotherapy. Two months after the CR was achieved, cytogenetic analysis showed t(6;9) in his morphologically normal bone marrow. After 5 months of remission, the AML relapsed and was resistant to further chemotherapy. The second patient, a 19-year-old man who had not achieved remission after two courses of chemotherapy, was treated with allogeneic bone marrow transplantation (BMT). The transplant resulted in CR and the disappearance of t(6;9). Seventeen months after the transplant, polymerase chain reaction analysis revealed molecular remission, confirmed by the absence of DEK-CAN mRNA. This patient has been in a leukemia-free state for more than 3 years. The third patient, a 54-year-old woman, was diagnosed with RAEB. AML developed 6 months later and she died 12 months after the diagnosis of RAEB. We suggest that BMT should be performed if a suitable donor can be found, otherwise the outcome is poor.

Analysis of bone marrow and peripheral blood immunoregulatory lymphocytes in patients with myelodysplastic syndrome

The cell surface phenotype of immunoregulatory lymphocytes in bone marrow (BM) and peripheral blood (PB) in myelodysplastic syndrome (MDS), a stem cell disorder, was analyzed. Mononuclear cells from 25 patients with refractory anemia (RA) and nine with RA with an excess of blasts (RAEB) were characterized by two-color flow cytometry using various monoclonal antibodies. No significant change of CD3+, CD4+, and CD8+ cells in PB, but a decrease of the percent of positive cells for CD8++ among the total lymphocyte (%CD8++) was noticed in RA patients. On the other hand, in BM of RA patients, a decrease in the number of CD4+ cells, but not CD8++ cells, was noted. In RAEB patients, the absolute numbers of CD3+, CD4+, CD8+, and CD8++ cells in BM were decreased; however, the ratio of these lymphocytes was not changed. No change was observed among the CD4+ subsets in PB of RA or RAEB patients. In BM, a decrease in percentage of CD4+CD45RA+ (%CD4+CD45RA+; naive cell) and increases in CD4+CD45RO+ (%CD4+CD45RO+; memory cell) and CD4+CD29+ (%CD4+CD29+; helper/inducer) among CD4+ cells were found in both RA and RAEB patients. Analysis of the CD8++ subset showed an increased number of CD8++CD11a+ cells (activated CTL) in both BM and PB of RA patients, but not of RAEB patients. Furthermore, increments in CD56+ and CD16+ cells among CD3- cells (natural killer; NK cells) were seen in RA patients but not in RAEB patients. It remains unclear whether lymphocytes in MDS patients were involved in the abnormal (MDS) clones, but our results regarding the increments of CD8++CD11a+ and NK cells in RA patients suggest that the mechanism of immune surveillance against the abnormal MDS clones was activated in these RA patients, but not in RAEB patients. Further investigation is required to clarify the functions of these immunoregulatory lymphocytes in MDS patients.

Clinical characteristics of Japanese patients with primary myelodysplastic syndromes: A co-operative study based on 838 cases

The characteristics of Japanese (JPN) patients with myelodysplastic syndromes (MDS) were investigated in 838 retrospectively collected cases. The median age of the JPN patients was 60 years, about 10 years younger than that in most of the reports based on Western patients. Median survivals were 65 months for refractory anemia (RA), 58 months for RA with ring sideroblasts (RARS), 16 months for RA with an excess of blasts (RAEB), 10 months for RAEB in transformation (RAEBT), and 20 months for chronic myelomonocytic leukemia (CMML). Cumulative leukemia-free rates at final observation were 73% for RA, 79% for RARS, 24% for RAEB, 20% for RAEBT, and 53% for CMML. When low-risk (RA and RARS) patients were divided into two groups, those 40 years of age and older, and those under 40, the cumulative leukemia-free rate was 94% for the younger patients ( n = 101), compared with 66% for the older patients ( n = 318). The prognostic factors for survival were different from those in Western reports, i.e., variables representing quantitative abnormalities (hemoglobin levels, granulocyte, and platelet counts) were not major prognostic factors, while variables representing qualitative abnormalities (morphological abnormalities in granulocytic and megakaryocytic series cells) were highly significant. Two scoring systems for overall survival and for leukemic transformation were developed, based on multivariate prognostic factor analysis. Neither system included variables representing the degree of cytopenia. Whatever the reason for the different prognostic factors in JPN and Western MDS patients, the use of a scoring system based on Western patients for clinical decision-making in a JPN patient could be misleading, and vice versa.

Double-minute chromosomes appearing in a patient with myelodysplastic syndrome with disease evolution

We present the first case of a myelodysplastic syndrome (MDS) demonstrating an association between the appearance of double-minute chromosomes (dmin) and disease progression. This 59-year-old Japanese woman showed a deletion of the long arm of chromosome 5 [del(5)(q21q34)] and monosomy 9, when she was diagnosed as having refractory anemia with an excess of blasts (RAEB). Subsequential cytogenetic analyses demonstrated that the neoplastic cells in the peripheral blood had six copies of dmin, when the disease progressed into RAEB in transformation (RAEBt). This cytogenetic change was consistently observed when the patient developed the leukemia phase. The findings in this case suggest that the appearance of dmin may be linked to progression of the disease.

Genetic lesions and clinical outcome in myelodysplasia (MDS)

The characteristics of Japanese (JPN) patients with myelodysplastic syndromes (MDS) were investigated in 838 retrospectively collected cases. The median age of the JPN patients was 60 years, about 10 years younger than that in most of the reports based on Western patients. Median survivals were 65 months for refractory anemia (RA), 58 months for RA with ring sideroblasts (RARS), 16 months for RA with an excess of blasts (RAEB), 10 months for RAEB in transformation (RAEBT), and 20 months for chronic myelomonocytic leukemia (CMML). Cumulative leukemia-free rates at final observation were 73% for RA, 79% for RARS, 24% for RAEB, 20% for RAEBT, and 53% for CMML. When low-risk (RA and RARS) patients were divided into two groups, those 40 years of age and older, and those under 40, the cumulative leukemia-free rate was 94% for the younger patients (n = 101), compared with 66% for the older patients (n = 318). The prognostic factors for survival were different from those in Western reports, i.e., variables representing quantitative abnormalities (hemoglobin levels, granulocyte, and platelet counts) were not major prognostic factors, while variables representing qualitative abnormalities (morphological abnormalities in granulocytic and megakaryocytic series cells) were highly significant. Two scoring systems for overall survival and for leukemic transformation were developed, based on multivariate prognostic factor analysis. Neither system included variables representing the degree of cytopenia. Whatever the reason for the different prognostic factors in JPN and Western MDS patients, the use of a scoring system based on Western patients for clinical decision-making in a JPN patient could be misleading, and vice versa.

Clonality in myelodysplastic syndromes: demonstration of pluripotent stem cell origin using X-linked restriction fragment length polymorphisms.

Restriction fragment length polymorphisms (RFLP) of the X-chromosome genes phosphoglycerate kinase (PGK) and hypoxanthine phorphoribosyltransferase (HPRT) were used to determine the clonal nature of myelodysplastic syndromes (MDS) in 22 patients. These included eight with refractory anaemia (RA), four with RA with ring sideroblasts (RARS), six with RA with an excess of blasts (RAEB), three with RAEB in transformation (RAEB-T), and one with chronic myelomonocytic leukaemia (CMML). Monoclonal X-inactivation patterns were observed in 19/22 patients. The remaining three cases, one each with RA, RARS and RAEB, were of polyclonal composition. Separated T-lymphocyte and granulocyte fraction analyses in six patients of the former cases revealed that T-lymphocyte as well as granulocyte fractions showed a monoclonal pattern of X-inactivation. These results support the view that the majority of MDS arise from a pluripotent stem cell capable of myeloid and lymphoid differentiation.

A phase II trial of recombinant human granulocyte colony‐stimulating factor in the myelodysplastic syndromes

We conducted a phase II study of the intravenous administration of a glycosylated recombinant human granulocyte colony-stimulating factor (rhG-CSF) for 7-14 d in 41 patients with the myelodysplastic syndromes (MDS). Administration of rhG-CSF elicited striking rises in both leucocyte and neutrophil counts in the majority of the patients irrespective of the FAB subtypes of MDS. The rises in neutrophil counts were dose dependent and 5 micrograms/kg/d of rhG-CSF yielded approximately an 8-fold increase in neutrophil counts. Leucocytes and neutrophil counts started to increase shortly after the first injection of 5 micrograms/kg, was maintained at significantly elevated levels during 14 d of treatment, and returned to the pretreatment levels within several days following discontinuation of rhG-CSF. The action of rhG-CSF was specific for neutrophils since leucocytosis was due exclusively to neutrophilic increase associated with an increased marrow myeloid maturation. There were no consistent changes in the monocyte, eosinophil, lymphocyte, platelet or reticulocyte counts. After treatment, the percentage of marrow blast cells was reduced in eight of 13 evaluable patients with refractory anaemia with an excess of blasts (RAEB) or RAEB in transformation (RAEB-t). No patients developed acute leukaemia during the treatment or in the immediate follow-up period. The treatment was well tolerated with only minimal toxicity. The results suggest that rhG-CSF is a safe and effective way to promptly improve neutropenia in MDS patients.

Responsiveness of bone marrow erythropoietic stem cells (CFU‐E and BFU‐E) to recombinant human erythropoietin (rh‐Ep) in vitro in aplastic anemia and myelodysplastic syndrome

Responsiveness of bone marrow erythropoietic stem cells (CFU-E and BFU-E) to recombinant human erythropoietin (rh-Ep) was examined in vitro in 23 patients with aplastic anemia and 14 with myelodysplastic syndrome (MDS) to investigate the clinical use of rh-Ep for these diseases. Bone marrow mononuclear cells were cultured by methylcellulose methods for CFU-E and BFU-E assays. In normals, the CFU-E numbers reached a plateau of increase at Ep doses of almost 2-5 units, and no further increase was observed with the addition of larger Ep doses. In aplastic anemia, the responses of CFU-E to Ep were relatively good in nonsevere type and generally poor in severe type. However, the CFU-E numbers increased with increasing doses of Ep in some of the patients with aplastic anemia. Among the patients with MDS, the responses of CFU-E to Ep were relatively good in primary acquired refractory anemia (PARA) and primary acquired sideroblastic anemia. On the other hand, the responses of CFU-E to Ep were poor in refractory anemia with an excess of blasts (RAEB) and RAEB in transformation among the MDS patients. BFU-E responses to Ep were poor in severe aplastic anemia, RAEB, and RAEB-T. However, there are Ep responsive patients in some of aplastic anemia and PARA. High titers of rh-Ep were suggested to be effective clinically in some patients with aplastic anemia and those with PARA.

The transferrin receptor system is not involved in the pathogenesis of hematological disorders with 3q inversion

To clarify the idea that an alteration of the transferrin receptor (TF-R) gene, localized to 3q26, may be of pathogenetic significance in hematological disorders with 3q anomaly, we studied the TF-R systems of erythroblasts from both functional and genetic aspects. The patient described here had refractory anemia with an excess of blasts (RAEB), with paracentric inversion, inv(3)(q21q26). The patient had the characteristic findings of micromegakaryocytosis and thrombocytosis, with giant platelets. There was no functional abnormality of TF-R as far as number of binding sites, affinity, molecular weight, or recycling kinetics were concerned. Furthermore, we could not recognize any rearrangement of the TF-R gene with Southern blot analysis. These data suggest that TF-R is not involved in the pathogenesis of leukemogenesis and thrombocytosis of the disease.

Clinical-cytogenetic correlations in myelodysplasia (preleukemia)

Cytogenetic studies detected abnormalities in 107 (43%) of the 247 patients in this series. Some degree of overt clinical progression occurred in 55 patients (22%), this being 29% of those patients with cytogenetic abnormalities and 17% of those with normal chromosomes. The presence and complexity of a clonal cytogenetic abnormality correlated with shorter survival. In each clone category of a complexity classification (simple, complex, very complex), patients with some normal cells appeared to have better survival than those with none. In multiple regression analyses, the prognostic value of chromosomes was independent of (and second in importance to) the FAB type of myelodysplastic syndrome (MDS) whichever chromosome classification was used. Patients with refractory anemia (RA) had the lowest incidence of chromosome abnormalities and no cases were found to have only abnormal cells (AA). A greater proportion of patients with refractory anemia with an excess of blasts (RAEB) and RAEB in transformation (RAEB-t) had clonal abnormalities. Morphology alone is not at present able to distinguish between RA or refractory anemia with ringed sideroblasts and similar disorders that may not be MDS in the strict sense. Demonstration of a clonal cytogenetic abnormality remains a positive indication of the presence of the neoplastic nature of the disease.

Analysis of leucocyte differentiation antigens in blood and bone marrow in patients with refractory anaemia (RA) and RA with sideroblasts. Prognostic implications of sequential and follow-up data.

34 patients with primary myelodysplastic syndrome (MDS), initially diagnosed as subtypes refractory anaemia (RA) and RA with ringed sideroblasts (RA-S), were followed to investigate the distribution of lymphoid and myeloid differentiation antigens in the blood and bone marrow in search of potential prognostic significance with regard to progression to RA with an excess of blasts (RAEB) or acute myeloid leukaemia, and for relations to clinical, morphological and cytogenetic findings. Patients who later progressed to RAEB had significantly decreased percentages of anti-T8 positive T-suppressor cells in the blood at diagnosis compared to those who did not (p = 0.05). Sequential analysis showed a decrease with time also in the percentages of anti-T8-positive cells (p = 0.05). In the bone marrow, progressing patients initially showed significantly increased percentages of anti-My9-positive immature myeloid cells (p less than 0.001), and the percentages of anti-My9-positive cells in the bone marrow increased with time (p less than 0.005). Analysis of the pooled data revealed a statistically significant relation between increasing percentages of anti-My9-positive cells and the frequencies of clonally abnormal (p less than 0.001) and abnormal (p = 0.004) metaphases.

Prognostic value of clonal chromosomal abnormalities in patients with primary myelodysplastic syndromes.

Chromosome analyses were carried out on bone marrow cells from 43 consecutive patients with primary myelodysplastic syndromes (MDS), classified according to the French-American-British (FAB) cooperative group criteria. The objective was to evaluate the prognostic value of clonal chromosomal abnormalities and of an excess of blasts for early death from acute nonlymphocytic leukemia (ANLL) and/or bone marrow failure (BMF). Patients were subdivided into two main groups: (1) refractory anemia without an excess of blasts (RAWEB), grouping patients with refractory anemia (RA) and refractory anemia with ringed sideroblasts (RARS), and (2) refractory anemia with an excess of blasts (RAEB), grouping patients with refractory anemia with an excess of blasts (RAEB) and refractory anemia with an excess of blasts in transformation (RAEBt). There were 29 patients with RAWEB and 14 with RAEB. The median time of observation was 26 months for RAWEB and 12 months for RAEB. Ten RAWEB patients (34%) and 11 RAEB patients (78%) had clonal chromosomal abnormalities. Among the ten RAWEB patients with clonal abnormalities, one (10%) died from ANLL, while of 19 RAWEB patients with a normal karyotype, two (10%) died from ANLL or BMF. The median survival for patients with RAWEB and an abnormal karyotype was not reached. In contrast, eight of the 11 RAEB patients with clonal chromosomal abnormalities (74%) died from ANLL or BMF. The median survival in this sub-group was 7 months. By using a Cox proportional hazard regression analysis, it was determined that a karyotype abnormality was not a significant predictory of survival once the contribution of the RAWEB/RAEB variable was taken into account. Being in the RAEB group was associated with a relative risk of 10.6 of dying from ANLL or BMF (beta = 2.36, standard error (SE) = 0.68, P = .0001). We conclude that classifying patients according to an excess of blasts will lead to a better prediction of survival than determining karyotype abnormality.

Specific minor chromosome deletions in myelodysplastic syndromes: Clinical and morphologic correlations

Thirty-four patients with myelodysplastic syndrome (MDS) subtypes refractory anemia (RA) and RA with ringed sideroblasts (RA-S) (26 and eight patients, respectively) were investigated for clinical and morphologic significance of the most frequently occurring minor chromosome deletions [del(17)(p12), del(8)(p22), del(2)(p24), and del(9)(p22)]. The occurrence of 17p− was statistically significantly related to a low initial bone marrow cellularity (p = 0.01) and severe granulocytopenia (p = 0.05). A diagnosis of RA was seen more frequently among patients with 17p−, also. 17p− alone was not related to progression to RA with an excess of blasts (RAEB). The occurrence of 8p− was statistically significantly related to a higher initial frequency of bone marrow myeloblasts (p = 0.05), but not to bone marrow cellularity or initial granulocytopenia. 8p− alone was not related to initial diagnosis, but a statistically significant relation to progression to RAEB was found (p = 0.05). 2p− was related to progression to RAEB, also (p = 0.02), but not to any of the other investigated parameters. No significant relations between the occurrence of 9p− and other parameters were demonstrated. The simultaneous occurrence of 17p− and 8p− was also statistically significantly related to progression to RAEB (p = 0.02). These relationships suggest that 17p− is involved in the development of bone marrow and peripheral blood granulocytopenia and that 8p−, and possibly 2p−, interferes with differentiation of primitive granulocyte precursors and, thus, play a part in the process leading to RAEB and acute myeloid leukemia.

Prognostic significance of morphologic and cytogenetic findings for progression in myelodysplastic syndromes.

Within the group of myelodysplastic syndromes (MDS) two subgroups are defined [refractory anemia (RA) and RA with ringed sideroblasts (RA-S)] where the percentages of peripheral blood and bone marrow blast cells, by definition, do not exceed 1% and 5%, respectively [1]. Therefore, the applicability of these parameters would be expected to be of limited value with regard to the prediction of progression to RA with an excess of blasts (RAEB) and/or acute myeloid leukemia (AML). The present investigation was undertaken to evaluate the predictive value of peripheral blood cytopenia and to investigate whether a causal relationship between peripheral blood cytopenia, bone marrow morphology, and cytogenetic abnormalities could be envisaged.