Acquired Idiopathic Sideroblastic Anemia Research Articles

Lack of Efficacy of Pyridoxine (Vitamin B6) Treatment In Acquired Idiopathic Sideroblastic Anemia, Including Refractory Anemia with Ring Sideroblasts

AbstractAbstract 2919 Background:Sideroblastic anemias can be either hereditary due to congenital mutations in factors critical for iron processing or heme biosynthesis, or acquired; acquired sideroblastic anemias may be induced by alcohol or medications, but are usually idiopathic. Pyridoxine, a form of vitamin B6, plays a critical role in heme synthesis as a cofactor for δ-aminolevulinic acid synthetase (ALAS). Some subtypes of congenital sideroblastic anemia, such as those associated with mutations in the ALAS2 gene encoding the erythrocyte-expressed isoform of ALAS, may respond to pyridoxine therapy at doses ranging from 5–500 mg/day. Anecdotal reports of improvement with pyridoxine therapy in cases of acquired idiopathic sideroblastic anemia (AISA) have led to widespread clinical use of this agent in patients with refractory anemia with ring(ed) sideroblasts (RARS) and refractory cytopenia with multilineage dysplasia associated with ring sideroblasts (RCMD-RS). However, there are no systematic studies of the effectiveness of pyridoxine in AISA. Methods:We reviewed clinical and laboratory data from 231 adult patients with marrow aspirate-proven AISA (i.e., RARS or RCMD-RS, based on 2001 WHO criteria) evaluated at our institution between 1994 and 2007. Responses to pyridoxine were assessed using 2006 International Working Group (IWG) standardized criteria for MDS (erythroid response with hemoglobin increase by '1.5 mg/dl). The relationship between response to pyridoxine and disease subtype or International Prognostic Scoring System (IPSS) stratification was assessed using χ2 test, using a p-value limit of <0.05 for statistical significance. Results:86 of the 231 patients (42%) were treated with pyridoxine for an average of 19 months (range 1–114 months) at a mean dose of 167 mg/day (range 50–600 mg/day). Sufficient follow-up data to allow response evaluation were available from 74 (86%) of the 86 patients who received pyridoxine. Only 5/86 patients (6.8%) receiving pyridoxine met IWG response criteria for hematological improvement, but 3 of these 5 patients also received erythropoetin and 1 also received prednisone concomitantly with pyridoxine therapy. Therefore, only 1/86 (1.4%) patient's improvement in hemoglobin could be attributed to pyridoxine monotherapy. ALAS2 genotype data were not available from these 5 patients. The dose of pyridoxine was not associated with response to therapy (187.5 mg daily in responders vs. 157 mg daily in non-responders (p=0.60).Patients with RCMD-RS were more likely to be treated with vitamin B6 compared to patients with RARS (p=<0.001), possibly because of more severe anemia, but response to pyridoxine did not differ significantly between subtypes (3/49 vs. 2/25, response in RARS vs. RCMD-RS; p=0.76). Among the 74 evaluable patients, 3/46 patients in the low IPSS risk group responded to pyridoxine, compared to 2/24 of patients in the Intermediate-1 risk group and 0/4 in the Intermediate-2 risk group (p=0.82). Adverse effects associated with pyridoxine included new onset of irreversible symptomatic peripheral neuropathy in 2/86 patients (2.3%). Conclusions:Pyridoxine is commonly prescribed to patients with AISA in clinical practice, and this agent is often continued for a long period of time despite lack of evidence of objective response. Pyridoxine is an ineffective therapy in AISA that induces symptomatic peripheral neuropathy in some patients. Therefore, pyridoxine therapy should be limited to patients with known or suspected congenital mutations that confer pyridoxine responsiveness, and therapeutic trials should be brief to avoid adverse effects. Disclosures:No relevant conflicts of interest to declare.

Two types of acquired idiopathic sideroblastic anaemia (AISA): a time-tested distinction.

In 1982, acquired idiopathic sideroblastic anaemia (AISA) was included by the French-American-British (FAB) Co-operative Group in their classification of myelodysplastic syndromes (MDS). However, the malignant potentiality of AISA has always been a matter of debate. In different series, median survival and rates of transformation into acute myeloid leukaemia (AML) varied extensively. On cytomorphological grounds, AISA can be divided into pure (dyserythropoietic) sideroblastic anaemia (PSA), in which dysplasia is confined to erythropoietic cells, and a true myelodysplastic form (RARS), which is characterized by additional dysplastic features of granulopoiesis and/or megakaryopoiesis. In a previous study, based on retrospective analysis of 94 patients with AISA, we found that both types of sideroblastic anaemia differed considerably in terms of survival and risk of AML transformation. Almost identical results have now been obtained through a prospective study of 232 new patients with AISA. The difference in survival between PSA and RARS remained significant over the whole period of follow-up (survival after 3 years being 77% vs. 56%; P = 0.003), and the incidence of AML did not increase with time in the PSA group, even in the long term. This prospective study strongly supported our conclusion that cytomorphological distinction between PSA and RARS provides valuable prognostic information.

From sideroblastic anemia to the role of mitochondrial DNA mutations in myelodysplastic syndromes

A primary mitochondrial defect may be pivotal in the pathogenesis of acquired idiopathic sideroblastic anemia (AISA). The mitochondrial respiratory chain is involved in mitochondrial iron uptake and supply of ferrous iron (Fe 2+) for heme synthesis. Mitochondrial DNA (mtDNA) comes into play because several subunits of the respiratory chain are encoded by the mitochondrial genome. We have identified heteroplasmic mutations of mtDNA, which may not only impair mitochondrial iron metabolism and heme synthesis, but through impairment of mitochondrial energy production may have much broader implications for MDS pathogenesis. For example, increased apoptosis and genetic instability may be phenomena linked to mitochondrial dysfunction.

Heteroplasmic Point Mutations of Mitochondrial DNA Affecting Subunit I of Cytochrome c Oxidase in Two Patients With Acquired Idiopathic Sideroblastic Anemia

Mitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA (mtDNA), because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron (Fe3+) to ferrous iron (Fe2+). The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. It is not yet understood to which part of the respiratory chain the reduction of ferric iron is linked. In two patients with AISA we identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase (COX I; ie, complex IV of the respiratory chain). The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. One of the mutations involves a T → C transition in nucleotide position 6742, causing an amino acid change from methionine to threonine. The other mutation is a T → C transition at nt 6721, changing isoleucine to threonine. Both amino acids are highly conserved in a wide range of species. Both mutations are heteroplasmic, ie, they establish a mixture of normal and mutated mitochondrial genomes, which is typical of disorders of mtDNA. The mutations were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in buccal mucosa cells obtained by mouthwashes and in cultured skin fibroblasts examined in one of the patients. In both patients, this pattern of involvement suggests that the mtDNA mutation occurred in a self-renewing bone marrow stem cell with myeloid determination. Identification of two point mutations with very similar location suggests that cytochrome c oxidase plays an important role in the pathogenesis of AISA. COX may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.

Heteroplasmic Point Mutations of Mitochondrial DNA Affecting Subunit I of Cytochrome c Oxidase in Two Patients With Acquired Idiopathic Sideroblastic Anemia

AbstractMitochondrial iron overload in acquired idiopathic sideroblastic anemia (AISA) may be attributable to mutations of mitochondrial DNA (mtDNA), because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron (Fe3+) to ferrous iron (Fe2+). The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis. It is not yet understood to which part of the respiratory chain the reduction of ferric iron is linked. In two patients with AISA we identified point mutations of mtDNA affecting the same transmembrane helix within subunit I of cytochrome c oxidase (COX I; ie, complex IV of the respiratory chain). The mutations were detected by restriction fragment length polymorphism analysis and temperature gradient gel electrophoresis. One of the mutations involves a T → C transition in nucleotide position 6742, causing an amino acid change from methionine to threonine. The other mutation is a T → C transition at nt 6721, changing isoleucine to threonine. Both amino acids are highly conserved in a wide range of species. Both mutations are heteroplasmic, ie, they establish a mixture of normal and mutated mitochondrial genomes, which is typical of disorders of mtDNA. The mutations were present in bone marrow and whole blood samples, in isolated platelets, and in granulocytes, but appeared to be absent from T and B lymphocytes purified by immunomagnetic bead separation. They were not detected in buccal mucosa cells obtained by mouthwashes and in cultured skin fibroblasts examined in one of the patients. In both patients, this pattern of involvement suggests that the mtDNA mutation occurred in a self-renewing bone marrow stem cell with myeloid determination. Identification of two point mutations with very similar location suggests that cytochrome c oxidase plays an important role in the pathogenesis of AISA. COX may be the physiologic site of iron reduction and transport through the inner mitochondrial membrane.

23 Heterogeneity of acquired idiopathic sideroblastic anemia (AISA): Results of a prospective follow-up study in 189 patients

23 Heterogeneity of acquired idiopathic sideroblastic anemia (AISA): Results of a prospective follow-up study in 189 patients

Heterogeneity of acquired idiopathic sideroblastic anaemia (AISA)

Clinical, haematological and outcome data were studied in 84 patients with acquired idiopathic sideroblastic anaemia (AISA) from a registry of 613 consecutive myelodysplastic syndromes (MDS) recorded by five institutions in western France. Two groups could be identified and compared: ‘pure’ erythroblastic AISA (AISA-E: 59 pts), and AISA with myelodysplastic features, i.e. dysgranulo and/or dysmegakaryopoiesis (AISA-M: 25 pts). Results were also compared to those of a series of 71 cases of refractory anaemia without sideroblastosis (RA) carried out from the same registry. Dyserythropoiesis was present in 90% of all AISA subtypes, dysgranulopoiesis in 88% of the AISAM cases; dysmegakaryopoiesis was observed in 44% of AISA-M. Ten patients with both forms of AISA showed high platelet counts. These cases appeared particular in that four of them were associated with a splenomegaly and/or a hyperleucocytosis. They had to be distinguished from myeloproliferative syndromes. Outcome comparison of AISA-E with AISA-M showed a significant discrepancy of survival duration (60 vs 38 months respectively). Progression towards refractory anaemia with excess of blasts or acute leukaemia, was significantly higher for AISA-M than for AISAE. The risk of transformation increased to 24% for the AISA-M group similarly to those of RA patients (17%). We conclude that AISA must be divided into two categories, ‘pure’ AISA and AISAM, because survival duration and risk of transformation are different.

(A8) Heterogeneity of acquired idiopathic sideroblastic anaemia (AISA)

(A8) Heterogeneity of acquired idiopathic sideroblastic anaemia (AISA)

Two types of acquired idiopathic sideroblastic anaemia (AISA)

On cytological bone marrow examination we distinguished between pure sideroblastic anaemia (PSA), which is confined to dyserythropoiesis, and refractory anaemia with ring sideroblasts (RARS), which is characterized by additional dysplastic features of granulopoiesis and/or megakaryopoiesis. In a follow-up study of 94 patients with AISA diagnosed according to FAB criteria for myelodysplastic syndromes we found a striking difference in the risk of leukaemic transformation between PSA and RARS (5 year cumulative rate 1.9% v. 48%). Overall survival was much better in PSA than in RARS (5 year cumulative chance 69% v. 19%). Infections and haemorrhages were frequent causes of death in RARS but not in PSA. Bone marrow culture studies (CFU-GM) were performed on 10 consecutive patients with PSA and RARS, respectively. RARS patients showed grossly impaired colony growth, typical of the myelodysplastic syndromes. Patients with PSA had persisting colony formation, even if moderately decreased in frequency, with numbers of CFU-GM being inversely correlated with the degree of erythroid hyperplasia in the bone marrow. We conclude that on cytomorphological grounds AISA can be divided into pure (dyserythropoietic) sideroblastic anaemia (PSA) and a true myelodysplastic form (RARS), with both types differing considerably in terms of survival, risk of leukaemic transformation and findings on bone marrow culture (CFU-GM).

Myelodysplastic syndromes: analysis of clinical and prognostic features in 96 patients.

In a retrospective study of 96 patients with a myelodysplastic syndrome the FAB classification, Bournemouth score and other parameters were correlated with leukaemic transformation and survival. Diagnosis was refractory anaemia (RA) in 7 patients, acquired idiopathic sideroblastic anaemia (AISA) in 2, chronic myelomonocytic leukaemia (CMML) in 31, refractory anaemia with excess of blasts (RAEB) in 34 and RAEB in transformation (RAEB-t) in 22. Median survival for all patients was 37 weeks (RA and AISA 103, CMML 67, RAEB 35, RAEB-t 27). Scoring according to the Bournemouth criteria showed significant differences in survival between groups A, B and C. Of the separate variables, only percentage of bone marrow blasts and haemoglobin level were prognostically significant. A modified scoring system based upon these two variables was even more discriminative. It proved to be particularly useful in CMML, a subtype with a wide range of survival times. Leukaemic transformation was seen in 39% (RA and AISA 0%, CMML 30%, RAEB 39%, RAEB-t 75%).

Cytogenetic evidence for involvement of B lymphocytes in acquired idiopathic sideroblastic anemias

We studied the cellular distribution of an unusual chromosomal abnormality, an interstitial deletion of the long arm of chromosome 13, in the peripheral blood lymphocytes of two patients with acquired idiopathic sideroblastic anemia (AISA). We found no metaphases containing the 13q- abnormality in preparations of phytohemagglutinin (PHA)-stimulated lymphocytes from either patient. In both cases, however, some metaphases from Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines contained the clonal karyotypic abnormality. These observations indicate that B lymphocytes but not T cells are expressed as members of the clonal cohort of cells. Our results strongly suggest that the initial pathogenetic events that led to expansion of the 13q- clone occurred in a progenitor cell capable of giving rise to both hematopoietic and B lymphoid cells.

Cytogenetic Evidence for Involvement of B Lymphocytes in Acquired Idiopathic Sideroblastic Anemias

AbstractWe studied the cellular distribution of an unusual chromosomal abnormality, an interstitial deletion of the long arm of chromosome 13, in the peripheral blood lymphocytes of two patients with acquired idiopathic sideroblastic anemia (AISA). We found no metaphases containing the 13qabnormality in preparations of phytohemagglutinin (PHA)-stimulated lymphocytes from either patient. In both cases, however, some metaphases from Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines contained the clonal karyotypic abnormality. These observations indicate that B lymphocytes but not T cells are expressed as members of the clonal cohort of cells. Our results strongly suggest that the initial pathogenetic events that led to expansion of the 13q– clone occurred in a progenitor cell capable of giving rise to both hematopoietic and B lymphoid cells.

Prognostic Implications of Morphology and Karyotype in Primary Myelodysplastic Syndromes

Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.

Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes

Forty-nine patients with primary myelodysplastic syndromes (MDS) were subclassified according to French-American-British (FAB) Cooperative Group criteria. Eight patients had acquired idiopathic sideroblastic anemia (AISA), ten had chronic myelomonocytic leukemia (CMMoL), 14 had refractory anemia (RA), nine had refractory anemia with excess blasts (RAEB), and five had refractory anemia with excess blasts in transformation (RAEB-T); three patients could not be subclassified. The actuarial median survival for patients with AISA or with RA had not been reached at 60 months of follow-up. The median survival times for patients with CMMoL, RAEB, and RAEB-T were 25, 21, and 16 months, respectively. The percentages of patients with each subtype who developed ANLL were none in AISA, 20% in CMMoL, 7% in RA, 56% in RAEB, and 40% in RAEB-T. Patients with CMMoL had a poor prognosis independent of transformation to acute nonlymphocytic leukemia (ANLL), whereas patients with RAEB and RAEB-T had a high incidence of transformation and short survival times. Clonal chromosomal abnormalities were present in bone marrow cells from 19 patients at the time of diagnosis, and two others developed an abnormal karyotype at the time of leukemic transformation. The most frequent abnormalities, including initial and evolutionary changes, were trisomy 8 (9 patients), deletion of 5q (4 patients), and deletion of 20q (4 patients). The median survival times were 32 months for patients with an abnormal karyotype, and 48 months for those with a normal karyotype (P = 0.2). Specific chromosomal abnormalities were not associated with particular histologic subtypes; however, a high percentage of patients with RAEB and RAEB-T had an abnormal clone (89% and 80%, respectively). The percentages of patients with clonal abnormalities were 13% for AISA, 20% for CMMoL, and 29% for RA. The MDS transformed to ANLL in 42% of patients with an abnormal karyotype, compared to 10% of those with an initially normal karyotype (P less than .01). Among patients with RA, RAEB, and RAEB-T, the risk of leukemic transformation was confined to those with an abnormal karyotype (P less than .01). Thus, in the present study, morphology and karyotype combined were the best indicators of outcome in patients with MDS.

Chromosome abnormalities in acquired idiopathic sideroblastic anemia with subsequent leukemic transformation

Chromosomal abnormalities were demonstrated in the bone marrow cultures of two patients with acquired idiopathic sideroblastic anemia (AISA). Both patients subsequently experienced leukemic transformation and developed acute myelomonocytic leukemia (type M4). A review of the literature revealed that approximately 40% of the AISA cases manifest chromosomal abnormalities, of which 20.5% underwent leukemic conversion.

Prognostic factors in the myelodysplastic syndromes: importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis.

An analysis of clinical, haematological, histological and cytogenetic data was performed in 85 consecutive patients with myelodysplastic syndromes (MDS). The criteria for diagnosis of refractory anaemia (RA), acquired idiopathic sideroblastic anaemia (AISA) and chronic myelomonocytic leukaemia (CMML) were clearly defined, since the inclusion criteria provided by the FAB co-operative group are imprecise. None of these patients has received chemotherapy during the follow-up period. The median survival of the whole group was only 15 months, with less than 10% of the patients surviving after 5 years. Fifteen patients (17.6%) were still alive at time of analysis, 31 (36.5%) have developed acute myeloid leukaemia (AML) and only one of them is still alive; 30 (35.3%) died of infectious and/or haemorrhagic complications. Patients who developed AML had a shorter survival (median survival time 9.5 versus 15 months) but this difference was not significant (P = 0.10). Factors with prognostic value are in order of significance: abnormal localized immature myeloid precursors (= ALIP) in the trephine biopsy, circulating myeloblasts, excess of blasts in the bone marrow smears, age, FAB classification and granulocyte count. In comparison to refractory anaemia with excess of blasts (RAEB), CMML and RAEB in transformation (RAEBt), patients with RA and AISA had a lower incidence of evolution to AML (11% versus 56%), but a higher mortality rate from infections and/or bleeding (59.2% versus 29%). ALIP negative cases were only found among patients with RA and AISA, whereas ALIP positivity was observed in all cases of RAEB and RAEBt, in 10/11 patients with CMML and in almost half the cases of RA and AISA. In RA and AISA patients survival was significantly different between ALIP positive and ALIP negative cases (P = 0.009). Among MDS patients, ALIP negative cases developed significantly less AML than ALIP positive cases (5% versus 44%), but a similar percentage of mortality from infectious and/or haemorrhagic complications was seen in both groups (33% versus 36.5%). Chromosomal analysis proved to be of no significant prognostic value, although a trend for shorter survival was observed in patients with complex karyotype anomalies or without mitoses. Because of their prolonged survival, antileukaemic chemotherapy is contra-indicated in ALIP negative patients (median survival 50 months). Nevertheless they only constitute a minor subgroup of MDS cases. Prognosis in ALIP positive patients is poor (median survival 12.5 months); in these patients therapeutic trials with cytostatic drugs or with inducers of differentiation of myeloid precursor cells seem to be justified.

Defective neutrophil function and microbicidal mechanisms in the myelodysplastic disorders.

Neutrophil function studies have been carried out in a series of 44 patients with primary myelodysplastic syndromes (MDS). In vitro tests of phagocytosis and killing of Candida guilliermondii and Staphylococcus aureus identified 13 patients with abnormal neutrophil function at presentation and a further 10 who developed abnormalities during the course of their disease. The incidence of defective function in the five disease categories in this series was: refractory cytopenia (RC) 8/17; refractory cytopenia with sideroblastic change (RC + SC) 5/8; acquired idiopathic sideroblastic anaemia (AISA) 2/4; refractory anaemia with excess blasts (RAEB) 7/11; chronic myelomonocytic leukaemia (CMML) 1/4. Eleven of 23 patients with defective neutrophil function experienced severe infective complications; in only three of these patients were neutrophil counts less than 1 X 10(9)/l and susceptibility to infection was considered to reflect, at least partially, qualitative neutrophil abnormalities. There was no correlation between absolute neutrophil count and defective function. Abnormal overall neutrophil microbicidal activity was equally associated with impaired and normal phagocytosis. Some patients with intracellular killing defects had reduced myeloperoxidase (MPO) activities and one had reduced hexose monophosphate shunt (HMPS) activity. In two patients, whose neutrophils showed markedly impaired candidacidal activity, levamisole corrected function when added in vitro at 10(-7) M and also when administered in therapeutic dosage. It is suggested that deranged function, probably reflecting abnormalities in maturation of the granulocyte series, occurs across the myelodysplastic spectrum and that several microbicidal mechanisms may be defective.

Cytogenetic findings in the dysmyelopoietic syndrome.

Cytogenetic studies of bone marrow specimens from 15 patients with dysmyelopoietic syndrome are presented. The group consists of nine patients with refractory anemia with excess of blasts (RAEB), three patients with chronic myelomonocytic leukemia (CMMoL), and three patients with acquired idiopathic sideroblastic anemia (AISA). None of these patients had a prior history of therapeutic or occupational exposure to potential carcinogenic agents, G(TG)-banding revealed clonal abnormalities in nine of the 15 patients. Five of these patients exhibited one or more of the following cytogenetic abnormalities: 5q deletion, -7, +8, or +21. The AISA group appeared to be unique as chromosome abnormalities were seen in two of the three patients and the clinical course in these patients had been prolonged without progression to acute leukemia. No other clinical correlation could be made in the blast RAEB and CMMoL groups, except for possible survival benefit in patients with normal karyotypes.

The 5a-chromosome abnormality in haematological disorders: a collaborative study of 34 cases from the Netherlands.

Summary. Clinical, haematological and cytogenetic data of all patients with an acquired 5q ‐ abnormality, diagnosed in four cytogenetic laboratories, were studied. The 5q‐ arose de novo in 24 patients, while 10 patients exhibited it after radiation and/or chemotherapy. Sixteen cases with a dysmyelopoietic syndrome (DMPS) and one case with acute nonlymphocytic leukaemia (ANLL) had no chromosome abnormalities other than 5q‐ . All nine patients with refractory anaemia (RA) belonging to the de novo group had a normal cell line. So far none of them has transformed to acute leukaemia, while three patients with refractory anaemia with excess of blasts (RAEB), pure red cell aplasia (PRCA) and acquired idiopathic sideroblastic anaemia (AISA), having the 5q‐ in 100% of the cells showed such a transformation. The second group consisted of nine patients with a 5q‐ and additional chromosome abnormalities: three of them died of progression of the disease, while four died of unrelated causes. Eight out of nine patients with a 5q‐ and acute leukaemia, either de novo (five) or secondary (four) to radiation and/or chemotherapy, had additional chromosome abnormalities. Among the changes (partial) monosomy of chromosome 7 was most frequently found.The median survival time of the group of patients with an isolated 5q‐ in the presence of a normal cell line was significantly longer than that of patients with additional chromosomal changes with or without acute leukaemia.All patients with an isolated 5q‐ abnormality showed the previously reported megakaryocytic abnormalities (small mono‐ or bilobulated). In most of the other patients these megakaryocytic abnormalities were also found, whereas others were definitely normal in this respect. A striking and unexplained preponderance of females (1 2 out of 16) was found in the group with an isolated 5q‐ anomaly.All deletions studied with banding techniques appeared to be interstitial but the breakpoints were variable. The shortest region of overlap is near band 5q22.

Leukemia in patients with acquired idiopathic sideroblastic anemia: An evaluation of prognostic indicators

The initial clinical and laboratory data of 25 patients with acquired idiopathic sideroblastic anemia (AISA) were analyzed. Criteria for accepting the diagnosis were hyperferremia, ringed marrow sideroblasts, ineffective erythropoiesis, and exclusion of associated hematologic disorders. The findings of a mean age at onset of 70 years, increased mean corpuscular volume, relative neutropenia; and occasional splenomegaly at diagnosis corresponded with previous reports. During the followup for a median period of 32 months, 6 patients (25%) transformed to acute myelogenous or myelomonocytic leukemia after widely variable intervals. The initial data base of these patients was compared to that of the remaining 19 patients in order to isolate predictive features. Only a lesser degree of hyperferremia (P less than 0.001) made the group going on to leukemia distinctive. The median survival of these patients was 20 months. The median survival of 19 patients not developing leukemia was 72 months for males and 42 months for females. Hemochromatosis was diagnosed in four patients and was a primary or associated cause of death in three. Analysis of the transfusion history suggested that intrinsic iron leading was a major factor in these patients. We conclude that leukemic transformation in AISA is a common, poorly predictable event which required lengthy followup for detection. Hemochromatosis in AISA occurs frequently and shortens the median survival.