Specificity of haematological indicators for '5q- syndrome' in patients with myelodysplastic syndromes

83 patients with myelodysplastic syndromes were analyzed for the presence of three haematological features: (1) macrocytic anaemia, (2) normal or high platelet count and (3) megakaryocytic hypolobulation in most megakaryocytes. In 10 of the 83 patients, a 5q- chromosome was the only clonal aberration; 31 patients had other chromosomal aberrations (including 6 patients with 5q- chromosome and other abnormalities in the same clone) and 42 patients had a normal karyotype in their bone marrow cells. 9 patients displayed all three haematological features investigated. In 8 of these patients the 5q- chromosome was the only clonal aberration. The 9th patient had a karyotype of 47,XX, + 8. None of the 6 patients with 5q- chromosome and additional abnormalities in the same clone fulfilled all criteria. The '5q- syndrome', a situation with the 5q- chromosome as a sole aberration, should be accepted as a diagnostic entity within the macrocytic anaemias. This syndrome can be suspected on the basis of the above haematological indicators and the diagnosis confirmed with bone marrow karyotype analysis.     

Antithymocyte globulin for patients with myelodysplastic syndrome

Twenty-five transfusion-dependent myelodysplastic syndrome (MDS) patients (with < 20% blasts) were treated in a phase II study with antithymocyte globulin (ATG) at 40 mg/kg/d for four doses and then followed with blood counts every 2 weeks and clinic visits every 3 months, for a median of 14 months (range 1–38 months). 11 (44%) patients responded and became transfusion-independent after ATG, including three complete responses, six partial responses, and two minimal responses. Responses were observed in 9/14 patients (64%) with refractory anaemia (RA) and 2/6 patients (33%) with refractory anaemia with excess blasts (RAEB). Median response duration was 10 months (range 3–38 months). The Kaplan-Meier estimate of overall survival was 84% at 38 months, with one early death due to pneumonia and two deaths from disease progression to leukaemia. Side-effects consisted mainly of mild serum sickness in all patients. A single course of ATG restored haemopoiesis in some patients with MDS and was well tolerated.     

Red cell antibodies in patients with homozygous sickle cell disease: a comparison of patients in Jamaica and the United Kingdom

The transfusion history and frequency of red cell antibodies in patients with homozygous sickle cell (SS) disease have been compared in 190 subjects from the Jamaican cohort study and 37 patients attending a sickle cell clinic in Manchester, England. The proportion of patients transfused did not differ between the groups although the number of units transfused and the frequency of red cell antibodies were significantly greater in the Manchester group. Immune antibodies occurred in three Jamaicans (2.6% of those transfused) and 16 UK subjects (76% of those transfused). Multiple antibodies occurred in 10 (63%) UK subjects but in no Jamaicans. Indications for transfusion also differed between the groups, Jamaican patients typically receiving 1-2 units for acute anaemia or acute chest syndrome, whereas UK patients frequently had multiple transfusions in preoperative exchange or prophylaxis programmes. The greater red cell alloimmunization among UK patients probably reflects both the greater use of transfusion and the disparity between donor and recipient populations in the UK.     

Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia

Acute leukaemia or advanced myelodysplastic syndrome (MDS ≥ 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre‐transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen‐matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft‐versus‐host disease was 19%. 5‐year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups.     

Red cell transfusion thresholds in myelodysplastic syndromes: a clinician survey to inform future clinical trials

Optimal red cell transfusion thresholds in myelodysplastic syndrome are not established. In this survey of 110 Australasian haematologists’ practice in myelodysplastic syndrome‐related anaemia, 92% of respondents set transfusion thresholds, and would typically transfuse at a haemoglobin <80 g/L aiming for a post‐transfusion haemoglobin 90–100 g/L, reflecting a restrictive transfusion strategy. Higher thresholds were typically used for patients with cardiovascular disease or anaemia symptoms. These results will inform the design of clinical trials comparing transfusion thresholds.     

Patterns of blood product use among patients with myelodysplastic syndrome

Background and Objectives Most patients with myelodysplastic syndrome (MDS) require blood product support to manage the severe anaemias, which frequently accompany MDS. Our objective was to show the feasibility of linking the Surveillance, Epidemiology and End Results (SEER) database with records from Puget Sound Blood Center (PSBC) to characterize blood product use over time in successive cohorts of patients with MDS. Materials and Methods We identified patients with MDS in the SEER registry. The cohort was then linked to PSBC records to discern blood product use. Results Included in the analysis were 783 patients with MDS entered in the SEER database from 2001 to 2007 for whom data were also available in the PSBC database. Among patients with MDS who received transfusions, 97% received packed red blood cells; 52% received platelets. The proportion of patients with MDS receiving blood products declined from 2001 to 2007. Conclusion These data show a recent decline in blood product use for patients with MDS. Future studies are needed to further evaluate the reasons for this finding, specifically exploring the impact of newer medications on blood product use in patients with MDS.     

Quality of life measurement in patients with transfusion-dependent myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are clonal disorders characterized by dysplasia in at least two myeloid cell lines. Fatigue is one of the most significant symptoms. MDS patients are treated with blood transfusions to improve their health-related quality of life (HRQoL). A cross-sectional pilot study was performed for psychometric evaluation of three internationally established HRQoL measures in MDS patients, and for investigation of the association between the severity of chronic anaemia and HRQoL. Fifty consecutive MDS patients completed the Short Form 36, the Multidimensional Fatigue Inventory and the EuroQoL-5D Visual Analogue Scale. Hb level was measured during the same visit. Psychometric analysis focused on feasibility, construct validity and reliability. The questionnaires showed a high feasibility, reliability and validity. MDS patients had worse HRQoL scores than the age- and sex-matched general population. We found a positive correlation between haemoglobin (Hb) level and HRQoL. This study provides insights into the suitability of established HRQoL measures for the evaluation of interventions in MDS patients. Hb value and HRQoL are complementary variables for evaluation of the severity of chronic anaemia in patients with MDS.     

Bone marrow patterns in patients with aplastic anaemia and myelodysplastic syndrome: observations with magnetic resonance imaging

Abstract: Bone marrow magnetic resonance imaging (MRI) was obtained in 48 patients with myelodysplastic syndrome (MDS) (35 cases) or aplastic anaemia (AA) (13 cases). The lower thoracic and lumbar spine were evaluated on sagittal plane using a 1.5 Tesla superconducting MR unit with a surface coil. Pulse sequence of STIRs (TR 2000 msec, TI 160 msec, TE 20 msec) were applied. Four distinct patterns of signal intensity (SI) on the STIR images were classified as follows: pattern 1, homogeneously low SI; 2, marginally high SI; 3, heterogeneously high SI; 4, homogeneously high SI. In all 13 patients with AA, STIR images initially revealed pattern 1. In 25 of 35 cases with MDS patients, the STIR images were initially classified as pattern 3. The STIR images of 6 AA and 5 MDS patients with a clinical response to treatment showed pattern 2 similar to that of normal marrow distribution. The STIR images of MDS patients showed an abnormal distribution of SI. Significant signal changes in the STIR images can be observed in successive examinations of the patients, thus facilitating follow-up of the disease and treatment. MRI of the bone marrow provides a noninvasive means of grossly examining a large fraction and is a useful technique in patients with aplastic anaemia or myelodysplastic syndrome.     

Autologous haematopoietic cell transplantation in elderly patients with multiple myeloma

High‐dose chemotherapy with melphalan followed by autologous haematopoietic cell transplantation (AHCT) is a standard of care in young patients (<65 years) with multiple myeloma. Most myeloma patients, however, are older than 65 years at the time of diagnosis, and the findings of numerous single‐centre and registry studies provide evidence that AHCT can be a feasible and effective treatment option in these patients. Nevertheless, AHCT is not generally recommended as standard treatment in the elderly, due to the fact that a benefit of AHCT over conventional‐dose therapy has not been demonstrated by prospective randomized trials. Yet, the use of AHCT has increased substantially in older patients in recent years, and an increasing number of reports suggest comparable outcomes for older and younger patients after AHCT. In this review we summarize the results of AHCT for elderly patients with multiple myeloma.     

Low-dose arabinosyl cytosine in acute leukemia after a myelodysplastic syndrome and in elderly leukemia

Low-dose arabinosyl cytosine (ARA-C) was tested in 15 patients with acute leukemia after a myelodysplastic syndrome (MDS) and in six elderly patients with acute nonlymphoid leukemia (ANLL). The drug was given subcutaneously at 10 mg/m2, every 12 hr for 2 weeks, every 28 days. The overall response rate was 19% (one complete remission, three partial responses), and the median duration of response was 4 months. No particular features at diagnosis were predictive of response. Pancytopenia and marrow hypoplasia occurred after 44 (78%) of 56 courses of therapy and were more severe in nonresponders. Four patients died during the aplasia following ARA-C therapy. Subcutaneous low-dose ARA-C was of limited benefit and bore a noticeable hematologic toxicity.     

Quantitative and qualitative studies of red cell ferritin in refractory anemia of myelodysplastic syndrome

Abstract: The red cell ferritin (rFt) level in 10 patients with refractory anemia (RA) was measured and analyzed by column isoelectric focusing (IEF). The levels in 9 of the 10 patients (90.0%) were higher than the upper limit in healthy controls (MV ± SD: male 14.3 ± 10.3 ag/cell, female 7.5 ± 3.6 ag/cell). The isoelectric point (pI) of rFt determined by IEF in healthy subjects ranged from 5.1 to 5.7. However, the pI ranges for RA patients varied widely; the pI value was thought to correlate with the severity of the morphological abnormalities of bone marrow (BM) erythroblasts. That is, the greater the proportion of morphologically abnormal erythroblasts with respect to all erythroid precursors, the lower the pI range for rFt. The rFt content was not related to serum iron, transferrin saturation, serum ferritin, reticulocyte count, red cell iron content, or BM erythroblast count. These data suggest that rFt synthesis in RA patients is influenced by factor(s) other than iron; this is considered an essential feature of erythropoiesis in myelodysplastic syndrome (MDS).     

Folate Concentration in Top,Middle and Bottom Layer of Packed Red Cells in Patients with Vitamin B12 Deficiency: Relation to Treatment

In response to specific treatment of vitamin B₁₂ deficient, anaemic patients there is an influx of folate into the young, circulating red cells. To separate new and old cells, capillary tubes filled with whole blood were centrifuged and the packed red cell column divided into top (T), middle (M) and bottom (B) layer. The newest cells are found in the T layer. The increase in red cell folate (RCF) concentration starts before, during or after the reticulocyte response, and is therefore not directly related to folate metabolism in the red precursor cells in the marrow. The low RCF concentration at the peak of the reticulocyte response in some of the cases demonstrates that the folate material, which may have been accumulated in the red precursor cells in the marrow, may be lost by the time the red cells enter the peripheral blood. The influx of folate into the young, circulating red cells is rapidly followed by an efflux of folate, suggesting that much of the folate material is still in the monoglutamate form. A new influx of folate is noted after a time lapse of from 5 to 10 d. Iron deficiency seems to prevent the uptake of folate by the circulating red cells.     

Modulation of angiogenesis in patients with myelodysplastic syndrome

Current investigations have revealed that angiogenesis plays a role in the pathogenesis of high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia, and in the mechanisms of disease progression. Secretion of cytokines and growth factors modulates angiogenesis in the marrow leading to increased vascularity and sustenance of the clonal population. For high-risk MDS patients older than 60 years who are not eligible for aggressive chemotherapy or stem cell transplant, there are few therapeutic options other than supportive treatment. Recent delineation of the pathobiology of MDS has resulted in the development of new agents and treatment modalities that impact on these mechanisms. One of the features of bone marrow pathology is the presence of new vessels, which appear to sustain growth and the hypercellularity of the marrow. Blocking angiogenesis may reduce the microvessel density of the marrow, cellularity, and disease progression. Angiogenesis can be targeted by inhibition of vascular endothelial growth factor (VEGF), which modulates new vessel growth, by the use of antibodies aimed at VEGF and its receptors, as well as receptor tyrosine kinases that block VEGF signaling. Other agents include inhibitors of farnesyl transferase and protein kinase C, which affect upstream modulators of growth factors and their receptor interactions; matrix metalloproteinases, which disrupt matrices and adhesion function promoting vessel growth; and other inhibitors with broader function, such as endostatin, thalidomide, and related analogues.