Pierre Zachee

Myelodysplastic Syndromes With Bone-marrow Fibrosis - a Myelodysplastic Disorder With Proliferative Features

SummaryWe report on 22 patients with myelodysplastic syndrome (MDS), all of whom showed striking marrow fibrosis. Variable blood counts, often with teardrop poikilocytosis and a leukoerythroblastic picture, were present at diagnosis. Visceral enlargement was detected in 17 patients with a distinct splenomegaly in seven cases. All cases demonstrated dysplasia in at least two cell lineages. No specific cytogenetic abnormality seems to characterize this group of patients. Southern blot analysis showed no breakpoint cluster region rearrangement as observed in classical chronic myeloid leukemia. Ferrokinetic studies revealed quantitatively deficient erythropoiesis in all except two cases and an abnormally high fraction of ineffective erythropoiesis in all. Splenic erythropoiesis was present in eight patients. The median survival was 18 months. At the time of this report, 12 patients had died. The causes of death were disease progression (7 patients) and infection (5 patients). One might speculate that the present series of cases represents a transition between MDS and myeloproliferative disease, thereby dysplaying characteristics of both groups of diseases.

Hematologic aspects of end-stage renal failure

SummaryRenal dysfunction may give rise to a variety of hematologic disturbances, including anemia, leukocyte dysfunction, and coagulopathy. The anemia of renal failure has been attributed to a relative deficiency of erythropoietin, but absolute deficiencies of iron or folate may also play a role. Other contributing factors include heavy-metal toxicity, blood loss, and a reduction in red cell survival induced by toxic radicals. The treatment of the anemia of renal disease has advanced with the development of recombinant human erythropoietin. At subcutaneous doses of 50–75 IU/kg triweekly in selected patients, normalization of hemoglobin is presently possible. The coagulopathy of renal disease consists of an acquired qualitative platelet defect, best remedied by dialysis but also treated successfully by rHuEPO, cryoprecipitate or DDAVP, and conjugated estrogens. Uremia-induced leukocyte dysfunctions include diminished granulocyte chemotaxis, phagocytosis, and bactericidal activity. Cell-mediated immune defects and hypogammaglobulinemia have also been described. The pathophysiology of the hematologic manifestations of uremia is discussed. Therapeutic recommendations for dealing with anemia, bleeding, and infectious complications of renal failure are described.

Feasibility of peripheral blood progenitor cell harvest and transplantation in patients with poor-risk myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of clonal haematological disorders with a highly unfavourable prognosis. Allogeneic bone marrow transplantation offers the sole possibility for cure and prolonged survival, but is only available for a minority of patients. Therefore, we investigated the feasibility of PBPC collection and transplantation in 11 patients with high‐risk myelodysplasia who were not eligible for allogeneic bone marrow transplantation. In six patients, PBPC were harvested after mobilization with G‐CSF alone. Five patients were harvested during the recovery phase of intensive chemotherapy combined with G‐CSF. This resulted in seven patients in an adequate CD34 progenitor yield >1 × 106/kg. Six patients obtained a CFU‐GM content of the PBPC harvest >10 ×104/kg. Five patients were subsequently transplanted following a standard BuCy4 regimen. The median to ANC (absolute neutrophil count) ≥0.5 and 1.0 × 109/l was respectively 14 d (range 10–18) and 16 d (range 11–25). Platelets were self‐supporting ≥20 × 109/l after a median of 41 d (range 8–144). One patient had a persistent lack of platelet engraftment unresponsive to infusion of back‐up bone marrow.

Risks of rhG-CSF treatment in drug-induced agranulocytosis

Nine patients with drug-induced agranulocytosis received recombinant human granulocyte colonystimulating factor (rhG-CSF) to accelerate myeloid recovery because of life-threatening infections related to neutropenia. All patients showed a quick recovery of their granulocyte counts. Side effects were substantial, however. Three patients, two with a severe infection and one with preexisting pulmonary infiltrates, developed worsening of their respiratory status during neutrophil recovery, resulting in clinical manifestations of the adult respiratory distress syndrome (ARDS). In view of these major complications, the exact place of hematopoietic growth factors in the treatment of drug-induced agranulocytosis remains to be determined.

Recombinant human erythropoietin for the treatment of anemia in the myelodysplastic syndromes: A clinical and erythrokinetic assessment

SummaryThe clinical and ferrokinetic effects of escalating doses of subcutaneously administered recombinant human erythropoietin (rh-EPO) were studied in ten patients with myelodysplastic syndromes and severe transfusion-dependent anemia. Red blood cell transfusion requirements diminished in four patients, and one of the patients eventually became transfusion independent with an EPO-induced rise of Hb from 7.7 g/dl to 12.3 g/dl. Endogenous serum levels of EPO were significantly increased in all patients (100–5700 mU/ml), but three of four responders had a relatively low baseline level. The effective red cell iron turnover (RCIT) improved in two responding patients and even normalized in one patient. This increase in RCIT was accompanied with a decline in the ineffective red cell iron turnover (IIT). The other responding patients had a relatively preserved RCIT before EPO treatment. EPO therapy further increased the fraction of IIT in the latter patients. Red cell survival time did not increase during EPO therapy, even in the responding patients. One transient and one maintained increase in platelet count were observed. Disease progression with a sustained increase in blast cells in one patient and a transient elevation of blasts in another patient was seen. No other side effects of EPO therapy were observed. These results suggest that anemic MDS patients with low serum EPO levels and relatively spared effective erythropoiesis as measured by ferrokinetic studies may be the best candidates for treatment with recombinant human EPO.

Patients with high-risk myelodysplastic syndrome can have polyclonal or clonal haemopoiesis in complete haematological remission.

The clonality of mature peripheral blood‐derived myeloid and lymphoid cells and bone marrow haemopoietic progenitors from 18 females with myelodysplasia (MDS) (five refractory anaemia, RA; one RA with ringed sideroblasts, RARS; three chronic myelomonocytic leukaemia, CMML; four RA with excess of blasts, RAEB; five RAEB in transformation, RAEB‐t) was studied by X‐chromosome inactivation analysis. Using the human androgen‐receptor (HUMARA) assay, we analysed the clonal patterns of highly purified immature CD34+38− and committed CD34+38+ marrow‐derived progenitors, and CD16+14− granulocytes, CD14+ monocytes, CD3+ T and CD19+ B lymphocytes from peripheral blood. In high‐risk patients (RAEB, RAEB‐t), clonality analysis was performed before and after intensive remission‐induction treatment. All patients, except one with RA, had predominance of a single clone in their granulocytes and monocytes. The same clonal pattern was found in CD34+ progenitor cells. In contrast, CD3+ T lymphocytes were polyclonal or oligoclonal in 14/18 patients. X‐chromosome inactivation patterns of CD19+B cells were highly concordant with CD3+ T cells except for two patients (one RA, one CMML) with monoclonal B and polyclonal T lymphocytes, therefore suggesting a clonal mutation in a progenitor common to the myeloid and B‐lymphoid lineages or the coexistence of MDS and a B‐cell disorder in these particular patients. After high‐dose non‐myeloablative chemotherapy, polyclonal haemopoiesis was reinstalled in the mature myeloid cells and immature and committed marrow progenitors in three of four patients achieving complete haematological remission. Therefore we conclude that most haematological remissions in MDS are associated with restoration of polyclonal haemopoiesis.

Translocation t(6;9) occurring in acute myelofibrosis, myelodysplastic syndrome, and acute nonlymphocytic leukemia suggests multipotent stem cell involvement☆

The cytological and cytogenetic features of six patients with myeloid neoplasia and t(6;9)(p23;q34) including a case of acute myelofibrosis (AMF), a refractory anemia with excess of blasts (RAEB), and four cases of acute nonlymphocytic leukemia (ANLL) are described. Two patients in this series, both affected by ANLL type M2, presented an increase of bone marrow basophils, suggesting that this cytological-cytogenetic association is not absolute and that it may be more frequently observed in ANLL with maturation. All patients with de novo ANLL showed associated myelodysplastic features, and one patient presented a dysmyelopoietic syndrome, later evolving into ANLL. The presence of the t(6;9) in a range of myeloid neoplasias, with either concurrent myelodysplastic features or a preleukemic phase in cases of ANLL, provide evidence that this chromosome aberration may always involve a multipotent myeloid stem cell. Data on toxic exposure of the patients suggests that myeloproliferative disorders with the t(6;9) may frequently represent environmentally induced neoplasias.

Comparative study of peripheral blood progenitor cell collection in patients with multiple myeloma after single-dose cyclophosphamide combined with rhGM-CSF or rhG-CSF

Summary. Patients suffering from high‐risk multiple myeloma (MM) were randomized to receive single high‐dose cyclophosphamide followed by either rhGM‐CSF or rhG‐CSF in order to harvest circulating peripheral blood progenitor cells. The safety of the procedure, the mobilization kinetics, the relative efficacy of rhGM‐CSF and rhG‐CSF to mobilize progenitor cells and their relative toxicity were studied. Special attention was paid to the antigenic profile of CD34+ progenitor cells.

Reduced Glutathione for the Treatment of Anemia during Hemodialysis: A Preliminary Communication

In 4 chronic hemodialysis patients we have tested whether the administration of reduced glutathione (GSH; Glutamed, Boehringer Mannheim Italia; 1,200 mg i.v.) at the end of each hemodialytic session during 90 days could minimize oxidative damage to the red blood cells (RBC) and reduce the recombinant human erythropoietin requirements. Treatment with GSH was followed by an increase in RBC GSH content (n = 3), a normalization of the ascorbine cyanide test (n = 4), an increase in RBC survival (n = 3), and a reduction in 2 patients of the erythropoietin need (41 and 26%, respectively, after 3 months of therapy). When the GSH supplements were terminated, we noticed after 3 months a re-establishment of the baseline values. On the other hand, malonyldialdehyde, RBC deformability, and RBC splenic pool were abnormal before and remain abnormal during the test period. Since no adverse reactions were noticed, these findings seem to indicate the GSH could ameliorate the intraerythrocytic oxidative defense and could be as useful drug in the treatment of anemia in patients affected by chronic renal failure.

Controversies in selection of epoetin dosages : issues and answers

SummaryEpoetin (recombinant human erythropoietin) is now a widely available though expensive treatment for the anaemia of chronic renal failure, and is effective in more than 95% of patients. Complications of epoetin in this context include hypertension in a third of cases, including hypertensive encephalopathy in a few, and thrombosis of shunts or vascular access devices. Fears that epoetin would cause progression of renal failure have not generally been confirmed, but hyperkalaemia may be a problem in the initial phase of treatment. Epoetin is up to twice as effective when administered subcutaneously rather than intravenously. Responding patients will normally do so within 3 months of starting epoetin. Failures to respond are usually due to iron deficiency or intercurrent disease. Other diseases associated with anaemia and an inappropriately low serum epoetin level include prematurity, the anaemia of cancer and rheumatoid arthritis. The baseline serum endogenous erythropoietin may provide a guide to response in some of these cases. Some encouraging results are being published. Situations where the serum erythropoietin levels are normal or elevated where epoetin has been employed include boosting of haematocrit presurgery as an adjunct to autologous blood donation, treatment of anaemic patients with myelodysplastic syndromes, and improvement of athletic performances.