Condensed versus standard schedule of high-dose cytarabine consolidation therapy with pegfilgrastim growth factor support in acute myeloid leukemia.

The aim of this cohort study was to compare a condensed schedule of consolidation therapy with high-dose cytarabine on days 1, 2 and 3 (HDAC-123) with the HDAC schedule given on days 1, 3 and 5 (HDAC-135) as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in younger patients with acute myeloid leukemia in first complete remission. One hundred and seventy-six patients were treated with HDAC-135 and 392 patients with HDAC-123 with prophylactic pegfilgrastim at days 10 and 8, respectively, in the AMLSG 07-04 and the German AML Intergroup protocol. Time from start to chemotherapy until hematologic recovery with white blood cells >1.0 G/l and neutrophils >0.5 G/l was in median 4 days shorter in patients receiving HDAC-123 compared with HDAC-135 (P<0.0001, each), and further reduced by 2 days (P<0.0001) by pegfilgrastim. Rates of infections were reduced by HDAC-123 (P<0.0001) and pegfilgrastim (P=0.002). Days in hospital and platelet transfusions were significantly reduced by HDAC-123 compared with HDAC-135. Survival was neither affected by HDAC-123 versus HDAC-135 nor by pegfilgrastim. In conclusion, consolidation therapy with HDAC-123 leads to faster hematologic recovery and less infections, platelet transfusions as well as days in hospital without affecting survival.

Risk-adapted induction and consolidation therapy in adults with de novo AML aged

We treated 305 de novo acute myeloid leukemia (AML) patients aged

Prior and concurrent administration of recombinant human megakaryocyte growth and development factor in patients receiving consolidation chemotherapy for de novo acute myeloid leukemia--a randomized, placebo-controlled, double-blind safety and efficacy study.

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) administered after acute myeloid leukemia (AML) chemotherapy (CT) failed to shorten the time of transfusion-dependent thrombocytopenia in a previous study. In this multicenter, randomized, placebo-controlled, double-blind study we determined the effect of administration of PEG-rHuMGDF prior to CT and of administration prior, concurrent, and 1 day post CT on platelet recovery and transfusion requirements in patients receiving consolidation CT for de novo AML. Patients were randomized to receive either 30 microk/kg PEG-rHuMGDF as a single dose on day -6 ( n=37), placebo as a single dose on day -6 ( n=9), 30 microk/kg PEG-rHuMGDF administered on day -6 followed by 10 microg/kg on days -5 to day 6 (through CT and including the day after CT, n=35), or placebo administered on day -6 to day 6 ( n=9). The median times to transfusion-independent platelet recovery to >20x10(9)/l were 24.5 and 24.0 days in the PEG-rHuMGDF day -6 group and PEG-rHuMGDF day -6 to 6, respectively, compared to 21.0 days in the placebo group. There were no significant differences in the number of days of platelet transfusions between either PEG-rHuMGDF schedule or placebo. The PEG-rHuMGDF day -6 to 6 group had a delayed absolute neutrophil count (ANC) recovery compared to either placebo or PEG-rHuMGDF day -6 treated patients. Thus, alteration of the scheduling of PEG-rHuMGDF in terms of earlier dosing before and during chemotherapy did not improve platelet recovery but rather delayed hematopoietic reconstitution. Although unexpected, these observations may be of major relevance for the design of future clinical trials with recombinant thrombopoietins.

Paroxysmal nocturnal haemoglobinuria: a replacement of haematopoietic tissue?

Acquired somatic mutations of the PIG-A gene lead to deficient expression of glycosyl-phosphatidyl-inositol-anchored proteins (GPI-AP) by haematopoietic cells and play a causative role in the pathogenesis of paroxysmal nocturnal haemoglobinuria (PNH). However, PIG-A mutations do not explain how the defective PNH clone can expand. It was hypothesized that a selection process conferring a relative advantage to the GPI-AP-deficient population is required. Since GPI-AP-deficient cells are also detectable in a substantial proportion of patients with otherwise typical aplastic anaemia (AA), the mechanisms inducing bone marrow failure might selectively spare the GPI-deficient cells. In order to examine the growth characteristics of GPI-AP-deficient cells in more detail, we performed repeated analyses of GPI-AP expression on peripheral blood cells in 41 patients with AA. We observed four patterns of the course of GPI-AP-deficient populations: (1) 13 patients showed normal expression of GPI-AP in the first analysis and in at least two follow-up studies at a median time of 709 days after the first analysis. (2) Secondary evolution of a GPI-AP-deficient population was a rare event. Only 4 patients with initially normal GPI-AP expression developed a GPI-AP-deficient population during follow up after immunosuppressive treatment. (3) Persistence of GPI-AP-deficient cells was observed in 16 patients during a median follow-up time of 774 days. However, in some patients, the size of the GPI-AP-deficient population increased substantially. (4) Disappearance of a GPI-AP-deficient population was observed in 8 patients. The time course of GPI-AP expression in relation to the treatment suggests that therapeutic interventions might modulate the ratio of normal versus GPI-AP-deficient haematopoiesis. Overall, these data argue against an 'absolute growth advantage' of GPI-AP-deficient cells. Our data are consistent with the hypothesis that haematopoietic failure caused by damage to normal haematopoiesis allows the outgrowth of a GPI-AP-deficient population. Thus, in at least some patients GPI-AP-deficient cells might pre-exist at a very low percentage and replace haematopoiesis after an insult to the normal cells.

Association between structural and numerical chromosomal aberrations in acute myeloblastic leukemia: a study by RT-PCR and FISH in 447 patients with de-novo AML.

We analyzed 447 patients with de novo AML using alpha-satellite probes for the chromosomes 7, 8, X, and Y and RT-PCR for t(8;21), t(15;17) and inv(16). In 130/447 patients (29%) chromosomal aberrations were found. Thirty-three patients (7%) had a t(8;21); 11 of these had the additional loss of a sex chromosome (p<0.001) and two a trisomy 8. Twenty-nine patients (6%) had a t(15;17); four of these had a trisomy 8. Sixteen patients (4%) displayed an inv(16); four of these had a trisomy 8. Twenty-two patients (5%) had a sole trisomy 8 and one patient the combination of trisomy 8 and trisomy X. Five patients (1%) displayed the loss of a Y-chromosome as the sole abnormality and two patients had a sole trisomy X. In 22 patients (5%) a monosomy 7 was found, and in none of these patients were additional chromosomal aberrations detected by RT-PCR (p < 0.05). In conclusion, trisomy 8 and the loss of a gonosome are frequently associated with structural chromosomal aberrations with a significant association of -X/Y and t(8;21). The absence of these genomic lesions in AMLs with monosomy 7 suggests that the monosomy 7 has a specific role in the development of these leukemias and their clinical course.

Prospective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party.

We report the results of the first prospective randomized multicenter study of immunosuppressive treatment in patients with previously untreated nonsevere aplastic anemia (AA) as defined by a neutrophil count of at least 0.5 x 10(9)/L and transfusion dependence. Patients were randomized to receive cyclosporin (CSA) alone or the combination of horse antithymocyte globulin ([ATG] Lymphoglobuline; Merieux, Lyon, France) and CSA. The endpoint of the study was the hematologic response at 6 months. One hundred fifteen patients were randomized and assessable with a median follow-up period of 36 months; 61 received CSA and 54 ATG and CSA. In the CSA group, the percentage of complete and partial responders was 23% and 23%, respectively, for an overall response rate of 46%. A significantly higher overall response rate of 74% was found in the ATG and CSA group, with 57% complete and 17% partial responders (P =. 02). Compared with CSA alone, the combination of ATG and CSA resulted in a significantly higher median hemoglobin level and platelet count at 6 months. Fewer patients required a second course of treatment before 6 months due to a nonresponse. In the CSA group, 15 of 61 (25%) patients required a course of ATG before 6 months because of disease progression, compared with only 3 of 54 (6%) in the ATG and CSA group. The survival probabilities for the two groups were comparable, 93% (CSA group) and 91% (ATG and CSA group), but at 180 days, the prevalence of patients surviving free of transfusions, which excluded patients requiring second treatment because of nonresponse, death, disease progression, or relapse, was 67% in the CSA group and 90% in the ATG and CSA group (P =.001). We conclude that the combination of ATG and CSA is superior to CSA alone in terms of the hematologic response, the quality of response, and early mortality, and a second course of immunosuppression is less frequently required.

Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party.

BACKGROUND: Immunosuppressive therapy has been used for successful treatment of severe aplastic anemia, but little information is available on outcome in older patients. OBJECTIVE: To evaluate outcome in patients older than 50 years of age who received immunosuppressive therapy for aplastic anemia. DESIGN: Retrospective cohort study. SETTING: 56 centers of the European Group for Blood and Marrow Transplantation (EBMT). PATIENTS: 810 patients with aplastic anemia reported between 1974 and 1997. Patients were evaluated according to age group: 60 years of age or older (n = 127), 50 to 59 years of age (n = 115), and 20 to 49 years of age (n = 568; reference group). INTERVENTION: Antilymphocyte globulin, cyclosporine, or both. MEASUREMENTS: Survival, cause of death, response to treatment, relapse rate, and risk for late complications were analyzed in all patients and by age group. RESULTS: The 5-year survival rate was 57% (95% CI, 46% to 66%) in patients 50 to 59 years of age and 50% (CI, 39% to 60%) in patients 60 years of age or older compared with 72% (CI, 68% to 76%) in patients younger than 50 years of age (P < 0.001). Response to therapy, relapse rate, and risk for clonal complications were similar in all three age groups (P > 0.2). Age was significantly associated with an increased risk for death (relative risk compared with patients 20 to 49 years of age, 1.80 [CI, 1.29 to 2.52] for patients 50 to 59 years of age and 2.57 [CI, 1.87 to 3.53] for patients > or = 60 years of age), mainly because of bleeding or infection (P = 0.02). Response to immunosuppressive therapy in all patients at 12 months was 62% (CI, 58% to 66%); no difference was seen among the age groups in multivariate analysis (P > 0.2). Sixty-six of the 379 responding patients (17%) subsequently had relapse. The risk for clonal disorders at 10 years was 20% (CI, 15% to 27%). CONCLUSIONS: Response to immunosuppression in aplastic anemia is independent of age, but treatment is associated with increased mortality in older patients.

High levels of thrombopoietin in sera of patients with essential thrombocythemia: cause or consequence of abnormal platelet production?

Thrombopoietin (TPO) is the most important regulator of megakaryocyte development and platelet production. Platelet production is thought to be regulated by a negative regulatory feed back loop. In an attempt to evaluate the role of TPO in the pathobiology of essential thrombocythemia (ET), we have examined levels of TPO and other cytokines with thrombopoietic activity (interleukin-6 and interleukin-11) in sera obtained from 25 patients with ET (ten treated, 15 untreated) and 117 healthy control subjects. TPO serum levels were assessed using a sandwich-antibody ELISA that utilizes a polyclonal rabbit antiserum for both capture and signal. The mean serum TPO level in 25 ET patients was significantly elevated (545+/-853 pg/ml) as compared with that in healthy controls (95.3+/-54.0 pg/ml,p<0.001). The difference in TPO serum levels between ten treated (781+/-1229 pg/ ml) and 15 untreated ET patients (388+/-458 pg/ml) did not reach statistical significance (p = 0.09). We conclude that either consumption or production of TPO is altered in ET. Failure of appropriate feedback regulation and continued megakaryocyte stimulation by an elevated TPO may play an important role in the pathobiology of ET.

Thrombopoietin serum levels in patients with aplastic anaemia: correlation with platelet count and persistent elevation in remission.

In an attempt to evaluate the role of thrombopoietin (TPO) in the pathobiology of aplastic anaemia (AA), we have examined TPO levels in sera from 54 AA patients and 119 healthy controls. A total of 92 samples were collected from AA patients: 43 samples were harvested at diagnosis, 23 samples in the cytopenic period after treatment, and 26 samples when patients were in partial (n=10) or complete remission (n=16) following immunosuppressive treatment. TPO serum levels were assessed by a sandwich-antibody ELISA that utilized a polyclonal rabbit antiserum for both capture and signal. Serum samples from normal donors revealed a mean TPO level of 95.3 +/- 54.0 pg/ml (standard deviation). Mean TPO levels in AA sera collected at diagnosis and before onset of treatment were 2728 +/- 1074 pg/ml (P<0.001 compared to normal controls: mean platelet count at that time: 27x10(9)/l). TPO serum levels of AA patients in partial or complete remission after immunosuppressive treatment were significantly lower than TPO levels at diagnosis (P<0.001). However, despite normal platelet counts (mean 167x10(9)/l), TPO levels remained significantly elevated in complete remission (mean TPO 1009 +/- 590 pg/ml, P<0.001 compared to normal controls). There was a significant inverse correlation between serum TPO levels and platelet counts in AA patients who were not transfused for at least 2 weeks prior to sample collection (coefficient of correlation (r) = -0.70, P<0.0001). In summary, TPO levels were highly elevated in sera of patients with AA. Thus there is no evidence to suggest an impaired TPO response contributing to thrombocytopenia in AA. Thrombopoietin did not return to normal levels in remission, indicating a persisting haemopoietic defect in remission of AA. We hypothesize that elevated levels of TPO may be required to maintain normal or near normal platelet counts in remission of AA.

Long-term interleukin-3 and intensive immunosuppression in the treatment of aplastic anemia.

We have assessed in a phase I/II clinical study the tolerability and efficacy of long-term application of recombinant human interleukin-3 (rh-IL-3) in combination with antithymocyte globulin (ATG) and cyclosporin A (CSA) in 13 patients with aplastic anemia who were refractory to or relapsed after previous immunosuppressive treatment. Four cohorts of three patients were consecutively enrolled so that they received rh-IL-3 on days 9, 6, 3 and 1 after start of ATG/CSA treatment. Yeast-derived recombinant human IL-3 was administered by daily subcutaneous injection until day 90 at a dosage of 250 micrograms/m2. Long-term application of rh-IL-3 was well tolerated. The combination of rh-IL-3 with immunosuppression did not modify the known toxicities of ATG and CSA. Incidence and severity of rh-IL-3-related adverse events was less than in other phase I/II trials of rh-IL-3 as single-agent therapy. One might speculate that co-medication with CSA alleviates rh-IL-3-induced side effects. Three of eight patients with refractory AA and all four patients with relapsed AA responded to the combined treatment within four months. The median time to response was 91.5 days. There was evidence for an rh-IL-3-dependent response in two patients. Long-term rh-IL-3 did not cause stem cell exhaustion. One patient died early during the course of the study from EBV-driven lymphoproliferative disease. Two patients developed acute myeloid leukemia 4 and 22 months after cessation of rh-IL-3. In conclusion, long-term rh-IL-3 in combination with immunosuppression is well tolerated. The response rate to the combined treatment in refractory and relapsed AA was high. Recombinant human IL-3-dependent responses suggest efficacy. A prospective randomized trial comparing immunosuppression alone versus a combination with rh-IL-3 is warranted.

Quantitative analysis of cobblestone area-forming cells in bone marrow of patients with aplastic anemia by limiting dilution assay.

In the past, the analysis of primitive human hematopoietic progenitor cells with repopulating activity was limited by lack of appropriate in vitro assay systems. It was recently shown that cobblestone area-forming cells (CAFC) giving rise to cobblestone areas after 5 weeks in long-term marrow cultures (LTMC) represent a population of pluripotent progenitor cells with long-term marrow-repopulating activity. We have used a microtiter limiting dilution-type human LTMC system to quantitate the frequency of CAFC (week 5) in aplastic anemia (AA). In bone marrow mononuclear cells (BM-MNC) of healthy donors (n = 36) we observed a mean frequency of 84.4 CAFC per 10(5) BM-MNC (95% confidence interval limits, 66.4 to 102.4). The mean frequency of CAFC in BM of 31 AA patients was 6.6 per 10(5) BM-MNC (95% confidence interval limits, 5.3 to 7.9; n = 47). This frequency is significantly lower as compared with controls (P < .0001). The frequency of CAFC was reduced not only in pancytopenic AA patients (6.2 per 10(5) BM-MNC; P < .0001 v control), but also in patients in remission after immunosuppression (7.6; P < .0001 v control; P = .1 v pancytopenic AA patients). The CAFC frequency did not correlate with the severity or duration of the disease and did not predict response to immunosuppressive treatment. In summary, the frequency of primitive hematopoietic progenitor cells, as measured by the CAFC assay, is significantly reduced in AA. CAFC remain severely reduced even after hematologic recovery after immunosuppressive treatment. The low frequency of CAFC in remission patients is in keeping with other data pointing to a persisting defect of hematopoiesis in patients in remission after immunosuppressive treatment.

Clonal hematopoiesis as defined by polymorphic X-linked loci occurs infrequently in aplastic anemia.

We evaluated the methylation status of the X-linked gene phosphoglycerate kinase (PGK1) and the DXS 255 locus detected by probe M27 beta to study clonality in acquired aplastic anemia (AA). A total of 30 females were suitable for clonal analysis of peripheral blood polymorphonuclear cells (PMN) and mononuclear cells using a polymerase chain reaction-based procedure in 24 patients and Southern blotting in 9. Overall, 10 of 30 patients exhibited an imbalanced X-inactivation pattern. However, in 4 patients, analysis of constitutional DNA suggested a skewed methylation pattern and 2 further cases had to be excluded because of the lack of an appropriate control. A truly clonal pattern was thus established in 4 of 30 (13%) patients. In 7 patients who later developed clonal disorders of hematopoiesis, X-inactivation analysis did not predict this event in any case. In patients with a paroxysmal nocturnal hemoglobinuria phenotype, there was no correlation between the proportion of phosphatidylinositol glycan anchored protein (PIG-AP)-deficient blood cells and the corresponding X-inactivation pattern. X-inactivation analysis detected clonal hematopoiesis in only 3 of 10 patients with a deficiency in PIG-AP in the cell population under study, but sorting of nucleated cells on the basis of PIG-AP expression showed the clonal nature of PIG-AP-deficient cells. We conclude that the majority of patients with AA show polyclonal hematopoiesis using X-linked clonal analysis, but that minor clonal populations, such as PIG-AP-deficient cells, may not be detected unless sorted cell populations are separately analyzed.

Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B-cell non-Hodgkin lymphoma.

CD52 is a phosphatidylinositolglycan (PIG)-anchored glycoprotein (PIG-AP) expressed on normal T and B lymphocytes, monocytes, and the majority of B-cell non-Hodgkin lymphomas. We observed the emergence of CD52- T cells in 3 patients after intravenous treatment with the humanized anti-CD52 monoclonal antibody Campath-1H for refractory B-cell lymphoma and could identify the underlaying mechanism. In addition to the absence of CD52, the PIG-AP CD48 and CD59 were not detectable on the CD52- T cells in 2 patients. PIG-AP-deficient T-cell clones from both patients were established. Analysis of the mRNA of the PIG-A gene showed an abnormal size in the T-cell clones from 1 of these patients, suggesting that a mutation in the PIG-A gene was the cause of the expression defect of PIG-AP. An escape from an immune attack directed against PIG-AP+ hematopoiesis has been hypothesized as the cause of the occurrence of PIG-AP-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia. Our results support the hypothesis that an attack against the PIG-AP CD52 might lead to the expansion of a PIG-anchor-deficient cell population with the phenotypic and molecular characteristics of PNH cells.

A phase I/II trial of recombinant human interleukin-6 in patients with aplastic anaemia.

In a phase I/II study, 11 patients with marrow failure (10 with acquired aplastic anaemia and one with pancytopenic Fanconi anaemia) were treated with recombinant human interleukin-6 (rhIL-6) to assess the safety and tolerability of rhIL-6 and its effects on peripheral blood counts, bleeding complications and transfusion requirements. All patients with acquired aplastic anaemia were refractory to immunosuppressive treatment or had relapsed after immunosuppressive therapy and were not bone marrow transplantation candidates. Recombinant hIL-6 was to be given as a once-daily subcutaneous injection for 28 d at doses ranging from 0.5 to 5.0 micrograms/kg. After an observation period of 2 weeks, five patients received a second treatment course of 28 d. Only one patient had a sustained increase in platelet count from 18,000 to 72,000/microliters. Bleeding occurred in four patients and caused premature discontinuation of rhIL-6 therapy in three patients. A deterioration of pre-existing anaemia was observed in nine patients. No significant changes of leucocyte counts were observed during the first cycle. During the second cycle the peripheral blood monocyte counts decreased significantly. No significant changes in bone marrow cellularity were observed. Recombinant hIL-6 induced a dose-dependent increase in acute-phase reactants in all patients. Other adverse events included fever, headache, arthralgia, tachycardia and hypertension. In conclusion, rhIL-6 given alone at low doses does not increase platelet counts in the majority of patients with aplastic anaemia and can precipitate a sudden worsening of pre-existing anaemia and thrombocytopenia. This study was discontinued prematurely on account of the toxicity of rhIL-6 seen in patients with aplastic anaemia.

A pathogenetic link between aplastic anemia and paroxysmal nocturnal hemoglobinuria is suggested by a high frequency of aplastic anemia patients with a deficiency of phosphatidylinositol glycan anchored proteins.

The clinical interrelationship between paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) promoted a search for a pathogenetic link. Since the molecular defect in PNH is a failure to express phosphatidylinositol glycan-anchored proteins (PIG-AP), we investigated whether this defect could also be demonstrated on peripheral blood cells of patients with typical AA. Quantification of the expression of PIG-AP was performed by flow cytometry using the monoclonal antibodies (MAbs) CD16 and CD66b for granulocytes, CD14 and CD48 for monocytes, CD48 and CD52 for lymphocytes, and CD55 and CD59 for erythrocytes. We analyzed cells from 52 patients with acquired AA. A PIG-AP-defective population was identified in 27 of 52 patients (52%) in at least one cell lineage. Granulocytes were involved in 25 of 27, monocytes in 18 of 25, lymphocytes in seven of 27, and erythrocytes in seven of 27 AA patients who were affected by a PIG-AP deficiency. The response rate to standard immunosuppressive therapy was significantly higher in the group of patients without a PIG-AP-deficient population than in patients with a PIG-AP-deficient population in at least one cell lineage (85.7 vs. 30.4%; p < 0.0003). Our results demonstrate that on the basis of PIG-AP expression, the proportion of AA patients who show features of typical AA along with a PNH phenotype is substantially higher than previously recognized. The pattern of PIG-AP expression might identify subgroups of AA patients who differ in the underlying mechanism as well as in the course of their disease.

Serum erythropoietin and serum transferrin receptor levels in aplastic anaemia.

Serum erythropoietin (EPO) and soluble transferrin receptor levels were serially measured in 74 patients with aplastic anaemia (AA). As control groups we investigated healthy controls (n = 24) and patients with iron-deficiency (n = 23) or haemolytic anaemia (n = 16). There was a significant negative correlation of log EPO on haematocrit both in AA patients and in the anaemic control group. However, for the same degree of anaemia, log EPO levels in AA were significantly higher than in iron-deficiency or haemolytic anaemia. EPO levels at diagnosis did not correlate with severity of aplastic anaemia, nor did they predict outcome after immunosuppression. During immunosuppressive treatment of AA with anti-thymocyte globulin and cyclosporine A, EPO levels were significantly lower compared with pre-treatment values without a corresponding change in haematocrit. This impaired EPO response to anaemia during immunosuppression might affect recovery of erythropoiesis. In AA patients, EPO levels declined with haemopoietic recovery. However, compared with normal controls, EPO levels in remission patients were still higher with respect to their haematocrit. Results of this study argue against the model of a simple feedback regulation of EPO via hypoxic anaemia. Our data support the hypothesis that cytokines and the erythropoietic progenitor pool are involved in the regulation of EPO production. The results illustrate that serial measurements of EPO along with therapeutic interventions are necessary to identify patients who might benefit from treatment with exogenous recombinant human EPO.

Haemopoietic growth factors in aplastic anaemia: a cautionary note. European Bone Marrow Transplant Working Party for Severe Aplastic Anaemia.

We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome.

Graft rejection and second bone marrow transplants for acquired aplastic anaemia: a report from the Aplastic Anaemia Working Party of the European Bone Marrow Transplant Group.

Six hundred and eighteen patients with acquired aplastic anaemia grafted from an HLA-identical sibling donor between 1976 and 1990 in eight European centres were reported to the Working Party for Severe Aplastic Anaemia (SAA) Registry and were evaluable for analysis of the incidence of graft failure/rejection and the outcome of second bone marrow transplants (BMT). The number of patients experiencing graft rejection declined significantly over the study period from 32% to 8% (p < 0.0001). This coincided with the introduction of cyclosporine to the conditioning regimen for BMT. The graft rejection rate in the post-hepatitis SAA group was significantly lower than in the group with idiopathic SAA (4% vs 20%) (p = 0.001). The use of irradiation in the conditioning regimen significantly reduced the number of patients experiencing graft rejection (7% vs 21%) (p = 0.004). Age, sex and severity of disease did not influence the rate of sustained engraftment. Of the 85 patients experiencing graft rejection, 41 received a second transplant: their survival is 33% vs 8% for patients not transplanted a second time (p = 0.003). The major factor predicting the outcome of second BMT for SAA was the interval from first BMT. Patients receiving a second BMT within 60 days from the first BMT had a significantly poorer outcome.

Relapse of aplastic anaemia after immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group SAA Working Party.

This study was designed to determine the incidence of relapse and factors predictive for relapse in 719 patients with severe aplastic anaemia (SAA) after immunosuppressive treatment (IS). Patients developing myelodysplasia or acute leukaemia after IS, and patients receiving a transplant, were excluded from this analysis. Response was defined as reaching complete independence from transfusions, relapse was defined as becoming again transfusion dependent. This criteria was validated by similar figures when using other 'relapse criteria' such as drop in neutrophil or platelet counts. Of 358 patients responding to IS. 74 patients relapsed after a mean time of 778 d after treatment. The actuarial incidence of relapse is 35.2% at 14 years after IS. The risk for relapse was higher in patients responding within 120 d from IS (48%) compared to patients responding between 120 and 360 d (40%) and only 20% for slow responders (> 360 d from IS) (P < 0.00001). In multivariate analysis this factor still proved significant (P < 0.0001). The mean time between diagnosis and treatment was significantly longer in patients relapsing compared to patients who did not relapse (260 v 134 d, P = 0.037). Relapse was not predicted by the severity of the disease, age, and sex. In 39 of the 74 relapsing patients a second response could be achieved. Responses after relapse were associated in univariate analysis with early response to previous IS and early occurrence of relapse. The actuarial survival of patients not relapsing is significantly better than survival of patients relapsing (79.8% v 67.1%, P = 0.0024). However, the actuarial survival of 39 relapsing patients who responded again to IS was similar to patients not relapsing (86%) and significantly better than in 35 patients not reaching a second response after relapse (49.3%, P = 0.0015). This study indicates that relapse is a relevant problem in the treatment of aplastic anaemia, and does have an impact on overall survival. Prospective studies of immunosuppressive regimens, looking at responses, should also address this problem in the future.