Splenectomy as an adjuvant measure in the treatment of severe aplastic anaemia

The role of splenectomy in aplastic anaemia (AA) is controversial. The hazards of operating on a severely pancytopenic patient, the fear of compromising the patient’s immune function, and the improvement of non-surgical treatment have made splenectomy unpopular in this disease. We have evaluated positive and adverse effects of splenectomy in 80 patients with severe aplastic anaemia (SAA) treated with antilymphocyte globulin (ALG) (group A), using 52 nonsplenectomized ALG patients as controls (group B). All patients survived the operation. Nonfatal complications of surgery occurred in 10 (12.5%). Splenectomy induced a significant increase of peripheral blood neutrophils, reticulocytes and platelets within 2 weeks, followed by a continuous increase of all values over the following weeks. 28/132 patients (21%) developed a late clonal disorder of haemopoiesis, paroxysmal nocturnal haemoglobinuria (PNH) or myelodysplastic syndrome (MDS), or both. Their incidence was identical in groups A and B. 13/28 (59%) died, 10/17 (59%) in group A and 3/11 (27%) in group B (not significant (n.s.)). Overall probability of survival at 18 years after ALG was 51 ± 6% for group A and 61 ± 7% for group B (n.s.). We conclude that splenectomy in AA is safe. It induces an immediate increase of peripheral blood counts and, thereafter, a continuous improvement of haemopoiesis. It does not increase the incidence of late clonal complications but has a borderline effect on mortality from these disorders. Splenectomy should be reconsidered in selective nontransplanted patients who have prolonged transfusion requirements despite otherwise optimal treatment.     

Splenectomy as an adjuvant measure in the treatment of severe aplastic anaemia

The role of splenectomy in aplastic anaemia (AA) is controversial. The hazards of operating on a severely pancytopenic patient, the fear of compromising the patient's immune function, and the improvement of non-surgical treatment have made splenectomy unpopular in this disease.
We have evaluated positive and adverse effects of splenectomy in 80 patients with severe aplastic anaemia (SAA) treated with antilymphocyte globulin (ALG) (group A), using 52 nonsplenectomized ALG patients as controls (group B). All patients survived the operation. Nonfatal complications of surgery occurred in 10 (12.5%). Splenectomy induced a significant increase of peripheral blood neutrophils, reticulocytes and platelets within 2 weeks, followed by a continuous increase of all values over the following weeks. 28/132 patients (21%) developed a late clonal disorder of haemopoiesis, paroxysmal nocturnal haemoglobinuria (PNH) or myelodysplastic syndrome (MDS), or both. Their incidence was identical in groups A and B. 13/28 (59%) died, 10/17 (59%) in group A and 3/11 (27%) in group B (not significant (n.s.)). Overall probability of survival at 18 years after ALG was 51 ± 6% for group A and 61 ± 7% for group B (n.s.).
We conclude that splenectomy in AA is safe. It induces an immediate increase of peripheral blood counts and, thereafter, a continuous improvement of haemopoiesis. It does not increase the incidence of late clonal complications but has a borderline effect on mortality from these disorders. Splenectomy should be reconsidered in selective nontransplanted patients who have prolonged transfusion requirements despite otherwise optimal treatment.     

Clinical relevance of cytogenetic abnormalities at diagnosis of acquired aplastic anaemia in adults

The outcome of 81 adult aplastic anaemia patients who had successful cytogenetics at diagnosis and received immunosuppressive therapy was evaluated. Ten patients had an abnormal karyotype, six of which had a trisomy. Four of five evaluable patients with a trisomy responded. One patient with monosomy 7 achieved a complete response and later developed haemolytic paroxysmal nocturnal haemoglobinuria but no recurrence of monosomy 7. None of the patients with a non-numerical karyotypic abnormality responded. No significant differences in survival or later clonal disorders were observed between patients with a normal karyotype and those with an abnormal karyotype.     

Incidence of Fanconi anaemia in phenotypically normal aplastic anaemia patients in West Bengal

Objectives: Fanconi anaemia (FA) is a rare inherited bone marrow failure and autosomal recessive blood disorder. FA patients have a higher risk of cancer, including acute myeloid leukaemia and squamous cell carcinoma. Maximum, but not all, affected individuals have one or more somatic abnormalities, including skin, skeletal, genitourinary, gastrointestinal, cardiac and neurological anomalies, etc. Positive stress cytogenetics has immense implications for the treatment and management of FA. The aim of our study was to find out the incidence of FA in the population of phenotypically normal aplastic anaemia (AA) patients in West Bengal.

Methods: Ethical clearances were obtained from the corresponding institutional committees. A total of 117 AA cases was selected. Stress cytogenetics was performed from peripheral venous blood (PVB) samples of 63 AA patients (age?≤?50 years) and 63 age- and sex-matched healthy individual (control) using Mitomycin C (MMC).

Results: Out of 63 AA patients, 6 (9.25%) cases showed positive stress cytogenetics suggestive of FA, which is statistically significant (p-value – 0.000532), analysed by chi-square test.

Discussion: A considerable percentage of patients showing sensitivity towards MMC, even if they are phenotypically normal and did not have any distinguishable features which are generally found in FA.

Conclusion: This observation may indicate that stress cytogenetics analysis of phenotypically normal AA patients (≤50 years) is essential for the improvement of the treatment procedure.     

Haematopoietic stem cell transplantation for hepatitis-associated aplastic anaemia and non-hepatitis-associated aplastic anaemia: A propensity score-matched analysis

To validate the efficacy and safety of haematopoietic stem cell transplantation (HSCT) in hepatitis-associated aplastic anaemia (HAAA) patients, we reviewed 260 patients who underwent HSCT for acquired aplastic anaemia and eventually included 30 HAAA patients and 90 non-HAAA patients using propensity score matching. In the HAAA group, the estimated 5-year overall survival rate (75.8% vs. 86.5%, p = 0.409), failure-free survival (FFS) rate (74.0% vs. 83.2%, p = 0.485), graft-versus-host disease (GVHD)-free FFS rate (61.2% vs. 67.6%, p = 0.669) after HSCT were slightly lower but not statistically significant than those in the non-HAAA group. Both groups did not significantly differ in engraftment, post-transplant severe infection, cytomegalovirus (CMV) or Epstein-Barr virus viraemia, or GVHD incidences. The patterns of immune reconstitution were broadly consistent between the two groups. When stratifying HAAA patients according to donor type, no significant differences in survival, transplant-related mortality, or GVHD cumulative incidences were observed. CMV viraemia (68.7% vs 8.3%, p = 0.009) occurred more commonly in haploidentical donor (HID) transplants than in matched sibling donor transplants. However, early CMV disease incidence (5.6% vs. 0.0%, p = 1.000) was low. Overall, the post-transplant outcomes of HAAA patients were comparable to those of non-HAAA patients after balancing potential confounders, and HID-HSCT can offer an alternative curative option for HAAA.     

Myelodysplasia and acute myeloid leukaemia in cases of aplastic anaemia and congenital neutropenia following G-CSF administration

Summary. Myelodysplasia and acute myeloid leukaemia (MDS/AML) developed in three cases of severe aplastic anaemia (SAA) and one case of congenital neutropenia (CN, Kostmann's disease) who received recombinant human granulocyte colony-stimulating factor (G-CSF) are reported. In these four MDS/AML cases, age at diagnosis of SAA/CN was 0–13 years, the cumulative dose of G-CSF was 98 μg/kg to 10 mg/kg over 1–57 months, and the interval from initiation of G-CSF to MDS/AML was 25, 23, 31 and 57 months, respectively. These results suggest a link between SAA/CN and MDS/AML in relation to G-CSF administration; however, large studies are necessary to determine if such a risk is significant in patients with SAA/CN who are treated with G-CSF.     

Abnormal cytogenetic clones in patients with aplastic anaemia: response to immunosuppressive therapy

We report the response to immunosuppressive therapy with antithymocyte globulin (ATG) and cyclosporin or oxymetholone in 13 cases of aplastic anaemia (AA) with an abnormal cytogenetic clone detected at or sometime after diagnosis. Blood and bone marrow examination showed no distinctive morphological features of myelodysplasia (MDS) at diagnosis. Haematological response occurred promptly in eight cases; the remainder responded after additional immunosuppression with or without oxymetholone. Three patients had a late relapse of AA, treated successfully by allogeneic bone marrow transplantation in one; the others responded to oxymetholone. Transformation to MDS or acute leukaemia was not observed after a median follow-up of 4.1 years (range 1.2-11.2). In four patients the cytogenetic clone disappeared after treatment.     

Treatment responses of childhood aplastic anaemia with chromosomal aberrations at diagnosis

The clinical outcome of childhood aplastic anaemia (AA) with aberrant cytogenetic clones at diagnosis was surveyed. Among 198 children with newly diagnosed AA registered with the AA Committee of the Japanese Society of Paediatric Hematology between 1994 and 1998, cytogenetic studies of bone marrow (BM) cells were completed in 159 patients. Apart from one Robertsonian translocation, seven patients (4.4%) showed clonal chromosomal abnormalities in hypoplastic BM without myelodysplastic features. The patients included six girls and one boy with a median age of 11 years (range 5-14 years). Six patients had del(6), del(5), del(13), del(20), or -7, and one showed add(9). Four patients responded to the first immunosuppressive therapy (IST: cyclosporin A plus anti-thymocyte globulin) and one obtained a spontaneous remission. Cytogenetic abnormalities remained in two patients with an IST response. On the other hand, two patients showed no IST response. One did not respond to repeat IST and died of acute graft-versus-host disease after an unrelated-BM transplant. Another obtained a complete response after a successful BM transplant. No haematological findings at diagnosis predicted the treatment response. No significant morphological changes developed during the course of the illness. A literature review revealed that half of 24 AA patients with chromosomal abnormalities responded to the first IST, and that +6 was the sole predictable marker for IST unresponsiveness. These results suggest that IST can be applied as the initial therapy for AA with cytogenetic abnormalities in the absence of completely matched donors.     

Acetazolamide-associated aplastic anaemia

Eleven cases of acetazolamide-associated aplastic anaemia were reported in Sweden during a 17-year period. There were six women and five men with a median age of 71 years (range 63-85 years). The median dose of acetazolamide was 500 mg, and the median duration of treatment was 3 months (range 2-71 months). Ten of the eleven patients died, all within 8 weeks after detection of their aplastic anaemia. The relative risk of developing aplastic anaemia when taking acetazolamide was 13.3 (95% confidence limits (CL); 6.8-25.3). The estimated incidence of reported acetazolamide-associated aplastic anaemia is approximately one in 18,000 patient years. The results strongly indicate that acetazolamide treatment is associated with a substantial increase in the risk of developing aplastic anaemia.     

Prognosis in aplastic anaemia: a review of 138 cases

The outcome of 138 patients with aplastic anaemia was studied to ascertain whether prognostic factors at the onset of the disease are predictive. Applying four classic prognostic criteria, two groups of patients were identified: (1) those with an absolute granulocyte count of less than 0.5 × 10⁹/l, platelet count less than 20 × 10⁹/l, reticulocyte count less than 15 × 10⁹/l, and non-myeloid marrow cellularity greater than 75% who had 100% mortality in the first three months from the onset of the disease, (ii) patients who fulfilled three or fewer of these criteria who had a 20% three month mortality. The survival of these groups differed significantly (P = less than 0.001). The variable that most closely correlated with prognosis was the number of non-haematopoietic cells in the bone marrow aspirate. When Lynch's prognostic formula for patients with aplastic anaemia was applied to the same group of patients, the correlation with prognosis was less close and the calculations were tedious. The identification of a group of patients with severe aplastic anaemia is important because these patients do not benefit from conventional forms of therapy and alternative approaches such as transplantation and immunosuppression are justified.     

Serum thrombopoietin levels in patients with aplastic anaemia

Endogenous serum thrombopoietin (TPO) levels were measured in 31 patients with aplastic anaemia (AA) using an enzyme immunoassay with a sensitivity of 20 pg/ml. The median platelet count for all AA patients was 30 ± 29 × 10⁹/l (range 5–102) compared with a median of 284 ± 59 × 10⁹/l (range 148–538) for normal controls. Serum TPO levels were significantly elevated in all patients compared with normals (1706 ± 1114.2, range 375–5000 v 78 ± 54, range 16.5–312.9, P  < 0.0001). There was no correlation between serum TPO levels and the degree of thrombocytopenia in AA patients, but TPO levels were significantly higher in patients who were platelet transfusion dependent than in patients who were transfusion independent ( P  < 0.01). There was a trend for higher TPO levels in patients with severe AA compared with non-severe AA patients. Clinical trials of TPO and a related truncated, pegylated molecule, megakaryocyte growth and development factor (PEG-rHuMGDF), are awaited to determine whether treatment with these drugs will result in increased platelet counts in patients with AA.     

How I manage aplastic anaemia in children

Aplastic anaemia (AA) is a rare heterogeneous condition in children. 15–20% of cases are constitutional and correct diagnosis of these inherited causes of AA is important for appropriate management. For idiopathic severe aplastic anaemia, a matched sibling donor (MSD) haematopoietic stem cell transplant (HSCT) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. IST with horse anti‐thymocyte globulin (ATG) is superior to rabbit ATG and has good long‐term results. In contrast, IST with rabbit ATG has an overall response of only 30–40%. Due to improvements in outcome over the last two decades in matched unrelated donor (MUD) HSCT, results are now similar to that of MSD HSCT. The decision to proceed with IST with ATG or MUD HSCT will depend on the likelihood of finding a MUD and the differing risks and benefits that each therapy provides.     

Pregnancy and severe aplastic anaemia: causal relation or coincidence?

The relationship between aplastic anaemia (AA) and pregnancy remains uncertain. To assess whether an association between pregnancy and severe aplastic anaemia (SAA) exists, we compared the frequency of pregnancy in 35 young women with newly diagnosed SAA with the expected frequency in the general population. The observed pregnancy rate in the SAA group was 3–6%. This percentage approximates the expected pregnancy rate of 4.4% in the general population and is not compatible with a strong association between pregnancy and SAA.     

Advances in understanding the pathogenesis of acquired aplastic anaemia

This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity and inflammation. We also consider how the course of the disease and the response to immuno‐suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl‐phosphatidyl‐inositol ‐specific auto‐immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto‐immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre‐leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis.     

Stem cells and the microenvironment in aplastic anaemia

Normal blast colony-forming cells (BI-CFC) bind to stroma cultured in the presence of methylprednisolone (MP⁺) but not to MP^- stroma. In aplastic marrow, the incidence of BI-CFC is variable (0–4 x normal values) and there is no consistent relationship with the CFU-GM (granulocyte-macrophage colony-forming cell) content. Normal stroma require MP to induce BI-CFC binding function and form fat cells whereas MP^- stroma grown from 4/9 aplastic patients formed fat cells and bound BI-CFC. The 5/9 aplastic cases that did not form fat cells spontaneously also bound BI-CFC moderately better than normal stroma. This suggests that the haemopoietic microenvironment in aplastic anaemia responds physiologically to bone marrow failure by increasing its haemopoietic support capacity.     

Cyclosporin A response and dependence in children with acquired aplastic anaemia: a multicentre retrospective study with long-term observation follow-up

Immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporin A (CyA) is the standard treatment for children with acquired aplastic anaemia (AAA) lacking a matched donor. Survival rates of more than 80% at 5 years are achieved, but the response is drug-dependent in 15–25% of cases. This study, of 42 consecutive children with AAA treated with IST, assessed the incidence of CyA-dependence, CyA and granulocyte colony-stimulating factor (G-CSF) tapering schedules and the impact of drug accumulation on progression to myelodysplasia/acute myeloid leukaemia (MDS/AML). Overall survival was 83% at 10 years. CyA-dependence without a predictive marker was observed in 18% of responders. Probability of discontinuing CyA was 60·5% at 10 years; a slow CyA tapering schedule was performed in 84% of patients; the cumulative incidence of relapse was 16% at 10 years. Relapse risk was significantly associated with rapid CyA discontinuation: 60% compared to 7·6% in the slow tapering group ( P  = 0·001). Cumulative incidence of MDS/AML was 8% at 10 years, with a significant correlation with both G-CSF cumulative dose and second IST. This long-term follow-up of children with AAA shows that IST with a slow CyA tapering course is an effective treatment with a low-relapse rate in these cases.