Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide,fludarabine and thymoglobulin in children with severe aplastic anaemia

When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti-thymocyte globulin (ATG) are frequently administered, but to-date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low-dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non-Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft-versus-host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2, two ANKRD26, two TINF2, one LZTFL1, one RTEL1 and one DNAJC21). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post-transplant, the event-free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low-dose Cy as part of a fludarabine-based regimen is safe and effective in SAA/non-Fanconi anaemia IBMFS.     

Unmanipulated haploidentical haematopoietic stem cell transplantation for children with severe aplastic anaemia

Haploidentical haematopoietic stem cell transplantation (haplo‐HSCT) used to be a third‐line treatment option for childhood severe aplastic anaemia (SAA). We conducted this retrospective study of 36 children (38 transplants) who received haplo‐HSCT from human leucocyte antigen (HLA)‐mismatched related donors between July 2002 and November 2013 at five HSCT centres in China, including 17 cases that were 5/6 HLA matched (Group 1) and 21 that were 4/6 or 3/6 HLA matched (Group 2). Although patients in Group 2 had a higher incidence of grade II‐IV acute graft‐versus‐host disease (57·9% vs. 5·9%, P = 0·001), they had similar rates of graft failure (5·3% vs. 5·9%, P = 0·742) and overall survival (80·8% vs. 93·8%, P = 0·234) as Group 1. Unmanipulated haplo‐HSCT is an effective treatment for SAA children with satisfactory outcome of this cohort, especially in the 5/6 HLA‐matched group. For patients in critical situations, such as unresponsive to immunosuppressive therapy, refractory infection and failing first HSCT, to bring forward the timing of haplo‐HSCT is a feasible salvage strategy with better and faster donor accessibility.     

Single institution outcomes of treatment of severe aplastic anaemia

Background: In severe aplastic anaemia, the treatment of choice for young patients with a human leucocyte antigen‐matched sibling is now established as allogeneic bone marrow transplantation (BMT). In older patients and in those without a matched sibling donor, immunosuppressive therapy is the usual first option. ‘Alternative’ marrow donors are emerging as an option for those without a matched sibling donor. Aims: To review 10 years of local experience in treating severe aplastic anaemia with BMT and immunosuppressive therapy with emphasis on long‐term outcomes. Methods: A retrospective analysis was performed of all patients with severe aplastic anaemia presenting to the Royal Brisbane and Royal Children’s Hos‐ pitals between 1989 and 1999. Data were abstracted regarding patient demographics, pretreatment characteristics and outcome measures, including response rates, overall survival and long‐term complications. Results: Twenty‐seven consecutive patients were identified, 12 treated with immunosuppression alone and 15 with BMT. In these two groups, transfusion independence was attained in 25% and 100%, respectively, with overall survival being 36% and 100%, respectively. Those treated with immunosuppression were significantly older (median 41.5 versus 22 years, P = 0.008). Long‐term survivors of either treatment had extremely low morbidity. Three patients carried pregnancies to term post‐transplant. Three patients received alternative donor BMT with correspondingly excellent survival. Conclusions: Patients treated with allogeneic BMT for severe aplastic anaemia enjoyed extremely good long‐term survival and minimal morbidity. Patients treated with immunosuppressive therapy had a poorer outcome reflecting their older age and different usage of therapies over the past decade. Optimal treatment strategies for severe aplastic anaemia remain to be determined. (Intern Med J 2001; 31: 337–342)     

Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant

This study analysed the outcome of 563 Aplastic Anaemia (AA) children aged 0–12 years reported to the Severe Aplastic Anaemia Working Party database of the European Society for Blood and Marrow Transplantation, according to treatment received. Overall survival (OS) after upfront human leucocyte antigen‐matched family donor (MFD) haematopoietic stem cell transplantation (HSCT) or immunosuppressive treatment (IST) was 91% vs. 87% (P 0·18). Event‐free survival (EFS) after upfront MFD HSCT or IST was 87% vs. 33% (P 0·001). Ninety‐one of 167 patients (55%) failed front‐line IST and underwent rescue HSCT. The OS of this rescue group was 83% compared with 91% for upfront MFD HSCT patients and 97% for those who did not fail IST up‐front (P 0·017). Rejection was 2% for MFD HSCT and HSCT post‐IST failure (P 0·73). Acute graft‐versus‐host disease (GVHD) grade II‐IV was 8% in MFD graft vs. 25% for HSCT post‐IST failure (P < 0·0001). Chronic GVHD was 6% in MFD HSCT vs. 20% in HSCT post‐IST failure (P < 0·0001). MFD HSCT is an excellent therapy for children with AA. IST has a high failure rate, but remains a reasonable first‐line choice if MFD HSCT is not available because high OS enables access to HSCT, which is a very good rescue option.     

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.     

Similar outcome of upfront‐unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party,Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT

We explored the feasibility of unrelated donor haematopoietic stem cell transplant (HSCT) upfront without prior immunosuppressive therapy (IST) in paediatric idiopathic severe aplastic anaemia (SAA). This cohort was then compared to matched historical controls who had undergone first‐line therapy with a matched sibling/family donor (MSD) HSCT (n = 87) or IST with horse antithymocyte globulin and ciclosporin (n = 58) or second‐line therapy with unrelated donor HSCT post‐failed IST (n = 24). The 2‐year overall survival in the upfront cohort was 96 ± 4% compared to 91 ± 3% in the MSD controls (P = 0·30) and 94 ± 3% in the IST controls (P = 0·68) and 74 ± 9% in the unrelated donor HSCT post‐IST failure controls (P = 0·02).The 2‐year event‐free survival in the upfront cohort was 92 ± 5% compared to 87 ± 4% in MSD controls (P = 0·37), 40 ± 7% in IST controls (P = 0·0001) and 74 ± 9% in the unrelated donor HSCT post‐IST failure controls (n = 24) (P = 0·02). Outcomes for upfront‐unrelated donor HSCT in paediatric idiopathic SAA were similar to MSD HSCT and superior to IST and unrelated donor HSCT post‐IST failure. Front‐line therapy with matched unrelated donor HSCT is a novel treatment approach and could be considered as first‐line therapy in selected paediatric patients who lack a MSD.     

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.     

Long-term outcome of acquired aplastic anaemia in children: comparison between immunosuppressive therapy and bone marrow transplantation

A total of 100 children under the age of 17 years with acquired aplastic anaemia (AA) were initially treated with immunosuppressive therapy (IST) (n = 63) or bone marrow transplantation (BMT) (n = 37) from an HLA-matched family donor. The projected 10-year survival rates were 55 +/- 8% and 97 +/- 3% respectively (P = 0.004). Because the IST group included 11 non-responders who were salvaged by BMT from an HLA-matched unrelated donor, we compared failure-free survival (FFS) between the groups. The probability of FFS at 10 years was 97 +/- 3% for the BMT group, compared with 40 +/- 8% for the IST group (P = 0.0001). Seven patients evolved to myelodysplastic syndrome (MDS) with monosomy 7 and the estimated cumulative incidence of MDS 10 years after diagnosis was 20 +/- 7% in the IST group. We compared the outcome of children treated with IST during the two consecutive periods of 1983-91 (group A, n = 40) and 1991-8 (group B, n = 23) to assess the impact of combined therapy with antithymocyte globulin and cyclosporin. The probability of FFS at 7 years follow-up was the same in the two groups (50 +/- 8% vs. 40 +/- 15%, P = 0.40). We recommend BMT as first-line therapy in paediatric severe AA patients with an HLA-matched family donor. Alternative donor BMT is recommended as salvage therapy in patients who relapse or do not respond to initial IST.     

Allogeneic transplantation using CD34+ selected peripheral blood progenitor cells combined with non‐mobilized donor T cells for refractory severe aplastic anaemia

Allogeneic haematopoietic stem cell transplantation is curative for severe aplastic anaemia (SAA ) unresponsive to immunosuppressive therapy. To reduce chronic graft‐versus‐host disease (GVHD ), which occurs more frequently after peripheral blood stem cell (PBSC ) transplantation compared to bone‐marrow transplantation (BMT ), and to prevent graft rejection, we developed a novel partial T‐cell depleted transplant that infuses high numbers of granulocyte colony‐stimulating factor‐mobilized CD 34⁺ selected PBSC s combined with a BMT ‐equivalent dose of non‐mobilized donor T‐cells. Fifteen patients with refractory SAA received cyclophosphamide, anti‐thymocyte globulin and fludarabine conditioning, and were transplanted with a median 8 × 10⁶ CD 34⁺ cells/kg and 2 × 10⁷ non‐mobilized CD 3⁺ T‐cells/kg from human leucocyte antigen‐matched sibling donors. All achieved sustained engraftment with only two developing acute and two developing chronic GVHD . With a 3·5‐year median follow‐up, 86% of patients survived and were transfusion‐independent. When compared to a retrospective cohort of 56 bone‐marrow failure patients that received the identical transplant preparative regimen and GVHD prophylaxis with the exception that the allograft contained unmanipulated PBSC s, partial T‐cell depleted transplant recipients had delayed donor T‐cell chimerism and relative reduction of 75% in the incidence of acute grade II ‐IV GVHD (13% vs. 52%; P  =  0·010) and of 82% in chronic GVHD (13% vs. 72%; P  =  0·0004). In multivariate analysis, partial T‐cell depleted transplants remained significantly associated with a reduced risk of GVHD . In conclusion, for patients with refractory SAA , this novel transplant strategy achieves excellent engraftment and survival when compared to unmanipulated PBSC transplants and dramatically reduces the incidence of both acute and chronic GVHD .     

Lack of evidence for a role of HCV in hepatitis-associated aplastic anaemia

Summary Hepatitis-associated aplastic anaemia (HAAA) is usually related to non-A, non-B hepatitis agents but the prevalence of anti-hepatitis C virus (HCV) antibodies is similar in HAAA and aplasia of other origins according to the results of the ELISA1 assay. This fact could reflect either that HCV is not involved in HAAA or that HAAA-associated defective immune function could yield false negative assays despite on-going HCV infection.
To test these hypotheses, we compared 19 patients with HAAA, including three ELISAl-positive, to 23 patients with aplasia of known and unknown origin, including eight ELISA1-positive. who were matched for age, sex and blood transfusion units. HCV infection was searched for by the second-generation recombinant-immunoblot assay (RIBA2), and by the polymerase chain reaction which detects HCV viraemia. HCV viraemia was detected in four among the 19 patients with HAAA and in six among the 23 patients with aplasia of other causes.
HCV does not clearly appear responsible for hepatitis-associated aplastic anaemia which could be due to non-A. non-B, non-C hepatitis virus. HCV viraemia is frequent in severe aplastic anaemia, even without detectable anti-HCV antibodies, and reflects mainly transfusion-associated HCV infection.     

Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience

We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy (IST) or matched unrelated donor (MUD) haematopoietic stem cell transplantation (HSCT). The 6-month cumulative response rate following rabbit antithymocyte globulin (ATG)/ciclosporin (IST) was 32·5% (95% CI 19·3-46·6) (n = 43). The 5-year estimated failure-free survival (FFS) following IST was 13·3% (95% confidence interval [CI] 4·0-27·8). In contrast, in 44 successive children who received a 10-antigen (HLA-A, -B, -C, -DRB1, -DQB1) MUD HSCT there was an excellent estimated 5-year FFS of 95·01% (95% CI 81·38-98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab (FCC) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88-100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST.     

Effect of androgens on the response to antithymocyte globulin in patients with aplastic anaemia

30 patients with aplastic anaemia (18/30 with severe aplastic anaemia) were prospectively randomized to be treated with 100 mg/kg ATG with or without the oral androgen Methenolone (3 mg/kg). 15 of 30 patients responded. Among the 15 patients receiving ATG plus androgen, 11 patients (73%) responded, including 8 complete and 3 partial responses. 4 of the 15 patients (31%) receiving ATG only responded, including 2 complete and 2 partial responses. The difference in response rate was statistically significant (p = 0.01). The survival rate in the total population of 30 patients was 64%. The survival rate in the group receiving ATG plus androgen was 87%; in the group receiving ATG only it was 43%. The difference in survival rates between both groups did not reach statistical significance (p = 0.15). Toxicity of ATG and androgens was considerable but manageable. These data support the result of the recent European reevaluation of a large pool of patients by the EBMT (39), that androgens in addition to ATG increase survival in patients with aplastic anaemia. They are, however, in contradiction to a controlled American study showing no benefit of a combined treatment with androgens as compared to ATG only. Further controlled studies on a larger number of patients are indicated to determine the therapeutic efficacy of androgens in addition to immunosuppression in aplastic anaemia.     

Unrelated donor bone marrow transplantation to treat severe aplastic anaemia in children and young adults

Alternative donor bone marrow transplantation (BMT) to treat severe aplastic anaemia (SAA) in children and young adults has been complicated by high rates of graft rejection and severe graft-versus-host disease (GVHD). We hypothesized that increased immunosuppression combined with T-cell depletion of the marrow graft would enable successful use of unrelated donor BMT in this disease. Preconditioning consisted of cytosine arabinoside, cyclophosphamide, and total body irradiation (TBI). T-cell depletion was with the anti-CD3 antibody T10B9. GVHD prophylaxis consisted of cyclosporine A. 28 previously transfused patients were transplanted. Nine donor/recipient pairs were HLA matched. As of 1 January 1996, 15/28 (54%) patients are alive, transfusion independent and well with a range of follow-up of 13 months to 8 years (median 2.75 years). Fatalities include all three patients with non-engraftment and all three patients with grade III/IV GVHD. Other fatalities were due to infections or therapy-related toxicity. The incidence ≥ grade II acute GVHD was 28%. These data show that in children with SAA who have failed immunosuppression, unrelated donor BMT offers a reasonable hope of long-term survival.     

Results and follow-up of a phase III randomized study of recombinant human-granulocyte stimulating factor as support for immunosuppressive therapy in patients with severe aplastic anaemia

In patients with idiopathic severe aplastic anaemia who are treated with immunosuppressive agents to combat T lymphocyte-mediated destruction of haematopoietic progenitor cells, neutropenia is a major cause of infections and toxicity. Evidence from preliminary studies suggests that recombinant human glycosylated granulocyte colony-stimulating factor (lenograstim) increases the number and functionality of neutrophils in patients with severe aplastic anaemia. This randomized, parallel-group, multicentre study was conducted to evaluate the efficacy and safety of subcutaneous lenograstim during the first 12 weeks of standard immunosuppressive therapy in 102 patients with de novo severe aplastic anaemia. The addition of lenograstim to standard therapy resulted in an increase in the proportion of patients showing complete neutrophil response (83.0%vs 44.9%; P < 0.0001). This was seen even among patients with very severe aplastic anaemia (69.2%vs 31.6%; P = 0.012). In patients receiving lenograstim, median time to complete neutrophil response was shorter (6.3 vs 16.1 weeks; P = 0.0001) and mean duration of first neutrophil response was longer (P = 0.0248) than in the control group. At a median follow-up of 5 years, no difference was observed between the groups in term of survival, haematological response and occurrence of secondary leukaemia (one patient in each group). We conclude that lenograstim support of immunosuppressive therapy might be used for patients with severe aplastic anaemia as it significantly enhances neutrophil recovery but does not modify the overall response and survival.     

Transplantation of highly purified CD34+ progenitor cells from alternative donors in children with refractory severe aplastic anaemia

Without transplantation from a human leucocyte antigen-identical family donor, refractory severe aplastic anaemia (SAA) has an unfavourable prognosis. Conventional transplantation from a matched unrelated donor carries a high rate of mortality. We transplanted large numbers of highly purified CD34+ cells from matched unrelated (n = 4), mismatched unrelated (n = 4) and mismatched related (n = 1) donors into nine children with refractory SAA. The grafts consisted of granulocyte colony-stimulating factor-mobilized peripheral positively selected CD34+ cells. A median of 15.1 x 106/kg CD34+ stem cells and 11 x 103/kg CD3+ T-lymphocytes were infused. No additional pharmacological graft versus host disease (GVHD) prophylaxis was given. At a median follow-up of 47 (range 37-72) months, eight patients (89%) were in complete remission with >90% donor chimaerism and no evidence of GVHD. One patient died on day +238 as a consequence of GVHD. The use of highly purified mobilized CD34+ stem cells warrants further clinical exploration in children with refractory SAA.     

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.     

Unrelated donor bone marrow transplantation for children and adolescents with aplastic anaemia or myelodysplasia

Allogeneic transplantation from an HLA-matched family member has been shown to be effective in reconstituting normal haemopoiesis in young people with severe cytopenias, classified as myelodysplastic syndrome (MDS) or severe aplastic anaemia (SAA). Unrelated donor transplant is a therapeutic choice for patients without a suitable family member donor. We report the outcome of seven patients < 20 years old with SAA and 10 with MDS treated with BMT from an HLA A,B DRB1 matched ( n  =8) or A or B locus mismatched ( n  =9) unrelated donor at the University of Minnesota between March 1988 and August 1995. Primary graft failure occurred in two patients and secondary graft failure in one, who was subsequently successfully engrafted with a second donor marrow infusion. Grades II–IV GVHD occurred in 10/16 (63%), and grades III–IV in 6/16 (37%) evaluable patients. Nine of the 17 patients (six with MDS and three with SAA) survive with full donor chimaerism, a median of 1.2 years post-BMT (range 3 months to 7 years). We recommend early referral for consideration of unrelated donor BMT for young patients with MDS, and patients with SAA without response to immunosuppression.     

Prevalence of GBV-C/HGV, a novel 'hepatitis' virus, in patients with aplastic anaemia

GBV-C or hepatitis G virus (GBV-C/HGV) is a novel RNA virus with similarities to members of the Flaviviridae family, especially hepatitis C. Viral RNA is detected in about 1.5% of American blood donors, with higher prevalence in multiply transfused patients and in individuals with hepatitis or liver disease. Some cases of aplastic anaemia follow apparent non-A, non-B, non-C viral hepatitis, and GBV-C viraemia has been described in three case reports of hepatitis-associated aplastic anaemia. We tested clinical samples from patients with aplastic anaemia with or without recent hepatitis for the presence of GBV-C/HGV. Virus was detected in a total of 15/57 (26.3%) of patients with aplastic anaemia and 12/52 (23.1%) of multiply transfused control patients. Sequencing of the 188 base pair NS3 helicase PCR product in the serum of five individuals indicated the same high degree of sequence variation as has been seen among other isolates of the virus. GBV-C/HGV does not appear to be implicated in the aetiology of aplastic anaemia.     

Allogeneic marrow transplantation for aplastic anaemia associated with dyskeratosis congenita

Eight patients with aplastic anaemia associated with dyskeratosis congenita received allogeneic marrow grafts from either HLA-identical siblings (six patients) or HLA-matched unrelated donors (two patients). Patients who received marrow from HLA-identical siblings were conditioned with cyclophosphamide (140–200 mg/kg), with or without antithymocyte globulin. Patients who received unrelated donor marrow were conditioned with cyclophosphamide (120 mg/kg) and total body irradiation (1200 cGy). The six patients who survived for >2 weeks following transplant all had haematological evidence of engraftment, and all three patients who survived for at least a year following transplant recovered normal haematological function. Three patients died with respiratory failure and pulmonary fibrosis at 70 d, 8 years and 20 years post-transplant; three patients died during the neutropenic period of invasive fungal infections; one patient died on day 44 of refractory acute graft-versus-host disease; and one patient remains alive 463 d following transplant. The surviving patient recently underwent surgical resection of a Dukes' stage C rectal carcinoma diagnosed 14 months post-transplant.
The aplastic anaemia associated with dyskeratosis congenita can be successfully treated by allogeneic bone marrow transplantation; however, this approach does not reverse the other systemic manifestations of the syndrome. The pathogenesis of the interstitial lung disease observed in dyskeratosis congenita patients following marrow transplantation is not understood.     

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.