Aplastic Anemia

Implications of CD34+ cell dose on clinical and haematological outcome of allo-SCT for acquired aplastic anaemia

Abstract

The precise effects of CD34+ cell dose on the outcome of allogeneic transplantation for aplastic anaemia (AA) are not known. Previous studies have used the total mononuclear cell count to quantify stem cell dose. We evaluated the effects of CD34+ cell dose on the clinical and haematological end points of transplantation. The transplant variables and outcome parameters on 46 patients with acquired AA were assessed by comparing low vs high CD34+ cell doses. Infusion of less than 2 × 106/kg of CD34+ cells was associated with an increased incidence of graft failures (P=0.03), higher incidence of bacterial infections (P=0.006) and a delay in the engraftment of neutrophils (P=0.046). The latter was found to be an effect of stem cell source (non-PBSC) rather than the CD34+ count. Other parameters, such as plt engraftment (P=0.63), red cell (P=0.94) and plt (P=0.31) transfusion independence, chimerism, acute and chronic GVHD (P=1.0) and OS (P=0.57), were not significantly influenced by the CD34+ cell dose. These findings are different to the published studies on the relevance of CD34+ cell dose in allogeneic transplantation for haematological cancers.

Introduction

CD34 is a type 1 transmembrane protein expressed on haemopoietic stem cells with the capacity to repopulate BM for all lineages.1 In clinical practice, CD34+ expression is considered to be the equivalent of a pluripotent haemopoietic stem cell with the ability of self-renewal.

The number of infused CD34+ cells is known to be a significant predictor of the outcome of autologous and Allo-SCT for haematological malignancies. In 2000, Siena et al. reviewed the relevance of CD34+ cell dose for all forms of haemopoietic transplantation for malignancies.2 They suggested that the optimal CD34+ dose for successful autologous transplantation was 8 × 106/kg and the dose for allogeneic transplants was unclear. In the same year, Singhal et al. recommended a CD34+ dose of 2 × 106/kg as the minimum threshold for allogeneic sibling blood or marrow SCT.3 Two years later, Bittencourt et al. concluded that a CD34+ dose of 3 × 106/kg was optimal for allogeneic BMT in terms of faster engraftment, decreased treatment-related mortality and increased OS.4

Allo-SCT is a potentially curative therapeutic option for aplastic anaemia (AA). All the above-mentioned studies were predominantly, if not exclusively, on patients with haematological malignancies. Compared to leukaemia, lymphoma and myeloma, AA is a rare haematological disorder for which many patients are treated without transplantation. Consequently, very little literature is available on the implications of CD34+ cell dose for allo-SCT in AA patients.

The stem cell dose for AA has traditionally been reported as the number of total nucleated cells and not the actual CD34+ cell count.5, 6 The importance of infusing at least 3 × 108/kg of total nucleated cells has been well recognized. A significant increase in the incidence of graft failure and a reduction in OS have been shown at doses below this threshold.5, 6, 7 We evaluated the influence of CD34+ cell dose on the outcome of transplantation in 46 patients with acquired AA. The effects on haematological engraftment, graft failure, chimerism, transfusion dependency, GVHD and OS were compared by classifying patients into those who received a high cell dose and those who received a low cell dose.

Methods

Study setting

The study was a retrospective evaluation of acquired AA patients transplanted using HLA-identical sibling or HLA-matched unrelated donors at St George's Hospital in London over a continuous 10-year period. The study plan was discussed with the hospital ethics committee and approval was obtained for the non-interventional study, limited to analysis of retrospective data. The patients received standard treatment and confidentiality was ensured at all the stages of analysis.

Relevant data were extracted from a combination of clinical notes, electronic patient record, blood bank records and the transplantation database.

Patients and eligibility

Between January 1998 and August 2008, 56 patients with BM failure syndromes had allogeneic transplants. Consecutive non-probability sampling was done to recruit patients to the study population. Ten patients with congenital marrow failure (Fanconi anaemia, Schwachman Diamond syndrome) were excluded from the analysis. For patients who had multiple transplants, only the first episode was considered for the study. After exclusions, the final sample population consisted of 46 patients. The median follow-up of survivors was 4.68 years, with a range of 0.57–11.08 years.

Study definitions

‘Severe’ AA was defined as marrow cellularity of <25% with any two of the following: neutrophils <0.5 × 109/l, plts <20 × 109/l and reticulocyte count <20 × 109/l. The patients were categorized as ‘very severe’ if, in addition, the neutrophil count was <0.2 × 109/l.8, 9

The dose of infused stem cells was classified as ‘low’ (<3.4 × 106/kg) or ‘high’ (3.4 × 106/kg) based on the median CD34+ cell count across the study population.

The first of 3 consecutive days of ANC of >0.5 × 109/l was assigned as the point of ‘neutrophil engraftment’. ‘Platelet engraftment’ was considered as the first of 3 consecutive days of plt count of >20 × 109/l without plt transfusion requirement for 7 preceding days.

‘Red cell transfusion independence’ was defined as the earliest point at which the patient remained untransfused with packed red cells for 30 consecutive days and continued to maintain Hb 80 g/l unsupported thereafter. ‘Platelet transfusion independence’ corresponded to the earliest point at which the patient remained untransfused with plts for 7 consecutive days. The threshold for plt transfusion was a plt count of <10 × 109/l, provided the patients were clinically well and had no bleeding manifestations other than bruises.

‘Graft failure’ was defined as either the absence of haematological recovery in patients surviving 21 days after transplantation (primary graft failure) or recovery followed by recurrent pancytopenia (late graft failure) with a hypocellular marrow in the absence of severe GVHD.10

Whole blood and cell lineage-specific chimerism was analysed on recipient marrow and blood for transplants since 2003. A semi-quantitative PCR-based method involving amplification of genes containing short tandem repeat sequences was performed. Whole blood donor cell percentage 99% was defined as ‘complete donor chimerism’ and <99% as ‘mixed chimerism’. The latter was subclassified into ‘stable mixed chimerism’ when donor cells were persistently >70% and ‘increasing mixed chimerism’ when donor cells fell to 70%.11

‘GVHD’ was diagnosed on clinical grounds along with histological confirmation where possible and graded according to standard criteria.12, 13 GVHD was classified as ‘acute’ if the onset was within 100 days of SCT and ‘chronic’ beyond this period.

Collection, storage and infusion of CD34+ cells

Stem cells were harvested from donor marrow or venous blood after G-CSF mobilization. CD34+ cell quantification was performed using the standard technique of immunofluorescence flow cytometry.14 The immunophenotyping section of our laboratory is validated every 2 months by mandatory participation in the UK National External Quality Assessment Service and the CD34+ cell count results have shown consistency and comparability to other similar laboratories within the country. CD34+ cells were infused on the same day or cryopreserved with DMSO, stored in liquid nitrogen and thawed at 37 °C before infusion at a later date.

Conditioning, immunosuppression and supportive care

Conditioning regimen varied according to the age of the patient, year of transplant, type of donor, previous treatment and comorbidities (Table 1).

Table 1 Patient characteristics

For a majority of children and for most of the recent HLA-matched unrelated donor adult transplants, alemtuzumab (MabCampath)-based conditioning regimen was used. This included a combination of 10 mg (0.2 mg/kg for children) alemtuzumab for 5 days and 50 mg/kg CY for 4 days. For those patients receiving fludarabine-based conditioning regimens, CY dose was 300 mg/m2 for 4 days with 30 mg/m2 fludarabine for 4 days. The majority of patients conditioned without alemtuzumab received a combination of 50 mg/kg CY for 4 days and antithymocyte globulin (ATG; Genzyme, Cambridge, MA, USA) 1.5 vials per 10 kg for 3 days (Table 1).

Post-transplant immunosuppression consisted of 5 mg/kg ciclosporin, starting on day −1 and continued for 12 months, with tapering from 9 months. Levels were measured using mouse monoclonal Ab assays at least weekly and maintained within the 200–300 ng/ml range with close monitoring of renal function. Short-course MTX was given at a dose of 15 mg/m2 on day +1, followed by 10 mg/m2 on days +3, +6 and +11. MTX was omitted for patients who received campath-based conditioning.

CSFs were not routinely used to help with engraftment. G-CSF use was restricted to selected patients who were neutropenic and septic. For Pneumocystis carinii prophylaxis, 300 mg pentamidine was nebulised monthly until achievement of a neutrophil count of >1 × 109/l and a plt count of >75 × 109/l. After this, the prophylaxis was switched to 480 mg cotrimoxazole orally twice daily for 3 days per week, until 12 months after transplant. Itraconazole 2.5 mg/kg twice daily and 200 mg aciclovir thrice daily were administered orally for prevention of fungal and viral infections.

Outcome measures and statistical analysis

The clinical end points were graft failure, acute GVHD, chronic GVHD and OS. Haematological outcome was assessed in terms of neutrophil engraftment, plt engraftment, red cell transfusion independence, plt transfusion independence and chimerism. The patients were classified into low and high CD34+ dose subgroups and the end points were compared.

Mann–Whitney test was used for comparison of mean ranks on continuous variables for the two patient subgroups. The differences between categorical variables were assessed with chi-square or Fisher's exact test as appropriate. Kaplan–Meier estimator with log-rank test was used to evaluate the cumulative incidences between the two subgroups. Univariate Cox regression was applied to determine the predictive effect of individual variables for haematological outcomes. The risk of graft failure was assessed using logistic regression. Covariates with P0.1 were added to the model for multivariate analysis.

All statistical tests were two sided and P<0.05 was considered significant. Data were analysed using SPSS version 16.0 for Windows (SPSS Inc., Chicago, IL, USA) statistical software.

Results

For the whole study population, the median CD34+ cell dose was 3.4 × 106/kg (range 0.5–10.1). The baseline characteristics of the 46 patients are shown in Table 1. There were no major differences between the CD34+ cell dose subgroups with respect to age, gender, severity of AA, median disease duration, type of donor or conditioning regimen (Table 2). A significant difference in CD34+ cell count was noted between the subgroups with regard to cell source, with higher counts from donors who had PBSC harvest.

Table 2 Comparison of disease characteristics, donor type, cell source, conditioning and outcome in low and high CD34+ subgroups

Concurrent CD34+ and total nucleated cell counts were available only for a minority (7 of 46) of patients. Spearman's correlation test performed on these patients showed a positive linear relationship between the two (P=0.014; correlation coefficient r=0.85).

Initial analysis using a cutoff CD34+ cell count of 3.4 × 106/kg

The cutoff CD34+ cell dose of 3.4 × 106/kg did not influence the time to engraft neutrophils (P=0.25) or plts (P=0.34) (Figures 1a and c). No difference was observed between the two groups in the time to achieve red cell (P=0.65) or plt (P=0.83) transfusion independence (Figures 2a and c).

Figure 1
figure1

The effect of CD34+ dose on engraftment of neutrophils and plts.

Figure 2
figure2

The effect of CD34+ dose on red cell and plt transfusion independence.

Grades II–IV of acute GVHD were observed in only 3 of 46 (6.5%) patients. Extensive chronic GVHD was encountered in only 2 of 46 (4.3%) patients. The CD34+ cell dose was not observed to affect the risk for acute (P=1.0) or chronic (P=1.0) forms of GVHD (Table 2).

The data on chimerism were available for only 22 patients, all of whom had transplants in or after 2003. Increasing mixed chimerism was observed in only 2 and 1 patients in the low and high cell dose subgroups, respectively, and hence statistical tests could not be performed.

In all, eight patients had graft failure, of which three were primary failures. The median (1.68 × 106/kg) and range (0.5–5.1 × 106/kg) of CD34+ cell dose was lower for patients who had graft failure compared with the median (3.75 × 106/kg) and range (1.0–10.1 × 106/kg) of CD34+ dose for those who did not have graft failure, but without statistical significance (P=0.09). Five patients in the low CD34+ group and three in the high CD34+ group suffered graft failure, but the difference was not significant (P=0.70).

In total, five patients died on days +10 (Candidal sepsis), +13 (bacterial sepsis), +102 (invasive aspergillosis), +427 (cytomegalovirus pneumonia) and +705 (bronchiolitis obliterans), respectively. No patient was lost to follow-up. OS was not different (P=0.69) between the two patient groups (Figure 3a).

Figure 3
figure3

The effect of CD34+ dose on OS.

Subsequent analysis using cutoff CD34+ cell count of 2.0 × 106/kg

As the median CD34+ level of 3.4 × 106/kg did not influence any of the clinical or haematological outcome measurements, we evaluated values above and below this count. It was found that the cutoff count, which showed a significant influence, was much lower. The population was re-analysed by dividing into tertiles. The highest CD34+ count of the lowermost tertile was 2 × 106/kg and the lowest CD34+ count of the middle tertile was 2.15 × 106/kg. The latter value did not show a significant effect on the outcome (data not shown). Hence, the patients were re-classified into low and high CD34+ subgroups based on a CD34+ threshold dose of 2 × 106/kg. Two patients had CD34+ counts of exactly 2 × 106/kg and were included under the high cell dose group.

Using this lower CD34+ threshold, statistical significance was found for the time to neutrophil engraftment (P=0.046; Figure 1b) and graft failure (P=0.03; Table 2). All other parameters, such as plt engraftment (P=0.63; Figure 1d), red cell transfusion independence (P=0.94; Figure 2b), plt transfusion independence (P=0.31; Figure 2d), acute and chronic GVHD, chimerism (Table 2) and OS (P=0.57; Figure 3b) remained unaffected by the CD34+ cell dose. The patients who received a lower CD34+ cell dose were significantly more likely to have post-transplant bacterial infections (P=0.006), whereas no difference was noted between the low and high CD34+ cell subgroups with respect to viral or fungal infections (Table 3).

Table 3 Post-transplant infections with respect to CD34+ cell dose

Multivariate analysis showed PBSC source to be associated with a faster neutrophil engraftment (P=0.008) and CD34+ cell dose of 2.0 × 106/kg to be associated with a lower incidence of graft failure (P=0.03) (Table 4).

Table 4 Univariate and multivariate analyses of significant risk factors identified by regression

Discussion

Unlike SCT for malignancies, the influence of CD34+ cell dose on specific outcome parameters has not been evaluated in AA transplants. Two studies have mentioned the median CD34+ cell count but have not analysed its significance with respect to outcome, as this was not their primary study objective.15, 16 Some researchers have considered the total mononuclear cell count as a variable with potential influence on graft failure and OS.5, 6, 17, 18, 19 Other published studies to date have not included CD34+ cell dose in their analysis.20, 21, 22, 23, 24 We used the median CD34+ count to define the cutoff to ensure an even distribution of patients in the low- and high-dose arms.

Neither Kaplan–Meier analysis (with log-rank test) nor Cox regression using the median CD34+ cell count showed any statistically significant influence on outcome. Using a lower cutoff of 2.0 × 106/kg, a significant difference was identified in the cumulative incidence of neutrophil engraftment between the two cell dose subgroups and a lower risk of graft failure for the higher cell dose subgroup. However, on multivariate analysis, it was observed that in patients with faster neutrophil engraftment, the effect was mainly as a result of the CD34+ cell source (PBSC) rather than the actual CD34+ count. These findings are in contrast to SCT for haematological malignancies, in which direct correlation has been identified between infused CD34+ cell count and a variety of end points. In an analysis of 212 patients who underwent BMT mainly for malignancies (176 patients; 83%), Bittencourt et al. showed that a CD34+ cell dose of >3 × 106/kg was associated with faster recovery of the neutrophil, plt, red cell, monocyte and lymphocyte counts, higher transplantation-related mortality and lesser OS.4 Similar results were observed with other studies on haematological cancers, including a review of the long-term transplant data from Seattle.25 The reasons behind the favourable influence of PBSC source rather than actual CD34+ cell count on neutrophil recovery are not clear from our study. However, it may be because of the fact that our lower CD34+ cell dose subgroup had only 13 patients, which compromises statistical power.

In total, 3 out of 46 patients (6.5%) had severe acute GVHD and 2 out of 46 patients (4.3%) had extensive chronic GVHD. These figures are considerably lower when compared with most previous reports on allogeneic transplantation for AA.15, 16, 17, 18, 19 Because of the small number of patients with GVHD, it is not possible to conclude from our study whether a high stem cell dose increases its risk. For haematological disorders in general, investigators have found a greater risk of chronic GVHD with PBSC transplant in the setting of a large CD34+ cell dose.25, 26, 27 This may be due to increased type-2 cytokines and IL-10-producing monocytes, which together result in late immune dysregulation.28 The notable reduction in the incidence of severe forms of GVHD could partly be attributed to the extensive use of alemtuzumab for conditioning in the majority of our patients. The superiority of the alemtuzumab-based conditioning for AA transplants in terms of decreased incidence of acute and chronic GVHD has been brought out by previous work from our centre as well as other studies from Toronto and Houston.29, 30, 31, 32 Most of our patients (36 out of 46; 78.3%) had donor marrow as the stem cell source, as recommended by the national guideline.33 This is another likely explanation for the low incidence of GVHD in our analysis.

In the low CD34+ cell dose subgroup, a significantly higher proportion of patients had post-transplant bacterial infections. This was found to be independent of the time to neutrophil engraftment. There was no significant difference between the two subgroups with respect to viral and fungal infections after allo-SCT. This is in contrast to the similar study on haematological malignancies by Bittencourt et al., which showed a higher incidence of fungal, but not bacterial or viral post-transplant infections.4

In conclusion, our study shows that an infusion of less than 2 × 106/kg of CD34+ cells increases the risk of graft failure. Delayed neutrophil engraftment in patients whose stem cell dose is below this threshold was noted to be an effect of cell source rather than actual CD34+ number. Bacterial infections were significantly more common in patients who received lower CD34+ cell dose. The CD34+ cell count did not affect the time to engraft plts or achieve transfusion independence. High CD34+ cell dose was not associated with an increased risk of GVHD and had no significant influence on OS. These differences in the implications of CD34+ cell dose for AA transplants when compared with haematological malignancies is possibly because of the unique biological nature of disease process in the former. The BM in AA is characterized by fewer haemopoietic progenitors, higher number of suppressor T cells and limited ability of mesenchymal stem cells to inhibit T-cell function.28, 34, 35

Our study has a modest sample size in spite of performing a 10-year analysis from a national referral centre for BM failure syndromes. This is a reflection of the rarity of acquired AA as well as the fact that not all patients are treated with transplantation. Despite the size of the sample, definite adverse effects on outcome in recipients of a low stem cell dose have been identified from our analysis. Pooled multicentric data from similar institutions could provide a bigger study population with adequate statistical power. Such a multicentric study may help to further clarify the precise effects of CD34+ cell dose on the outcome of allo-SCT for AA.

References

  1. 1

    Holyoake TL, Alcorn MJ . CD34+ positive haemopoietic cells: biology and clinical applications. Blood Rev 1994; 8: 113–124.

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Siena S, Schiavo R, Pedrazzoli P, Carlo-Stella C . Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy. J Clin Oncol 2000; 18: 1360–1377.

    CAS  Article  Google Scholar 

  3. 3

    Singhal S, Powles R, Treleaven J, Kulkarni S, Sirohi B, Horton C et al. A low CD34+ cell dose results in higher mortality and poorer survival after blood or marrow stem cell transplantation from HLA-identical siblings: should 2 x 10(6) CD34+ cells/kg be considered the minimum threshold? Bone Marrow Transplant 2000; 26: 489–496.

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Bittencourt H, Rocha V, Chevret S, Socie G, Esperou H, Devergie A et al. Association of CD34 cell dose with hematopoietic recovery, infections, and other outcomes after HLA-identical sibling bone marrow transplantation. Blood 2002; 99: 2726–2733.

    CAS  Article  Google Scholar 

  5. 5

    Niederwieser D, Pepe M, Storb R, Loughran Jr TP, Longton G . Improvement in rejection, engraftment rate and survival without increase in graft-versus-host disease by high marrow cell dose in patients transplanted for aplastic anaemia. Br J Haematol 1988; 69: 23–28.

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Bai LY, Chiou TJ, Liu JH, Yen CC, Wang WS, Yan MH et al. Hematopoietic stem cell transplantation for severe aplastic anemia: experience of an institute in Taiwan. Ann Hematol 2004; 83: 38–43.

    CAS  Article  PubMed  Google Scholar 

  7. 7

    McCann SR, Bacigalupo A, Gluckman E, Hinterberger W, Hows J, Ljungman P et al. 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. Bone Marrow Transplant 1994; 13: 233–237.

    CAS  PubMed  Google Scholar 

  8. 8

    Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint MT et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol 1988; 70: 177–182.

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP et al. Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality. Blood 1976; 48: 63–70.

    CAS  PubMed  Google Scholar 

  10. 10

    Champlin RE, Horowitz MM, van Bekkum DW, Camitta BM, Elfenbein GE, Gale RP et al. Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results. Blood 1989; 73: 606–613.

    CAS  PubMed  Google Scholar 

  11. 11

    Hoelle W, Beck JF, Dueckers G, Kreyenberg H, Lang P, Gruhn B et al. Clinical relevance of serial quantitative analysis of hematopoietic chimerism after allogeneic stem cell transplantation in children for severe aplastic anemia. Bone Marrow Transplant 2004; 33: 219–223.

    CAS  Article  Google Scholar 

  12. 12

    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  13. 13

    Lee SJ, Vogelsang G, Flowers ME . Chronic graft-versus-host disease. Biol Blood Marrow Transplant 2003; 9: 215–233.

    CAS  Article  Google Scholar 

  14. 14

    Morariu-Zamfir R, Rocha V, Devergie A, Socie G, Ribaud P, Esperou H et al. Influence of CD34(+) marrow cell dose on outcome of HLA-identical sibling allogeneic bone marrow transplants in patients with chronic myeloid leukaemia. Bone Marrow Transplant 2001; 27: 575–580.

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Gomez-Almaguer D, Vela-Ojeda J, Jaime-Perez JC, Gutierrez-Aguirre CH, Cantu-Rodriguez OG, Sobrevilla-Calvo P et al. Allografting in patients with severe, refractory aplastic anemia using peripheral blood stem cells and a fludarabine-based conditioning regimen: the Mexican experience. Am J Hematol 2006; 81: 157–161.

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Buchholz S, Dammann E, Koenecke CH, Stadler M, Franzke A, Blasczyk R et al. Allogeneic stem cell transplantation from related and unrelated donors for aplastic anemia in adults: a single-centre experience. Ann Hematol 2008; 87: 551–556.

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Min CK, Kim DW, Lee JW, Han CW, Min WS, Kim CC . Hematopoietic stem cell transplantation for high-risk adult patients with severe aplastic anemia; reduction of graft failure by enhancing stem cell dose. Haematologica 2001; 86: 303–310.

    CAS  Google Scholar 

  18. 18

    Maury S, Balere-Appert ML, Chir Z, Boiron JM, Galambrun C, Yakouben K et al. Unrelated stem cell transplantation for severe acquired aplastic anemia: improved outcome in the era of high-resolution HLA matching between donor and recipient. Haematologica 2007; 92: 589–596.

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Kojima S, Matsuyama T, Kato S, Kigasawa H, Kobayashi R, Kikuta A et al. Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program. Blood 2002; 100: 799–803.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Locasciulli A, Oneto R, Bacigalupo A, Socie G, Korthof E, Bekassy A et al. Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT). Haematologica 2007; 92: 11–18.

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Ades L, Mary JY, Robin M, Ferry C, Porcher R, Esperou H et al. Long-term outcome after bone marrow transplantation for severe aplastic anemia. Blood 2004; 103: 2490–2497.

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Bacigalupo A, Hows J, Gordon-Smith EC, Gluckman E, Van Lint MT, Congiu M et al. Bone marrow transplantation for severe aplastic anemia from donors other than HLA identical siblings: a report of the BMT Working Party. Bone Marrow Transplant 1988; 3: 531–535.

    CAS  PubMed  Google Scholar 

  23. 23

    Resnick IB, Aker M, Shapira MY, Tsirigotis PD, Bitan M, Abdul-Hai A et al. Allogeneic stem cell transplantation for severe acquired aplastic anaemia using a fludarabine-based preparative regimen. Br J Haematol 2006; 133: 649–654.

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Bacigalupo A, Oneto R, Bruno B, Socie G, Passweg J, Locasciulli A et al. Current results of bone marrow transplantation in patients with acquired severe aplastic anemia. Report of the European Group for Blood and Marrow transplantation. On behalf of the Working Party on Severe Aplastic Anemia of the European Group for Blood and Marrow Transplantation. Acta Haematol 2000; 103: 19–25.

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Heimfeld S . Bone marrow transplantation: how important is CD34 cell dose in HLA-identical stem cell transplantation? Leukemia 2003; 17: 856–858.

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Mielcarek M, Martin PJ, Heimfeld S, Storb R, Torok-Storb B et al. CD34 cell dose and chronic graft-versus-host disease after human leukocyte antigen-matched sibling hematopoietic stem cell transplantation. Leuk Lymphoma 2004; 45: 27–34.

    Article  PubMed  Google Scholar 

  27. 27

    Schrezenmeier H, Passweg JR, Marsh JCW, Bacigalupo A, Bredeson CN, Bullorsky E et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood 2007; 110: 1397–1400.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Bacigalupo A, Podesta M, Raffo MR, Piaggio G, Van Lint MT, Vimercati R et al. Lack of in vitro colony (CFUC) formation and myelosuppressive activity in patients with severe aplastic anemia after autologous hematologic reconstitution. Exp Hematol 1980; 8: 795–801.

    CAS  PubMed  Google Scholar 

  29. 29

    Gupta V, Ball SE, Sage D, Ortin M, Freires M, Gordon-Smith EC et al. Marrow transplants from matched unrelated donors for aplastic anaemia using alemtuzumab, fludarabine and cyclophosphamide based conditioning. Bone Marrow Transplant 2005; 35: 467–471.

    CAS  Article  Google Scholar 

  30. 30

    Gupta V, Ball SE, Yi QL, Sage D, McCann SR, Lawler M et al. Favorable effect on acute and chronic graft-versus-host disease with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies for marrow transplantation from HLA-identical sibling donors for acquired aplastic anemia. Biol Blood Marrow Transplant 2004; 10: 867–876.

    CAS  Article  Google Scholar 

  31. 31

    Siegal D, Xu W, Sutherland R, Kamel-Reid S, Kuruvilla J, Lipton JH et al. Graft-versus-host disease following marrow transplantation for aplastic anemia: different impact of two GVHD prevention strategies. Bone Marrow Transplant 2008; 42: 51–56.

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Kennedy-Nasser AA, Leung KS, Mahajan A, Weiss HL, Arce JA, Gottschalk S et al. Comparable outcomes of matched-related and alternative donor stem cell transplantation for pediatric severe aplastic anemia. Biol Blood Marrow Transplant 2006; 12: 1277–1284.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Marsh JC, Ball SE, Darbyshire P, Gordon-Smith EC, Keidan AJ, Martin J et al. British Committee for Standards in Haematology (BCSH) General Haematology Task Force. Guidelines for the diagnosis and management of acquired aplastic anaemia. Br J Haematol 2003; 123: 782–801.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Selleri C, Maciejewski JP, Sato T, Young NS . Interferon gamma constitutively expressed in the stromal microenvironment of human marrow cultures mediates potent hematopoietic inhibition. Blood 1996; 87: 4149–4157.

    CAS  PubMed  Google Scholar 

  35. 35

    Bacigalupo A, Valle M, Podesta M, Pitto A, Zocchi E, De Flora A et al. T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol 2005; 33: 819–827.

    CAS  Article  PubMed  Google Scholar 

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Islam, M., Anoop, P., Datta-Nemdharry, P. et al. Implications of CD34+ cell dose on clinical and haematological outcome of allo-SCT for acquired aplastic anaemia. Bone Marrow Transplant 45, 886–894 (2010). https://doi.org/10.1038/bmt.2009.267

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Keywords

  • CD34+
  • stem cells
  • aplastic anaemia
  • allogeneic transplantation

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