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

Islam, M S; Anoop, Parameswaran; Datta-Nemdharry, Preeti; Sage, D.; Gordon‐Smith, E. C.; Turner, David M.; Wiltshire, S. P.; O'Regan, L; Marsh, Judith

doi:10.1038/bmt.2009.267

Cited by 14 publications

(16 citation statements)

References 31 publications

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“…42,43 We have recently shown that infusion of Ͻ 2.0 ϫ 10 6 CD34 cells/kg is associated with increased graft failure, increased incidence of bacterial infections and delay in neutrophil engraftment, although neutrophil engraftment is more dependent on stem cell source. 28 One study reported more chronic GVHD when Ͼ 3.7 ϫ 10 8 nucleated cells/kg were infused, but data on CD34 cells were lacking. 44 We have shown in this study that the use of PBSC with alemtuzumab-based conditioning permits collection of an adequate cell dose without causing significant chronic GVHD.…”

Section: Discussionmentioning

confidence: 99%

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Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

Marsh

Gupta

Lim

et al. 2011

Blood

148

130

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We evaluated a novel alemtuzumab-based conditioning regimen in HSCT for acquired severe aplastic anemia (SAA). In a multicenter retrospective study, 50 patients received transplants from matched sibling donors (MSD; n ‫؍‬ 21) and unrelated donors (UD; n ‫؍‬ 29), using fludarabine 30 mg/m 2 for 4 days, cyclophosphamide 300 mg/m 2 for 4 days, and alemtuzumab median total dose of 60 mg (range:40-100 mg). Median age was 35 years (range 8-62). Overall survival at 2 years was 95% ؎ 5% for MSD and 83% for UD HSCT (p 0.34). Cumulative incidence of graft failure was 9.5% for MSD and 14.5% for UD HSCT. Full-donor chimerism (FDC) in unfractionated peripheral blood was 42%; no patient achieved CD3 FDC. Acute GVHD was observed in only 13.5% patients (all grade I-II) and only 2 patients (4%) developed chronic GVHD. A low incidence of viral infections was seen. Factors influencing overall survival were HSCT comorbidity 2-year index (92% with score 0-1 vs 42% with score > 2, P < .001) and age (92% for age < 50 years vs 71% > 50 years, P < .001). Our data suggest that the use of an alemtuzumabbased HSCT regimen for SAA results in durable engraftment with a low incidence of chronic GVHD. (Blood. 2011;118(8): 2351-2357) IntroductionAllogeneic HSCT offers the chance of long-term cure for patients with severe aplastic anemia (SAA), 1-5 but chronic GVHD represents a current major challenge that impacts on quality of life as well as survival. 6 The ideal conditioning regimen for SAA is one that results in sustained engraftment, minimal regimen-related toxicity, and absence of both acute and chronic GVHD. There is no advantage for any degree of chronic GVHD in AA, in contrast to the beneficial impact of GVL effect on HSCT for myeloid malignancies.Over the past few decades, survival after HSCT for acquired SAA has improved greatly. HLA-matched sibling donor (MSD) HSCT results in long-term survival in at least 80% of patients. 1,2,4,5,7,8 The standard of care conditioning for young patients undergoing MSD BM transplantation (BMT) for AA is high-dose cyclophosphamide (CY) 200 mg/kg and ATG, with cyclosporin (CSA) and methotrexate (MTX) as post-graft immunosuppression. Long-term survival occurs in 80%-90% of patients, although this is age-dependent, with only 50% survival above the age of 40-50 years. 3,9,10 Graft rejection occurs in 5%-10%, and acute GVHD in 12%-30%. Notably, chronic GVHD remains a major problem for 30%-40% of patients. In addition, incremental impact of increasing age is observed on the cumulative incidence of acute and chronic GVHD. 3 Unrelated donor (UD) HSCT had previously been reserved for those patients who fail to respond to 2 courses of immunosuppressive therapy (IST), but outcomes after UD HSCT have improved significantly during the past decade. 11-15 A prospective pediatric study from Japan comparing repeat course of IST with UD HSCT showed benefit in favor of early UD HSCT in AA. 16 UD HSCT is now considered after failing 1 course of IST. [17][18] Improved outcomes are likely because of improved HLA-matching ...

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Section: Discussionmentioning

confidence: 99%

“…20,23,28,29 All patients were screened for CMV infections/ reactivation at least weekly for the first 3-6 months using CMV antigenemia or PCR-based assay.…”

Section: Supportive Carementioning

confidence: 99%

Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

Marsh

Gupta

Lim

et al. 2011

Blood

148

130

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“…These analyses almost always showed that the best correlation is between committed progenitors and rapidity of hemato poietic reconstitution [5254] in comparison with total cells and CD34+ cells. Other studies have shown the absence of correlation between the total cell number, CD34+ number and clinical and hematologic outcomes [55] . This confirms a relative progenitor and stem cell source dependent value of these parameters [unfortunately, the progenitor (CFC) number analysis was not shown].…”

Section: Clinical Vs Experimentalmentioning

confidence: 99%

Hematopoietic stem cells in research and clinical applications: The “CD34 issue”

Ivanović¹

2010

WJSC

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In this paper, experimental findings concerning the ki netics of hematopoietic reconstitution are compared to corresponding clinical data. Although not clearly ap parent, the transplantation practice seems to confirm the basic proposals of experimental hematology con cerning hematopoietic reconstitution resulting from successive waves of repopulation stemming from different subpopulations of progenitor and stem cells. One of the "first rate" parameters in clinical transplantations in hematology; i.e. the CD34+ positive cell dose, has been discussed with respect to the functional heterogeneity and variability of cell populations endowed by expression of CD34. This parameter is useful only if the relative proportion of stem and progenitor cells in the CD34+ cell population is more or less maintained in a series of patients or donors. This proportion could vary with respect to the source, pathology, treatment, processing procedure, the graft ex vivo treatment and so on. There fore, a universal dose of CD34+ cells cannot be defined. In addition, to avoid further confusion, the CD34+ cells should not be named "stem cells" or "progenitor cells" since these denominations only concern functionally characterized cell entities.

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“…Evaluation of infused BM CD34? cell dose showed that the risk of graft failure increased significantly with doses of \2 9 10 6 /kg [36]. Thus, it is important to ensure an adequate stem cell dose, although data are lacking in terms of the optimal number of CD3?…”

Section: Early Studies Using Campath-1 Antibodies In Saa Hsctmentioning

confidence: 99%

Allogeneic stem cell transplantation using alemtuzumab-containing regimens in severe aplastic anemia

et al. 2013

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Alemtuzumab, a humanized anti-CD52, IgG1 monoclonal antibody, is used to reduce graft-versus-host disease (GVHD) and aid engraftment after allogeneic haemopoietic stem cell transplant (HSCT). Its associated low incidence of GVHD makes it an attractive alternative to anti-thymocyte globulin (ATG) in transplant conditioning regimen for severe aplastic anaemia (SAA). We have reviewed the use of alemtuzumab-based conditioning regimen for HSCT in SAA and show that it results in sustained haematological engraftment, a very low incidence of chronic GVHD without an increase in viral infections. Intriguingly, alemtuzumab appears to induce tolerance post-HSCT with the findings of stable mixed T cell chimerism with full donor myeloid chimerism and the absence of chronic GVHD, and which persist on withdrawal of post-graft immunosuppression. Finally, its low toxicity profile may permit future application of HSCT to older patients with SAA who fail to respond to immunosuppressive therapy.

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

Cited by 14 publications

References 31 publications

Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

Hematopoietic stem cells in research and clinical applications: The “CD34 issue”

Allogeneic stem cell transplantation using alemtuzumab-containing regimens in severe aplastic anemia

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