Long‐term Stable Mixed Chimaerism Following Allogeneic Marrow Transplantation for Severe Aplastic Anaemia

Spitzer, Thomas R.; Himoe, Eleanor; Cottler‐Fox, Michele; Cahill, Richard A.; Deeg, H. Joachim

doi:10.1111/j.1365-2141.1990.tb07850.x

Cited by 16 publications

(7 citation statements)

References 7 publications

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“…In the present study, we have defined the incidence of MC in a cohort of patients transplanted for SAA. The overall incidence of MC was 56% and while a number of other studies indicate similar results (Hill et al , 1986; Hassan et al , 2004), this is a higher level of MC when compared to the majority of previously described studies (Weitzel et al , 1988; Hows et al , 1989; Keable et al , 1989; Spitzer et al , 1990; Browne et al , 1991; Nakao et al , 1992; Socie et al , 1992; Hoelle et al , 2004; Mao et al , 2005), perhaps reflecting the bias of the study towards patients receiving non‐irradiation‐containing conditioning regimens or a regimen containing Campath 1G monoclonal antibody (Hamblin et al , 1996). The number of prior red blood cell transfusions may also influence the degree of chimerism/engraftment following allogeneic SCT for SAA but, unfortunately, we could not access sufficient data from the records of the participating centres to comment on the significance of this issue.…”

Section: Discussionsupporting

confidence: 76%

Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): indication for routine assessment of chimerism post SCT for SAA

et al. 2009

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Summary Ninety‐one patients were studied serially for chimeric status following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA) or Fanconi Anaemia (FA). Short tandem repeat polymerase chain reaction (STR‐PCR) was used to stratify patients into five groups: (A) complete donor chimeras (n = 39), (B) transient mixed chimeras (n = 15) (C) stable mixed chimeras (n = 18), (D) progressive mixed chimeras (n = 14) (E) recipient chimeras with early graft rejection (n = 5). As serial sampling was not possible in Group E, serial chimerism results for 86 patients were available for analysis. The following factors were analysed for association with chimeric status: age, sex match, donor type, aetiology of aplasia, source of stem cells, number of cells engrafted, conditioning regimen, graft‐versus‐host disease (GvHD) prophylaxis, occurrence of acute and chronic GvHD and survival. Progressive mixed chimeras (PMCs) were at high risk of late graft rejection (n = 10, P < 0·0001). Seven of these patients lost their graft during withdrawal of immunosuppressive therapy. STR‐PCR indicated an inverse correlation between detection of recipient cells post‐SCT and occurrence of acute GvHD (P = 0·008). PMC was a bad prognostic indicator of survival (P = 0·003). Monitoring of chimeric status during cyclosporin withdrawal may facilitate therapeutic intervention to prevent late graft rejection in patients transplanted for SAA.

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Section: Discussionsupporting

confidence: 76%

Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): indication for routine assessment of chimerism post SCT for SAA

et al. 2009

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“…We characterised a pattern of sustained MC in the majority of Cy‐only conditioned patients and in one patient conditioned with Cy + ATG. Sustained MC was previously reported in three SAA patients conditioned with Cy + CsA + MTX as GVHD prophylaxis following allo‐BMT (10).…”

Section: Discussionmentioning

confidence: 75%

“…Following transplantation, a full donor haematopoiesis (complete chimaerism, CC) or, alternatively, cohabitation of residual haematopoietic cells with donor cells (MC) may develop in the recipient. In SAA, the relevance of MC is controversial, especially with respect to late graft rejection, which is the main cause of allo‐BMT failure (10–13).…”

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confidence: 99%

A systematic approach to molecular quantitative determination of mixed chimaerism following allogeneic bone marrow transplantation: an analysis of its applicability in a group of patients with severe aplastic anaemia

Hassan

Bonamino

Braggio

et al. 2004

European J of Haematology

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Mixed chimaerism (MC) following allogeneic bone marrow transplantation (allo-BMT) is defined as the persistent cohabitation of haematopoietic cells from recipients and donors. Its kinetics, clinical implications and more efficient laboratory approaches for MC detection are the object of ongoing research in view of the possibility of developing useful markers. Here we describe a sequential analysis of chimaerism using variable number of tandem repeat (VNTR) polymerase chain reaction (PCR) followed by quantitative, fluorescent labelled, short tandem repeat (STR) PCR. A set of four, highly discriminative VNTR and four STR markers was used to assess chimaerism. Sensitivity and regression analysis indicated that this approach was reliable for routine application in a single BMT centre. We studied 12 patients with severe aplastic anaemia (SAA) who had received allo-BMT, and had been conditioned with cyclosphosphamide (Cy) with or without anti-thymocyte globulin (ATG). We found a 50% prevalence of MC in the whole group, with levels between 4% and 37% of recipient cells. A sustained stable MC pattern after BMT was characteristic of the Cy-only conditioned patients but was also recorded in one patient treated with the Cy + ATG regime who showed a sustained MC pattern over a period of 24 months post-BMT. In none of our patients, MC was associated with an increased risk of graft rejection in a median follow-up of 39.5 months.

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“…33,[38][39][40] Progressive mixed chimerism carries a high risk of graft rejection but stable mixed chimerism is associated with absence of chronic GVHD and excellent survival. Analysis of chimersim showed that while the majority of patients attain FDC in the unfractionated BM by day 100, none of the patients achieve CD3 FDC even at 1-year post-HSCT.…”

Section: Discussionmentioning

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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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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Long‐term Stable Mixed Chimaerism Following Allogeneic Marrow Transplantation for Severe Aplastic Anaemia

Cited by 16 publications

References 7 publications

Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): indication for routine assessment of chimerism post SCT for SAA

Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): indication for routine assessment of chimerism post SCT for SAA

A systematic approach to molecular quantitative determination of mixed chimaerism following allogeneic bone marrow transplantation: an analysis of its applicability in a group of patients with severe aplastic anaemia

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

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