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

Lawler, Mark; McCann, Shaun R.; Marsh, Judith; Ljungman, Per; Hows, Jill; Vandenberghe, Elisabeth; O’Riordan, Joan; Locasciulli, Anna; Socié, Gèrard; Kelly, Alan; Schrezenmeier, Hubert; Marı́n, Pedro; Thewis, André; Passweg, Jakob; Dickenson, Anne; Ryan, Joseph P.; Bacigalupo, Andrea

doi:10.1111/j.1365-2141.2008.07533.x

Cited by 86 publications

(67 citation statements)

References 48 publications

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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%

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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

149

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%

“…Patients who showed mixed donor-recipient chimerism but who subsequently reverted to full donor chimerism were classified as having transient mixed chimerism. 33 Declining donor chimerism was defined as a 10% or greater increase in recipient chimerism on 2 consecutive measurements. …”

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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

149

130

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“…Currently, it may be possible to predict graft rejection by monitoring donor chimerism, using short tandem repeat polymerase chain reaction analysis: patients with complete donor chimerism do not experience graft rejection, whereas patients with progressive mixed chimerism, and increasing levels of autologous cells, are at high risk of graft rejection, especially when cyclosporine is withdrawn. 7 In a previous report, the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) described a TBI-free regimen, consisting of fludarabine, cyclophosphamide and antithymocyte globulin (FCA), for patients with severe aplastic anemia undergoing an unrelated donor transplant. 8 The overall graft rejection rate in patients given this conditioning regimen was 18%, with the rate being higher (32%) in patients older than 14 years (median age) and lower in children younger than 14 (5%).…”

Section: Introductionmentioning

confidence: 99%

Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party

Bacigalupo¹,

Socié

Lanino³

et al. 2010

Haematologica

195

154

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BackgroundWe analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed. Design and MethodsAs a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years). ResultsWith a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versushost disease grade III-IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4). ConclusionsThis study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.Key words: aplastic anemia, unrelated transplants, graft failure, graft versus host disease, fludarabine. Citation: Bacigalupo A, Socie' G, Lanino E, Prete A, Locatelli F, Locasciulli A, Cesaro S, Shimoni A, Marsh J, Brune M, Van Lint MT, Oneto R, and Passweg J for the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation, (SAA WP-EBMT).Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party. Haematologica 2010;95:976-982. doi:10.3324/haematol.2009 This is an open-access paper.Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party

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“…During this initial period (< 2 years) some studies have shown that a high mixed chimerism of over 30% recipient leads to increased risk of graft rejection [61][62][63] while others have failed to confirm this [60,64]. Only a very small portion of patients have been reported to still 58].…”

Section: Mixed Donor Recipient Chimerism After Allogeneic Stem Cell Tmentioning

confidence: 99%

Mixed Chimerism after Allogeneic Stem Cell Transplantation – Focus on Double Cord Blood Transplantation

Gertow¹,

Stikvoort²,

Watz³

et al. 2012

J Blood Disord Transfus

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Allogeneic hematopoietic Stem Cell Transplantation (ASCT) is well established as a curative treatment for many hematological malignancies and non-malignant disorders. The aim of ASCT in these diseases is to achieve sustained donor engraftment to fight leukemic cells in malignant disease, improve hematopoietic function, provide immune competence or normalize enzyme deficiency. Peripheral blood or bone marrow is commonly used to monitor engraftment after ASCT. The presence of mixed donor/recipient chimerism after transplantation, donor/donor chimerism after double cord blood transplantation can be used and interpreted differently based on the initial disease status. In patients with malignant diseases, chimerism is primarily used to detect early relapse but can also indicate threatening rejection. In individuals with non malignant disease, chimerism is merely used to monitor successful engraftment. After double cord blood transplantation, the unique situation with two existing donor immune systems can occur. Most often one of the immune systems rapidly succumbs with one immune system prevailing, but in certain situations mixed donor/donor chimerism can exist for prolonged periods. This review describes the importance of mixed chimerism and the possible interpretation after ASCT in patients with both malignant and non-malignant diseases. It also focuses specifically on the situation and mechanisms donor/ donor chimerism after double cord blood transplantation.

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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

Cited by 86 publications

References 48 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

Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA working party

Mixed Chimerism after Allogeneic Stem Cell Transplantation – Focus on Double Cord Blood Transplantation

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