Volume 16, Issue 2 , Pages 292-293, February 2010
Falling Chimerism after Reduced Intensity Conditioning Transplantation
Article Outline
A 54-year-old man with acute myelogenous leukemia (AML) in second complete remission received a reduced-intensity conditioning (RIC) stem cell transplant using fludarabine and intravenous busulfan. The donor was an 8/8 HLA-A, -B, -C, and -DRB1 matched unrelated male. Graft-versus-host disease (GVHD) prophylaxis was antithymocyte globulin, tacrolimus, and methotrexate (MTX) 5 mg/m2 on days 1, 3, 6, and 11, with a plan to taper tacrolimus by 30% at day 60, 30% on day 120, and discontinue at 6 months after transplantation. His tacrolimus was tapered at day 60 as planned.
Evaluation at 4 months after transplantation demonstrated a slightly hypocellular marrow with no evidence of recurrent disease by either morphology or cytogenetics. His counts are normal, and he has no evidence of acute or chronic GVHD (aGVHD, cGVHD). Tacrolimus level at this time is 2.1 ng/mL. Serial chimerism studies show:
| % Donor in Peripheral Blood | ||
| Time Point | Unfractionated | CD3+ |
| 2 months | 90% | 60% |
| 4 months | 60% | 40% |
What would you recommend?
Reader Responses
In a recent issue of the ASBMT eNEWS, readers were presented with the above Clinical Challenge and invited to use an online poll to recommend a course of treatment. The reader recommendations for therapy were:
Commentary
This case highlights several issues regarding the importance of falling chimerism posttransplant and possible therapeutic interventions to reverse it. The first issue is whether the fall in donor chimerism reflects graft rejection, the presence of recurrent disease, or both. Some studies have demonstrated that mixed chimerism more commonly occurs early after reduced intensity conditioning (RIC) in patients with myelogenous disease compared with patients with lymphoid diseases [1]. It is not clear whether the achievement of high levels of donor chimerism after transplantation is related to the patient's disease, pretransplant treatment, or the intensity of therapy received for conditioning. Studies have demonstrated that “low” degrees of donor chimerism early after transplantation are associated with decreased progression-free survival (PFS) in patients with myeloid diseases 2, 3. Specifically, T cell chimerism of <50% is associated with a higher relapse rate [2]. Serial chimerism analyses showing falling chimerism in patients with AML may also predict relapse [4]. I would be worried about impending relapse in this patient despite the recent study showing normal morphology and cytogenetics.
There is general agreement that falling chimerism requires intervention. The majority of respondents (83%) recommended a rapid taper or discontinuation of immune suppressive therapy. Although this would be the course I would recommend, the rate of taper in patients with unrelated or HLA-mismatched donors is often more measured because of the concern for developing severe GVHD. Continuing with the original taper schedule was recommended by about 8% of respondents, but in many cases the clinical result is unsatisfactory, with patients eventually relapsing. Once off immune-suppressive therapy, donor lymphocyte infusion (DLI) is often pursued as a next step, with only partial success in reversing mixed chimerism [5]. It is not clear that other strategies such as prophylactic DLI while on immune suppressive therapy, as suggested by 10% of those responding, will reverse the fall in chimerism. No one voted to increase immune suppressive therapy.
Although high levels of donor chimerism are associated with an improved outcome in patients with AML, the best method to achieve high levels early after transplantation and maintain them is under investigation. Whether maintaining high levels of donor chimerism or reversing falling chimerism results in improved disease control remains unproved, although the close relationship between donor chimerism and outcome in myelogenous diseases suggests that there is a common hematopoietic target of the graft-versus-leukemia reaction.
References
- . Predictive factors and impact of full donor T-cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation. Haematologica. 2007;92:1004–1006
- Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23:1993–2003
- Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2006;12:1047–1055
- . Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia. Bone Marrow Transplant. 2007;39:285–291
- Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood. 2004;103:790–795
PII: S1083-8791(08)00222-X
doi:10.1016/j.bbmt.2008.05.012
© 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 16, Issue 2 , Pages 292-293, February 2010
