Haematologica 2002; 87:(10)ECR32
[Medline] [prev] [index] [next]Successful management of impending late graft failure in a thalassemic bone marrow transplant recipient
Johannes L. Zakrzewski, MD
Bone Marrow Transplantation Center Idar-Oberstein, Dr. Ottmar-Kohler-Str. 2, 55743 Idar-Oberstein, Germany
Correspondence: Johannes L. Zakrzewski, University Hospital Essen, Department of Pediatric Hematology, Oncology and Endocrinology, Hufelandstrasse 55. 45122 Essen, Germany. Tel.: +49-201-7232500. Fax: +49-201-7235942. E-mail: johannes.zakrzewski@uni-essen.de
Graft failure is a common cause of morbidity and mortality after bone marrow transplantation for beta-thalassemia, yet a gold standard for the management of this critical clinical condition does not exist. This report is on a 2-year old thalassemic girl who received matched related allogeneic bone marrow containing 2.37x106/kg CD34(+) cells following the established conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine A and prednisolone. After initial alloengraftment we saw a continuously decreasing total donor chimerism but donor T-cells predominating. Withdrawal of immunosuppression led to allogeneic recovery. In patients with mixed chimerism and decreasing allogeneic signals, additional analysis of the T-cell chimerism may be a helpful diagnostic tool with regard to making the right therapeutic decision in this difficult clinical situation. In mixed chimerism with predominance of donor T-cells, discontinuation of the immunosuppressive medication can lead to full allogeneic recovery.
Despite considerable risks, to date the only curative treatment in beta-thalassemia major is allogeneic bone marrow transplantation (BMT). As yet, more than 1500 transplantations for beta-thalassemia have been performed worldwide.1 According to the established Pesaro classification patients are divided into 3 classes depending on the presence of hepatomegaly, liver fibrosis and inadequacy of iron chelation therapy given before transplant. The probability of post-transplant event-free survival is influenced significantly by these risk factors.1 Besides conditioning regimen-related organ toxicity, infectious complications and graft-versus-host disease (GVHD), graft failure (GF) is one of the major causes of morbidity and mortality after allogeneic BMT for thalassemia. GF is classified as primary graft failure (failure of engraftment) or late graft failure (graft failure after initial engraftment) and is found either with autologous hematological reconstitution or with (re)-occurrence of aplastic marrow.2 This report highlights the management of impending late graft failure in a 2-year old girl who underwent allogeneic bone marrow transplantation for beta-thalassemia in March 2001. Risk factors, prophylactic and therapeutic strategies are discussed.Case Report. The propositus is a 2-year old girl who underwent HLA identical sibling donor BMT for beta-thalassemia major in March 2001. We used the established conditioning regimen with busulfan and cyclophosphamide, GVHD prophylaxis consisted of cyclosporine A and prednisolone. Detailed patient and transplant characteristics are presented in Table 1.White blood cell engraftment, defined as the first of three consecutive days with an absolute neutrophil count higher than 500/µL, was demonstrated on day +15. Chimerism analysis by molecular genetic techniques initially showed mixed chimerism (MC) with predominating donor hematopoiesis: studies on day +17, +24 and +32 revealed 90%, 80 % and 86 % donor cell origin in peripheral blood (PB) samples, chimerism analysis of bone marrow (BM) on day +32 revealed 91% donor cell origin. Associated with a CMV infection and ganciclovir therapy the total donor cell chimerism decreased to 36% (PB) and 26% (BM) on day +100 resembling secondary graft failure. The donor T-cell subset, however, continuously comprised >=90%. Allogeneic recovery occurred after having withdrawn the immunosuppressive medication (Figure 1): within 6 weeks the total donor chimerism (PB) increased from 36% to 88%.
Today the patient is alive and well, however she subsequently developed chronic cutaneous GVHD so that she again had to be started on immunosupressive medication.
The fact that a considerable number of thalassemic transplant recipients suffer from graft failure is well known. Persistence of residual host hematopoietic cells (mixed chimerism and primary graft failure with autologous reconstitution) is found in approximately 30% of cases after BMT for beta-thalassemia.3 It is therefore important to be aware of risk factors and to establish effective prophylactic and therapeutic strategies. GF-risk factors include T-cell depletion (in particular, decreased number of donor CD3(+) cells in the inoculum),3 transplants from HLA-mismatched and unrelated donors, inadequate busulfan blood levels, alloimmunization due to blood transfusions or pregnancies prior to BMT and transplants with a low hematopoietic stem cell inoculum.1,2 Low leukocyte counts between days 12 and 22 have also been reported to be associated with an increased probability of GF.4 The incidence of persistent MC averages 10%.5 The development of early mixed chimerism (MC before day 100) predisposes to subsequent GF (especially if host cell levels are above 25%)1 whereas especially late MC tends to be stable indicating that host and donor cell are able to coexist in a state of tolerance. The incidence of GF (primary and late) after transplants for thalassemia varies from 7% to some 50% depending on the type of donor and risk class with the highest risk for class 3 patients with mismatched unrelated donors.1,6 GF may be initiated by immunologic reactions of residual host T-cells (= host versus graft (HvG) phenomenon or rejection),1,7 CMV infections, drug toxicity or microenvironment dysfunction due to damage to the host derived marrow stroma, secondary to GvHD, chemotherapy, radiation or viral infections, amongst others.2,8 In our patient GF was associated with a CMV infection, drug administration (ganciclovir) and a low stem cell inoculum. In patients with an increased risk of GF the addition of anti-thymocyte-globulin (ATG) to the preparative regimen and intensification of the immunosuppressive treatment have been described as effective prophylactic strategies.2,9 However, GF cannot always be prevented that way. In order to detect MC as early as possible, chimerism studies should be performed regularly and at short time intervals especially in newly-transplanted patients, e.g., once a week until day 100 and at least every 4 weeks until 12 months post transplant. Upon the occurrence of mixed chimerism with decreasing allogeneic patterns, analysis of the T-cell chimerism may reveal important additional information about the immunologic function of the transplant contributing to a successful management of this difficult clinical problem.
A gold standard for the treatment of mixed chimerism/graft failure in thalassemic BMT recipients does not exist, yet therapeutic recommendations based on the status of immunologic reconstitution could be as follows: (a) if T-cells are predominantly donor- derived: reduce immunosuppressive medication as quickly as possible. The now increasingly developing donor-T-cell mediated immunity might help the transplant to prevail and subsequently initiate allogeneic recovery. Even though this case report supports this theory, a prospective systematic study of T-cell chimerism in a series of patients with graft failure is still required for verification. It is also important to stress that the above described procedure in no way guarantees conversion to complete donor chimerism. In addition, rapid discontinuation of immunosuppressive therapy is associated with a considerable risk of provoking GVHD, careful monitoring of the corresponding clinical parameters is therefore required. (b) In non-responders, and if T-cells are predominantly host-derived: intensify immunosuppression and give a boost dose of donor hematopoietic stem cells ± ATG, but without additional chemotherapy or total body irradiation, to support the graft.10 Watch carefully for signs of GVHD. (c) Stop myelotoxic drugs. (d) In patients with neutropenia: give hematopoietic growth factors (G-CSF / GM-CSF). (e) In patients with aplastic marrow refractory to conventional therapy: perform second transplantation. However, the transplant-related morbidity and mortality is significant.2 Since host and donor cells were found to be able to coexist, the persistence of stable mixed chimerism without transfusion need does not require any specific therapy.1,11References