Haematologica 2002; 87:(12)ECR44
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Basiliximab for the treatment of graft rejection in haploidentical peripheral blood stem cell transplantation

G. Messina, E. Quartarone, M. Fujo, G. Irrera, G. Console, M. Martino, R. Mandaglio, F. Morabito, P. Iacopino Centro Trapianti di Midollo Osseo e Terapia Sovramassimali Emato-Oncologiche "Alberto Neri", Azienda Ospedaliera "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.
Correspondence: Dr. Giuseppe Messina, MD, Centro Trapianti Midollo Osseo "A. Neri", Azienda Ospedaliera
Bianchi-Melacrino-Morelli, 89100 Reggio Calabria, Italy. Phone: international + 39.0965.397680.
Fax: international +39.0965.25082. E-mail:gspmessina@virgilio.it

Basiliximab is mainly indicated for the prophylaxis of acute graft rejection in patients receiving renal or liver transplantation. We describe a case of acute graft rejection successfully treated with basiliximab in an adult male patient affected by acute non-lymphoid leukemia and transplanted in second complete remission with a full mismatched HLA-haplotype peripheral blood stem cell transplantation from a sibling donor. Graft rejection was successfully treated with basiliximab with no complications. Unfortunately, the patient died in complete hematologic remission nine months after transplant of interstitial pneumonia due to the reactivation of CMV infection. Basiliximab (Simulect, Novartis) is an IgG chimeric monoclonal antibody that binds and blocks the interleukin-2 (IL-2) receptor alpha chain on the surface of activated T-lymphocytes. It functions by inhibiting IL-2 mediated stimulation of cytotoxic and NK lymphocytes, a critical event in the process of allograft rejection. Basiliximab is uniquely indicated for the prophylaxis of acute graft rejection in patients receiving renal transplantation, as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids,¹ though there are reports on its use in liver transplantation.² We report a case of acute graft rejection successfully treated with Basiliximab in an adult male patient affected by acute non-lymphoid leukemia (ANLL) and transplanted in second complete remission (CR) with a full mismatched HLA-haplotype peripheral blood stem cell transplantation (PBSCT) from a sibling donor.
Case report. A 36 year-old man affected by FAB M4 ANLL in second remission was transplanted. The first relapse had occurred 16 months after autologous PBSCT and the second CR was achieved after MEC protocol for 6 days. Since a matched related donor was not available and the patient was at high risk for relapse, the full-haplotype mismatched brother,³ NK alloreactive against the recipient at the HLA loci B and C, was chosen as donor. The chemotherapy-based conditioning regimen consisted of thiotepa (10 mg/Kg on day -9 from infusion), fludarabine (40 mg/m² on days -8 to -4), rabbit anti-thymocyte globulin (ATG) Fresenius (5 mg/Kg on days -7 to -3) and melphalan (140 mg/m² on day -2). The donor was treated with subcutaneous G-CSF (10 µg/Kg) and PBSC (CD34⁺ cells) were collected starting on the fifth day. CD34⁺ cells were enriched and, to prevent graft versus host disease and lymphoproliferative disorders, T and B lymphocytes were depleted by an immunomagnetic procedure with Isolex 300i (Nexeel, USA). PBSC were stored at a temperature of -180°C. The final number of CD34⁺, CD3⁺/DR⁺ and CD19⁺/CD20⁺ cells infused were 8.7x10⁶/Kg, 10x10³/Kg and 13x10³/Kg, respectively. The post-transplant period (day +5) was complicated by fever of unknown origin. After a primary granulocyte engraftment (day +11), the patient experienced a steroid-resistant immunologic graft rejection. Fever persisted, serum lactate dehydrogenase level increased up to 1,500 U/I and large, phagocytic, lymphomonocytoid CD8⁺/CD56^- and CD45⁺ cells appeared (Figure 1). High-dose steroids were immediately attempted, with no response. Thirty-five days after the first transplant, the patient underwent a second haploidentical transplant from the same donor after further immunosuppressive conditioning with rabbit thymoglobulin (Sangstat) at the dose of 5 mg/kg over 5 days, fludarabine 120 mg/m² over 3 days, cyclophosphamide 160 mg/kg over 2 days and an inoculum containing 10x10⁶/Kg CD34⁺, 10x10³/Kg CD3⁺/DR⁺ and 15x10³/Kg CD19⁺/CD20⁺ cells.
Eleven days after the second transplant, the patient developed a clinical and hematological picture compatible with an immunologic graft rejection. Because rejection of the first transplant had been resistant to steroids, we attempted basiliximab, given at 20 mg/each on days +11 and +15, after having obtained the patient's informed consent. Of note, T-cells expressed CD25 and the chimerism study detected only the presence of informative loci belonging to patient (RR status) before this treatment. Basiliximab was well tolerated, neutrophil count improved to 1.0x10⁹/L on day +14 and >25x10⁺/L platelets were reached on day +22. The other signs of graft rejection completely disappeared within 10 days. At day +81, the patient showed full donor chimerism and CD25 reduced significantly. Unfortunately, six months after transplant the patient revealed CMV reactivation and at nine months he died of interstitial pneumonia.
Discussion. Full haploidentical transplant is reserved for patients with high risk acute leukemias.
The likelihood of success depends of relapse of disease, the appearance of severe infection disease and graft rejection. In particular, for patients with AML⁴ choosing donors with KIR epitope incompatibility in the GvH direction offers a striking advantage for survival. In our case, the patient showed a complete continuous remission and full donor chimerism. The inoculum of a megadose of purified CD34⁺ cells,⁵ and the use of TBI in the conditioning regimen⁶ represent the current strategies for the prevention of graft rejection. Because of previous heavy treatment and lacking of a second donor, we did not perform TBI and we utilized the same source of stem cells of the first transplant also for the second transplant. Although a high number of CD34⁺ cells were infused, the patient had graft rejection. In addition to standard drugs, new agents, such as basiliximab,⁷ are now part of the immunosuppressive strategies. The use of this drug, that inhibits IL-2 mediated stimulation of cytotoxic and NK lymphocytes, caused the disappearance of the clinical and immunologic picture of the graft rejection. We demonstrated that basiliximab may be successfully used for the immunologic control of graft rejection in the setting of allogeneic bone marrow transplantation. Moreover, the role of basiliximab should also be emphasized in this particular case in which the patient showed resistance to very potent, commonly used, immunosuppressive drugs. Basiliximab may represent a therapeutic option for the treatment of graft rejection after BMT, though future studies are warranted to support this new indication. Noteworthy, acute rejection in the bone marrow transplantation setting is typically associated with a CD3/CD8/CD25 phenotype,⁸ while CD4⁺ T cell effector function seems to be sufficient for mediating solid organ allograft failure.⁹ This findings should be taken into account in approaching a treatment of acute graft rejection with basiliximab in the two different settings. In any case, our report should be considered anecdotal in the specific setting of bone marrow transplantation. Finally, because of heavy immunosuppressive treatment, the patient died of interstitial pneumonia due to reactivation of CMV. In this respect, the choice of non-host-reactive donor-derived clones, devoid of GvHD potential, raised against whole CMV,¹⁰ should offer an effective transfer of functional immune cells across HLA barriers, reducing transplant-related mortality.

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