Immunosuppressive therapy has an important role in the prevention and treatment of acute and chronic GVHD after allo-SCT. However, there exists a fine balance between too much and too little immunosuppression. Too little immunosuppression may lead to increased mortality and morbidity from acute and chronic GVHD and/or graft rejection. In contrast, too much immunosuppression may abrogate the GVL effect, resulting in relapse. In this study we report a patient with CML who had achieved complete molecular remission after a low-intensity matched unrelated donor BMT. The patient developed very little acute GVHD, but experienced aggressive chronic skin GVHD, several years after transplantation. After four doses of TNF inhibitor (infliximab), the patient developed a complete hematologic relapse within 2 months.
A 52-year-old white female was well until she developed a rising WBC count with a leukoerythroblastic picture in 1996. A BM biopsy confirmed panmyelosis with myeloid predominance, and cytogenetics showed the classic t(9;22) translocation of the Ph chromosome consistent with CML in chronic phase. She was treated initially with IFN and achieved a complete hematological but no cytogenetic remission. After 1 year, she progressed on IFN and was therefore referred for a matched unrelated donor stem cell transplant in 1999. She was conditioned initially with fludarabine (120 mg/m2) and cytoxan (120 mg/kg). GVHD prophylaxis used cellcept and tacrolimus. She was transplanted with a 10/10 allele-matched unrelated male donor using BM as a source of stem cells in March 2000. After initial chimerism studies using FISH XX/XY markers showed early engraftment, she eventually experienced graft rejection within 60 days with return of her CML and was therefore reconditioned with fludarabine (120 mg/m2) and melphalan (140 mg/m2). GVHD prophylaxis again used tacrolimus and cellcept, and BM stem cells were obtained from the same 10/10-matched unrelated donor used in the first transplant. Over the next 100 days after transplant, the patient engrafted and achieved a complete cytogenetic remission with full donor chimerism. Subsequently, molecular studies for bcr-abl (Q-PCR) confirmed a complete molecular remission at the level of at least 4 logs. She remained in complete molecular remission for 42 months, but developed aggressive scleradermatous fasciitis of the upper and lower extremities and remained on tacrolimus (1 mg twice daily) and prednisone (20–60 mg daily) continuously. Clinical trials of mycophenolate mofetil, acitretin and extracorporeal photopheresis with Psoralen and UVA light therapy resulted in only partial responses. During all of these trials, her CML remained in CR. She subsequently received four doses of infliximab at 10 mg/kg once weekly i.v. in September 2004. After the third dose of infliximab (remicade), her skin lesions improved dramatically with clear evidence of healing and new granulation tissue appeared after the fourth dose. However, within 4 weeks of completion of the fourth dose of infliximab, the platelet count trended up from 400 000 to 800 000 per mm3 and peaked at over 3 155 000 per mm3 by the twelfth week after infliximab. Her white blood count was 6900/mm3 with a differential of 36 polymorphonuclear leucocytes, 3 bands, 33 lymphocytes, 6 monocytes, 22 eosinophils, 10 basophils, 3 nucleated RBCs and 7 atypical lymphocytes. The T cells and marrow testing showed that male donor chimerism by FISH XX/XY probes had dropped to just 9% of total cells in the marrow and blood T cells. Recipient cells had risen to 89%. Cytogenetics documented that 100% of the metaphases were positive for the t(9;22) translocation and FISH for bcr-abl was 100% positive, consistent with full relapse. The patient was subsequently placed on hydroxyurea 500 mg twice a day and imatinib 600 mg once a day and monitored carefully. After 5 months, she achieved a complete molecular remission as determined by quantitative PCR testing for bcr-abl. The patient's skin disease achieved a significant response but persisted. She subsequently received four doses of rituximab in 2007 while on imatinib without any evidence of relapse of her CML.
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