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Evidence for a graft-versus-leukemia effect in the central nervous system

Patients with acute leukemia who relapse after alloSCT have a poor prognosis: without further treatment the survival time is less than 6 months. Even among patients who achieve remission after reinduction chemotherapy, only about 1 in 10 survive for more than 2 years [1]. The optimal treatment strategy for these patients is unclear. Repeat conventional allo-SCT is an option, but it carries a high treatment-related mortality [2]. In addition, in patients who have CNS relapse after allo-SCT, and especially in children, neurological toxicity from additional CNS irradiation, long-term intrathecal therapy (IT), and systemic chemotherapy is a particular concern [3]. Although it is well established that the graft-versusleukemia (GVL) effect contributes substantially to the eradication of hematological malignancies after allo-SCT, there are few data on a possible GVL effect within the brain [4]. We report the cases of three patients with recurrent and refractory aggressive acute leukemia who had CNS relapse after multiple treatments, including allo-SCT. Durable remission was achieved, likely owing to a GVL effect within the CNS. Patient 1. In April 1998 an 11-year-old boy was diagnosed with primary refractory acute myeloid leukemia (AML) FAB M2. Two induction courses of the daunorubicin and cytarabine (Ara-C) combination failed to achieve complete remission (CR). In August 1998 he underwent allo-SCT with his HLA-identical dizygotic twin brother as donor. Conditioning included busulfan 16 mg/kg and cyclophosphamide (CTX) 120 mg/kg. The graft consisted of 3.1610 mononuclear cells/kg. Cyclosporine A (CsA) 2 mg/kg/day and methotrexate (MTX) were used for GVHD prophylaxis. He engrafted on day þ12 and developed no signs of GVHD. He remained in CR until December 1999, when a medullary relapse was diagnosed. A second allo-SCT with a reduced-intensity conditioning regimen (RIC) was performed. Conditioning consisting of fludarabine 30 mg/m for 5 days, Ara-C 2 g/m for 5 days and idarubicin 12 mg/m for 3 days. Peripheral blood stem cell (PBSC) transplantation was performed with the same donor. The graft consisted of 2.68610 CD34þ cells/kg. CsA alone was used for GVHD prophylaxis. Engraftment occurred on day þ18, with no signs of GVHD; full chimerism in the peripheral blood was documented on day þ30. Four months after the second transplantation, while still on CsA, he developed neurogenic bladder. Cerebrospinal fluid (CSF) analysis revealed leukemic blasts and MRI studies showed diffuse leptomeningeal infiltration of the spinal cord, whereas a bone marrow aspirate was normal. Isolated CNS relapse was diagnosed and MTX, Ara-C and dexamethasone were given intrathecally once a week, simultaneously with systemic high-dose Ara-C, MTX and L-asparaginase.