A Pilot Study of Reduced-Intensity Conditioning Stem Cell Transplantation with T-Cell Replete HLA-Mismatched Allograft from Child to Parent Patient for the Treatment of Refractory Adult T-Cell Leukemia.

[Background/Purpose] Adult T-cell leukemia (ATL) is a most aggressive lymphoid malignancy with poor prognosis, and at present, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been an only curative modality. Nevertheless, not only the aggressive nature of disease itself, but also the aging of patients older than 55 y.o. contribute to therapeutic impediments by comorbidity and difficulty of timely acquiring HLA-matched sibling donor. In this setting, allograft from child to parent patient is a realistic modality. We report a result of a prospective study evaluating the efficacy of reduced -intensity conditioning SCT (RIST) with HLA-mismatched allograft from child to parent for ATL patients. [Patients/methods] 5 patients (2 males, and 3 females) with ATL in progressive disease (PD) after induction chemotherapy with LSG15 regimen who had no HLA-identical sibling donors were enrolled. Patient median age was 59 y.o. All donors were sons with haploidentical HLA. Median age of donor was 29 y.o. KIR ligands were matched. Preparatory regimen consisted of fludarabine (180mg/m 2 ), busulfan (8mg/m 2 ) or cyclophosphamide (120mg/kg) and rabbit antithymocyte globulin (2.5mg or 5.0mg/kg). Stem cell source was G-CSF mobilized PBSC. Mean infused CD34 cell number was 8.3×10 6 /kg (from 4.1 to 23.3 × 10 6 /kg). GVHD prophylaxis consisted of tacrolimus or cyclosporine and short term methotraxate and mycophenolate mofetil. [Results] Median interval from induction chemotherapy to transplantation was 5 months. Median observation interval was 8 mo. (from 3.5 mo. to 31 mo.). All 5 cases had neutrophil engraftment at day 15 after transplantation. In 5 of 5 cases, complete donor T-cell chimerism were obtained by day 30. Overall survival (OS) and progression free survival (PFS) at 1 year was 50%, and 26.7%, respectively. Evaluation of peripheral residual disease demonstrated by HTLV-I proviral load and soluble interleukin-2 receptor (sIL-2R) value documented the strong disease suppression by this transplants. Analysis of NK cell kinetics revealed that donor-derived NK cells expanded and exerted killing activity mainly until 4 months after transplantation, and decreased in number thereafter. These findings indicated all achieved complete donor T-cell chimerism followed by clinical observations for graft vs. ATL effect. Although, disease progression occurred 4 of 5 cases, 2 achieved remission again with the longest response duration of 31 mo. All but UPN2 experienced GVHD (grade 2 to 4), and UPN2 had early relapse and died of ATL at 4 mo. after allo-HSCT. Frequent reactivations of cytomegalovirus were observed, but well controlled by ganciclovir. [Summary] In our pilot study, RIST with T-cell replete HLA-mismatched allograft from child to parent patient could provide timely donor acquisition and durable remission for all patients with refractory ATL. This setting may be one of realistic modalities for ATL patients who need alternative donors.