Allogeneic Peripheral Blood Stem Cell Transplantation Using Reduced-Intensity Conditioning Regimen with Fludarabine and Busulfan from HLA-Matched Related Donor for Elderly Adult T-Cell Leukemia/Lymphoma: Results of Multicenter Phase II Study (ATL-NST-3)

Background: Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type 1 (HTLV-1) infection and commonly affects individuals at an average age of 67 years. Since the prognosis of aggressive ATL patients (pts) treated with conventional chemotherapy has been dismal, we had so far conducted two clinical trials to evaluate the feasibility of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from an HLA-identical sibling donor using reduced-intensity conditioning regimen (RIC) consisting of fludarabine and busulfan. We reported that allo-PBSCT using RIC provided a long-term survival in about one third of ATL pts and that it exerted not only graft-versus-ATL effects but also graft-versus-HTLV-1 effects (Okamura J, et al. Blood 2005; Tanosaki R, et al. Biol Blood Marrow Transplant 2008; Choi IL, Bone Marrow Transplant 2011). To confirm these promising results in a larger number of ATL pts, we conducted a phase II study (UMIN C000000409).

Patients and Methods: Between September 2006 and July 2011, 20 pts were registered in this study. Because ATL is a rare disease affecting elderly people, their siblings were also old and were not appropriate for donors, and the enrollment of pts needed much more time than we had expected. Therefore, though we had originally planned to enroll 35 pts, we had to close this study incompletely. The conditioning regimen consisted of fludarabine 30 mg/m²/day intravenously days -8 to -3, and busulfan 3.2 mg/kg/day intravenously or 4 mg/kg/day orally days -6 and -5. GVHD prophylaxis was CsA alone from day -1 and PBSCs (CD34⁺ cells >2x10⁶/kg) were infused on day 0. Primary endpoint was 2-year overall survival (OS). Engraftment, adverse events such as graft-versus-host disease (GVHD) and infectious events, and progression free survival (PFS) were also evaluated as well as donor chimerism by STR-PCR analysis, HTLV-1 proviral load, and Tax-specific cytotoxic T lymphocytes (CTL) by tetramers. The eligibility criteria at registration included acute- or lymphoma-type ATL, pts with an HLA-matched related donor, age between 50 and 70, disease status of CR, PR or NC with stable disease, no uncontrollable active infections, no major organ dysfunction, and no active CNS involvement.

Results: Median age was 54 years (range 50-68), genders were 10 males and 10 females, ATL types were 13 acute and 7 lymphoma, and disease status at transplantation was 9 CR, 8 PR, and 3 NC. 13 donors were HTLV-1 positive. Engraftment as confirmed by donor chimerism analysis was achieved in all pts. OS and PFS were 95% (95%CI, 86-100%) and 60% (95%CI, 39-82%) at day 100, 74% (95%CI, 55-94%) and 45% (95%CI, 23-67%) at 1 year, and 53% (95%CI, 31-76%) and 40% (95%CI, 19-62%) at 2 years. Acute GVHD occurred in 13 pts (grade I in 2, II in 5, III in 6 pts), and chronic GVHD developed in 12 pts (63%) out of 19 evaluable pts. Eleven pts died at the time of analysis; ATL 6, GVHD 3, IP 1, PCP 1. There was no significant relationship between OS and grades of acute GVHD. While HTLV-1 proviral load decreased as early as 1 month after transplantation and became undetectable level in 14 pts (70%) out of 20, the increase of A2- or A24-restricted Tax-specific CTLs in HLA-A2 or A24-positive pts, respectively, were observed in some pts after 3 months or later, and there was no clear relationship between them. With a median follow-up of 36 months (range 24-86), 9 pts (5 CR and 4 PR at transplantation) were alive without disease.

Conclusions: It was confirmed that allo-PBSCT using RIC consisting of fludarabine and busulfan was relatively safe and effective, and provided a long-term survival at least in chemo-sensitive aggressive ATL pts.