Phase II trial of natalizumab with corticosteroids as initial treatment of gastrointestinal acute graft-versus-host disease.

The α4ß7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri®, Biogen Inc.) acts against the α4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300 mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was 63 years (range 38-74), and 15 (71%) were male. Eighteen (86%) underwent RIC, 15 (71%) received MUD, and all received PBSCs. Overall GVHD at enrollment was grade II in 4 and grade III in 17. The primary endpoint, day 56 GVHD-free survival rate, was attained in 33.3%. The overall response rate at day 28 and 56 was 57% and 52%, respectively. Six of eight CRs were durable for 1 year. Five experienced toxicity possibly related to natalizumab and ten had infections before day 100. 2-year OS was 43% (95% CI 22-62%) and 2-year NRM was 52% (95% CI 29-71%). Natalizumab with corticosteroids as initial treatment of acute GI GVHD is safe, effective, and durable.

A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial.

Hematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell-replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.).