A phase I trial of high-dose clofarabine, etoposide, and cyclophosphamide and autologous peripheral blood stem cell transplantation in patients with primary refractory and relapsed and refractory non-Hodgkin lymphoma.

Clofarabine has significant single-agent activity in patients with indolent and aggressive non-Hodgkin lymphoma and synergizes with DNA-damaging drugs. Treatment, however, may be associated with severe and prolonged myelosuppression. We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine in combination with high-dose etoposide and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with refractory non-Hodgkin lymphoma (NHL). Patients received clofarabine at 30-70 mg/m(2)/day on days -6 to -2 in successive cohorts, in combination with etoposide 60 mg/kg (day -8), and cyclophosphamide 100 mg/kg (day -6), followed by filgrastim-mobilized PBSC on day 0. Sixteen patients of median age 57 (range: 32-67) years with diffuse large B cell (n = 8), follicular (n = 5), or mantle cell (n = 3) lymphoma that was either primary refractory (n = 2) or relapsed and refractory (n = 14) were treated at 5 clofarabine dose levels: 30 (n = 3), 40 (n = 3), 50 (n = 3), 60 (n = 3), and 70 mg/m(2)/day (n = 4) in combination with etoposide and cyclophosphamide. All patients had grade 4 neutropenia and thrombocytopenia. Grade 3-4 nonhematologic toxicity was evenly distributed across all 5 dose levels, and included diarrhea (n = 3), mucositis (n = 1), nausea (n = 1), reversible elevation of alanine aminotranferease/aspartate aminotransferase (AST/ALT) (n = 1) or bilirubin (n = 1), and hemorrhagic cystitis (n = 1); all resolved by day +30 following transplantation. The MTD was not reached. No treatment-related deaths occurred. At day +30, 13 patients achieved a complete remission (CR) or unconfirmed CR (CR(U)), and 2 patients achieved a partial response, for an overall response rate of 94%. After a median follow-up of 691 days, the 1-year progression-free survival (PFS) and overall survival (OS) were 63% (95% confidence interval [CI]: 43%-91%) and 68% (95% CI: 49%-96%), respectively. We recommend clofarabine 70 mg/m(2)/day × 5 days as a phase II dose in combination with high-dose etoposide and cyclophosphamide for further testing as a preparative regimen in NHL patients undergoing autologous PBSC transplantation.

In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies.

Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21-58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days -1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5-5.2)×10(7)/kg, engrafted at median of 21 (range, 13-50) days with cumulative incidence of 94% (95% confidence interval, 84%-100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA <6,000 activity·h engrafted within ≤21 days, while all 6 with higher AUCA engrafted later (P=0.002). Seven patients receiving red cell replete grafts had 10-fold lower colony forming units after thawing compared with RCD grafts, with poor engraftment. Systemic DPP-4 inhibition was well tolerated and may enhance engraftment. Optimizing sitagliptin dosing to achieve more sustained DPP-4 inhibition may further improve outcome.