FT1050 (16,16-dimethyl Prostaglandin E2)-Enhanced Umbilical Cord Blood Accelerates Hematopoietic Engraftment After Reduced Intensity Conditioning and Double Umbilical Cord Blood Transplantation

Abstract 653

Umbilical cord blood (UCB) transplantation relies on a small number of hematopoietic stem cells (HSCs) to restore hematopoiesis. Even with double umbilical cord blood transplantation, engraftment times are prolonged and immune reconstitution delayed. Preclinical studies have suggested that ex vivo treatment of HSCs with FT1050 (16,16-dimethyl PGE2) can enhance engraftment of HSCs without stem cell expansion or differentiation of HSCs to committed progenitors. Using both murine and human-xenograft model systems, the mechanisms of action of FT1050 treatment of HSCs have been demonstrated to involve improved homing via CXCR4-SDF-1, increased proliferation and entry into the cell cycle, and decreased rates of apoptosis (North 2007; Goessling 2009; Hoggatt 2009; Goessling 2011). A Phase Ib trial was designed to evaluate the safety of FT1050-treated HSCs and whether this ex vivo treatment can enhance engraftment after double UCB transplantation in adults. The competitive engraftment dynamic of double UCB transplantation also permits determination of whether FT1050-HSCs are able to out-compete untreated HSCs. Methods: Patients without a matched sibling or matched-unrelated donor were conditioned with fludarabine (30 mg/m²/day IV Day −8 to −3), melphalan (100 mg/m²/day IV Day −2), and rabbit ATG (1 mg/kg/day Days −7, −5, −3 and −1). GvHD prophylaxis was with sirolimus (target 3–12 ng/mL) and tacrolimus (target 5–10 ng/mL). Patients received 2 UCB units: the first UCB unit (FT1050-UCB) was thawed, washed and treated with FT1050 for 2 hours at 37°C. After an additional wash to remove residual FT1050, the FT1050-UCB was infused without further manipulation. The second untreated UCB was thawed, washed and infused 2–6 hours later. The primary objective of the study was to determine the safety of FT1050-UCB based upon engraftment by Day 42 with > 5% chimerism of the FT1050-UCB unit. Secondary objectives included time to engraftment, the rates of non-hematologic toxicity, graft failure, acute and chronic GvHD, relapse, treatment related mortality (TRM), fractional chimerism, and relapse-free and overall survival. Results: A total of 12 subjects received FT1050-UCB in this fashion, of which 11 are currently evaluable. The median age was 57.5 years (range 19–66) and 67% were male. Diagnoses included: AML(5), MDS(4) and NHL/CLL(3). The median precryopreservation UCB sizes were FT1050-UCB: 2.7×10⁷ TNC/kg (range 2.0–5.1) with 1.3×10⁵ CD34/kg (range 0.3–6.3); untreated UCB: 2.0×10⁷ TNC/kg (range 1.8–5.0) with 1.1 × 10⁵ CD34/kg (range 0.5–3.4). The median combined cell dose was 4.7×10⁷ TNC/kg (range 3.9–10.1) with 2.1×10⁵ CD34/kg (range 1.4–9.7). The FT1050 incubation did not result in significant cell loss, with a mean viable CD34 cell recovery of 90%. The adverse events attributed to FT1050-UCB consisted of five Grade 1/2 infusion-related events in 4 subjects, consisting of chills, flushing, abdominal pain, and cough. One additional subject with known coronary artery disease experienced transient Grade 4 ST-elevation following infusion and evidence of myocardial ischemia by cardiac troponin assay. The median time to neutrophil recovery (> 500 cells/μL) was 17 days (range 15–27 days), which compares favorably to a median of 21 days for a historic control group of similarly treated patients at our institution (n=53; p= 0.025). The median time to an unsupported platelet count of 20,000/μL was 42 days (n=9 evaluable). There were no instances of primary or secondary graft failure. The FT1050-UCB was the dominant source of hematopoiesis in 9 of the 11 evaluable subjects, and the median total chimerism of FT1050-UCB at day 14 was 90%, with long-term dominance again by the FT1050-UCB unit. To date, 2 cases of Grade 2 acute GvHD have been observed and one patient developed NIH mild chronic GvHD. No cases of EBV-lymphoproliferative disease were noted. TRM was 9% (1 subject) and 1 patient has relapsed; 9 subjects remain alive without relapse with a median follow-up of 5.0 months (range 1.6–9.4). Conclusions: These data support the potential benefit of a novel ex vivo modulation approach to improving engraftment in patients undergoing UCB transplantation. Additional studies exploring the potential use of FT1050-HSCs in other low cell dose settings are planned, including whether FT1050-UCB can enable single UCB transplant in adults.