Addition of Umbilical Cord Blood (UCB) Unit to Reduced Intensity Conditioning (RIC) Regimen to Augment Graft Versus Tumor (GVT) in Patients (pts) with Advanced Hematologic Malignancies
Authors: Kebriaei Partow , Giralt Sergio , Jones Dan , Gutierrez Karla , De Lima Marcos , Korbling Martin , Khouri Issa F. , Popat Uday , Qazilbash Muzaffar H. , Alousi Amin , Ciurea Stefan O , Cooper Laurence , Shpall Elizabeth , Champlin Richard 
Published: October 2019

Allogeneic stem cell transplantation (SCT) is associated with a potent GVT effect, mediated by donor immunocompetant cells. The major risk of SCT is graft versus host disease (GVHD), and a major goal is to separate GVT from GVHD. UCB is an effective alternative source of hematopoietic stem cells for transplantation. UCB T-cells have a lower potential to produce GVHD despite transplantation of HLA partially mismatched units, and confer potent GVT effects. We hypothesized that cord blood could be an effective cell source for adoptive immunotherapy. We examined the efficacy of adding one HLA partially mismatched UCB unit to a conventional RIC peripheral blood (PB) SCT from an HLA matched sibling donor in efforts to augment GVT without increasing the rate of GVHD.

Methods: The conditioning regimen consists of Fludarabine 30 mg/m2 administered daily for 4 days (days -10 to -7) followed by one dose of Melphalan 140mg/m2 (day -7). One UCB unit, 4/6 HLA matched with pt, containing at least 1.5 x 107TNC/kg is infused on day -5, followed by infusion of HLA-matched sibling PBSC 5 days later (day 0). Patients with CD20+ disease receive rituximab 375 mg/m2 x 4 doses on day -7, -1, +7, +14. GVHD prophylaxis consists of tacrolimus and mini-dose methotrexate for all pts. Hematopoietic chimerism was evaluated in bone marrow and in GVHD biopsy specimens by restriction fragment length polymorphisms for existing recipient and donor cells (PBSC and cord).

Results: 14 pts (10 M/4 F) with median age 54 years (range 21–67) have been enrolled to date: ALL (n=4), AML or MDS (n=6), MM (n=1), NHL (n=1), CLL (n=2). The median number of prior chemotherapy regimens was 3 (range 1–7), with 8 pts having had a prior allogeneic SCT. At time of study entry, 2 pts were beyond CR1, 3 were in sensitive relapse, 8 were in refractory relapse, and 1 in PR with concurrent NHL and therapy-related AML. The median PB CD34+ cell dose infused was 4.85 x 106/kg (range 2.6–7.7). The median UCB TNC dose infused was 2.8 x 107/kg (range 1.5–4.6). Median time to ANC ≥ 0.5 x 109/L and platelet count ≥ 20 x 109/L were 15 days (range 11–22) and 25 days (range 16–92), respectively. All pts achieved full donor chimerism from the matched sibling donor at a median of 18 days (range 15–147), except for 1 pt with primary graft failure. This patient had slower engraftment from the cord blood unit. UCB cells were noted in the day 30 chimerism analysis of only 1 other pt: 96% sibling donor, 3% recipient, 1% UCB. Of note, this pt relapsed at day 100 post SCT. Six pts are alive at a median follow-up of 4.4 months from SCT (range 1–16.6). The incidence of acute GVHD, grades II–IV and III–IV were 50% and 21%, respectively; 4 pts developed hyperacute GVHD, manifested by fever and diffuse skin rash, occurring 3 to 10 days following SCT (8 to 15 days following UCB infusion); symptoms resolved promptly with initiation of steroids. UCB cells were noted in the GVHD biopsies of 1 pt who developed GI GVHD at day 14, and 1 pt who developed skin GVHD at day 44. The incidence of TRM at 100 days was 21%. Five pts progressed at a median of 4.3 months (range 1.3–11). Among 8 deaths, 2 were related to disease recurrence, 4 related to infection and 2 related to GVHD.

Conclusion: This novel SCT approach is feasible, with a favorable toxicity profile, and without excess GVHD, as compared to the historic data for the FM140 regimen [Giralt et al. Blood 1997, 89(12):4531]. Hyperacute GVHD occurring shortly after UCB infusion suggests an immunologic effect of the cord blood cells. Preliminary data suggests favorable disease control for pts with advanced disease. Longer follow-up is needed to assess the long-term efficacy of this approach.