Randomized Study of Double Cord Blood Transplantation (CBT) with Versus without Ex-Vivo Expansion (EXP).
Authors: de Lima Marcos , McMannis J. , Komanduri K. , Worth L. , Karandish S. , Jones R. , Giralt S. , Cooper L. , Padua L. , Patah P. , Petropoulos D. , Thall P. , Zhang W. , Qiao W. , Robinson S. , Qureshi S. , Khouri I. , Hosing C. , Alousi A. , Rondon G. , Andersson B.S. , Champlin R. , Shpall E.J. 
Published: April 2020

The use of CB for stem cell transplantation is increasing. A major disadvantage of CB is delayed and failed engraftment when compared to marrow or blood transplantation. Double CBT and ex-vivo expansion are both strategies being investigated in order to improve hematopoietic reconstitution. We compared these approaches with the aim of improving the clinical outcomes of CBT patients. 48 patients were randomized to receive either two unmanipulated (UNM) CB units (N=24) or one UNM unit and one unit from which all the cells were EXP ex-vivo (N=24). Most CB units were HLA 4/6 matches. Diagnoses were AML (N=16), ALL(N=13), NHL(N= 5), HD(N=7), CML (N=5), and CLL(N=2). Patients (Table 1) were heavily pre-treated, with a median of 3 (1–8) prior regimens including autotransplants in 18%. Preparative regimens included ATG and either fludara plus dose-adjusted busulfan(N=13; myeloid diseases), or melphalan and thiotepa (N=21; lymphoid malignancies/HD); patients not eligible for high-dose therapy received non-myeloablative fludara plus cyclophosphamide and 200 GyTBI (=11) or melphalan(n=3). GVHD prophylaxis was tacrolimus plus either 3 doses of 5 mg/m2 methotrexate or MMF (table 1). Ex-vivo expansion: the smallest unit was CD133-selected using the CliniMACS device (day -14). The T cell-containing CD133-negative fraction was frozen. The CD133+ fraction was cultured for 14 days in media containing SCF, G-CSF and TPO. On day 0, the 2nd UNM unit was infused, followed by the CD133-negative and the EXP fractions. Results. Infused median total nucleated cells (TNC)×108/Kg was 0.36 and 0.36, and median CD34×106/Kg was 0.16 and 0.13, respectively for EXP and UNM pts. Median TNC fold-expansion was 26 (0.44–275) and for CD34+ cells, 2.2 (0–18). There was a nonsignificant trend to more rapid engraftment in patients receiving EXP cells. Patients with &gt;50-fold versus &lt;50-fold TNC expansion engrafted in a median of 19 days(11–21) versus 23 (16–31), and achieved platelets&gt;20K/ul at a median of 29 days(17–44) versus 42(29–56). 25 patients are alive [median follow up is 11.1 mo (2–33.6)]. 100-day and 1-year non-relapse mortality rates are 10% and 22%, respectively (table 2). Chimerism showed that 1 CB unit dominated in all patients. Among 19 evaluable EXP patients, in 63% the UNM unit provided 100% of the hematopoiesis from day +30; the EXP unit was predominant in 3 cases (for 12, 2 and 2 mo.) and present but not predominant in 4 (5–25%, for 12, 7, 3 and 3 mo).

Conclusion: EXP CBT was safe. The range of fold-expansion was highly variable. Accrual continues focusing on strategies which improve CB expansion.

Outcomes Expanded Unmanipulated P C.Incid.: cumulative incidence Time to ANC500 (median/95%CI) 20 days (15, 31) 23.5 (21, 34) 0.4 Proportion engrafting ANC500 82% (n=19) 79% (n=19) 1 Time to PLT20K (median/95%CI) 41 (32, NA) 54 (40, NA) 0.4 Proportion engrafting PLT 67% (n=16) 58% (n=14) 0.38 1-year survival 60% 40% 0.45 aGVHD gd II–IV/ III–IV 32% / 5% 41% / 9% NS C.Incid. cGVHD 47% (28–78) 31% (15–65) NS Expanded Unmanipulated P Complete remission at UCBT 42% 67% 0.15 Median weight 82 (20-113) 76 (51-144) 0.6 Median age 40.4 (4-66) 38.1 (9-65) 0.8 Ablative preparative regimen 67% 75% 0.8 GVHD prophylaxis with methotrexate 48% 48% NS