Double-Unit Cord Blood Transplantation for Hematological Malignancies in Japan: Multicenter Phase II Study (C-SHOT 0507)

Double-unit cord blood transplantation (dCBT) has been widely applied for patients with less dose single-unit cord blood (sCB) because of a higher engraftment failure. Although several reports have suggested that dCBT may have impact on increasing GVHD incidence and reducing disease relapse, pre-transplant conditioning and GVHD prophylaxis varied too much to read the results. We therefore conducted a prospective multi-center phase II study assessing safety and efficacy of dCBT by using relatively uniform myeloablative conditioning and GVHD prophylaxis in Japan.

From Apr. 2006 to Jan. 2010, patients younger than 55 years with hematological malignancies who lack any adequate unrelated and related donors and without prior history of transplantation were prospectively enrolled. Thirty-nine centers participated following approval by each institutional review board (Trial identifier: UMIN :C000000359, C-SHOT0507). Patients were eligible when there is no single unit with total nucleated cell (TNC) dose of > 2.5 × 10⁷ /kg available, and at least 2 units available that have combined TNC > 2.5 × 10⁷ /kg, with one of each > 1.5 × 10⁷ /kg and the other < 2 × 10⁷ /kg. CB units mismatched at 0–2 antigen in HLA-A, -B, -DR between unit and patient were selected. Preparative regimens were 12 Gy of TBI, Ara-C (12 g/m²) combined with G-CSF, and 120 mg/kg of CY for myeloid diseases, while TBI + CY for lymphoid diseases (S.Takahashi, et al. Blood 109;1322, 2007). GVHD prophylaxis was short term MTX and CsA.

Seventy patients were enrolled and 61 patients (AML 29, ALL 17, CML 6, MDS 6, ML 3) received dCBT. Nine patients did not receive dCBT due to disease progression (n=7) and other SCT (n=2). Disease status at dCBT was 27 in standard (CR1, CP1) and 34 in advanced (beyond CR1 or CP1). The median age was 37 years (range; 10–54) and median weight was 70.5kg (50.1–129.8). Median total and CD34⁺ cell doses (both units combined) at cryopreservation were 3.52 × 10⁷ /kg (2.25 – 4.43) and 1.04 × 10⁵ /kg (0.39 – 2.67), respectively. Median TNCs of larger and smaller unit were 1.90 × 10⁷ /kg (1.47 – 2.48) and 1.60 × 10⁷ /kg (0.74 – 1.97), respectively. Cumulative incidence of neutrophil recovery (NR, >0.5 × 10⁹/L) was 67%(53–77) at day28, and 85%(73–92) at day 50. The median time to NR was day 26 (18–50) and median time to transfusion-independent platelet recovery (>20 × 10⁹/L) was day 53 (32–98). Four died early before day 30 (2 on day8, 1 each on day11 and day 29) and 6 received 2^nd transplantation due to engraftment failure (on day30, 33, 37, 42, 50, 54). Among engrafted 51 patients, all 50 patients assessed for chimeric status showed single donor-derived engraftment; 27 were from larger unit and 23 from smaller dose of TNC. Number of TNC of engrafted smaller unit was ranged from 0.74 – 1.96 × 10⁷ /kg, including 6 that were even less than 1.5 × 10⁷ /kg. There is no correlation between unit dominance and the number of TNC, CD34⁺ cell dose, CFU-GM dose, degrees of HLA/sex/ABO mismatches between units and recipients, and graft viability. Acute GVHD progressed in 33 (65%) of 51 evaluable patients (29% grade II-IV), and chronic GVHD was observed in 18 (36%) of the 50 evaluable patients (18% extensive). Actual EFS, RFS and OS at 1y and 3y was 48%(37–58) and 46%(35–56), 49%(36–61) and 47%(34–59), 57%(44–69) and 54%(40–65), respectively. Median follow-up period of survivors (n=32) are 1226.5days (365–1721). EFS at 1y of standard and advanced status patients was 67%(46–81) and 32%(18–48), respectively (p=0.023). Dose of TNC, CD34 and HLA disparity did not significantly affect on survival. Cumulative incidence of day100-TRM was 26%, and relapse late at 3y was 16.3%. Cause of death were disease progression in 11 and TRM (infection and organ failures) in 18.

Myeloablative dCBT can be a safe and effective alternative option for those who only have insufficient sCB available (less than 2.5×10⁷/kg of TNC). So far, parameters assessed, such as the engraftment kinetics, survival rate, cumulative incidence of GVHD and relapse in dCBT seem to be comparable to our historical data of sCBT. Determinants of engrafting units after dCBT are still unclear.

Off Lavel Use: G-CSF at pre-conditioning for myeloid malignancies is an off-label use in Japan. This study was supported by a Research Grant for Tissue Engineering (H17-014) and a Research Grant for Allergic Disease and Immunology (H20-015) from the Japanese Ministry of Health, Labor and Welfare.

Off Label Use: G-CSF at pre-conditioning for myeloid malignancies is an off-label use in Japan. Kato:Research Grant for Tissue Engineering (H17-014) and a Research Grant for Allergic Disease and Immunology (H20-015) from the Japanese Ministry of Health, Labor and Welfare.: Research Funding.