First Results of a Prospective I/II Clinical Trial in Adult Patients Using TCR Alpha/Beta Depleted Stem Cell Transplantation from Matched Related and Unrelated Donors

Introduction: We report the first analysis of a multicenter prospective single-arm phase I/II study that assesses the safety and feasibility of transplantation of TCRalpha/beta depleted stem cells from matched related or unrelated donors using the CliniMACS plus System (Miltenyi Biotec, Germany) in combination with a non-myeloablative conditioning in adult patients (trial nr NL48606.000.14). The conditioning regimen consisted of ATG (Thymoglobulin®) 1.5mg/kg i.v. days -12 to -9; fludarabine i.v. 40 mg/m2 days -5 to -2 and busulfan i.v. (Busivex®) days -5 to -2 (cumulative AUC of 80-90mg*h/L), followed by 28 days of mycophenolic acid. All 35 subjects were eligible to address the primary endpoint which is the incidence of acute GVHD at day 100.

Results: 2 centers enrolled 10 female and 25 male patients (median age 59 years, range 19 - 69 years), including 9 AML, 4 ALL, 2 CML, 5 MM, 1 NHL, 10 MDS, 4 MPN. Diseases were in CR (n=17), VGPR (n=1), PR (n=5) or non-remission (n=12). 4 subjects had one or more previous allogeneic SCTs. Donors included 4 MRD, 24 10/10 matched MUD and 7 9/10 matched MUD. 8 male patients received stem cells of female donors. The median number of CD34+ cells and αβ TCR cells/kg was 6.1x 10^6 (range, 1.9-10) and 14.5x10^3 (range, 0-136), respectively. One primary graft failure was observed. Primary engraftment of ANCs > 500 cells/μL was reached at a median of 14 days (range 9 - 48 days) and of platelets > 20 at a median of 17 days (range 10 - 99) days.

The median time of follow-up of this first analysis was 190 days (range 110-400 days). 3/35 patients developed acute GVHD grade III-IV during the first 100 days, 9/35 patients developed acute GVHD grade II-IV and 16/35 patients grade I-IV at day 100. At day 100 the cumulative incidence (CI) of CMV was 31%, of EBV 36% and of BK cystitis 20%. The combined CI of CMV/EBV/BK infections with a CTC-AE grade III-V was 53% at day 100.

Immune reconstitution was rapid with a median of 227 (range 34 - 1626) CD3+ cells/µl on day 100 but varied substantially between patients. The median numbers of CD3/CD4+ and CD3/CD8+ at day 100 post transplant were 60 (range 30 - 120) and 124 (range 5 - 1450) cells/µl. The median numbers of NK were 289 (range 32-1140) at day 30 and 128 (range 24 - 1228) cells/µl at day 100 post transplant. The median numbers of γδ T cells were 38 (range 4-143) at day 30 and 50 (range 8-556) cells/µl at day 100 post transplant.

26 out of 35 patients were alive, 2 patients died of a relapse, 2 of GVHD and 5 of infectious complications. Kaplan Meier estimates of the OS are 88% (+/- 6%) at day 100 and 68% (+/- 9%) at 1Y. Kaplan Meier estimates of the EFS are 77% (+/- 7%) at day 100 and 52% (+/- 10%) at 1Y. 2 patients developed a relapse before day 100 and 5 patients before 1Y. It is noted that the outcome of 5 patients with MM was very poor in this cohort (3 patients developed a relapse and 2 patients died of complications).

Conclusion: Allo-SCT of αβ T cell depleted PBMCs form matched related or unrelated donors, in combination with early ATG and a non-myeloablative conditioning regimen, resulted in favorable rates of primary engraftment (34/35), a CI of aGVHD II-IV of 26% with only minimal immuno-suppression and an encouraging early disease control (Fig 1). OS survival was mainly impacted by NRM (Fig 1), by which the majority of complications were of infectious nature. While all patients with MM suffered from NRM or relapse, all other disease categories had a rather favorable outcome. Reducing inter-individual variations in immune reconstitution early after transplantation will be key to further improve outcomes.

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