Addition of Anti-T-Lymphocyte-Globuline As Graft Versus Host Disease Prophylaxis for Matched Unrelated Donors Equalizes Outcomes with Matched Sibling Donors: Results from the AML SCT-BFM 2007 Trial

BACKGROUND: AML SCT-BFM 2007 was a prospective, on site monitored, and standardized hematopoietic stem cell transplantation trial for patients with pediatric acute myeloid leukemia (AML). In this trial the graft was the investigational product and therefore needed approval by the Paul-Ehrlich-Institute (PEI). Here we report the outcomes of transplants with matched unrelated donors (MUDs) in comparison to matched sibling donors (MSDs).

METHODS: Bone marrow as graft source was utilized in 90, peripheral blood stem cells in 50 patients. Children and adolescents with high-risk de novo AML or relapsed AML were eligible for enrolment. Between May 2010 and February 2016, 140 children (age < 12 years, n=91) and adolescents (age > 12, years, n=49) were recruited in Germany, Austria and the Czech Republic. A matched donor was either a MSD or an at least 9/10 HLA-matched MUD. Subjects with AML in CR1 (n=45) or CR2 (n=47) were conditioned with a myeloablative regiment consisting of Busulfan (age adjusted i.v. dosing: 3.2 – 4,8 mg/kg BW on days -7 through -4), Cyclophosphamide (60mg/kg i.v. on days -3 and -2), and Melphalan (140 mg/m² i.v. on day -1) (BuCyMel). Graft-versus-Host disease (GvHD) prophylaxis was cyclosporine (CSA) and short-term methotrexate. Patients with MUD received anti-T-lymphocyte globuline at a dose of 20 mg/kg/day on days -3 through -1) in addition. Patients with poor response to AML induction therapy (n=48) were stratified to receive a reduced-intensity regimen consisting of a cytoreductive block with Fludarabine (30mg/m²/d i.v.), Amsacrine (100 mg/m²/d i.v.), and Cytarabine (2g/m²/d i.v.) (FLAMSA) on days -12 through -9, immediately followed by 4 Gy TBI on day -5 and Cyclophosphamide (60 (unrelated)/40 (related) mg/kg/day i.v.) on days -4 through -3. After early taper of MMF and CSA, three prophylactic donor lymphocyte infusions were scheduled on days 120, 150, and 180. ATLG was added for MUDs (20 mg/kg x d) and MSDs (10 mg/kg x d) on days -4 through -2.

RESULTS: Of the 140 patients (68 female, 72 male), 99 received a graft from a MUD (10/10 n=70, 9/10 n=29), 32 from a MSD. Data on ethnicity were not collected. Nine patients without a matched donor were eligible for Haplo-HCT and excluded from this analysis. Overall survival (OS) at 4 years was 65% (SE 5%) for patients transplanted from MUD and not different from that for MDS transplants with 62% (SE 9%). Similarly, there was not difference for MUD and MSD transplants in the 4-years cumulative incidence rates (CI) of aGvHD II-IV with 33% (SE 5%) versus 28% (SE 8%), cGVHD 12% (SE 3%) versus 7% (SE 7%), relapse 28% (SE 5%) versus 34% (SE 9%), and TRM 14% (SE 4%) versus 16% (SE 6%), respectively. Patients in CR1 or CR2 conditioned with BuCyMel had a similar OS after MUD and MDS transplants of 76% (SE 5%) versus 62% (SE 10%), and similar CI rates of aGVHD II-IV 33% (SE 16%) versus 30% (SE 6%), relapse 21% (SE 5%) versus 29% (SE 10%) and TRM 12% (SE 5%) versus 17% (SE 5%). OS after FLAMSA-RIC was 33% (SE 10%) versus 63% (SE 17%) (p=0.17), and CIs of aGvHD II-IV 31% (SE 9%) versus 25% (SE 17%), relapse 46% (SE 10%) versus 50% (SE 20%), and TRM 20% (SE 8%) versus 0% (SE 0%) (p=0.18) in MUD and MSD transplants, respectively.

CONCLUSION: With improving HLA-typing technology, OS and CI of chronic and acute GvHD II-IV are identical after MUD- and MSD-transplantation for pediatric AML, if ATLG is added for MUDs at a dose of 20 mg/kg x day on days -4 through -2. This result may have major ethical implications for the current use of minor sibling donors.