Improved Outcomes of Haploidentical Blood and Marrow Transplantation with Giac-3 Protocol That Haploidentical Bone Marrow from the Second Donor As the Third Party Cells

Introduction: With GIAC regimen (G: G-CSF priming; I: intensified immune-suppression; A: ATG application; C: combination of peripheral blood stem cell and bone marrow (BM) as graft), haploidentical blood and marrow transplantation (haplo-BMT) has been an important alternative option for patients with hematological malignancies who need urgent transplant but without HLA matched either sibling or unrelated donor (Dao-Pei Lu et al., Blood 2006; 107:3065). In a murine model, we have first demonstrated that the animals transplanted with three mixed cells (A+B+C to A) were survived much longer due to milder acute GVHD (aGVHD) compared with the mice transplanted with single allogeneic BM (B to A). Our previous clinical study has shown that with GIAC-3 protocol (GIAC with the third party cells in order to induce immune-tolerance) that unrelated cord blood (UCB) as the third party cells, the incidences of aGVHD, especially for severe aGVHD, and also treatment-related mortality in haplo-BMT have been significantly reduced.

Objective: In present clinical study, we examine whether haploidentical bone marrow (BM) from the second donor that substitutes for UCB as the third party cells could also reduce aGVHD and improve survival in haplo-BMT setting.

Patients and Methods: Between April 2012 and June 2013, total 158 haplo-BMT patients with hematological malignancies were enrolled. The median age was 18 (1.8 to 56) years old. The diagnosis included AML (46.2%), ALL (42.4%), lymphoma (3.8%), CML (2.5%), MDS (1.9%), acute mix leukemia (1.9%), JCMML(0.6%)and plasma cell leukemia (0.6%). Transplants at CR1, ≥CR2 or CML-AP, and advanced disease (refractory/relapsed acute leukemia or CML-BC) were 34.8%, 24.7% and 40.5%. All patients received unmanipulated blood and marrow transplant after BUCy2 or CyTBI plus antithymocyte globulin as pre-conditioning. Fludarabine was substituted for cyclophosphamide in some patients due to impaired organ function or high tumor burden. Cyclosporine, short-term Methotrexate, and Mycophenolate mofetil were employed for GVHD prophylaxis. 1ml/kg (recipient’s body weight) haploidentical BM from the second donor was infused right after haplo-BMT as the third party cells.

Results: All patients but two achieved engraftment. One case had primary graft failure and the other one had secondary graft failure. Both patients obtained durable hematopoietic reconstitution after the second BMT. Low levels of the third party cells were detected in a few patients at early stage after transplantation. No long-term third party cell engraftment was found. The cumulative incidences of grade II to IV aGVHD and grade III to IV aGVHD were 30.5%, 14.0%, respectively. With the median follow-up time of 17 months, two-year leukemia-free survival (LFS) rates in CR and NR cases were 73.2%, 41%, respectively, and 2-year overall survival (OS) rates in CR and NR patients were 86.9%%, 55.5%, respectively.

Conclusions: Our preliminary clinical results have shown that with current GIAC-3 protocol,the outcomes of haplo-BMT have been improved remarkably with lower aGVHD and better LFS and OS compared with our historic control. Haploidentical BM from the second donor as the third party cells is more feasible and cost effective compared with UCB. The mechanism of this strategy need to be further investigated.