Induction of Graft Versus Leukemia Effect by Mixed Bone Marrow Transplantation.

Mixed bone marrow transplantation (MBMT) is a special kind of stem cell transplant by combining autologous bone marrow transplantation (ABMT) with HLA mismatched haploidentical (3/6 loci mismatched) sibling bone marrow stem cells for the those patients who failed finding HLA matched sibling donor or HLA matched unrelated donor(MUD). As the main aim of MBMT is to induce graft versus leukemia (GVL) effect, there is no any prophylaxis regimen to be used for preventing graft versus host disease (GVHD) during the MBMT. In this study, we explore the relationship of graft versus leukemia effect induced by MBMT and long disease-free survival (DSF) of patients between two different transplant groups. (1) MBMT group: 8 patients treated by MBMT were 5 male and 3 female aged 8–40 years old suffering from acute myelocytic leukemia (AML) 6 cases (M3 2 cases, M4 2cases, M5 2case) and actue lymphoblast leukemia 2 cases (L1 and L2). After getting complete remission(CR), all of patients had received 3–5 courses of chemotherapy and then were treated by MBMT. At day +2 to +5, after autologous stem cell infusion at day 0, 20–50 ml allogenic born marrow stem cells were collected from HLA mismatched-haploidentical (3/6 loci mismatch) and ABO, Rh blood type identical sibling donor of patients with the mean number of mononuclear cell (MNC) 2.39x10⁸ ( 0.5–5.0 x10⁸ ) and then were infused intravenously immediately to receptor. The mean number of MNC from allogenic bone marrow accounts for 1/20 to 1/50 (1/30) of that from autologous bone marrow. Prophylaxes regimen for preventing GVHD had not been used in all cases with MBMT. (2) ABMT group: 10 cases of ABMT were compared as control including 6 male and 4 female aged from 21 to 44 year old suffering from acute myelocytic leukemia (AML) 5 cases (M3 1 cases, M2 2 cases, M5 2 case) and NHL 5 cases. We find quiet different results in two groups: (1) All cases in MBMT group had developed typical or atypical manifestations of acute GVHD in clinic within day +10 to day +100, which were diagnosed by skin pathologic biopsy. 3 patients were died because of severe aGVHD (III^o–IV^o) in the early stage after transplant. 5 cases with mild aGVHD were treated with prednisone, CSA and MTX and got control quickly, whose marrow finally kept mixed chimeris for half a year conformed by HLA gene detection and sex cheomosome analysis. All of these 5 patients are non-relape up to now and have acquired long disease-free survival for 129, 118, 113, 97 and 92 months respectively. The total relapse rate is 0%. (2) AMBT group: 6 cases of 10 were relapsed and died within 2 years after AMBT. 3 cases have get DFS for 119, 100 and 35 months respectively. The total relapse rate in 2 year is 60% in ABMT group. The results and conclusions we have get from the study indicate that MBMT may be an effective and safe therapy with much lower relapse and longer DFS because of inducing and existing of GVL effects. Patients with long DSF in MBMT group have showed close relationship with their mixed chimeris and GVL effects after MBMT. However, there are still some problems should be solved in MBMT:

1. A more suitable infusion ratio of MNC from HLA mismatched haploidentical sibling donor and autologous marrow,

2. A better strategy for co-infusion or delayed infusion of allogeneic stem cell,

3. Does MBMT need GVHD prophylaxis or not?

4. Immunotherapy for post-MBMT with DLI or DSI.