Clinical Tumor Responses Despite Graft Rejection after Nonmyeloablative Conditioning and Transplantation of Partially HLA-Mismatched (Haploidentical) Bone Marrow.

A variety of hematologic malignancies that are resistant to standard chemotherapy can be treated by nonmyelaoblative allogeneic stem cell transplantation, or NST. At our institution, 84 patients have enrolled onto sequential Phase I and II protocols of NST for hematologic malignancies utilizing haploidentical donors. Patients received non-T cell-depleted marrow after conditioning with fludarabine 30 mg/m2 (days −6 to −2), cyclophosphamide (Cy; 14.5 mg/kg/d, days −6 and −5) and 200 cGy total body irradiation on day −1. Novel post-transplantation immunosuppression included high dose Cy (50 mg/kg/d on day 3 only or (n=23) days 3 and 4 (n=40), mycophenolate mofetil from days 5–35 and FK-506 from day 5–180. Sixteen patients (19%) experienced graft rejection, defined as absence of donor chimerism on day 60, including 6/10 patients with myelodysplastic syndrome (MDS), 3/7 patients with chronic myeloid leukemia (CML), 2/3 patients with chronic myelomonocytic leukemia (CMML), 2/21 patients with acute myeloid leukemia (AML), and three patients with lymphoid malignancies. Fourteen patients recovered autologous hematopoiesis, whereas two (1 MDS, 1 NHL) died in aplasia. Interestingly, objective clinical responses were observed in 3/6 of the rejectors with MDS (1 CR, 2 PR), 2/3 rejectors with CML (2 molecular CR), and in both rejectors with CMML (1 CR, 1 PR). Two of the five patients with MDS and blast counts of greater than 20% survived for greater than 2 years with a decrease in blast counts and need for transfusions. Both patients with CML had disease refractory to imatinib mesylate, and both achieved molecular complete responses following transplantation. One of the patients has relapsed, and the other remains in hematologic and cytogenetic complete remission, though in minimal molecular relapse, at 6+ months after transplantation. Of the patients with CMML, one achieved a morphologic and hematologic complete remission at six months after transplantation, and the other achieved improved blood counts and disappearance of marrow blasts before relapsing at six months after transplant. In summary, fatal graft rejection is uncommon following nonmyeloablative BMT with post-transplantation cyclophosphamide. Clinical responses occurred despite graft rejection, particularly among patients with chronic myeloid malignancies. Potential mechanisms of the anti-tumor effect include an effect of conditioning, a transient graft-versus-host reaction by donor T or NK cells, or an abrogation of host tolerance to tumor by either the graft-versus-host or host-versus-graft reaction.