Mini-Haploidentical Transplantation for Refractory Acute Myeloid Leukemia.

Abstract

The quest for effective, yet less toxic means of treating advanced diseases has led the bone marrow transplantation (BMT) researchers and clinicians searching for the optimal balance between host immune suppression, stable chimerism, effective graft versus tumor response and overall survival. We asked the question “how low can you go?” and approached this from the minimalist view. Born out of murine studies, mini-HLA-identical bone marrow transplantation (BMT) using 100cGy as host conditioning followed by non-mobilized peripheral blood lymphocyte infusion of 1×108 CD3 cells/kg was successful in achieving a complete responses (CR) in 4 of 11 refractory hematologic malignancy patients (Blood100:442, 2002). This study has been extended using HLA-haploidentical donors. We have evaluated CD3+ cell dose escalation with HLA-haploidentical transplantation in patients with refractory malignancies. We have performed 42 HLA-haplo transplants with escalation of the CD3 dose from 1x106–2x108cells/kg using G-CSF primed peripheral blood stem cells, with a conditioning regimen of 100cGy TBI. Twenty patients were treated at the highest level. The CD34 dose infused was always >2x106cell/kg. Ages ranged from16–82 years. We have treated 15 patients with solid tumors and 27 patients with hematologic malignancies consisting of AML (13), NHL (5), Multiple Myeloma (5) CML (3), and HD (1). One treatment related death occurred from grade IV aGVHD. Most patients had a transient febrile engraftment syndrome believed to be immunologically based and represents neither hyperacute nor acute graft versus host disease. There were no objective responses in the patients with solid tumors. One of 5 patients with NHL had a partial response. We observed several encouraging responses in patients with refractory AML. We treated 13 patients with AML and have obtained a complete response in three patients and transient responses in 7 of 12 evaluable patients (survival >2wks after BMT). The median time of transient response was19 days± 5 days and was defined as a persistent loss of peripheral blood blasts and/or more than 50% reduction in marrow blasts as seen on biopsy. In these patients, improvement in blood counts was seen in 3 patients and an improved performance status in 6 of 12. All responses occurred at CD3 levels of 1–2x108 cells/kg. All complete and transient responses occurred in the absence of measurable donor chimerism (<5%). Donor cells labeled with indium111 analyzed 1,2,3 and six days following BMT in one patient showed persistent signal in the bone marrow and spleen. The kinetics of detectable donor cells in the peripheral blood and marrow show near complete homing to the marrow by 24 hours with a subsequent loss of detectable chimerism 6 days after BMT. Serial bone marrow biopsies performed in several patients show evidence for large tumor reduction and early resumption of normal hematopoiesis. In summary, TBI of 100cGy followed by HLA-haplo transplant is a biologically active therapy for refractory AML. The responses outside of chimersim are intriguing and warrant further investigation. This well tolerated treatment produced minimal toxicity for the majority of patients. Theories on biological effect include an initial graft vs. tumor cell kill, altered host immune response breaking host tumor tolerance, persistent non-detectable microchimerism or a combination of any of the three.