ENGRAFTMENT OF HLA-MATCHED SIBLING HEMATOPOIETIC STEM-CELLS AFTER IMMUNOSUPPRESSIVE CONDITIONING REGIMEN IN PATIENTS WITH HEMATOLOGIC NEOPLASIAS

Background and Objective. The main objective of this pilot study was t o assess the possibility of achieving engraftment of HLA-matched sibli ng donor mobilized hematopoietic stem cells after immunosuppressive no n-myeloablative therapy. The second objective was to verify whether hi gh-dose therapy with autologous stem cells rescue followed by allograf ting conditioned by only an immunosuppressive regimen, can be combined in order to achieve the reduction of tumor burden after autografting and the central of residual disease with immune-mediated effects after allografting. Design and Methods. To enter the pilot study the patien ts had to fulfil the following criteria: advanced resistant disease, p resence of an HLA matched sibling donor, no general contraindications to stem cell transplantation. Our data refers to 9 patients: Hodgkin's disease (n=4), non-Hodgkin's lymphoma (n=2), advanced chronic myeloge nous leukemia (n=2) (one patient with accelerated phase Ph-negative bu t p190 BCR-ABL gene positive by RT-PCR and one with Ph-positive blasti c phase), refractory anemia with excess of blasts t(1;3) (p36;q21) (n= 1). All patients but one received the combined approach. At a median o f 40 days (range 30-96), after high-dose therapy and autologous stem c ell engraftment, the patients were treated with immunosuppressive ther apy consisting of fludarabine and cyclophosphamide (Flu-Cy protocol) a nd then HLA matched donor mobilized stem cells were infused into the p atients. GVHD prophylaxis consisted of cyclosporin and methotrexate. R esults. To date, with a median observation period of 4 months (range, 2-10), complete chimerism (100% donor cells) has been achieved in 6 pa tients. Three patients did not achieve complete chimerism: one patient died of progressive Hodgkin's disease when he reached 55% of donor ce lls, another patient Is now in increasing phase of donor cell engraftm ent and the last patient (blastic phase-CML) was the only case who app ears to have had autologous recovery. Two of the Hodgkin's disease pat ients, who were in partial remission after autografting, achieved comp lete remission after allografting and both are disease free 2 and 6 mo nths after. Another Hodgkin's disease patient is alive at 10 months bu t she has progressive disease. One of the two patients with non-Hodgki n's lymphoma, who achieved partial remission after autografting obtain ed complete remission and he is disease free 2 months after allografti ng. The other patient maintains partial remission obtained after autog rafting. The accelerated phase-CML patient obtained hematologic and mo lecular remission; the RAEB patient achieved hematologic and cytogenet ic remission. In two patients severe aGVHD (grade II-III) was the sing le major complication but neither patient died of it. Mild aGVHD was s een In another patient. In only one patient did the ANC decrease to be low 1x10(9)/L and In no case did platelets decrease below 20x10(9)/L. No patients required a sterile room or any red cell or platelet transf usions. Interpretation and Conclusions. Immunosuppressive therapy with a Flu Cy protocol allowed engraftment of HLA-matched sibling donor st em cells without procedure-related deaths; moreover, we have demonstra ted that this combined procedure can be pursued in safety in a serious ill population and some of these patients achieved a complete remissi on. This procedure is not likely to be curative, but a fascinating ste p along the path to curing these diseases. Of course, the follow up is too short to document the incidence of cGvHD. (C) 1998, Ferrata Stort i Foundation.