Engraftment of HLA-matched sibling hematopoietic stem cells after immunosuppressive conditioning regimen in patients with hematologic neoplasias.
OBJECTIVE
The main objective of this pilot study was to assess the possibility of achieving engraftment of HLA-matched sibling donor mobilized hematopoietic stem cells after immunosuppressive non-myeloablative therapy. The second objective was to verify whether high-dose therapy with autologous stem cells rescue followed by allografting conditioned by only an immunosuppressive regimen, can be combined in order to achieve the reduction of tumor burden after autografting and the control of residual disease with immune-mediated effects after allografting.


METHODS
To enter the pilot study the patients had to fulfil the following criteria: advanced resistant disease, presence 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 myelogenous leukemia (n = 2) (one patient with accelerated phase Ph-negative but p190 BCR-ABL gene positive by RT-PCR and one with Ph-positive blastic 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 of 40 days (range 30-96), after high-dose therapy and autologous stem cell engraftment, the patients were treated with immunosuppressive therapy consisting of fludarabine and cyclophosphamide (Flu-Cy protocol) and then HLA matched donor mobilized stem cells were infused into the patients. GvHD prophylaxis consisted of cyclosporin and methotrexate.


RESULTS
To date, with a median observation period of 4 months (range, 2-10), complete chimerism (100% donor cells) has been achieved in 6 patients. Three patients did not achieve complete chimerism: one patient died of progressive Hodgkin's disease when he reached 55% of donor cells, another patient is now in increasing phase of donor cell engraftment and the last patient (blastic phase-CML) was the only case who appears to have had autologous recovery. Two of the Hodgkin's disease patients, who were in partial remission after autografting, achieved complete remission after allografting and both are disease free 2 and 6 months after. Another Hodgkin's disease patient is alive at 10 months but she has progressive disease. One of the two patients with non-Hodgkin's lymphoma, who achieved partial remission after autografting, obtained complete remission and he is disease free 2 months after allografting. The other patient maintains partial remission obtained after autografting. The accelerated phase-CML patient obtained hematologic and molecular remission; the RAEB patient achieved hematologic and cytogenetic remission. In two patients severe aGVHD (grade II-III) was the single major complication but neither patient died of it. Mild aGVHD was seen in another patient. In only one patient did the ANC decrease to below 1 x 10(9)/L and in no case did platelets decrease below 20 x 10(9)/L. No patients required a sterile room or any red cell or platelet transfusions.


CONCLUSIONS
Immunosuppressive therapy with a Flu-Cy protocol allowed engraftment of HLA-matched sibling donor stem cells without procedure-related deaths; moreover, we have demonstrated that this combined procedure can be pursued in safety in a serious ill population and some of these patients achieved a complete remission. This procedure is not likely to be curative, but a fascinating step along the path to curing these diseases. Of course, the follow-up is too short to document the incidence of cGvHD.
Carella
A M
AM
N.O.A., Hematology/ABMT, Division of Hematology II, Ospedale S. Martino, Genoa, Italy. amcarella@smartino.ge.it
Lerma
E
E
Dejana
A
A
Corsetti
M T
MT
Celesti
L
L
Bruni
R
R
Benvenuto
F
F
Figari
O
O
Parodi
C
C
Carlier
P
P
Florio
G
G
Lercari
G
G
Valbonesi
M
M
Casarino
L
L
De Stefano
F
F
Geniram
A
A
Venturino
M
M
Tedeschi
L
L
Palmieri
G
G
Piaggio
G
G
Podestà
M
M
Frassoni
F
F
Van Lint
M T
MT
Marmont
A M
AM
Bacigalupo
A
A
D000328:Adult; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D019337:Hematologic Neoplasms / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents