Unrelated Hematopoietic Stem Cell Transplantation with Reduced Intensity Regimens in High Risk Patients for Age or Disease: Results from Two Independent Prospective GITMO Studies.

Background. Despite reports on the feasibility of reduced intensity conditioning (RIC) transplants from unrelated donors (UD), many open questions remain, which involve the patient allocated to these programs (elderly with comorbidity), the disease (advanced and often uncertain indication) and the complications of the transplant (engraftment, immune reconstitution, graft versus host disease (GVHD).

Aim of the study. To test prospectively the outcome of patients activating an UD search leading to a transplant with two different RIC regimens, in a multicenter setting (GITMO).

Patients: patients aged 45–65 years, or with comorbidity - ineligible for conventional UD transplants. The Centre selected the transplant program (A or B) on the basis of its own preference, at the time of activation of the UD search. Between year 2002 and 2004, 392 patients entered these two parallel, prospective trials, and activated an unrelated donor search: 118 (30%) were transplanted at a median interval of 180 days from UD search, 161 (41%) stopped the UD search and 113 (29%) have ongoing UD search. The cause for the 161 search interruptions was death (42%), progression of the disease (21%), or other treatment programs in 27%.

Transplants. Of the 118 UD transplants 57 were performed with program A (Melphalan 30 mg/m2, Alemtuzumab 80 mg Fludarabine 90 mg/m2 and TBI 200 cGy), and 61 with program B (Thiotepa 10 mg/kg, Cyclophosphamide 100 mg/kg and ATG 7.5 mg/kg). The main indication was non Hodgkin or Hodgkin lymphoma (63 patients =54%) and the other patients had acute or chronic hematologic malignancies. The majority of patients had received more than 3 lines of chemotherapy (83%) and had advanced disease (78%).

The stem cell source was the Peripheral Blood (PB) in 49 and marrow (BM) in 69. Results. Time to 1000 neutrophils was 22 and 23 days in programs A and B, and time to 50.000 platelets 19 and 27 days. Graft failure was observed in 11 patients (9%) (9% and 14% in programs A and B), with most of the patients showing autologous reconstitution (9/11= 81%). Acute GvHD grade II–IV was seen in 41% and 18% of patients in programs A and B respectively (p= 0.2) and extensive chronic GvHD in 6% and 7%, respectively (p=0.5). With a median follow-up of 252 and 555 days, the overall survival is 56% and 57%. Transplant Related Mortality (TRM) at 100 days in 10% and 13% (p=ns) and cumulative TRM is 17% and 25%. Relapse related death is 17% and 18%.

Conclusions.This study shows that

1. UD search is feasible in patients aged 45–65 or unfit for conventional transplants with advanced disease;

2. progression of the disease or death is a common cause of failure of the UD search;

3. transplants after a RIC regimen were performed in 30% of patients who initially entered the trials;

4. TRM was relatively low in both programs;

5. graft failure was seen in 9% of patients and resulted mainly in autologous recovery;

6. GvHD was not a serious problem.

GITMO has now launched a randomised trial to better evaluate the overall antitumor activity and the safety profile of these two strategies.