Reduced Intensity Conditioning in Acute Leukemias: Long Term Follow-Up Confirms Sustained Complete Remissions.

Introduction:

Reduced intensity conditioning (RIC) now accounts for approximately one fourth of all allogeneic stem cell transplantations (SCT) worldwide (IBMTR database 2002). A reduction of transplant-related mortality has been observed in uncontrolled trials of patients with MDS, CLL, NHL and M. Hodgkin, but at the same time some of these trials revealed an increased relapse rate. Long term follow-up of acute leukemias after RIC has not been reported so far. Own results have demonstrated continuous complete remissions in patients with ALL transplanted early in the course of disease (Arnold 2002).

Patients and Methods:

Between August 1998 and December 2003, 40 pts with high-risk ALL (n = 11) or AML (n = 29) received allogeneic SCT after RIC with fludarabine, busulfan and ATG because of contraindications against standard high-dose conditioning (age > 50 years, prior allogeneic SCT, fungal infections, low performance status). 8/40 had already relapsed prior standard SCT. 13 pts were in CR-1, 7 were in subsequent CR and 20 had uncontrolled disease. Median age was 48 years (range 19 – 67), 24 were male and 16 were female. All but one patient with 1 HLA-class I mismatch were transplanted from HLA-identical related (n = 23) or unrelated (n = 17) donors. Stem cell sources were mobilized peripheral blood in 37 and bone marrow in 3 patients. Patients received 5.0 x 10E6 CD34+ cells/kg bw in median (range 2.1 – 19.8). GvHD-prophylaxis was performed with cyclosporine A (CSA) alone (n = 23) or CSA + mycophenolate mofetil (n = 17).

Results:

37/40 pts reconstituted and reached CR including 17/20 patients with uncontrolled disease before SCT. 1/40 had a primary graft failure and was successfully retransplanted; two patients had refractory disease. After a median follow-up of 14 months (range 2 – 64 months), cumulative transplant-related mortality is 8 % ( 3/40 patients). 9/40 patients had developed acute GvHD III–IV and 11/24 patients had chronic extensive disease. 19 patients relapsed (including 2 refractory patients and 7/8 patients with salvage transplantation). Probability of disease-free survival at 3 years is 49 %. Overall survival at 3-year is 37 %. Median survival for patients with ALL is 13 months (95% C.I., 1 – 26) and for AML 14 months (95% C.I. 4 – 24) (n.s.). Among 18 survivors in CR, 8 were transplanted in CR-1 and 10 with advanced disease.

Discussion:

RIC results in sustained complete remissions in patients with high-risk acute leukemias. Even advanced diseases can be cured by allogeneic SCT after RIC. The high relapse rate is worrisome and calls for effective post-transplant strategies like prophylactic DLI or maintenance therapy to reduce relapse risk. TRM is comparably low in this group despite intensive pre-treatment and high rates of GvHD.