The introduction of reduced intensity conditioning (RIC) regimens has dramatically changed the landscape of alloSCT. Decrease in dosages of TBI and chemotherapy has reduced acute side effects of the conditioning and nonrelapse mortality (NRM). In RIC transplants, the antileukemic activity of alloSCT is shifted toward the GVL effect. However, in aggressive leukaemia, RIC may not provide sufficient disease control to allow time for a GVL reaction. As a consequence, a variety of ‘moderate-intensity’ regimens have been developed for alloSCT in myeloid leukaemias. One such protocol, the FLAMSA regimen, was developed by the Munich group in 1999 for high-risk patients with AML and MDS.r A series of studies have reported results with FLAMSA-RIC conditioning in patients with high-risk and standard risk AML and MDS.
A German multi-centre study analysed results in 172 patients with AML/MDS with poor-risk cytogenetics who underwent FLAMSA-RIC alloSCT in 11 European centres between 1999 and 2008.r Donors were matched siblings, matched unrelated or mismatched unrelated donors in 34%, 47% and 19%. Indications for transplant were progressive MDS (10%), de novo AML (47.5%), or secondary AML (43.5%). Allo SCT was performed upfront, after primary induction failure, in CR1 and in relapsed disease in 17%, 33%, 22% and 28% of patients respectively. Median patient age was 53 (18-71) years. Ninety-five patients (56%) had a complex aberrant karyotype. After a median follow up of 20 months, overall survival (OS) at 2 and 4 years was 46.4% and 40.5%, the respective leukaemia-free survival was 37.7% and 32.0%. Causes of death were leukaemia in 30%, and non-relapse mortality in 21%. Encouraging results were observed in patients with chromosome 7 aberrations or with a complex karyotype (4y OS=49.3% and 40.3%). In contrast, results were inferior in patients with chromosome 5 aberrations (4y OS=30%), mainly due to an increased rate of leukaemia-associated death (p=.008). Patients with MDS, who received allogeneic SCT as first line treatment, achieved a 4y OS of 80%. Patients with secondary AML after MDS had an inferior outcome (4y OS=28%, p=.018). In a Cox regression model, stage of disease at transplantation, a 8/8 or 10/10 matched family or unrelated donor, and lack of monosomy 5 or deletion 5q were associated with superior OS (p=.025, .05, and .05). The results of this study suggest that alloSCT following the FLAMSA-RIC regimen is an effective treatment for MDS and AML with unfavourable karyotype and that long-term remission may be achieved in a substantial percentage of patients with complex karyotype disease and aberrations of chromosome 7.
Pfeiffer et al. retrospectively analysed 247 patients with cytogenetically normal acute myeloid leukaemia (CN-AML) who had received FLAMSA-RIC for alloSCT in 14 European centres.r The patients in this group had de novo AML (76%), sAML/MDS (21%), and tAML (4%). Median age was 52y (19-71). Donors were matched or mismatched family, and matched or mismatched unrelated donors in 30%, 2%, 50% and 18%, respectively. SCT was performed in untreated disease (6%), primary induction failure (PIF, 23%), 1st complete remission (CR1, 14%), and >CR1 (57%). Median follow-up of survivors was 19 months. Overall survival (OS) and leukaemia-free-survival (LFS) at 2y from SCT was 51% and 47%. The disease stage at SCT was the most important factor determining OS and LFS (p=.001 for OS, <.001 for LFS). Results were promising after SCT in CR1 (2y OS/LFS 76%), and PIF (2y OS/LFS 69%), but were inferior after SCT in untreated disease (2y OS/LFS 34%), or >CR1 (2y OS 42%, LFS 34%). Information on molecular markers was available in 183 pts. Patients with NPM1 mutation had a 4y OS/LFS of 75%/63% with identical outcome regardless of whether transplanted in PIF, CR1, or >CR1. Patients with other genotypes showed an OS/LFS of 51%/48% at 2y and of 40%/39% at 4y, without differences among patients with FLT-ITD and FLT3wt/NPM1wt. However, in this subgroup, outcome was highly dependent on the disease stage at SCT, with excellent results after SCT in CR1 (2y OS/LFS: 76%) or PIF (2y OS/LFS: 75%/74%), but inferior outcome after SCT >CR1 (2y OS/LFS 38%/33%; p=.004 for OS, .001 for LFS). The results of this study suggest that allo SCT following FLAMSA-RIC produces high rates of overall and leukaemia-free survival in patients with CN-AML, particularly when performed in CR1. Encouraging results in PIF also support an early SCT, regardless of molecular subgroup, when CR is not reached after double induction. However, a direct comparison of the FLAMSA-RIC approach versus a salvage chemotherapy re-induction, marrow recovery and then RIC approach has not been performed.
Smaller studies using FLAMSA-RIC conditioning in children undergoing haplo-identical transplants and in adults and adolescents with relapsed or high-risk ALL have also demonstrated promising results, suggesting that this conditioning regimen may have value in a larger range of haematological malignancies.rr