The introduction of reduced intensity conditioning (RIC) regimens has dramatically changed the landscape of allogeneic stem cell transplant (ASCT). A decrease in dosages of TBI and chemotherapy has reduced acute side effects of the conditioning and non-relapse mortality (NRM). In reduced intensity conditioning (RIC) transplants, the antileukaemic activity of ASCT is shifted towards the graft versus leukaemia (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 ASCT in myeloid leukaemias. The fludarabine, cytarabine, amsacrine (FLAMSA) regimen was developed by the Munich group in 1999 for high-risk patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS).r Several 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 ASCT in 11 European centres between 1999 and 2008.r Donors were matched siblings, matched unrelated or mismatched unrelated donors in 34%, 47% and 19% respectively. Indications for transplant were progressive MDS (10%), de-novo AML (47.5%), or secondary AML (43.5%). ASCT was performed upfront, after primary induction failure, in first complete remission (CR1) and in relapsed disease in 17%, 33%, 22% and 28% of patients respectively. The median patient age was 53 (18-71) years. 95 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 (LFS) was 37.7% and 32.0%. Causes of deaths 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 (4 year OS=49.3% and 40.3%). In contrast, results were inferior in patients with chromosome 5 aberrations (4 year OS=30%), mainly due to an increased rate of leukaemia-associated death (p=.008). Patients with MDS, who received ASCT as first-line treatment, achieved a 4 year OS of 80%. Patients with secondary AML after MDS had an inferior outcome (4 year OS=28%, p=.018). In a Cox regression model, stage of disease at transplantation, an 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 ASCT 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 pts with cytogenetically normal acute myeloid leukaemia (CN-AML) who had received FLAMSA-RIC for ASCT in 14 European centres.r The patients in this group had de-novo AML (76%), secondary AML/MDS (21%), and treatment-related AML (4%). Median age was 52 years (19-71). Donors were matched or mismatched families 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%). The median follow-up of survivors was 19 months. OS and LFS at 2 years from SCT were 51% and 47% respectively. The disease stage at SCT was the most important factor determining OS and LFS) (p=0.001 for OS, <0.001 for LFS. Results were promising after SCT in CR1 (2 years OS/LFS 76%), and PIF (2 years OS/LFS 69%), but were inferior after SCT in untreated disease (2 years OS/LFS 34%), or >CR1 (2 years OS 42%, LFS 34%). Information on molecular markers were available in 183 patients. Patients with nucleophosmin (NPM1) mutation had a 4 year OS/LFS of 75%/63% with identical outcomes regardless of whether transplanted in PIF, CR1, or >CR1. Patients with other genotypes showed an OS/LFS of 51%/48% at 2 years and 40%/39% at 4 years, without differences amongst patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and FLT3 wild type/NPM1 wild type. However, in this subgroup, the outcome was highly dependent on the disease stage at SCT, with excellent results after SCT in CR1 (2 years OS/LFS 76%) or PIF (2 year OS/LFS 75%/74%), but inferior outcome after SCT >CR1 (2 year OS/LFS 38%/33%; p=0.004 for OS, 0.001 for LFS). The results of this study suggests that ASCT following FLAMSA-RIC produces high rates of OS and LFS 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 haploidentical transplants and in adults and adolescents with relapsed or high-risk acute lymphoblastic leukaemia have also demonstrated promising results, suggesting that this conditioning regimen may have value in a larger range of haematological malignancies.rr