Over the past decade, numerous conditioning regimens have been developed, and reported, in different populations of patients undergoing reduced-intensity conditioned allogeneic SCT. This has created considerable confusion regarding dose intensity, degree of myelosuppression and toxicity, and the application of different conditioning regimens in different populations and in different disease groups. As a consequence, a number of groups have aimed to develop regimens that can be safely and effectively used in a range of different situations.
The Freiburg/Regensburg group under Jurgen Finke advanced the FluMelBCNU (or FBM) protocol on the basis that it enabled engraftment of stem cells from related and unrelated donors, provided moderate doses of cytotoxic agents with broad activity, good CNS penetration and negligible cardiac, pulmonary, renal, bladder or gastrointestinal toxicity, consistently resulted in marrow aplasia and led to complete donor chimerism in the large majority of recipients.r
Early reports of FluMelBCNU were in older patients with poor-prognosis malignancies. Bertz et al,r reported outcomes in 19 elderly patients (median age, 64 years; 60-70) who underwent RIC alloSCT from matched unrelated (n = 12) or sibling donors (n = 7) following conditioning with FluMelBCNU: fludarabine (5 x 30 mg/m2), BCNU (2 x 200 mg/m2), and melphalan (140mg/m2). Before transplantation, these patients had a median of 50% bone marrow blasts (range, 0 – 70%). GvHD prophylaxis consisted of cyclosporine (2.5 mg/kg bd from day -3) and mycophenolate mofetil (1g bd from day +1) or methotrexate (5 mg/m2 on days +1, +3 and +6). Eleven of the 12 patients with an unrelated donor also received ATG-Fresenius 40-60 mg/kg and all patients received G-CSF from day +7. With this regimen, engraftment was successful in all patients and 17 patients achieved a complete remission. While 4 patients subsequently relapsed, 3 achieved a second CR following donor lymphocyte infusion (n = 1) or a second allograft (n = 2). Six patients died as a result of relapse (n = 2), GvHD (n = 2) or fungal infections (n = 2) resulting in a 1-year nonrelapse mortality rate of 22%. With a median follow-up of 825 days, 13 of 19 patients were alive, giving a 1-year survival rate of 68% - an excellent outcome in an elderly poor-risk population, suggesting that FluMelBCNU provided a fair chance of cure with limited toxicity in older patients with poor-prognosis haematological malignancies.r
Finke et al., subsequently reported the results of RIC with FluMelBCNU in 30 patients with MDS who received transplants from unrelated donors. Despite a median marrow blast count of 27% at the time of transplant, the disease-free survival at a median of 11 months was 55%.r One year TRM and PFS were subsequently reported as 22% and 61% - which is impressive given the advanced disease state in many of the patients.r
Finally, the same group has subsequently reported the long-term follow-up results of 133 consecutive patients (median age: 55.6 years [23-73] with AML/MDS (n = 81), myeloproliferative syndromes (n = 20), and lymphoid malignancies (n = 32) who underwent reduced-intensity conditioned allogeneic stem cell transplant using FluMelBCNU as part of a 2-centre, prospective, nonrandomised, open-label phase 2 clinical trial. In this study patients under 55 received standard-dose FluMelBCNU [fludarabine (5 x 30 mg/m2), BCNU (2 x 200 mg/m2), and melphalan (140mg/m2)], while those aged 55 years or older received fludarabine with reduced BCNU (2 x 150 mg/m2), and melphalan (110 mg/m2)]. GvHD prophylaxis consisted of cyclosporin (CSA) starting at day – 3 at a dose of 2.5 mg/kg twice a day and methotrexate 5 mg/m2 on days +1, +3 and +6 in 23 patients or (die to toxicity problems with methotrexate) mycophenolate mofetil (MMF) 1g bd starting at day -1 in 103 patients. MMF was tapered from day 30 to day 45 and CSA was tapered from day 80 to day 100 in the absence of acute GvHD. In all unrelated donors ATG-Fresenius was administered at a total dose of 20-60 mg/kg on days -2 and -1. All but one patient engrafted, and after engraftment, chimerism analysis revealed complete donor chimerism in 95.7% of patients. Most (86.2%) showed complete remission while another 10 (7%) showed a partial response. Non-relapse mortality (NRM) at 100 days and 1 year were 15.8% and 26.3% respectively. Grade III/IV acute GvHD occurred in 16.9% of unrelated donors and 29.4% of related donors and extensive chronic GvHD occurred in 51.5% of related donors and 13.8% of unrelated donors - suggesting that ATG may be beneficial in both related and unrelated donors. With a median follow-up of 58.5 months, 3- and 5-year overall survival (OS) was 53% and 46.1%, event-free survival (EFS) was 46.4% and 41.9%. No significant differences in OS and EFS were evident considering disease status (early vs advanced), patient age (<55 vs. > 55 years), or donor type (related vs. unrelated) in univariate and multivariate analysis. The cumulative 5-year incidence of death due to relapse was 20.1%. Among patients with AML/MDS, advanced cases (n = 64, including 61 with active disease) showed an OS of 44.6% and 42.4% after 3 and 5 years respectively. These results suggest that FluMelBCNU (particularly with ATG) provides effective disease control with low NRM.r