The PARMA trial was a randomised, multicentre European study enrolling 215 patients with relapsed intermediate and high grade relapsed NHL.r Patients responding to salvage chemotherapy (DHAP) were randomised to receive further standard dose chemotherapy or intensive chemotherapy plus autologous bone marrow transplantation.
The primary end point demonstrated a 5 year survival advantage of 53% vs 32% for transplant vs chemotherapy (P=0.038). This established autologous transplantation as the standard of care for this group of patients. BEAM has become the most widely used conditioning regimen for HNL and HL due to concerns regarding the toxicity of TBI-containing regimens, ability to administer involved field radiation therapy post-transplant, and low regimen related toxicity and high remission rates reported with BEAM.r
There are no randomised prospective studies comparing BEAM to other conditioning regimens; most evidence is drawn from retrospective registry reviews or single cohort studies compared with historical controls. A retrospective analysis reported by the Spanish GEL/TAMO group compared BEAM, CBV, BEAC, and Cy/TBI in terms of both their efficacy and toxicity.r This study found that BEAM was associated with better RFS, DFS and OS than CBV but that this did not reach statistical significance. Both BEAM and CBV were associated with better anti-lymphoma activity and more rapid engraftment than Cy/TBI.
Chopra et al found a PFS of 50% and OS of 56% at 5 years in a single centre study of poor-risk HL patients treated with BEAM.r The study concluded that patients who may benefit from BEAM included those with HL resistant to conventional therapy at the time of ASCT, although patients with bulky disease at the time of relapse, those with primary refractory disease, and those who have received prior extensive therapy fared least well.
Mills et al reported patients with relapsed or resistant diffuse large B-cell NHL who received BEAM followed by ASCT.r Patients with chemo-sensitive disease at the time of transplant had a projected progression-free survival rate of 49% at 5 years, whereas those with resistant malignancy had only 13% 5 year survival. The actuarial event-free survival rates for both groups were 56% and 10% respectively.
Finally, Linch et al compared BEAM plus ASCT with mini BEAM (same drugs at lower doses not requiring bone-marrow rescue) for patients with resistant or relapsed HL.r Both event-free survival and progression-free survival showed significant differences in favour of BEAM plus ASCT with actuarial event-free survival of 53% in those undergoing ASCT with BEAM conditioning and 10% in those receiving standard therapy with mini-BEAM. Basem et al reported a retrospective comparison of patients on the Nebraska Lymphoma Study Group database with relapsed HL who underwent autologous transplantation following conditioning with BEAM or CBV (cyclophosphamide, carmustine and etoposide).r At 10 years PFS was 79% for BEAM and 59% for CBV (p=0.01) and OS 84% for BEAM and 66% for CBV (p=0.02).
In a randomised study comparing BEAM followed by ABMT with mini-BEAM in patients with relapsed chemo-sensitive disease both EFS and PFS were significantly superior for BEAM (P=0.025 and 0.005) (6). At 3 years, the actuarial EFS was 53% in the BEAM group and 10% in the mini-BEAM group.
In a multi-centre randomised trial that compared conventional chemotherapy (Dexa-BEAM) with high-dose chemotherapy with ABMT for relapsed chemo-sensitive HD, freedom from treatment failure at 3 years was significantly better in the BEAM group (55%) compared to the Dexa-BEAM group (34%; p=0.019).r Overall survival did not differ.
Chopra et al reported a single-centre study of 155 patients with poor risk HL who underwent BEAM followed by autologous BMT.r At 6 months 53 patients were assessed as in CR. A further 13, with PR at 3 months achieved CR by 6 months (with 8 patients receiving radiation therapy to residual masses). 51 patients had non-progressive disease, 26 patients had relapsed with progressive disease and 8 patients had died of progressive disease. Overall 104 (67%) had a meaningful response to ABMT. The actuarial overall survival was 55%, with a progression-free survival of 50%. A trend was seen in favour of patients with first remission lasting longer than 12 months, over remission that was less than 12 months, 57% vs 41% respectively (p = .393). Tumour mass at ABMT (p <.001), relapse status at ABMT (p = .007), lines of treatment before ABMT (p = .005), and gender (p = .042) were significant. Patients with bulky disease (tumour mass > 10cm) fared worst, with a progression-free survival of 13% at 5 years.
Regimen-related toxicities according to Bearman criteriar
Puig et al compared the morbidity and transplant-related mortality (TRM) associated with CBV and BEAM conditioning regimens in 113 patients with NHL and HL (9). CBV conditioning was associated with substantially greater toxicity, morbidity and mortality than BEAM. Of 20 transplant related deaths, 18 were in the CBV group and 2 in the BEAM group.
Mills et al reported an overall mortality rate at 100 days post-transplant in patients with poor-risk Non-Hodgkin’s disease of 8% within 100 days of completing high-dose chemotherapy - 12% in the chemo-resistant group.r The cause of early death was overwhelming sepsis in 3%, pneumonitis in 2%, intra-cerebral bleeding in 2% and veno-occulsive disease in 1%. In the study by Chopra et al, TRM in the first 90 days was 10% in poor-risk Hodgkin’s disease.r
Importantly, however, more recent studies of BEAM conditioning in ASCT have reported acceptable toxicity and substantially lower TRM rates with BEAM conditioned ASCT, with TRM rates of 2 -5%.r Equally as important, recent clinical studies have demonstrated that BEAM conditioning can be safely given to patients greater than 60 years of age, with data from the Mayo Clinic showing equal success and TRM rates compared to younger adults for 93 patients older than 60 years with a median age of 66 (up to 76), with the age-adjusted IPI being the only factor predictive of outcome.r
While a series of efforts have been made to improve the efficacy and tolerability of BEAM in patients with relapsed/refractory NHL/HL, modifications of each of the individual components of BEAM have not been demonstrated to have greater anti-tumour effect and no alternative regimen has been shown to yield better results in the management of relapsed intermediate-grade NHL or HL.r
© Leukaemia and Lymphoma 2006