Evidence and Efficacy
Storb et al initially established that suboptimal conditioning with 450cGy TBI and post grafting immunosuppression with ciclosporin alone could result in stable and predictable engraftment in a canine transplantation model.rFurther studies showed that sub-lethal TBI (200cGy) and post grafting immunosuppression with a novel combination of ciclosporin and mycophenolate mofetil could successfully establish stable mixed chimeras in DLA-identical littermates with minimal toxicity and only mild pancytopenia.rr
McSweeney et al went on to describe the outcomes of an initial trial involving 45 HLA identical sibling transplants, median age 56 yrs, with relative contraindications to myeloablative transplant.r Patients were conditioned using 200cGy TBI only and post-grafting immunosuppression with CSP/MMF. Non-fatal graft rejection occurred in 20%. aGVHD grades II-IV occurred in 47% patients. 53% of patients with sustained engraftment achieved a CR. At a median follow up of 417 days, OS was 66.7%, NRM 6.7% and relapse mortality 26.7%. 56% patients were managed entirely in the outpatient setting.
In 2003, Niederwieser et al presented the findings of a phase I clinical trial utilising low dose TBI (200cGy on day 0) and fludarabine (30mg/m2 days -4 to -2) based conditioning in HLA matched and mismatched unrelated transplants.r Included in this study were patients with haematological diseases treatable by allogeneic HCT who were ineligible for conventional allogeneic HCT because of age (greater than 50 yrs) and/or significant concomitant disease or preceding extensive therapies, such as failed autologous or allogeneic transplant. Exclusion criteria were CrCl less than or equal to 50 mL/min, LVEF less than or equal to 30%, bilirubin greater than 2 X ULN and/or transaminases greater than 4 X ULN, DLCO less than 35%, and Karnofsky performance score less than 50. Post transplant immunosuppression was with CSP and MMF. CSP levels were targeted at about 500 ng/mL and tapered from +64 or +100 through +180. MMF 15 mg/kg PO was given till +27 or +40 and tapered through +96. 52 patients, median age 48 yrs, 88% of whom had undergone previous conventional transplantation or had refractory/advanced disease, were included in this study. Primary endpoint was mixed chimerism at +28, with complete chimerism achieved for NK cells at +28, granulocytes +56 and +180 for CD3 cells. Primary and secondary graft rejection occurred in 12% pts. aGVHD rates were grade II 42%, grade III 8% and grade IV in 13%. GVHD was fatal in 9%. Day 100 TRM was 11%. 45% achieved CR, including molecular remissions. 1 yr. mortality from disease progression was 27%. 6 patients had donor leukocyte infusion (DLI) for relapsed or persistent disease. At a median follow up of 19 months, OS was 35%, with DFS 25%.
Two phase II multicentre clinical trials of Flu TBI (200cGy) conditioning have subsequently been reported. In CML, Kerbauy et al reported the outcomes of 24 patients, median age 58 yrs. (27–71 yrs.), 14 in CP1, 4 in CP2, 6 in AP receiving HLA-matched sibling transplants.r 8/24 were conditioned with 200cGy TBI alone and the remainder were conditioned with fludarabine 90mg/m2 together with TBI. All patients initially engrafted. However, 4/8 patients not given fludarabine experienced non-fatal rejection while all others had sustained engraftment. At median follow up of 36 months, NRM was 21% and DFS 54%. 2 yr estimated OS for CP1 70% and CP2 56%, with DFS at 36 months. Hegenbart et al presented the outcomes of Flu TBI 200 cGy based conditioning in 122 pts AML patients transplanted using both related and unrelated donors.r Median age 57 yrs. with 51/122 pts in CR1. Cumulative incidence of aGVHD grades II-IV at 6 months was 35% after related and 42% after unrelated HCT, respectively. Cumulative non-relapse mortalities were 10% and 22%, and cumulative mortalities from disease progression were 47% and 33% at 2 years for related and unrelated recipients, respectively. 2-yr OS was 48%, DFS was 44%. Patients transplanted in CR1 had 2-yr OS of 44% after related and 63% after unrelated transplant, respectively. Outcomes from this trial are summarised below.
A randomized, Phase III trial compared the addition of fludarabine to 2 Gy TBI (n=41) versus TBI alone (n=44). The incidence of acute and chronic GVHD was higher in the combined-modality group, but statistical significance was not achieved. There was a trend towards a higher progression/relapse rate in the TBI group, leading to a worse progression-free survival (3YR 36% v 53%, p=0.05). Furthermore, there was a trend toward higher OS in the FluTBI arm (54% v 65%, p=0.09).r A further randomized study compared FluBu-ATG (Arm A) with FluTBI (Arm B)r Whilst the FluBu-ATG was associated with a reduction in cumulative incidence of relapse (1YR CIR 14% v 37%, HR 2.49 CI 1.45-2.49, P<0.01), this was balanced by an increase in non-relapse mortality (1YR NRM HR 0.48; 95% CI, 0.25-0.92, P=0.027), leading to no detectable difference in overall survival at 1YR and 3YRS. A prospective Phase II study compared the FluTBI protocol (n=25 )with FluBu-ATG (n=41).r Scheduling was similar to previous studies, except for the use of tacrolimus, rather than ciclosporin, for GVHD prophylaxis. Overall survival, relapse-free survival, and cumulative incidences of acute and chronic GVHD were similar in both cohorts.
Overall survival outcomes from trialr
©Journal of Clinical Oncology 2006
Factors associated with outcome on multivariate analysisr
©Journal of Clinical Oncology 2006