A fludarabine, thiotepa reduced toxicity conditioning regimen designed specifically for allogeneic second haematopoietic cell transplantation after failure of previous autologous or allogeneic transplantation

Abstract

We present a phase II study of fludarabine 5 Â 30 mg/m 2 , thiotepa 3 Â 5 mg/kg as preparative regimen specifically for allogeneic second haematopoietic stem cell transplantation (HCT) after failure of previous HCT. Forty-nine patients (median age 52 years, range 27-68) received an allogeneic second HCT after failed autologous (n ¼ 29) or allogeneic (n ¼ 20) HCT. Diagnoses were AML (n ¼ 18), ALL (n ¼ 3), multiple myeloma (n ¼ 11), lymphoma (n ¼ 16) and CML (n ¼ 1). GVHD prophylaxis consisted of CYA and mainly low dose alemtuzumab (40 mg). The median follow-up for patients alive is 528 days (range 217-1344). In 43 of 49 (88%) evaluable patients response rates were CR ¼ 19, PR ¼ 14 and SD ¼ 10 at one month. At one year, the probability (95% confidence interval) of relapse is 55.1 (38.2-72)% and the nonrelapse mortality (NRM) is 29 (14.2-44.4)%. Estimated survival at one year is 42.6 (28.7-56.6)% and event free survival is 38.1 (24.4-51.8)%. Survival was significantly better for patients experiencing relapse beyond one year, than for patients relapsing within one year from first transplantation (51.2 (33.5-68.9)% vs 27 (7-48.5)%; P ¼ 0.013). We conclude that this regimen is feasible and well tolerated for allogeneic second HCT.

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML

“…3 Median time to relapse after the first allo-SCT was 326 days (range 47-2189), with 32/58 patients relapsing within one year.…”

“…The first 18 of these patients also formed the AML patient subgroup in the first report of this regimen in 2008. 3 A second allo-SCT was performed for fit patients failing treatment with DLI (previously given to 39/58 patients with a starting dose of 0.5-1 Â 10 6 CD3 þ cells per kg body weight) or deemed unsuitable for such because of active GVHD or high leukaemic burden. The data analysis was in September 2011.…”

“…In July 2005, the fludarabine dose was reduced to 30 mg/m 2 given on the same 3 days À 6, À 5, À 4 (total dose 90 mg/m 2 , n ¼ 40) as thiotepa to reduce infectious complications. 3 The unmanipulated graft was infused on day 0.…”

“…9 In 2008, we reported the results of a phase II RIC trial using fludarabine 5 Â 30 mg/m 2 and thiotepa 3 Â 5 mg/kg in patients with recurrent or persistent haematological malignancies after a previous auto-or allo-SCT. 3 In this series, a TRM (95% confidence interval) of 29 (14-44)% at 2 years despite heavy pretreatment demonstrated the feasibility of our regimen, but the low number of patients in each diagnostic subgroup and the relatively short follow-up precluded a thorough evaluation of efficacy.Here we analyse the long-term outcome of a larger, homogeneous patient cohort with AML at relapse after first allo-SCT treated in a similar manner. …”

“…First, many of these patients cannot tolerate a second allo-SCT because of accumulated organ toxicities and opportunistic infections, which increase the risk for TRM and severe GVHD. 3,4 Second, despite high TRM and GVHD rates, relapse remains the main cause of death in this very high-risk patient population. [5][6][7][8] The concept of allo-SCT with reduced-intensity conditioning (RIC) is based on the notion that the GVL contributes significantly to the curative potential.…”