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

Abstract

A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m 2 and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients p65 years old who relapsed 412 months after the first allograft (n ¼ 20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse. INTRODUCTIONFor patients with AML, relapsing after allo-SCT prognosis is very poor. A second allograft is currently the only therapeutic approach capable of inducing long-term remissions in patients who cannot be salvaged with DLI. 1,2 This approach has, however, two main limitations. 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. This permits dose reductions of preparative chemotherapy or radiation with a lower overall toxicity. 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.

Second allo-SCT in patients with lymphoma relapse after a first allogeneic transplantation. A retrospective study of the EBMT Lymphoma Working Party

“…With a 3-year OS probability of 29%, survival resembles that reported for second allotransplants for relapsed myeloid malignancies, ranging from 21% after 2 years to 32% after 5 years. [10][11][12][13][14]18 Second allogeneic transplantation for lymphoma relapse K Horstmann et al Importantly, the 3-year NRM of 23% observed here compares well with NRM figures observed in registry studies on first allotransplants in lymphoma, 2,[19][20][21][22][23][24][25] implying that a repeat allotransplant does not seem to be associated with an unacceptable increase in NRM.…”

“…Similar to leukemia, [10][11][12][13][14]18 the most important risk factors adversely affecting OS after alloHSCT_2 for lymphoma were remission status at second transplant and interval between alloHSCT_1 and alloHSCT_2 (as a surrogate marker for remission duration after alloHSCT_1). In contrast, selecting a donor for alloHSCT_2 different from that used for alloHSCT_1 had no significant impact on OS, PFS or RI in the patient sample studied here.…”

“…[10][11][12][13][14] In contrast, information on alloHSCT_2 in patients with lymphoma is sparse. The purpose of the present registry study was to assess the outcome of second allogeneic transplants performed for lymphoma relapse after a alloHSCT_1.…”

Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT

“…[5][6][7][8] Several other studies with shorter follow-up report results predicting 5-year survivals similar to those of the present study. [9][10][11][12][13][14] The moderate differences observed are likely to represent differences in the patient materials.…”

“…Factors that in previous studies have consistently been shown to have prognostic utility for survival are disease status, 6,8,[10][11][12][13]15,16 interval between the first transplantation and relapse 5,8,[12][13][14]16 and age. [5][6][7][8]12,14,15,17 A longer interval from the first transplantation to relapse predicts better survival. The length of the remission after which the prognosis has been found clearly better has usually ranged between 6 months and 1 year.…”