Second transplants for leukaemic relapse after bone marrow transplantation: high early mortality but favourable effect of chronic GVHD on continued remission. A REPORT BY THE EBMT LEUKAEMIA WORKING PARTY

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.

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 67%

See 1 more Smart Citation

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

Christopoulos

Schmoor

Waterhouse

et al. 2013

“…3 However, long-term benefit in that study was limited by relapse and a considerably high rate of cGvHD, leading to severe morbidity, as already described for RIC HSCT1. 38 Although in general the prognosis of leukaemic relapse after HSCT1 is poor, 39,40 overall outcome in our cohort was encouraging with an OS and RFS of 45% and 33% at 1 year after HSCT2 and compared favourably to earlier studies on HSCT2, demonstrating 1-year OS of 14-20%. 29,31,41 Donor change was performed either not at all 31 or ino 20% of the patients.…”

Section: Gi Tractsupporting

confidence: 59%

Second haematopoietic SCT using HLA-haploidentical donors in patients with relapse of acute leukaemia after a first allogeneic transplantation

Tischer

Engel

Fritsch

et al. 2014

Haploidentical haematopoietic SCT (HSCT) using T-cell-replete grafts and post-transplant high-dose CY has found increasing acceptance. Our purpose was to evaluate the feasibility and outcome of this strategy as second HSCT incorporating donor change for acute leukaemia relapse after a first allogeneic transplantation. The courses of 20 consecutive adults (median age 37 years, 12 male) with AML (n = 14), ALL (n = 5) and acute bi-phenotypic leukaemia (n = 1) were analysed retrospectively. Conditioning consisted of fludarabine, CY and either melphalan or TBI or tresosulfan+/ -etoposide. Engraftment was achieved in 17 (85%), and a second remission was induced in 15 patients (75%) on day +30. The rate of grade II-IV acute GvHD was 35%, while chronic GvHD occurred in five patients. Most commonly observed grade III-IV toxicities were mucositis (30%), hyperbilirubinemia (20%), elevation of transaminases (20%) and creatinine (20%), while invasive fungal infection affected 30%. One-year non-relapse mortality (NRM) was 36%. At a median follow-up of 17 months, estimated 1-year OS was 45%, and 1-year relapse-free survival was 33%. This strategy was feasible and allowed for successful engraftment with a moderate rate of toxicity. Early outcome and NRM are at least comparable with results after a second HSCT from HLA-matched donors without donor change at HSCT2.

“…[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.…”

Section: Discussionmentioning

confidence: 99%

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

Ruutu

Wreede

Biezen

et al. 2015

In patients treated with allogeneic stem cell transplantation (SCT) for malignant disease who suffer from a relapse after the transplantation, the role of second allogeneic SCT is often uncertain. In a retrospective analysis, 2632 second allogeneic transplantations carried out for a relapse after the first transplantation were analyzed to define indications and identify predictive factors. Fifteen percent of the patients remained relapse-free until 5 years after the second SCT. Patients with CML had a better survival than patients with other diseases. In a multivariate analysis, factors associated with better survival were low disease burden, longer remission duration after the first transplantation, longer interval between the transplantations, younger age, absence of grade II-IV acute GvHD or chronic GvHD after the first transplantation, and later year of transplantation. The European Society for Blood and Marrow Transplantation risk score predicted the outcome. Using the same donor as in the first transplantation vs another donor had no predictive value for survival. Sibling donor was a favorable predictive factor. In conclusion, second allogeneic SCT offers a reasonable option especially for young patients with a long remission after the first transplantation and a low disease burden. The present findings do not support the usefulness of changing the donor for the second transplantation.