1.
Reduced intensity conditioning regimens including alkylating chemotherapy do not alter survival outcomes after allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia compared to low-intensity non-myeloablative conditioning
Andersen, N. S., Bornhauser, M., Gramatzki, M., Dreger, P., Vitek, A., Karas, M., Michallet, M., Moreno, C., van Gelder, M., Henseler, A., et al
Journal of cancer research and clinical oncology. 2019
Abstract
PURPOSE The optimal dose intensity for conditioning prior to allogeneic hematopoietic stem cell transplantation (alloHSCT) for chronic lymphocytic leukemia (CLL) is unknown. METHODS We retrospectively compared outcomes of patients who received a first alloHCST after non-myeloablative (NMA) and reduced intensity conditioning (RIC). Data of 432 patients with a median age of 55 years were included, of which 86 patients underwent NMA and 346 RIC. RESULTS The median follow-up after alloHSCT was 4.3 years. Compared to the RIC group, more NMA patients had purine-analog-sensitive disease, were in complete remission and received matched related donor transplantation. After RIC, the probabilities for 5-year OS, EFS, CIR, and NRM were 46%, 38%, 28%, and 35% and after NMA the respective probabilities were 52%, 43%, 25%, and 32%. In multivariate analysis, remission status prior to conditioning but not RIC versus NMA conditioning had a significant impact on CIR, EFS, and OS. CONCLUSION Presumed higher anti-leukemic activity of RIC versus NMA conditioning did not translate into better outcomes after alloHSCT, but better remission status prior to conditioning did. Effective pathway inhibitor-based salvage therapies combined with NMA conditioning might thus represent the most attractive contemporary approach for alloHSCT for patients with CLL.
2.
Radioimmunotherapy in combination with reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in patients with advanced multiple myeloma
Fasslrinner, F., Stolzel, F., Kramer, M., Teipel, R., Brogsitter, C., Morgner, A., Arndt, C., Bachmann, M., Hanel, M., Rollig, C., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Radioimmunotherapy (RIT) has the potential to reduce the incidence of relapse after allogeneic hematopoietic cell transplantation (allo-HCT) in patients with advanced-stage multiple myeloma (MM). In this study, we evaluated the efficacy of RIT in combination with chemotherapy-based reduced-intensity conditioning (RIC). RIT was based on the coupling of an anti-CD66 antibody to the beta emitter 188-rhenium (188-re) for targeted bone marrow irradiation. Between 2012 and 2018, 30 MM patients, most of them heavily pretreated including various therapies with proteasome inhibitors, immunomodulatory drugs, anti CD38 antibodies, and autologous hematopoietic cell transplantation (auto-HCT), were treated with a RIT-RIC combination prior to allo-HCT. In addition to a fludarabine plus melphalan- or treosulfan-based RIC a median dose of 18.1 Gy (interquartile range (IQR) 14.6 to 24.1) was applied to the bone marrow. After a median follow-up time for surviving patients of 2.1 years (IQR 1.3-3.0), the two-year progression-free survival and overall survival rates were 43 % (95% CI 26-73%) and 55 % (95% CI 38-79), respectively. The two-year non-relapse mortality and cumulative incidence of progression were 17% (95% CI 3-30%) and 46 % (95% CI 25-67%), respectively. Renal toxicity and mucositis were the most frequently observed extramedullary side effects. In conclusion, the addition of RIT to RIC was safe and feasible, and resulted in promising outcomes compared to those previously reported for RIC-based allo-HCT-treated relapsed/refractory MM patients without RIT addition. Nevertheless, in spite of RIT addition, relapse after allo-HCT remained a major determinant of therapeutic failure. Therefore, development of novel RIT strategies (e.g., dual targeting strategies or combinations with adapter chimeric antigen receptor T cell-based therapies) are warranted.
3.
Long-term efficacy of reduced-intensity versus myeloablative conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: retrospective follow-up of an open-label, randomised phase 3 trial
Fasslrinner, F., Schetelig, J., Burchert, A., Kramer, M., Trenschel, R., Hegenbart, U., Stadler, M., Schafer-Eckart, K., Batzel, M., Eich, H., et al
The Lancet. Haematology. 2018
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Abstract
BACKGROUND The impact of the intensity of conditioning before allogeneic haemopoietic cell transplantation (HCT) has been studied in a randomised phase 3 trial comparing reduced-intensity conditioning with myeloablative conditioning in patients with acute myeloid leukaemia in first complete remission. Because of the short follow-up of the original trial, whether reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning remained unclear. To address this question, we present retrospective 10-year follow-up data of this trial and focus on late relapse. METHODS The original randomised phase 3 trial included patients aged 18-60 years, with intermediate-risk or high-risk acute myeloid leukaemia, an adequate organ function, and an available HLA-matched sibling donor or an unrelated donor with at least nine out of ten HLA alleles matched. Patients were randomly assigned (1:1) to 120 mg/m(2) fludarabine combined with four 2 Gy doses of total-body irradiation (reduced-intensity conditioning) or six 2 Gy doses of total-body irradiation and 120 mg/kg cyclophosphamide (myeloablative conditioning). The primary and secondary efficacy endpoints of this trial have been published previously. In this retrospective, long-term follow-up analysis, data were collected from medical reports from individual participating study centres, and from physician and patient interviews. Endpoints included in this analysis were cumulative relapse incidence, overall survival, disease-free survival, and non-relapse mortality in the original study population and in patients alive and relapse-free at 12 months after HCT (landmark analysis). 10-year time to event rates were calculated in the intention-to-treat population and were compared with the Gray test. The trial is registered with ClinicalTrials.gov, number NCT00150878. FINDINGS In the original trial, 195 patients were randomly assigned to receive reduced-intensity conditioning (n=99) or myeloablative conditioning (n=96). For this retrospective analysis, data were collected with a nearly complete follow-up (completeness index 99%). Median follow-up time for surviving patients was 9.9 years (IQR 8.5-11.4), during which the cumulative incidence of relapse in the complete study population was identical in both groups (30% [95% CI 20-39] in the reduced-intensity conditioning group vs 30% [21-40] in the myeloablative conditioning group; Gray test p=0.99). Relapse occurred at a median of 5.0 months (IQR 3.0-8.8) in the reduced-intensity conditioning group versus 9.5 months (4.5-20.5) in the myeloablative conditioning group. 10-year disease-free survival was 55% (95% CI 45-66) in the reduced-intensity conditioning group and 43% (34-55) in the myeloablative conditioning group (hazard ratio [HR] 0.76 [0.51-1.14]; p=0.19). 10-year non-relapse mortality was 16% (95% CI 8-24) in the reduced-intensity conditioning group and 26% (17-36) in the myeloablative conditioning group (subdistribution HR 0.60 [95% CI 0.32-1.11]; Gray test p=0.10). The incidence of long-term toxicities associated with total-body irradiation was comparable; secondary malignancies occurred in six (6%) of 94 patients in the reduced-intensity conditioning group and five (6%) of 90 in the myeloablative conditioning group (p=1.00). INTERPRETATION There is no evidence that reduced-intensity conditioning increases the risk of late relapse compared with myeloablative conditioning. Given that the reduced-intensity conditioning group in the original trial was associated with lower early morbidity and toxicity, reduced-intensity conditioning with moderately reduced total-body irradiation doses could be the preferred conditioning strategy for patients with acute myeloid leukaemia who are younger than 60 years and transplanted in first complete remission. FUNDING None.