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Sequential therapy patients with refractory AML
A sequential therapy approach, based on the FLAMSA protocol was designed to overcome these obstacles.13-15 This both shortened the time to transplant (thus reducing ongoing repeated chemotherapy and neutropenia-associ- ated side effects) and provided significant anti-leukemic activity; it results in remarkable complete remission rates and overall survival. Herein, we describe the German- Israeli experience using sequential protocols in patients with AML and primary induction failure, focusing on transplantation outcomes and highlighting the importance of this approach for patients with refractory AML and an available donor.
Methods
Patients
Only patients with primary refractory AML were included in this study. Patients received either FLAMSA/total body irradiation (TBI), FLAMSA/treosulfan, or FITCy conditioning regimen before HCT. Primary refractory AML was defined as unresponsiveness (at least 20% of blasts in marrow) after at least one course of 7+3 (defined on day 28-35 marrow), four courses of hypomethylating agent, TAD/HAM, or sequential HAM-induction (s-HAM). Percentage of blasts was documented just before the start of con- ditioning. FLAMSA/ treosulfan instead of FLAMSA/TBI was used in patients older than 65 years or in those with significant comor- bidities.15 Patients with relapsed AML were not included in this study. Details about the donor search procedures, the comprehen- sive treatment, and the supportive care are available in the Online Supplementary Appendix.
Evaluation of response
Engraftment was defined as the first of three days with a neu- trophil count of >0.5x109/L and a non-transfused platelet count of >20x109/L. Disease response and donor chimerism were assessed at day +30 and day +100 in peripheral blood (PB) and bone mar- row (BM). Complete remission (CR) was defined as <5% blast cells in BM by cytomorphology and flow cytometry, and neu- trophils of >1.5x109/L in PB. Hematologic relapse was defined by the reappearance of blast cells in the PB, or by >5% blast cells in BM. Death from leukemia was defined as death with refractory disease after transplantation or death from any cause after post- transplantation relapse. Non-relapse mortality (NRM) was defined as death from any cause other than refractory disease or relapse.
Statistical analysis
All patients gave informed consent to the planned treatment schedule as well as for anonymous data collection. The study was approved by the local ethics committee.
Continuous variables were described as the mean, median, standard deviation and range of number of observations, as appli- cable. Categorical data were described with contingency tables including frequency and percentage. Confidence intervals were calculated at two-sided 95% level of confidence. Two-sided P<0.05 was considered statistically significant.
Overall survival (OS) was defined as the time from HCT until the date of death from any cause. For subjects who are still alive, survival data were censored at the last known date of follow up. Disease response and disease progression were assessed according to the previously published response criteria.11
The probabilities of OS were estimated using the Kaplan-Meier method, and the log-rank test was used to evaluate the differences between groups. Probabilities of NRM were estimated with the use of cumulative incidence curves, with relapse treated as a com-
peting risk. Relapse incidence was evaluated with use of cumula- tive incidence curves, with NRM treated as a competing risk. The Fine and Gray method was used to evaluate the differences between groups. Multivariate analysis was performed using a Cox proportional hazard regression model for OS and competing risk regression by the Fine and Gray method for NRM and relapse. We used the Duval score to stratify patient populations; patients were scored on a scale of 1-4, considering the fact that all patients were in a primary refractory state.16 SPSS version 23, R 3.1.0 statistical software, and Prism version 5.0 were used for statistical analysis.
Results
Between March 2005 and January 2018, we identified 51 patients who had a primary refractory disease and were treated at the University of Cologne (n=30) or at the Tel Aviv Medical Center (n=21). Table 1 shows patients’ characteristics. Median follow up of surviving patients was 37 (2-154) months. Median age was 54 (range, 18-73) years. In the majority of patients, prior chemotherapy was either TAD/HAM or sHAM (n=30, 59%) or 7+3 only (n=11, 22%). Median time from induction chemotherapy to HCT was 84 (25-183) days. The preparative regimen was FLAMSA-TBI (n=13, 26%), FLAMSA-Treosulfan (n=17, 33%) or FITCy-TBI (n=21, 41%). Anti-thymocyte globulin (ATG) was given as part of the conditioning in 6 of 20 (30%) grafts derived from siblings and in 24 of 30 (80%) grafts derived from an unrelated donor. In almost all cases, the graft was derived from peripheral blood stem cells.
Early transplantation course
All 51 patients were evaluated for early transplantation toxicities. Eleven patients (22%) developed documented infections, including invasive aspergillus (n=2, 4%), gram- negative bacteremia (n=6, 12%), gram-positive bac- teremia (n=2, 4%) and C. difficile-associated diarrhea (n=1, 2%). In two patients (4%), the etiology of sepsis could not be determined.
Two (4%) patients developed acute respiratory distress syndrome (ARDS) and two (4%) patients developed sinu- soidal obstruction syndrome (SOS). In one case, ARDS resulted in early mortality at seven days post transplanta- tion. Data regarding mucositis were available in 21 of 51 patients (41%). Only two (10%) patients experienced grade 3-4 mucositis, whereas five (24%) did not develop any mucositis. Median time to neutrophil engraftment was 13 (range, 8-19) days and median time to platelet engraftment was 13 (range, 7-30) days. None of the patients had primary graft failure. In all patients, analyses of whole marrow chimerism showed 96-100% donor- derived cells on day 30 post HCT.
Graft-versus-host disease
Median onset of grade 2-4 acute GvHD was 26 (range,
7-162) days. Among those patients who developed acute GvHD, involvement of skin, gut, and liver occurred in 17 (50%), 14 (41%), and 10 (29%) of the patients, respective- ly. By day 100, the cumulative incidences of grade 2-4 and grade 3-4 acute GvHD were 50% (95%CI: 41-67%) and 12% (95%CI: 3-25%), respectively (Figure 1A). In uni- variate analysis, male gender was associated with a high- er incidence of acute GvHD, while older age and ATG administration were associated with a lower incidence of
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