Page 271 - Haematologica - Vol. 105 n. 6 - June 2020

Allogeneic transplantation for CBF AML
studies, in our group, patients with inv(16) had a higher probability of LFS, OS, and a lower risk of relapse than those with t(8;21). Interestingly, these end points reported in most papers for patients treated with chemotherapy alone are not usually different for inv(16) and t(8;21) AML. On the other hand, the MD Anderson study, for example, pointed out that patients diagnosed with t(8;21) have a worse prognosis than those with inv(16).5
Response to chemotherapy with clearance of RUNX1- RUNX1T1 and CBFB-MYH11 evaluated with RT-qPCR, as well as additional molecular aberrations detected at diag- nosis, but not type of CBF AML per se, are most frequently emphasized as the factors determining outcome in chemotherapy-treated patients.9,21,22 Presence of MRD assessed with flow cytometry in AML before transplanta- tion is a recognized risk factor for inferior outcome.23 Molecular evaluation of MRD in CBF AML before trans- plantation has not been extensively studied to date. In our cohort, MRDneg patients had a significantly decreased risk of relapse compared with MRDpos patients (HR=0.65, P=0.043); this translated into a trend for improved LFS (HR=0.76, P=0.08) and GRFS (HR=0.77, P=0.054) but showed no significant influence on OS (P=0.47). Data analysis revealed that MRDpos patients more frequently received donor lymphocyte infusions or subsequent transplants after relapse than MRDneg patients. Those therapeutic interventions, and probably lack of statistical power, may explain why we did not find a significant difference in OS in favor of MRDneg patients. The results of our study indicate that even patients who are MDRpos can expect survival advantage from trans- plantation compared to those who are treated with chemotherapy alone.9 A recent paper showed that evalua- tion of RUNX1-RUNX1T1 was useful to predict relapse not only before but also after HSCT.24 It should be empha- sized that the kinetics of relapse in inv(16) and t(8;21) patients differ, and the latter group requires more frequent molecular testing.25
According to the 2017 European Leukemia Net and National Comprehensive Cancer Network guidelines, additional cytogenetic aberrations in CBF AML do not modify disease risk.4,26 In our study group, the presence of concurrent three or more chromosomal abnormalities had a marked deleterious effect on relapse (HR=2.31, P=0.011), LFS (HR=2.09, P=0.004), and even OS (HR=1.68, P=0.037) after HSCT. Indeed, earlier reports documented worse outcomes in newly diagnosed CBF AML patients with three or more cytogenetic abnormalities.5 This find- ing may indicate a more complex clonal evolution, and could support the adoption of anticipated measures to avoid relapse, such as indication of transplantation in first remission.
Not surprisingly, in our study, performance status was a strong independent risk factor for NRM, LFS, and OS. Thus, patients with KPS ≥80 had decreased NRM and improved LFS and OS, which was similar to the findings of previous studies.27
The intensity of conditioning regimen in the current analysis favored MAC over RIC in terms of relapse. Comparable findings were described in a recent EBMT ALWP study in patients transplanted for secondary AML with additional benefit of higher probability of LFS and OS in individuals receiving MAC.28 The results of an
American phase III prospective randomized trial of MAC versus RIC in AML and myelodysplastic syndrome patients published in 2017 also revealed statistically higher relapse rates and worse LFS with a trend for decreased OS after RIC.29 In contrast, in a German randomized study including AML patients published a few years earlier, RIC and MAC yielded identical results for both types of con- ditioning, even in terms of disease recurrence.30 In our cohort, conditioning intensity had no significant impact on LFS or OS. In the German trial, MAC was also a pre- dictor for aGvHD. Similarly, in our study, MAC was the only independent risk factor for clinically significant, grade II-IV aGvHD. The same correlation had been described previously, and is supported by the concept of a more pronounced inflammatory reaction after MAC.31
Independent factors influencing cGvHD in our study were: in vivo TCD, the use of PBSC versus BM, and trans- plantation from CMV seropositive donors; these findings are in agreement with previous literature.32,33 Only recent- ly, possible mechanisms linking CMV immunity and cGvHD were studied in HSCT recipients. In patients with cGvHD, a higher proportion of donor-origin high-affinity CMV-specific cytotoxic T lymphocytes was demonstrat- ed.34 The composite end point described as GRFS repre- sents the most desirable outcome of HSCT. In our study, 2- and 5-year probabilities of GRFS were 40.2% and 34.6%, respectively. Recently, a large analysis of 5,059 AML patients from the EBMT database defined transplan- tation from unrelated donors, PB stem cell transplants, and unfavorable cytogenetics as prognostic factors for worse GRFS. In contrast, in vivo TCD was associated with better results and was the main beneficial factor for GRFS.35 In our cohort, type of donor and source of stem cells did not have a significant impact on GRFS, which may be due to a considerably smaller study sample. Adverse cytogenetics decreased, while in vivo TCD increased the probability of GRFS in our patients, which is in line with the results of the above-mentioned study.
Our registry-based, retrospective study has various well-known limitations. For example, due to low report- ing, we were not able to investigate the prognostic impact of additional genetic co-mutations frequently observed in CBF-AML, such as mutations in signaling pathways KIT, NRAS, KRAS and FLT3.36
The most important findings of our study show that HSCT in CBF AML in CR2 was able to cure a large pro- portion of patients, with 2-year and 5-year OS 65% and 58.2%, respectively. The survival of patients with inv(16) was better than those with t(8;21); an observation which confirms a substantial underlying difference between the two CBF AML subtypes also in the transplant setting. Based on our results, CBF AML patients should receive MAC rather than RIC, if eligible. Although patients who were MRDneg had lower risk of relapse and higher prob- ability of survival without recurrence of leukemia, a signif- icant proportion of MRDpos patients obtained durable response following HSCT. In view of our study, lack of MRD clearance should not be considered a contraindica- tion for allogeneic transplantation.
Acknowledgments
The authors would like to thank all colleagues from 181 report- ing centers for providing data for the analysis.
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