Page 70 - Haematologica May 2020

A. Tichelli et al.
IST. We could not demonstrate a higher risk for the devel- opment of MDS/AML or cytogenetic abnormalities in patients randomized to receive G-CSF. Patients were ana- lyzed for the risk of clonal evolution to a hematologic malignancy according to their initial randomization group (i.e. with or without G-CFS). However, data on patients in the non-G-CSF group who eventually received G-CSF (dose and duration) later in the course of their dis- ease are not available. Thus, it is fair to state that G-CSF given as part of the initial treatment within this random- ized clinical trial does not seem to increase the risk of clonal evolution to MDS/AML. Patients with SAA had a baseline risk of developing clonal evolution to a hemato- logic malignancy; this risk was not increased for patients treated with G-CSF, when compared to those in the non- G-CSF arm.
The strength of our trial is the prospective, random- ized design with a follow-up time (median 11.7 years) that is longer than the interval, 10 years after IST,15 with- in which secondary MDS/AML usually occur. Previous studies were less powerful to investigate this issue for various reasons. They were either retrospective,15,18,26 not randomized, randomized without a non-G-CSF arm16,17 or had a lower number of patients and shorter follow- up.10,12 However, it is not obvious why few among these studies showed a relationship between the use of G-CSF and a clonal evolution to MDS/AML. Factors explaining the difference from our results could be patient selection (more patients with pre-existing clonal karyotype at diagnosis of SAA).18 ethnic reasons, differences in dose and duration of G-CSF,16 or the retrospective nature of the analysis.15 The present study goes a step further in the long-term observation than most of the previous studies on SAA patients treated with ATG and CSA. We, too, could not demonstrate a higher risk of clinical PNH (the archetype of a benign clonal evolution), second solid cancer or non-malignant late events such as chronic kid- ney disease and aseptic osteonecrosis in the G-CSF group. Second solid cancers in SAA patients treated with immunosuppression have been shown to be more fre- quent than expected in a general population27 and to affect OS strongly.15 However, we found that G-CSF has no impact on the development of second solid cancers.
This study highlights two significant messages. First, G-CSF is unlikely to be linked with an increased risk of clonal transformation into a hematologic malignancy; however, available clinical data do not support the rou- tine unse of G-CSF along with IST. G-CSF can be consid- ered as an effective supportive care to combat or prevent infectious complications.25 Second, irrespectively of G- CSF, SAA patients receiving IST are particularly vulnera- ble to a number of late malignant and non-malignant complications, either because of an intrinsic pre-cancer- ous nature of the disease or alternatively because of long- term stressed hematopoiesis and prolonged immunosup- pression. Severity of the disease and age of the patient at first IST are the most important risk factors for survival. Interestingly, severity seems to have an impact only dur- ing the early phase after treatment, due to the higher risk of death from infections. In patients surviving 1 year or longer severity no longer has any impact on survival. It is somewhat disappointing that in this carefully followed cohort, irrespective of the age, less than 25% of patients
are alive and event-free 15 years after initial treatment, and about 20% of them required an allogeneic SCT. Among the late events, relapses remain the most com- mon, since, quite surprisingly, they continue to occur for at least 10 years after the initial treatment. Despite an excellent OS, young adults, have a similar risk of malig- nant and non-malignant complications after IST as older patients. The only difference is that the mortality rate in younger patients (aged <40 years) is lower, likely due to other salvage treatment options (mostly SCT) which are associated with different mortality based on age.28
Our study has a number of limitations. Firstly, despite it being the largest randomized study on the use of G-CSF in patients treated with horse ATG and CSA, because of the slow accrual for this rare disease and the withdrawal of horse ATG in Europe, the EBMT was forced to close the study early.14 However, it is unlikely that a larger number of patients would have changed the findings. Secondly, we do not have the cumulative dose of G-CSF, particularly for non-responding and relapsed patients who have been retreated with immunosuppression. The study design is based on the principle of an intention-to- treat analysis in order to provide unbiased assessments of treatment efficacy.29 Thirdly, not all late events have the same impact on the outcome of the patients. The occur- rence of secondary malignancy, MDS, AML or solid can- cer, strongly affect-OS.2 Relapse of aplastic anemia does not have the same poor prognosis as relapse of a malig- nant disease. Although relapse is common, the majority of relapsed patients respond to the reintroduction of IST and relapse does not influence survival.30 Finally, another limitation of our work is the non-exhaustiveness of the cytogenetic analysis in the context of clonal evolution, mainly related to failure to obtain results and also because the long-term evaluation had not been part of the original protocol.
Taken together, our data suggest that G-CSF added to standard IST has no impact on long-term outcome of patients with acquired aplastic anemia and is not directly related with late effects. However, regardless of the use of G-CSF, SAA patients treated with immunosuppression are particularly vulnerable to a number of late malignant and non-malignant complications. In particular, SAA patients treated with IST continue to relapse even at 10 years after initial treatment; therefore, alternative non-transplant treatment strategies are more than welcome. The addi- tion of eltrombopag on top of standard IST resulted in an increased response rate in a phase II study31,32 and is presently being evaluated in a randomized trial (EudraCT number 2014-000363-40). Furthermore, given the dramat- ic improvement of outcome after SCT, the possibility of early front-line SCT with an alternative donor might be considered for selected young patients who lack a matched sibling donor.33 Clinical trials in this setting remain the only opportunity to investigate the best strate- gies to improve the rate of cure in SAA, possibly minimiz- ing the risk of early and late events that affect survival.
Acknowledgments
The authors thank all the patients and the centers whose par- ticipation made this study possible. The list of participating cen- ters is shown in the appendix of the Online Supplementary Material.
1230
haematologica | 2020; 105(5)