Improved outcome in children compared to adolescents and young adults after allogeneic hematopoietic stem cell transplant for acute myeloid leukemia: a retrospective study from the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)

There are currently few available data on the outcome of Adolescent and Post-Adolescent (APA) patients after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) (Jaime-Pérez et al. 2018; Tomizawa et al. 2017; Canner et al. 2013; Nasir et al. 2017; Pemmaraju et al. 2016).

Acute myeloid leukemia represents about 15–20% of childhood leukemia, approximately 33% of adolescent leukemia, and approximately 50% of adult leukemia. After a peak in the first 2 years of life, the annual incidence of AML increases slowly and gradually after the age of 9 years old (Appelbaum et al. 2006). Pediatric and adult AML patients overall share biological parameters although some differences have not been systematically reviewed to date. Acute myeloid leukemia treatment has considerably improved for all age’s groups over the last 20 years, particularly through the improvement of allogeneic HSCT techniques. However, outcome appears to worsen with increased patient age. In comparison with pediatric and adult groups, the data of allogeneic HSCT for AML in adolescents are rare since they usually represent a small percentage within the cohorts of adults or children. However, these data are important since APA patients are treated in both pediatric and adult hematology departments, using different conditioning regimens—either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC)—and different graft sources, which might influence the disease outcome. We conducted a large retrospective study based on the French speaking Society for Bone Marrow Transplantation and Cell Therapy (SFGM-TC) registry to analyze and compare the outcome of AML patients classified in three age groups: children (0–14 years), APA patients (15–25 years) and young adults up to 40 years (26–40 years), who received an allogeneic HSCT from January 2005 to December 2017. In addition, we determined the factors influencing Overall Survival (OS), Event-Free Survival (EFS), Non-Relapse Mortality (NRM), Graft Versus Host Disease (GVHD) and Relapse Free Survival (GRFS) in the three age groups.

This is a retrospective multicenter analysis using the data set from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) registry. The study protocol was approved by the scientific council of the SFGM-TC and complied with French regulatory requirements. The study was conducted according to the Declaration of Helsinki. All patients provided written informed consent authorizing the use of their personal information for research purposes.

We collected data from all patients up to the age of 40 years old included in the SFGM-TC registry from January 2005 to December 2017 who received a first allogeneic HSCT for treatment of AML.

Inclusion criteria were: patients younger than 41 years old who accepted to be registered in the SFGM-TC registry, treated with a first allogeneic HSCT for AML in first or further remission and also in refractory state. We included patients during the period from 2005 to 2017. The hematopoietic stem cell source was indifferently peripheral blood or bone marrow or cord blood. Forty-three centers accepted to participate in this study.

Risk staging of AML was reported according to the 2016 European Leukemia Net classification: low-risk was defined as CBF leukemia: t(8; 21)(q22; q22) RUNX1-RUNX1T1 or inv(16)(p13.1q22) CBFB-MYH11, or leukemia with biallelic mutations of CEBPA, or leukemia with normal karyotype and mutated NPM1 without FLT3-ITD. Intermediate risk 1 was defined as leukemia with normal karyotype with either mutated NPM1 and FLT3-ITD (mutant/wild-type mutation ratio > 0.3), or wild-type NPM1 and mutated FLT3-ITD, or wild-type NPM1 without FLT3-ITD. Intermediate risk 2 was defined as t(9; 11)(p21.3; q23.3) MLLT3-KMT2A or cytogenetic abnormalities not classified as favorable or adverse. High-risk group was defined as t(6; 9)(p23; q34.1) DEK-NUP214, t(v; 11q23) KMT2A rearranged, t(9; 22)(q34.1; q11.2) BCR-ABL1, inv(3)(q21.3; q26.2) or t(3; 3)(q21.3; q26.2) GATA2, MECOM (EVI1), complex karyotype (≥ 3), -5 or del (5q), − 7; − 17/abn(17p), mutated RUNX1, mutated ASXL1 (if not in low risk cytogenetics) and mutated TP53 (Stölzel et al. 2016). The conditioning regimen was considered Myeloablative Conditioning (MAC) if the total IV busulfan dose exceeded 12 mg/kg or the total fractionated body irradiation (TBI) dose exceeded 8 Grays. The combination of fludarabine 150 mg/m² and IV busulfan 12.8 mg/kg (FB4) was defined as a reduced-toxicity MAC regimen. The other combinations have been defined as a Reduced-Intensity Regimen (RIC) (Bacigalupo et al. 2009).

Grading of acute GVHD was performed using the Glucksberg’s score (Glucksberg et al. 1974). Chronic GVHD was classified as limited or extensive according to previous published criteria (Filipovich et al. 2005).

This retrospective registry study from 2005 to 2017 showed that APA patients have a greater risk of NRM and chronic GVHD than children after allogeneic HSCT for AML. The relapse occurred slightly more frequently in the APA patient group, but age was not an independent factor for relapse. As far as NRM is concerned, we observed that the age group was an independent risk factor, but also the cytogenetics risk, the disease status, the HLA matching and the donor’s age; moreover, we observed a higher rate of chronic extensive GVHD in APA patients and young adults in comparison to children, with the age group as an independent risk factor.

Except for promyelocytic leukemia, APA patients with AML were described as presenting a poorer prognosis than children in a few studies due to a higher rate of relapse (Jaime-Pérez et al. 2018), higher risk of toxicity-related mortality (Tomizawa et al. 2017) owing to more frequent infections (Canner et al. 2013) and a higher early mortality rate (Nasir et al. 2017). Nevertheless APA patients had a better prognosis than adult AML patients (Pemmaraju et al. 2016). Age seems to be related to the outcome from childhood to adulthood (Appelbaum et al. 2006). Patients treated in pediatric trials had better outcomes than those treated on adult trials in an American study by the National Marrow Donor Program (NMDP), but age was a major confounding variable, making it harder to compare data sets by cooperative groups (Woods et al. 2013). Moreover, neither studies from the Nordic Society of Paediatric Haematology and Oncology (NOPHO), nor works from multi-center in Germany found no difference in outcomes for AML patients in overlapping age groups on pediatric versus adult protocols (Wennström et al. 2016; Büchner et al. 2009; Schlenk et al. 2003). Currently, there is a need for prospective studies to be able to issue a recommendation.

After allogeneic HSCT, a different survival rate for young AML patients was firstly reported from the International Bone Marrow Transplant Registry, from 1980 to 2005 (Majhail et al. 2012). Adolescent and post-adolescent patients were defined as aged 15 to 40 and had improved survival in comparison to older patients but also a worse prognosis compared to children of under 15 years of age. A further study from Minneapolis had reported no difference in children’s outcome compared to APA patients (aged 15–30) from 1995 to 2010, except for GVHD (Burke et al. 2014). A more recent study from the Japanese Group reported an inferior 5-year OS (54% versus 58%; p < 0.01) and an increased transplant-related mortality (TRM; 16% vs 13%, p = 0.02) in adolescent, post-adolescent and young adult patients (15–29 years) compared to children who received allogeneic HSCT for AML from 1990 to 2013 (Tomizawa et al. 2015). However, better HLA typing in recent years could eliminate this difference. Considering that last study, no difference in outcome of APA patients and children (OS, relapse-free survival and NRM) could be identified in the most recent period of their study between 2000 and 2013. This result is in contrast with our study on a more recent cohort of patients.

In our study, cytogenetics risk was strongly related to OS, EFS, NRM and GRFS in multivariable analysis. However, children had more often high-risk cytogenetics, but did not experience a higher incidence of relapse, and had a higher EFS, which was in concordance with the study of Alloin et al. that found a significant survival improvement for children with unfavorable karyotype due to the decrease of relapse risk over time (Alloin et al. 2017). Furthermore, through age groups, there are observable differences in mutated genes, somatic structural variants and DNA methylation patterns (Bolouri et al. 2018). From the study of Boulouri et al., it is important to notice, for instance, that the prevalence of gene fusions and focal deletions in MBNL1 and ZEB2 is much higher in young patients than in adults and the mutations in DNMT3A and TP53 are highly uncommon in children compared to adult patients. In the future, all of these genetic observations should allow targeted and age-suited treatment of AML (Bolouri et al. 2018).

Disease status remains a strong independent factor in relapse, toxicity and death after HSCT. In all recent studies, more advanced disease is still correlated with death for both adults (Konuma et al. 2018; Gaballa et al. 2017) and children (Bitan et al. 2017) in spite of improvements in salvage therapies (Rasche et al. 2018); it is the same for the minimal residual disease (MRD) which is a strong prognostic factor before HSCT (Gilleece et al. 2021; Candoni et al. 2017). Refractory AML has a very bad prognosis despite efforts to develop new strategies such as sequential regimen, except in patients with low medullar blast burden in primary refractory AML (Steckel et al. 2018). In our study, the disease status at the time of transplant was correlated with OS, EFS, NRM and GRFS.

Young adults and APA patients received myeloablative TBI more frequently in their conditioning regimen whilst almost all children received myeloablative chemotherapy without any irradiation. TBI was an independent risk factor of overall mortality. These results are consistent with previous studies reporting that the use of TBI in the conditioning regimen of AML patients, in comparison to busulfan-based MAC regimen, was deleterious for adults and children, despite this being the contrary in ALL studies (Champlin 2013; Bredeson et al. 2013). This deleterious effect of TBI compared to chemotherapy with busulfan was mostly explained by a higher rate of NRM (Berranger et al. 2014) and chronic GVHD incidence (Copelan et al. 2013; Nagler et al. 2013).

The increased NRM for APA (and adult) patients in our study was also possibly a result of the higher cumulative incidence of chronic GVHD compared to children under 15 years old. As far as extensive chronic GVHD is concerned, it was independently associated with PBSC, that were used as a stem cells source for more than 45% of APA patients and 60% of young adults, whereas children received mostly bone marrow and cord blood units. The observation of an increased incidence of chronic GVHD in APA patients has already been reported by Vignon et al. in a precedent study and is always an important matter due to the impact on quality of live (Vignon et al. 2017). As previously described, a high dose of Cyclophosphamide after HSCT reduced the risk of chronic GVHD, and also chronic extensive GVHD such as ATG did. Our results are consistent with previous studies on this point (Kröger et al. 2016; Martinez-Cibrian et al. 2020; Ruggeri et al. 2018; Luznik et al. 2012).

Moreover, we noted that allogeneic HSCT from 9/10 HLA matched unrelated donors resulted in a significantly worse OS than those from both 10/10 HLA matched unrelated donors and HLA identical sibling donors, which is mainly due to increasing NRM (Petersdorf et al. 2004; Flomenberg et al. 2004; Lee et al. 2009; Woolfrey et al. 2011; Horan et al. 2008). Cytomegalovirus serologic positivity for the recipient was also correlated to GRFS and grade III to IV acute GVHD, as previously described before the use of letermovir (Marty et al. 2017).

Donor age was higher in APA patients and young adults; besides, donor age was an independent factor in OS, EFS, NRM, GRFS and chronic extensive GVHD. According to previous publications, allogeneic HSCT from older donors could be associated with reduced OS (Kollman et al. 2001; Loren et al. 2006; Bastida et al. 2015; Ayuk et al. 2018; Shaw et al. 2018) for several reasons: on one hand, higher comorbidity and mobilization failure, on the other, to increased rates of acute and chronic GVHD, higher NRM and relapse rate (Kollman et al. 2001; Loren et al. 2006; Bastida et al. 2015). Recent study data from two works published in 2018 by Ayuk et al. and Shaw et al. showed the impact of the donor’s age and sex mismatch that could be comparable to a single HLA disparity (Ayuk et al. 2018; Shaw et al. 2018).

Adolescent and post-adolescent patients, like young adults, have a greater risk of NRM and chronic GVHD than children after allogeneic HSCT for AML. They also have a higher cumulative incidence of relapse, even if age is not an independent factor of relapse. Therefore, this study suggests that APA patients with AML could be beneficially treated with a conditioning regimen based on myeloablative chemotherapy associated with bone marrow graft. Moreover, donor age and HLA compatibility should also be carefully assessed prior to the procedure. A future prospective comparative study is needed to confirm these results and to assess this important issue of conditioning and stem cell source choice in APA patients who received an allogeneic HSCT for AML.