Characteristics and Outcomes of Children, Adolescents and Young Adults with Relapsed/Refractory Non-Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant

There is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous hematopoietic stem cell transplantation (ASCT). We analyzed 222 patients aged 0–39 years undergoing first ASCT for NHL between 2000 and 2020. The most common histological subtypes were DLBCL (44%), T-NHL (19%) and PMBCL (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (> 25 years) (P = 0.02). None of the younger patients had DH)/DE DLBCL, as compared to 14 patients in the older group (18%, P = 0.07). Younger patients had numerically better 15-year post-transplant PFS (67% vs. 54%) and OS (71% vs. 62%) compared to older patients, without statistically significant differences (P = 0.19 and P = 0.24, respectively). In MVA, not achieving a CR prior to ASCT was independently predictive of worse PFS (P < 0.0001). DH/DE status was an independent adverse predictor of PFS in MVA (HR 5.8, p = 0.03). 10 patients(4.5%) (all aged > 25 years) developed SPM Patients aged ≤ 25 years presented a distinct NHL histology as compared to older CAYA patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.


Introduction
There is growing recognition of the unique characteristics and challenges facing children, adolescents and young adults (CAYA) with cancer (1). NHL accounts for approximately 8% of reported malignancies in the AYA population. AYA with NHL have distinct clinical presentations, biological characteristics and outcomes compared to children or older adults (2). The most common NHL subtypes in this age group include diffuse large B-cell lymphoma (DLBCL), anaplastic large cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma and primary mediastinal large B-cell lymphoma (PMBCL). Compared to older adults, DLBCL in children and AYA is more likely to have a germinal center B-like (GCB) immunophenotype, MYC translocation or overexpression, high proliferative index and absence of BCL2 translocation (3)(4)(5).
CAYA patients undergoing hematopoietic stem cell transplantation (HSCT) face unique di culties, including social and psychological challenges (6, 7), yet there is paucity of data focusing on outcomes of ASCT in CAYA patients with NHL.
In the present study we aimed to examine the characteristics and outcomes of contemporaneous CAYA patients who received their rst ASCT due to NHL at our center. We evaluated potential impact of patient and disease-related variables on outcomes and compared the younger and older age groups within our cohort.

Study design and participants
We conducted a retrospective chart review of MD Anderson Cancer Center patients aged 0-39 years who received their rst ASCT for NHL between January 2000 and January 2020. We excluded patients who received a previous allogeneic or autologous transplant. We divided this cohort into two age groups: younger (≤ 25 years) and older (> 25 years) patients. This division was based on developmental stage: ≤25 years to include pediatric, adolescents and emerging adults, and > 25 years to include young adulthood patients (8). This retrospective chart review was approved by the Institutional Review Board.
We used standard criteria for staging, response and outcomes according to guidelines from the Lymphoma Imaging Working Group (9) and Harmonization Project in Lymphoma (10). As per these criteria, complete remission (CR) was de ned as the disappearance of any evidence of disease on positron emission tomography/computed tomography (PET/CT); partial remission (PR) was de ned as regression of measurable disease and no new sites on PET/CT; stable disease (SD) was de ned as failure to attain either CR/PR or progressive disease (PD); PD was de ned as any new lesion or increase by ≥ 50% of previously involved sites from nadir on PET/CT. Double/triple hit lymphoma and double expressor lymphoma were de ned according to the WHO classi cation of lymphoid neoplasms (11).

Statistical methods
Wilcoxon rank-sum tests were used to compare the distribution of continuous variables between age groups. Fisher's exact tests were used to compare the distribution of categorical variables between groups. The method of Kaplan and Meier was used to estimate the distribution of overall survival (OS) and progression-free survival (PFS) from the date of transplant. Patients who remained alive (OS) or alive and progression-free (PFS) were censored at the last follow-up date. Distributions were compared using the log-rank test. Cox proportional hazards regression models were t to each survival endpoint. In some cases, Firth's penalized likelihood method was used to t models when the number of patients in one or more categories was small. Univariate and multivariate Cox regression models were also t to each survival endpoint using factors speci ed by the investigator. Because there was substantial missing data in the second-line international prognostic index (sIPI) variable, two models were t for each: one considering sIPI and one without it.
All statistical analyses were performed using R version 4.1.1. All statistical tests used a signi cance level of 5%. No adjustments for multiple testing were made.

Discussion
In the present study we describe patient characteristics and long-term outcomes of a large cohort of CAYA who received ASCT for NHL at our center. The three most common histological subtypes of NHL in the entire cohort were DLBCL, T-NHL and PMBCL. More than 90% achieved ≥ PR prior to transplant. We found that patients aged ≤ 25 years presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. Disease status at ASCT was predictive of both PFS and OS, whereas DH/DE status was an adverse predictor of PFS.
We observed numerically better survival outcomes in younger patients, yet there was no statistically signi cant difference between the two age groups. A report by Berkman et al. examined long-term survivors of DLBCL AYA patients (de ned as age of 15-39 years) using the Surveillance Epidemiology and End Results (SEER) database (12) found that each additional year of age at diagnosis was associated with a decrease of 6% in overall survival (p < 0.0001). On the other hand, in the Japanese AYA registry study (13) patients in that study did have a higher rate of transplant related mortality (TRM) (5.1% vs. 0.8%, p = 0.0043). We observed higher rates of PFS and OS in our cohort, compared to the Japanese registry study: The 5-year PFS in our study was 76.5% for the younger age group and 63.8% in the older age group, and the 5-year OS were 86.4% and 72.5%, respectively. There are several methodological differences that can partially explain these differences in outcomes. First, we included a broader range of ages in our study, so that our study cohort comprised both pediatric patients as well as the most commonly used de nitions of AYA, up to the age of 39 (6). Furthermore, the two studies also had different proportions of the various NHL histological subtypes and used a different age cutoff for the younger/older age subsets.
Few previous reports have compared outcomes of ASCT to allogeneic HSCT in NHL with a varying range of ages within the CAYA spectrum (13)(14)(15)(16). Most of these reports showed similar outcomes between the two types of HSCT, including a small single center study that included 36 pediatric NHL patients (15) and a Center for International Blood and Marrow Transplant Research (CIBMTR) registry study that included 182 children and adolescent NHL patients (aged 0-18 years; 90 received ASCT) that were transplanted between 1990 and 2005 (16). A more recent analysis of the Japanese registry dataset compared outcomes of AYA patients (de ned as aged 16-30, n = 645) to pediatric patients (aged 0-15, n = 273) undergoing autologous or allogeneic stem cell transplant for NHL (13). Outcomes were similar between the two age groups among those who received an allogeneic transplant. However, as previously mentioned, TRM in the 55% of the cohort that received ASCT was signi cantly higher in children compared to AYA. A multi-national study included 639 patients with R/R NHL (mostly Burkitt lymphoma/leukemia and DLBCL) aged 0-18 years. Only 23% of the entire cohort (n = 150) received an ASCT, whereas 39% received allogeneic transplant and 37% did not undergo any transplant. The 8-year OS of patients who underwent ASCT was superior to those who received an allogeneic transplant or did not receive any transplant (55% vs.47% vs. 8%, respectively; p < 0.0001).
Our study focused only on rst ASCT, and included both the pediatric and AYA populations. We were able to elucidate variables that impacted survival outcomes in this setting. We showed that achieving pretransplant CR was associated with better PFS and OS in MVA. This nding complements previous studies that have shown the prognostic impact of responses prior to ASCT in adults with aggressive B-Cell (17) and  (20). To the best of our knowledge, we are the rst to report this nding in the CAYA DLBCL population.
With a median follow up period of 5.5 years, and some patients followed for more than 20 years, 4.5% of our CAYA cohort develop a SPM. This is lower than the 9% of SPM reported in a study that included 372 adult NHL patients who underwent ASCT (21), and slightly higher than the 2.6% reported in a large cohort of 1487 pediatric patients that were transplanted for a variety of indications (26% underwent ASCT due to lymphoma) (22). A joint study from European and German study groups analyzed 189 cases of SPM in children and adolescents (aged 0-18) after treatment for NHL (23). Half the SPM in that study were hematological malignances (23% myeloid and 27% lymphoid neoplasms), and an additional 25% were carcinomas. This distribution was overall similar to the types of SPM observed in our cohort. Of note, the aforementioned study did not report how many patients received ASCT.
The current study has several limitations inherent to its retrospective design, including heterogeneity in patient characteristics and treatments, as well as unidenti ed confounders that were not accounted for, despite the use of multivariable cox regression analysis. Furthermore, cohort size is rather modest, despite being one of the largest cohorts of CAYA NHL patients receiving ASCT in the published literature to date.
In conclusion, we described patient characteristics and long-term outcomes of a large cohort of CAYA who received ASCT for NHL. Patients aged ≤ 25 years presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed numerically better PFS and OS in younger patients, albeit without a statistically signi cant difference. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.
With the advent of novel therapeutic modalities, mainly CAR T therapy, the role of ASCT needs additional clari cation. Recently, two phase III trials have shown superiority of two anti-CD19 CAR T constructs for treatment of a subset of patients with R/R DLBCL (24,25). Both trials included only adult patients, and trials with autologous anti-CD19 CAR T in pediatric NHL patients are ongoing (NCT03610724, NCT02625480). Our data may serve as a benchmark for outcomes of future CAR T trial outcomes.

Declarations
Competing Interests: The authors declare no competing nancial interests