Hematopoietic stem cell transplantation for B-thalassemia major with alemtuzumab.

While matched related donor (MRD) allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for transfusion-dependent beta-thalassemia (TDT), the use of alternative sources has increased, resulting in the exploration of novel transplant-conditioning regimens to reduce the contribution of graft-versus-host disease (GVHD) and graft failure (GF) to transplant-related morbidity and mortality. Alemtuzumab is a CD52 monoclonal antibody that has been successfully incorporated into myeloablative conditioning regimens for other hematologic conditions, yet there have been limited studies regarding the use of alemtuzumab in HSCT for TDT. The purpose of this study was to evaluate engraftment, incidence of GVHD, and transplant related morbidity and mortality in patients with TDT who received alemtuzumab in addition to standard busulfan-based conditioning. The primary endpoint was severe GVHD-free, event-free survival (GEFS). Our cohort included 24 patients with a median age of 6.8 years (range 1.5-14.9). Eleven patients received a 10/10 MRD HSCT, eleven 10/10 unrelated donor (UD), and two mismatched UD. All patients achieved primary engraftment. For all patients, 5-year GEFS was 77.4% and 5-year overall survival (OS) was 91%. The 5-year cumulative incidence of GF (attributed to poor graft function) without loss of donor chimerism was 13.8% (95% CI: 4.5, 35.3). We report low rates of significant acute GVHD grade II-IV (12.5%) and chronic GVHD (4.4%). Younger age and MRD were associated with significantly improved GEFS, OS and EFS. Our results show that the use of alemtuzumab promotes stable engraftment, may reduce rates of severe GVHD, and results in acceptable GEFS, OS, and EFS.

A validated pediatric disease risk index for allogeneic hematopoietic cell transplantation.

A disease risk index (DRI) that was developed for adults with hematologic malignancy who were undergoing hematopoietic cell transplantation is also being used to stratify children and adolescents by disease risk. Therefore, to develop and validate a DRI that can be used to stratify those with AML and ALL by their disease risk, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n = 1224) or lymphoblastic (ALL; n = 1345) leukemia who underwent hematopoietic cell transplantation. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets, and separate prognostic models were derived for each disease. For AML, 4 risk groups were identified based on age, cytogenetic risk, and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups was 78%, 53%, 40%, and 25%, respectively (P < .0001). For ALL, 3 risk groups were identified based on age and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups was 68%, 51%, and 33%, respectively (P < .0001). We confirmed that the risk groups could be applied to overall survival, with 5-year survival ranging from 80% to 33% and 73% to 42% for AML and ALL, respectively (P < .0001). This validated pediatric DRI, which includes age and residual disease status, can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.

Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P = 0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P = 0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

The impact of total body irradiation-based regimens on outcomes in children and young adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Total body irradiation (TBI)-based conditioning is the standard of care in the treatment of acute lymphoblastic leukemia (ALL) that requires allogeneic hematopoietic stem cell transplantation (HSCT). However, TBI is known to be associated with an increased risk of late effects, and therefore, non-TBI regimens have also been utilized successfully. A recent study showed that patients that were next-generation sequencing-minimal residual disease (NGS-MRD) negative prior to allogeneic HSCT had a very low risk of relapse, and perhaps could avoid exposure to TBI without compromising disease control. We examined outcomes at our institution in patients that received a TBI or non-TBI regimen, as well as explored the impact of NGS-MRD status in predicting risk of relapse post transplant. PROCEDURES: This retrospective analysis included 57 children and young adults with ALL that received their first myeloablative allogeneic HSCT from 2012 to 2017 at the University of California San Francisco. Our primary endpoint was the cumulative incidence of relapse at 3 years post transplant. RESULTS: We demonstrated similar cumulative incidence of relapse for patients treated with either a TBI or non-TBI conditioning regimen, while NGS-MRD positivity prior to transplant was highly predictive of relapse. The presence of acute graft-versus-host disease was associated with decreased relapse rates, particularly among patients that received a TBI conditioning regimen and patients that were NGS-MRD positive prior to HSCT. CONCLUSIONS: Our data suggest that the decision to use either a TBI or non-TBI regimens in ALL should depend on NGS-MRD status, with conditioning regimens based on TBI reserved for patients that cannot achieve NGS-MRD negativity prior to allogeneic HSCT.

Successful Use of Hematopoietic Stem Cell Transplantation for 2 Pediatric Cases of Glanzmann Thrombasthenia and Review of the Literature.

Glanzmann thrombasthenia is a rare platelet disorder characterized by an abnormal integrin receptor on the surface of platelets that results in the failure of platelets to aggregate. Currently, curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT). The authors report 2 patients with Glanzmann thrombasthenia who successfully underwent allogeneic HSCT from unrelated donors, including one using umbilical cord blood stem cells. Although both patients had evidence of engraftment, hematopoietic recovery, and normalization of platelet aggregation, they also experienced several post-transplant complications. Allogeneic HSCT carries a significant risk of morbidity and mortality that should be considered before proceeding with the transplant.

Identifying risk factors associated with worse outcomes in adolescents and young adults undergoing hematopoietic stem cell transplantation.

BACKGROUND: Adolescents and young adults (AYAs) undergoing allogeneic hematopoietic stem cell transplantation (HSCT) have unique risk factors and poor outcomes when compared to children, but this population has not been well studied. A hematopoietic stem cell transplantation-comorbidity index (HCT-CI) has been developed in adults to help predict outcomes, yet this index does not seem suitable for a younger population. Therefore, we sought to examine the prevalence of various risk factors in AYAs undergoing allogeneic HSCT and determine which factors had the greatest impact on overall survival (OS) and treatment-related mortality (TRM). PROCEDURES: This was accomplished by retrospectively collecting data on 241 patients who received their first allogeneic HSCT at UCLA between 2005 and 2015. We investigated the effect of multiple predictors using the Cox proportional hazards model and Fine and Gray competing risk model for OS and TRM, respectively. RESULTS: Our results showed that AYAs undergoing allogeneic HSCT had poor outcomes, with 5-year OS and NRM of 48% and 30%, respectively. We demonstrated that compared to a baseline model, the addition of the HCT-CI did not improve its ability to predict OS, while substituting individual comorbidities, that is, an unweighted comorbidity score, resulted in significant improvement in model performance. The factors associated with inferior outcomes were used to develop an AYA-specific risk score. CONCLUSIONS: The comorbidities included in the HCT-CI as well as additional risk factors seen in younger populations need to be studied in prospective studies with the goal of validating and refining a risk score specific to AYA patients undergoing allogeneic HSCT.

Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma.

Although checkpoint inhibitor therapies have demonstrated significant efficacy in many malignancies, they have not been well studied in patients with a history of solid organ transplant. We describe two patients with recurrent, refractory, and progressive advanced fibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation who received programmed cell death protein 1 (PD-1) inhibitor, nivolumab, on a patient access, off-label basis. Both rapidly developed irreversible acute liver rejection shortly after starting therapy, and ultimately died. While checkpoint inhibitors clearly have tremendous potential as a targeted therapy, they should be avoided or used with extreme caution in the context of an organ transplant.

Fertility Potential and Gonadal Function in Survivors of Reduced-Intensity Hematopoietic Stem Cell Transplantation.

The use of reduced-intensity conditioning (RIC) regimens has increased in an effort to minimize hematopoietic stem cell transplantation (HCT) end-organ toxicity, including gonadal toxicity. We aimed to describe the incidence of fertility potential and gonadal function impairment in adolescent and young adult survivors of HCT and to identify risk factors (including conditioning intensity) for impairment. We performed a multi-institutional, international retrospective cohort study of patients age 10 to 40 years who underwent first allogeneic HCT before December 1, 2019, and who were alive, in remission, and available for follow-up at 1 to 2 years post-HCT. For females, an AMH level of ≥.5 ng/mL defined preserved fertility potential; an AMH level of ≥.03 ng/mL was considered detectable. Gonadal failure was defined for females as an elevated follicle-stimulating hormone (FSH) level >30 mIU/mL with an estradiol (E2) level <17 pg/mL or current use of hormone replacement therapy (regardless of specific indication or intent). For males, gonadal failure was defined as an FSH level >10.4 mIU/mL or current use of hormone replacement therapy. A total of 326 patients (147 females) were available for analysis from 17 programs (13 pediatric, 4 adult). At 1 to 2 years post-HCT, 114 females (77.6%) had available FSH and E2 levels and 71 (48.3%) had available AMH levels. FSH levels were reported for 125 males (69.8%). Nearly all female HCT recipients had very low levels of AMH. One of 45 (2.2%) recipients of myeloablative conditioning (MAC) and four of 26 (15.4%) recipients of reduced-intensity conditioning (RIC) (P = .06) had an AMH ≥.5 ng/m, and 8 of 45 MAC recipients (17.8%) and 12 of 26 RIC recipients (46.2%) (P = .015) had a detectable AMH level. Total body irradiation (TBI) dose and cyclophosphamide equivalent dose (CED) were not associated with detectable AMH. The incidence of female gonadal hormone failure was 55.3%. In univariate analysis, older age at HCT was associated with greater likelihood of gonadal failure (median age, 17.6 versus 13.9; P < .0001), whereas conditioning intensity (RIC versus MAC), TBI, chronic graft-versus-host disease requiring systemic therapy, and CED were not significantly associated with gonadal function. In multivariable analysis, age remained statistically significant (odds ratio [OR]. 1.11; 95% confidence interval [CI], 1.03 to 1.22) for each year increase; P = .012), Forty-four percent of the males had gonadal failure. In univariate analysis, older age (median, 16.2 years versus 14.4 years; P = .0005) and TBI dose (P = .002) were both associated with gonadal failure, whereas conditioning intensity (RIC versus MAC; P = .06) and CED (P = .07) were not statistically significant. In multivariable analysis, age (OR, 1.16; 95% CI, 1.06-1.27 for each year increase; P = .0016) and TBI ≥600 cGy (OR, 6.23; 95% CI, 2.21 to 19.15; P = .0008) remained significantly associated with gonadal failure. Our data indicate that RIC does not significantly mitigate the risk for gonadal failure in females or males. Age at HCT and (specifically in males) TBI use seem to be independent predictors of post-transplantation gonadal function and fertility status. All patients should receive pre-HCT infertility counseling and be offered appropriate fertility preservation options and be screened post-HCT for gonadal failure.

Expanded HCT-CI Definitions Capture Comorbidity Better for Younger Patients of Allogeneic HCT for Nonmalignant Diseases.

Allogeneic hematopoietic cell transplantation (HCT) can cure many nonmalignant conditions, but concern for morbidity and mortality remains. To help physicians estimate patient-specific transplant mortality risk, the HCT comorbidity index (HCT-CI) is used. However, pediatric physicians use the HCT-CI less frequently than adult counterparts. We used the Center for International Blood and Marrow Transplant Research database to expand the HCT-CI comorbidity definitions to be more inclusive of children and adolescent and young adult (AYA) patients, adding history of mechanical ventilation, history of invasive fungal infection, assessment of chronic kidney disease (CKD) by estimated glomerular filtration rate, expanding the definition of obesity, and adding an underweight category. A total of 2815 children and AYAs (<40 years old) who received first allogeneic HCT for nonmalignant diseases from 2008 to 2017 were included to create an expanded youth nonmalignant HCT-CI (expanded ynHCT-CI) and a simplified non-malignant (simplified ynHCT-CI) HCT-CI. The expanded comorbidities occurred frequently-history of mechanical ventilation (9.6%), history of invasive fungal infection (5.9%), mild CKD (12.2%), moderate/severe CKD (2.1%), obesity (10.9%), and underweight (14.5%). Thirty-nine percent of patients had an increase in their comorbidity score using the expanded ynHCT-CI, leading to a redistribution of scores: ynHCT-CI score 0 (35%), 1-2 (36.4%), and ≥3 (28.6%). Patients with an increase in their comorbidity score had an increased hazard of mortality compared to those whose score remained the same (hazard ratio = 1.41; 95% confidence interval, 1.01-1.98). Modifications to the HCT-CI can benefit children and AYA patients with nonmalignant diseases, creating a risk assessment tool that is clinically relevant and better captures comorbidity in this younger population.

Adapting the HCT-CI Definitions for Children, Adolescents, and Young Adults with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation is a curative procedure for hematologic malignancies but is associated with a significant risk of non-relapse mortality (NRM). The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) is a prognostic tool that discriminates this risk in all age groups. A recent survey of transplant physicians demonstrated that 79% of pediatric providers used the HCT-CI infrequently, and most reported concerns about its applicability in the younger population. We conducted a retrospective study using the Center for International Blood and Marrow Transplant Research database to examine the impact of expanded HCT-CI definitions on NRM in pediatric and young adult patients with hematologic malignancies. We included 5790 patients <40 years old receiving allogeneic transplants between 2008 and 2017 to examine broader definitions of comorbidities in the HCT-CI, including history of mechanical ventilation and fungal infection, estimated glomerular filtration rate, and body mass index (BMI) percentiles. Multivariable Fine-Gray models were created to determine the effect of each HCT-CI defining comorbidity and its modification on NRM and were used to develop 2 novel risk scores. We next developed the expanded HCT-CI for children and young adults (youth with malignancies; expanded ymHCT-CI), where 23% patients had an increased comorbidity score, compared to the HCT-CI. Comorbidities with hazard ratio < 1.2 were then removed to create the simplified HCT-CI for children and young adults (youth with malignancies; simplified ymHCT-CI), which demonstrated higher scores corresponded to a greater risk of NRM (P < .001). These novel comorbidity indexes with broader definitions are more relevant to pediatric and young adult patients, and prospective studies are needed to validate these in the younger patient population. It remains to be seen whether the development of these pediatric-specific and practical risk indexes increases their use by the pediatric transplant community.

Beyond steroids: A systematic review and proposed solutions to managing acute graft-versus-host disease in adolescents and young adults.

The outcomes of allogeneic hematopoietic cell transplantation (HCT) in adolescents and young adults (AYAs) with hematologic malignancies have been shown to be poorer when compared to results in children, due to a combination of higher relapse rates and greater treatment-related mortality (TRM). Although differences in relapse risk have been studied extensively, toxicity has been examined and reported less often. In this systematic review, we summarize recently published studies that have examined the differences in rates of TRM and acute graft-versus-host disease (GVHD) in AYAs and children with hematologic malignancies, and attempt to explain why these disparities exist and how they impact outcomes. In addition, we present best practices for management of steroid-refractory GVHD that are likely to improve survival in this patient population. Further, we propose the development of personalized, risk-based approaches for the prevention and treatment of GVHD that incorporate novel platforms and interventions. We believe this individualized approach is likely to reduce toxicity and greatly improve outcomes for this vulnerable population.

Rituximab as adjunctive therapy to BEAM conditioning for autologous stem cell transplantation in Hodgkin lymphoma.

While high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) leads to improved disease-free survival (DFS) for children and adults with relapsed/refractory Hodgkin lymphoma (HL), relapse remains the most frequent cause of mortality post-transplant. Rituximab has been successfully incorporated into regimens for other B-cell lymphomas, yet there have been limited studies of rituximab in HL patients. We hypothesized that adding rituximab to BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning would reduce relapse risk in HL patients post-transplant. Here, we retrospectively review the outcomes of patients with relapsed/refractory HL who received rituximab in addition to BEAM. The primary outcome was DFS. Our cohort included 96 patients with a median age of 28 years (range, 6-76). Majority of patients (57%) were diagnosed with advanced (Stage III-IV) disease, and 62% were PET negative pre-transplant. DFS was 91.5% at 1 year [95% CI 86-98%], and 78% at 3 years [95% CI 68-88%]. NRM was 0% and 3.5% at 1-year [95% CI 0-3%] and 3-years [95% CI 0-8.5%], respectively. 25% of patients developed delayed neutropenia, with 7% requiring infection-related hospitalizations, and one death. We have demonstrated excellent outcomes for patients receiving rituximab with BEAM conditioning for relapsed/refractory HL. Future comparative studies are needed to better determine whether rituximab augments outcomes post-transplant.

Post-Transplantation Cyclophosphamide Is Associated with an Increase in Non-Cytomegalovirus Herpesvirus Infections in Patients with Acute Leukemia and Myelodysplastic Syndrome.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in recipients of haploidentical and fully matched transplantations is on the increase. Published studies have reported an increased incidence of cytomegalovirus (CMV) infection with the use of PTCy. Limited data exist on the incidence and outcomes of infection with non-CMV herpesviruses (NCHV) in this setting. The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplantation-specific outcomes in recipients of haploidentical transplantation with PTCy (HaploCy), matched sibling donor transplantation with PTCy (SibCy), and matched sibling donor transplantation with calcineurin inhibitor-based prophylaxis (SibCNI). We hypothesized that, like CMV infection, HaploCy recipients of also will have a higher risk of NCHV infections. Using the Center for International Blood and Marrow Transplantation Research database, we analyzed 2765 patients (HaploCy, n = 757; SibCNI, n = 1605; SibCy, n = 403) who had undergone their first hematopoietic stem cell transplantation (HCT) between 2012 and 2017 for acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. The cumulative incidence of NCHV at 6 months post-NCT was 13.9% (99% confidence interval], 10.8% to 17.3%) in the HaploCy group, 10.7% (99% CI, 7.1% to 15%) in the SibCy group, and 5.7% (99% CI, 4.3% to 7.3%) in the Sib CNI group (P < .001). This was due primarily to a higher frequency of human herpesvirus 6 viremia reported in patients receiving PTCy. The incidence of Epstein-Barr viremia was low in all groups, and no cases of post-transplantation lymphoproliferative disorder were seen in either PTCy group. The incidence of NCHV organ disease was low in all 3 cohorts. The development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, or disease-free survival. Patients in PTCy cohorts who did not develop NCHV infection had lower rates of cGVHD. This study demonstrates that the use of PTCy is associated with an increased risk of NCHV infection. The development of NCHV infection was associated with increased nonrelapse mortality, especially in the HaploCy group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for a better understanding of the clinical relevance of viral reactivation in different HCT settings.

Population Pharmacokinetic Model Development of Tacrolimus in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplantation.

Background: With a notably narrow therapeutic window and wide intra- and interindividual pharmacokinetic (PK) variability, initial weight-based dosing along with routine therapeutic drug monitoring of tacrolimus are employed to optimize its clinical utilization. Both supratherapeutic and subtherapeutic tacrolimus concentrations can result in poor outcomes, thus tacrolimus PK variability is particularly important to consider in the pediatric population given the differences in absorption, distribution, metabolism, and excretion among children of various sizes and at different stages of development. The primary goals of the current study were to develop a population PK (PopPK) model for tacrolimus IV continuous infusion in the pediatric and young adult hematopoietic cell transplant (HCT) population and implement the PopPK model in a clinically available Bayesian forecasting tool. Methods: A retrospective chart review was conducted of 111 pediatric and young adult patients who received IV tacrolimus by continuous infusion early in the post-transplant period during HCT from February 2016 to July 2020 at our institution. PopPK model building was performed in NONMEM. The PopPK model building process included identifying structural and random effects models that best fit the data and then identifying which patient-specific covariates (if any) further improved model fit. Results: A total of 1,648 tacrolimus plasma steady-state trough concentrations were included in the PopPK modeling process. A 2-compartment structural model best fit the data. Allometrically-scaled weight was a covariate that improved estimation of both clearance and volume of distribution. Overall, model predictions only showed moderate bias, with minor under-prediction at lower concentrations and minor over-prediction at higher predicted concentrations. The model was implemented in a Bayesian dosing tool and made available at the point-of-care. Discussion: Novel therapeutic drug monitoring strategies for tacrolimus within the pediatric and young adult HCT population are necessary to reduce toxicity and improve efficacy in clinical practice. The model developed presents clinical utility in optimizing the use of tacrolimus by enabling model-guided, individualized dosing of IV, continuous tacrolimus via a Bayesian forecasting platform.

Is polycystic kidney disease associated with malignancy in children?

BACKGROUND: Polycystic kidney disease (PKD) is an inherited condition characterized by progressive development of end-stage renal disease, hypertension, hepatic fibrosis, and cysts in the kidney, liver, pancreas, spleen, thyroid, and epididymis. While malignancies have been reported in association with PKD in adults, the incidence of malignancies in children with PKD is not currently known. METHODS: We report on five patients with a known history of PKD who developed a malignancy as children at the University of California, Los Angeles and the University of Colorado Anschutz Medical Campus. Patients were included from 2012 to 2017. RESULTS: We present five patients with a history of PKD diagnosed with a malignancy during childhood without any additional known mutations to suggest a genetic predisposition to develop cancer. This includes the first reported case of hepatocellular carcinoma in a patient with autosomal recessive polycystic kidney disease. CONCLUSION: Our report illustrates the potential that PKD may be associated with an increased risk for developing cancer, even in children. Further research is necessary to better understand this relationship.

Closing the gap: Novel therapies in treating acute lymphoblastic leukemia in adolescents and young adults.

Acute lymphoblastic leukemia (ALL) is one of the most common cancer diagnoses identified in adolescents and young adults (AYAs). Although most children with ALL are cured of their disease, AYAs have experienced much worse outcomes over time, with event-free survival ranging from 30 to 45%. This survival disparity is likely due to differences in tumor biology, treatment-related toxicities, and nonmedical issues. This review summarizes these differences as well as focusing on the various trials that have demonstrated superior outcomes with pediatric protocols in AYAs with ALL. Even with the widespread use of these protocols, a treatment gap remains, and novel therapies are one way to address this problem. Still, these therapies also have significant toxicities and unique issues that need to be tested further, especially in the AYA population. The development of more AYA-specific trials will be an important way to examine novel therapies and interventions designed to reduce treatment-related toxicities and improve long-term outcomes.