Budget impact analysis of TPMT and NUDT15 pharmacogenomic testing for 6-mercaptopurine in pediatric acute lymphoblastic leukemia patients.

BACKGROUND: Pharmacogenomic testing identifies gene polymorphisms impacting drug metabolism, aiding in optimizing treatment efficacy and minimizing toxicity, thus potentially reducing healthcare utilization. 6-Mercaptopurine metabolism is affected by thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) polymorphisms. We sought to estimate the budget impact of preemptive pharmacogenomic testing for these genes in pediatric acute lymphoblastic leukemia (ALL) patients from an institutional perspective. METHODS: A Markov model was constructed to model the first cycle of the maintenance phase of chemotherapy for pediatric ALL patients transitioning between one of three health states: stable, moderately myelosuppressed, and severely myelosuppressed over 16 weeks, with each health state's associated costs derived from the literature. The patient's likelihood to experience moderate or severe myelosuppression based on metabolism phenotype was calculated from the literature and applied on a weekly basis, and the marginal budget impact of preemptive pharmacogenomic testing vs. no pharmacogenomic testing was calculated. One-way sensitivity analysis was conducted to assess parameter influence on results. RESULTS: Preemptive pharmacogenomic testing of TPMT and NUDT15 provided savings of up to $26 028 per patient during the maintenance phase. In the sensitivity analysis, the cost of outpatient management of moderate myelosuppression had the greatest impact on the budget, resulting in cost savings ranging from $8592 to $30 129 when the minimum and maximum costs of management were used in the model. CONCLUSION: Preemptive pharmacogenomic testing for TPMT and NUDT15 polymorphisms before initiation of maintenance therapy for pediatric ALL patients yielded considerable cost savings.

Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children's Oncology Group study.

Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children's Oncology Group frontline ALL trials (1996-2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.

Anti-CD7 allogeneic WU-CART-007 in patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma: a phase 1/2 trial.

Relapsed/refractory T-cell acute lymphoblastic leukemia (ALL)/lymphoma (LBL) represent a significant unmet medical need. WU-CART-007 is a CD7-targeting, allogeneic, fratricide-resistant chimeric antigen receptor T cell product generated from healthy donor T cells. WU-CART-007 was evaluated in a phase 1/2 study with a 3 + 3 dose-escalation design followed by cohort expansion in relapsed/refractory T-ALL/LBL. Patients received one infusion of WU-CART-007 after standard or enhanced lymphodepleting chemotherapy. The primary objectives, to characterize safety and assess the composite complete remission rate, were met. Of 26 patients enrolled, 13 received the recommended phase 2 dose (RP2D) of 900 million cells of WU-CART-007 with enhanced lymphodepletion. The most common treatment-related adverse event was cytokine release syndrome (88.5%; 19.2% grade 3-4). Biochemical abnormalities consistent with grade 2 hemophagocytic lymphohistiocytosis were seen in one patient (3.8%). Grade 1 immune effector cell-associated neurotoxicity syndrome events (7.7%) and one grade 2 acute graft-vs-host disease event occurred. Grade 5 events (11.5%) were due to fungal infection and multi-organ failure. The composite complete remission rate was 81.8% among 11/13 patients evaluable for response at the RP2D. WU-CART-007 at the RP2D demonstrated a high response rate in patients with relapsed/refractory T-ALL/LBL and has the potential to provide a new treatment option. ClinicalTrials.gov registration: NCT04984356.

Pediatric therapy-related hematologic neoplasms show enrichment for KMT2A rearrangement and lymphoblastic phenotype.

In children, therapy-related hematologic neoplasms (t-HN) are uncommon. Many are driven by genetic events independent of clonal hematopoiesis. We sought to understand the clinical and genetic factors of pediatric t-HN in a large independent cohort. Fifty-six t-HN were retrospectively identified. Chromosome microarray, next-generation and/or RNA sequencing were performed. Patients had primary hematologic, solid, or central nervous system tumors. t-HN included myeloid (t-MN) and lymphoblastic (t-ALL) phenotypes. Approximately half of the cases harbored KMTA2A rearrangement (KMT2Ar). Among t-HN without KMT2Ar, genetic drivers were heterogeneous, including diverse fusions or aneuploidy. Approximately 18% harbored 17p deletions and/or TP53 mutations. EFS/OS was not associated with t-HN lineage or KMT2Ar, but HSCT was associated with improved EFS and OS. We detail one of the largest cohorts to date of pediatric t-HN, confirming frequent KMT2Ar and t-ALL.

Optimizing early phase clinical trial washout periods: a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.

PURPOSE: The National Cancer Institute (NCI) issued a 2021 memorandum adopting the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) task force recommendations to broaden clinical study eligibility criteria. They recommended that washout periods be eliminated for most prior cancer therapy and when required, to utilize evidence/rationale-based criteria. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium responded to this guidance. PROCESS: A TACL task force reviewed the consortium's research portfolio, the relevant literature and guidance documents from ASCO-Friends, NCI, and US Food and Drug Administration (FDA) to make expert consensus and evidence-based recommendations for modernizing, broadening and codifying TACL-study washout periods while ensuring consistency with pediatric ethics and federal regulations. TACL's screening log was reviewed to estimate the impact that updated washout periods would have on patient inclusivity and recruitment. RESULTS: Over a 19-year period, 42 patients (14.6% of all screened ineligible (n = 287) patients), were identified as excluded from TACL early-phase studies exclusively due to not meeting washout criteria. An additional six (2.1%) did not meet washout and at least one other exclusion criterion. A new TACL washout guidance document was developed/adopted for use. Where washout criteria were not eliminated, rationale/evidenced-based criteria were established with citation. CONCLUSION: In an effort to reduce unnecessary exclusion from clinical trials, TACL created rationale/evidenced-based washout period standards largely following guidance from the NCI/ASCO-Friends recommendations. These new, expanded eligibility criteria are expected to increase access to TACL clinical trials while maintaining safety and scientific excellence.

Progression of brain injuries associated with methotrexate chemotherapy in childhood acute lymphoblastic leukemia.

BACKGROUND: Brain bases and progression of methotrexate-associated neurotoxicity and cognitive disturbances remain unknown. We tested whether brain abnormalities worsen in proportion to intrathecal methotrexate(IT-MTX) doses. METHODS: In this prospective, longitudinal study, we recruited 19 patients with newly diagnosed acute lymphoblastic leukemia 4-to-20 years of age and 20 matched controls. We collected MRI and neuropsychological assessments at a pre-methotrexate baseline and at week 9, week 22, and year 1 during treatment. RESULTS: Patients had baseline abnormalities in cortical and subcortical gray matter(GM), white matter(WM) volumes and microstructure, regional cerebral blood flow, and neuronal density. Abnormalities of GM, blood flow, and metabolites worsened in direct proportions to IT-MTX doses. WM abnormalities persisted until week 22 but normalized by year 1. Brain injuries were localized to dorsal and ventral attentional and frontoparietal cognitive networks. Patients had cognitive deficits at baseline that persisted at 1-year follow-up. CONCLUSIONS: Baseline abnormalities are likely a consequence of neuroinflammation and oxidative stress. Baseline abnormalities in WM microstructure and volumes, and blood flow persisted until week 22 but normalized by year 1, likely due to treatment and its effects on reducing inflammation. The cytotoxic effects of IT-MTX, however, likely contributed to continued, progressive cortical thinning and reductions in neuronal density, thereby contributing to enduring cognitive deficits. IMPACT: Brain abnormalities at a pre-methotrexate baseline likely are due to acute illness. The cytotoxic effects of intrathecal MTX contribute to progressive cortical thinning, reductions in neuronal density, and enduring cognitive deficits. Baseline white matter abnormalities may have normalized via methotrexate treatment and decreasing neuroinflammation. Corticosteroid and leucovorin conferred neuroprotective effects. Our findings suggest that the administration of neuroprotective and anti-inflammatory agents should be considered even earlier than they are currently administered. The neuroprotective effects of leucovorin suggest that strategies may be developed that extend the duration of this intervention or adapt it for use in standard risk patients.

Severe steroid-related neuropsychiatric symptoms during paediatric acute lymphoblastic leukaemia therapy-An observational Ponte di Legno Toxicity Working Group Study.

Steroids are a mainstay in the treatment of acute lymphoblastic leukaemia (ALL) in children and adolescents; however, their use can cause clinically significant steroid-related neuropsychiatric symptoms (SRNS). As current knowledge on SRNS during ALL treatment is limited, we mapped the phenotypes, occurrence and treatment strategies using a database created by the international Ponte di Legno Neurotoxicity Working Group including data on toxicity in the central nervous system (CNS) in patients treated with frontline ALL protocols between 2000 and 2017. Ninety-four of 1813 patients in the CNS toxicity database (5.2%) experienced clinically significant SRNS with two peaks: one during induction and one during intensification phase. Dexamethasone was implicated in 86% of SRNS episodes. The most common symptoms were psychosis (52%), agitation (44%) and aggression (31%). Pharmacological treatment, mainly antipsychotics and benzodiazepines, was given to 87% of patients while 38% were hospitalised due to their symptoms. Recurrence of symptoms was reported in 29% of patients and two previously healthy patients required ongoing pharmacological treatment at the last follow up. Awareness of SRNS during ALL treatment and recommendation on treatment strategies merit further studies and consensus.

IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B-lymphoblastic leukemia.

BACKGROUND: Compared to other ethnicities, Hispanics/Latinos (H/L) have a high incidence of acute lymphoblastic leukemia (ALL), enrichment of unfavorable ALL genetic subtypes, and worse outcomes, even after correcting for socioeconomic factors. We previously demonstrated increased incidence of the high-risk genetic drivers IKZF1 deletion and IGH::CRLF2 rearrangement in H/L compared to non-H/L children with B-ALL. Here in an expanded pediatric cohort, we sought to identify novel genetic drivers and secondary genetic alterations in B-ALL associated with H/L ethnicity. PROCEDURE: Comprehensive clinicopathologic data from patients with B-ALL treated from 2016 to 2020 were analyzed. Subtype was determined from karyotype, fluorescence in situ hybridization (FISH), chromosome microarray (CMA), and our next-generation sequencing (NGS) panel (OncoKids). Non-driver genetic variants were also examined. p-Values less than .05 (Fisher's exact test) were considered significant. RESULTS: Among patients with B-ALL at diagnosis (n = 273), H/L patients (189, 69.2%) were older (p = .018), more likely to present with CNS2 or CNS3 disease (p = .004), and NCI high-risk ALL (p = .014) compared to non-H/L patients. Higher incidence of IGH::CRLF2 rearrangement (B-ALL, BCR::ABL1-like, unfavorable; p = .016) and lower incidence of ETV6::RUNX1 rearrangement (favorable, p = .02) were also associated with H/L ethnicity. Among secondary (non-subtype-defining) genetic variants, B-ALL in H/L was associated with IKFZ1 deletion alone (p = .001) or with IGH::CRLF2 rearrangement (p = .003). The IKZF1PLUS profile (IKZF1 deletion plus CDKN2A/2Bdel, PAX5del, or P2RY8::CRLF2 rearrangement without DUX4 rearrangement) was identified as a novel high-risk feature enriched in H/L patients (p = .001). CONCLUSIONS: Our study shows enrichment of high-risk genetic variants in H/L B-ALL and raises consideration for novel therapeutic targets.

Nivolumab Plus 5-Azacitidine in Pediatric Relapsed/Refractory Acute Myeloid Leukemia (AML): Phase I/II Trial Results from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium.

Improvements in survival have been made over the past two decades for childhood acute myeloid leukemia (AML), but the approximately 40% of patients who relapse continue to have poor outcomes. A combination of checkpoint-inhibitor nivolumab and azacitidine has demonstrated improvements in median survival in adults with AML. This phase I/II study with nivolumab and azacitidine in children with relapsed/refractory AML (NCT03825367) was conducted through the Therapeutic Advances in Childhood Leukemia & Lymphoma consortium. Thirteen patients, median age 13.7 years, were enrolled. Patients had refractory disease with multiple reinduction attempts. Twelve evaluable patients were treated at the recommended phase II dose (established at dose level 1, 3 mg/kg/dose). Four patients (33%) maintained stable disease. This combination was well tolerated, with no dose-limiting toxicities observed. Grade 3-4 adverse events (AEs) were primarily hematological. Febrile neutropenia was the most common AE ≥ grade 3. A trend to improved quality of life was noted. Increases in CD8+ T cells and reductions in CD4+/CD8+ T cells and demethylation were observed. The combination was well tolerated and had an acceptable safety profile in pediatric patients with relapsed/refractory AML. Future studies might explore this combination for the maintenance of remission in children with AML at high risk of relapse.

Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.

BACKGROUND: Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. METHODS: MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). RESULTS: Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. CONCLUSION: We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

INSPIRED Symposium Part 4A: Access to CAR T Cell Therapy in Unique Populations with B Cell Acute Lymphoblastic Leukemia.

The approval of tisagenlecleucel (tisa-cel) for use in children with B cell acute lymphoblastic leukemia (B-ALL) was based on the phase 2 ELIANA trial, a global registration study. However, the ELIANA trial excluded specific subsets of patients facing unique challenges and did not include a sufficient number of patients to adequately evaluate outcomes in rare subpopulations. Since the commercialization of tisa-cel, data have become available that support therapeutic indications beyond the specific cohorts previously eligible for chimeric antigen receptor (CAR) T cells targeted to CD19 (CD19 CAR-T) therapy on the registration clinical trial. Substantial real-world data and aggregate clinical trial data have addressed gaps in our understanding of response rates, longer-term efficacy, and toxicities associated with CD19 CAR-T in special populations and rare clinical scenarios. These include patients with central nervous system relapsed disease, who were excluded from ELIANA and other early CAR-T trials owing to concerns about risk of neurotoxicity that have not been born out. There is also interest in the use of CD19 CAR-T for very-high-risk patients earlier in the course of therapy, such as patients with persistent minimal residual disease after 2 cycles of upfront chemotherapy and patients with first relapse of B-ALL. However, these indications are not specified on the label for tisa-cel and historically were not included in eligibility criteria for most clinical trials; data addressing these populations are needed. Populations at high risk of relapse, including patients with high-risk cytogenetic lesions, infants with B-ALL, patients with trisomy 21, and young adults with B-ALL, also may benefit from earlier treatment with CD19 CAR-T. It is important to prospectively study patient-reported outcomes given the differential toxicity expected between CD19 CAR-T and the historic standard of care, hematopoietic cell transplantation. Now that CD19 CAR-T therapy is commercially available, studies evaluating potential access disparities created by this very expensive novel therapy are increasingly pressing.

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group.

PURPOSE: Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. METHODS: We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. RESULTS: Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/µL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). CONCLUSION: Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

Transcriptome Sequencing Allows Comprehensive Genomic Characterization of Pediatric B-Acute Lymphoblastic Leukemia in an Academic Clinical Laboratory.

Studies have shown the power of transcriptome sequencing [RNA sequencing (RNA-Seq)] in identifying known and novel oncogenic drivers and molecular subtypes of B-acute lymphoblastic leukemia (B-ALL). The current study investigated whether the clinically validated RNA-Seq assay, coupled with a custom analysis pipeline, could be used for a comprehensive B-ALL classification. Following comprehensive clinical testing, RNA-Seq was performed on 76 retrospective B-ALL cases, 28 of which had known and 48 had undetermined subtype. Subtypes were accurately identified in all 28 known cases, and in 38 of 48 unknown cases (79%). The subtypes of the unknown cases included the following: PAX5alt (n = 12), DUX4-rearranged (n = 6), Philadelphia chromosome-like (n = 5), low hyperdiploid (n = 4), ETV6::RUNX1-like (n = 3), MEF2D-rearranged (n = 2), PAX5 P80R (n = 2), ZEB2/CEBP (n = 1), NUTM1-rearranged (n = 1), ZNF384-rearranged (n = 1), and TCF3::PBX1 (n = 1). In 15 of 38 cases (39%), classification based on expression profile was corroborated by detection of subtype-defining oncogenic drivers missed by clinical testing. RNA-Seq analysis also detected large copy number abnormalities, oncogenic hot-spot sequence variants, and intragenic IKZF1 deletions. This pilot study confirms the feasibility of implementing an RNA-Seq workflow for clinical diagnosis of molecular subtypes in pediatric B-ALL, reinforcing that RNA-Seq represents a promising global genomic assay for this heterogeneous leukemia.

B-cell acute lymphoblastic leukemia and juvenile xanthogranuloma in a patient with ETV6 thrombocytopenia and leukemia predisposition syndrome: novel clinical presentation and perspective.

Not available.

Chimeric Antigen Receptor T Cells as Salvage Therapy for Post-Chimeric Antigen Receptor T Cell Failure.

Outcomes for post-chimeric antigen receptor (CAR) T cell therapy (CART) relapse are poor. The utilization of a unique CAR T cell construct for post-CART failure is increasing, but this approach is not well described. In this study, with CART-A the first unique CAR T cell construct received and CART-B the second, the primary objective was to characterize outcomes following CART-B. Secondary objectives included evaluating safety and toxicity with sequential CART infusions; investigating the impact of potential factors, such as antigen modulation and interval therapy, on CART-B response; and characterizing long-term outcomes in patients receiving multiple CARTs. This was a retrospective review (NCT03827343) of children and young adults with B cell acute lymphoblastic leukemia (B-ALL) undergoing CART therapy who received at least 2 unique CART constructs, excluding interim CART reinfusions of the same product. Of 135 patients, 61 (45.1%) received 2 unique CART constructs, including 13 who received >2 CARTs over time. Patients included in this analysis received 14 distinct CARTs targeting CD19 and/or CD22. The median age at CART-A was 12.6 years (range, 3.3 to 30.4 years). The median time from CART-A to CART-B was 302 days (range, 53 to 1183 days). CART-B targeted a different antigen than CART-A in 48 patients (78.7%), owing primarily to loss of CART-A antigen target. The rate of complete remission (CR) was lower with CART-B (65.5%; 40 of 61) than with CART-A (88.5%; 54 of 61; P = .0043); 35 of 40 (87.5%) CART-B responders had CART-B targeting a different antigen than CART-A. Among the 21 patients with a partial response or nonresponse to CART-B, 8 (38.1%) received CART-B with the same antigen target as CART-A. Of 40 patients with CART-B complete response (CR), 29 (72.5%) relapsed. For the 21 patients with evaluable data, the relapse immunophenotype was antigennegative in 3 (14.3%), antigendim in 7 (33.3%), antigenpositive in 10 (47.6%), and lineage switch in 1 (4.8%). The median relapse-free survival following CART-B CR was 9.4 months (95% confidence interval [CI], 6.1 to 13.2 months), and overall survival was 15.0 months (95% CI, 13.0 to 22.7 months). Given the limited salvage options for post-CART relapse, identifying optimizing strategies for CART-B is critical. We raise awareness about the emerging use of CART for post-CART failure and highlight clinical implications accompanying this paradigm shift.

Asparaginase toxicity in Hispanic adult and pediatric patients with acute lymphoblastic leukemia: current understanding.

INTRODUCTION: Asparaginase is essential to chemotherapy regimens for acute lymphoblastic leukemia (ALL). Survival of patients with ALL has improved since incorporating asparaginase into chemotherapy backbones. Hispanic patients have a higher incidence of ALL than other ethnicities and suffer inferior outcomes. The inferior outcome of Hispanics is due to several factors, including the increased incidence of high-risk genetic subtypes and susceptibility to treatment-related toxicity. AREAS COVERED: We summarize the current knowledge of asparaginase-related toxicity by comparing their incidence between Hispanic and non-Hispanic patients. These toxicities include hypersensitivity, hepatotoxicity, pancreatitis, thrombosis, and hypertriglyceridemia. The PubMed database and Google Scholar were used to search for this review from October 2022 to June 2023. EXPERT OPINION: Except for hepatotoxicity and hypertriglyceridemia secondary to asparaginase-based treatments, which may develop more frequently among Hispanic patients with ALL, other toxicities were comparable between Hispanic and non-Hispanic patients. Nevertheless, studies with larger cohorts and more accurate capturing of Hispanic ethnicity should be conducted to fill the gaps in the current knowledge.

Children's Oncology Group blueprint for research: Acute lymphoblastic leukemia.

Cure rates for acute lymphoblastic leukemia (ALL), the most common childhood cancer have steadily improved over the past five decades. This is due to intensifying systemic therapy, recognizing and treating the central nervous system as a sanctuary site, and implementing modern risk stratification to deliver varying intensities of therapy based on age, presenting white blood count, sentinel somatic genetics, and therapy response. Recently, numerous Children's Oncology Group trials have demonstrated the lack of benefit of intensifying traditional chemotherapy, providing evidence that new approaches are needed to cure the patients for whom cure has been elusive. Distinguishing those who require intensive or novel therapeutic approaches from others who will be cured with minimal therapy is key for future trials. Incorporating new genomic biomarkers and more sensitive measures of minimal/measurable residual disease provide opportunities to achieve these goals.