[Management of children and adolescents receiving CAR-T cell therapy for acute lymphoblastic leukemia].

Tisagenlecleucel, a commercially available CD19-targeted CAR-T cell product, has dramatically changed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel infusion has been linked to distinct acute adverse events, including cytokine release syndrome, neurotoxicity, hemophagocytic lymphohistiocytosis and prolonged pancytopenia, which are rare with cytocidal chemotherapy. In addition, recent retrospective studies have revealed pre-infusion prognostic factors including high tumor burden (bone marrow leukemia cell fraction ≥5%) and non-response to blinatumomab, another CD19-targeting agent. Not only physicians providing CAR-T cell therapy but also those referring patients for this therapy should thoroughly understand the indications and limitations, characteristic acute complications, pre-treatment factors affecting prognosis, and late complications. This article outlines the current understanding regarding the use of tisagenlecleucel in children and adolescents with B-ALL.

Dynamic findings of brain magnetic resonance imaging in a haploidentical hematopoietic stem cell transplantation recipient with cytomegalovirus ventriculoencephalitis: a case report and systematic review.

Our case demonstrated unique cytomegalovirus (CMV) encephalitis post-haploidentical donor hematopoietic stem cell transplantation (HID-HSCT), with early findings on diffusion-weighted brain magnetic resonance imaging (MRI) in the absence of any neurologic symptoms. A 54-year-old Chinese man with acute lymphoblastic leukemia (Philadelphia chromosome-negative) underwent HID-HSCT. After HSCT, the patient developed CMV viremia and severe acute graft-versus-host disease. Recurrence of CMV viremia was observed. On day 129, brain MRI was performed to determine the cause for the intermittent fever. Diffusion-weighted imaging (DWI) revealed several bright spots in the cortex of the frontal lobes and anterior angle of the left lateral ventricle. Subsequently, he developed transplant-associated thrombotic microangiopathy, posterior reversible encephalopathy syndrome, and enlargement of lesions alongside the ventricular wall on a brain MRI series. Metagenomic next-generation sequencing (NGS) of the cerebrospinal fluid (CSF) led to the final diagnosis of CMV encephalitis. Although ganciclovir combined with foscarnet was administered, the patient's consciousness deteriorated, followed by respiratory failure. The patient died on day 198. Additionally, we performed a systematic review to comprehensively analyze this disease. Regarding treatment, immunological therapies, including virus-specific T cells from a third donor and CMV-cytotoxic T lymphocytes, may be more effective. This case report and systematic review underscores the complexities of managing CMV ventriculoencephalitis in HSCT recipients and emphasizes the importance of early diagnosis by brain MRI and CSF polymerase chain reaction or NGS and ongoing research in improving outcomes.

Acute lymphoblastic leukemia with pneumatosis cystoides intestinalis after hematopoietic stem cell transplantation: a case report.

Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by air accumulation within the subserosa or submucosa of the gastrointestinal wall. We herein report a case involving a woman in her early 30s who developed PCI after undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia. The patient had a history of multiple COVID-19 infections. Imaging revealed extensive pneumoperitoneum and mesenteric emphysema; nevertheless, the patient remained clinically stable with a benign abdominal examination. She eventually recovered after 1 month of conservative treatment. We believe the PCI in this case had a multifactorial etiology, potentially involving both HSCT and COVID-19. Raising awareness of PCI may help avoid unnecessary surgical interventions and associated morbidity.

Transient Myeloproliferative Disorder (TMD), Acute Lymphoblastic Leukemia (ALL), and Juvenile Myelomonocytic Leukemia (JMML) in a Child with Noonan Syndrome: Sequential Occurrence, Single Center Experience, and Review of the Literature.

Noonan syndrome (NS) is an autosomal dominant disorder that varies in severity and can involve multiple organ systems. In approximately 50% of cases, it is caused by missense mutations in the PTPN11 gene (12q24.13). NS is associated with a higher risk of cancer occurrence, specifically hematological disorders. Here, we report a case of a child who was diagnosed at birth with a transient myeloproliferative disorder (TMD). After two years, the child developed hyperdiploid B-cell precursor acute lymphoblastic leukemia (BCP-ALL), receiving a two-year course of treatment. During her continuous complete remission (CCR), a heterozygous germline mutation in the PTPN11 gene [c.218 C>T (p.Thr73lle)] was identified. At the age of ten, the child presented with massive splenomegaly, hyperleukocytosis, and thrombocytopenia, resulting in the diagnosis of juvenile myelomonocytic leukemia (JMML). After an initial response to antimetabolite therapy (6-mercaptopurine), she underwent haploidentical hematopoietic stem cell transplantation (HSCT) and is currently in complete remission. The goal of this review is to gain insight into the various hematological diseases associated with NS, starting from our unique case.

Searching for the Scale-Able Weight Loss Intervention: Can One Size Fit All? Lessons to Be Learned from the EQUAL Trial.

Overweight and obesity affect 71.2% of adults in the United States, with cancer survivors not far behind at 70.3%. Subgroups such as those diagnosed with acute lymphoblastic leukemia (ALL) face even greater challenges. The Exercise and Quality Diet after Leukemia (EQUAL) trial sought to address weight management issues among ALL survivors by implementing a remotely delivered weight loss intervention, leveraging the previously proven Practice-based Opportunities for Weight Reduction (POWER) program. Despite a strong foundation and design, the EQUAL trial yielded null results. Key differences in study populations and intervention contexts between the EQUAL and POWER trials, such as the lack of primary care physician involvement in EQUAL, contributed to these outcomes. EQUAL's failure to meet its accrual target and poor adherence among participants highlighted challenges in engaging this unique population. Contrary to EQUAL's conclusions, evidence from other studies supports the efficacy of remote interventions for weight loss among cancer survivors. The lack of qualitative assessment among ALL survivors and key integration to inform intervention adaptations undermined EQUAL's impact. However, EQUAL's impressive retention rate offers valuable insights. Lessons from EQUAL underscore the need for well-fitted, remotely delivered interventions and the importance of thoughtfully adapted and tailored approaches to specific survivor populations. See related article by Fiedmann et al., p. 1158.

Effectiveness of Nutrition Support Team Intervention in Pediatric Patients with Cancer.

Malnutrition in children with cancer is associated with poor prognosis. This study aimed to determine whether nutritional support team (NST) interventions prevent adverse events and improve the nutritional status in pediatric patients admitted for cancer treatment. This was a historical cohort study of pediatric patients with acute lymphocytic leukemia, acute myeloid leukemia, neuroblastoma, or brain tumor who received chemotherapy or underwent hematopoietic stem cell transplantation. Patients admitted between June 2013 and October 2014 were classified into the intervention group. Those admitted between January 2011 and December 2012 were classified into the control group. We created a homogeneous probability model using the inverse probability of treatment weighting method, and compared outcomes. A total of 75 patients were included in the study (38 and 37 in the intervention and control groups, respectively). The intervention group had significantly fewer incidents of nothing by mouth (nil per os [NPO]) (p=0.037) and days of NPO (p=0.046) than the control group. There was no significant difference between the intervention and control groups regarding the change in body mass index z-score between admission and discharge (p=0.376). NST interventions for children with cancer were associated with a reduction in the number of NPO occurrences and NPO days. These findings suggest that NST interventions contribute to continued oral intake.

[Chinese consensus for the bispecific T cell engager in the treatment of acute lymphoblastic leukemia (2024)].

Acute lymphoblastic leukemia (ALL) is one of the most common acute leukemias, with rapid onset and progression. The standardized application of chemotherapy and transplantation have improved the prognosis of patients, while the unmet therapeutic needs still exist. Recently novel immunotherapies including Bispecific T cell Engager develop rapidly, offering more options for ALL treatment and also demanding higher requirements for clinical diagnosis and treatment management. Based on the evidence of domestic and international medical evidence and clinical experience, the expert panel updated Chinese consensus for the Bispeific T cell Engager in the treatment of B-cell acute lymphoblastic leukemia (2022) and formulated this edition of the Chinese expert consensus.

Human leukocyte antigen evolutionary divergence as a novel risk factor for donor selection in acute lymphoblastic leukemia patients undergoing haploidentical hematopoietic stem cell transplantation.

Introduction: The human leukocyte antigen (HLA) evolutionary divergence (HED) reflects immunopeptidome diversity and has been shown to predict the response of tumors to immunotherapy. Its impact on allogeneic hematopoietic stem cell transplantation (HSCT) is controversial in different studies. Methods: In this study, we retrospectively analyzed the clinical impact of class I and II HED in 225 acute lymphoblastic leukemia patients undergoing HSCT from related haploidentical donors. The HED for recipient, donor, and donor-recipient pair was calculated based on Grantham distance, which accounts for variations in the composition, polarity, and volume of each amino acid within the peptide-binding groove of two HLA alleles. The median value of HED scores was used as a cut-off to stratify patients with high or low HED. Results: The class I HED for recipient (R_HEDclass I) showed the strongest association with cumulative incidence of relapse (12.2 vs. 25.0%, P = 0.00814) but not with acute graft-versus-host disease. The patients with high class II HED for donor-recipient (D/R_HEDclass II) showed a significantly higher cumulative incidence of severe aGVHD than those with low D/R_HEDclass II (24.0% vs. 6.1%, P = 0.0027). Multivariate analysis indicated that a high D/R_HEDclass II was an independent risk factor for the development of severe aGVHD (P = 0.007), and a high R_HEDclass I had a more than two-fold reduced risk of relapse (P = 0.028). However, there was no discernible difference in overall survival (OS) or disease-free survival (DFS) for patients with high or low HED, which was inconsistent with the previous investigation. Discussion: While the observation are limited by the presented single center retrospective cohort, the results show that HED has poor prognostic value in OS or DFS, as well as the associations with relapse and aGVHD. In haploidentical setting, class II HED for donor-recipient pair (D/R_HEDclass II) is an independent and novel risk factor for finding the best haploidentical donor, which could potentially influence clinical practice if verified in larger cohorts.

Circular RNA as a Biomarker for Diagnosis, Prognosis and Therapeutic Target in Acute and Chronic Lymphoid Leukemia.

Circular RNAs (circRNAs) are single-stranded RNAs that have received much attention in recent years. CircRNAs lack a 5' head and a 3' poly-A tail. The structure of this type of RNAs make them resistant to digestion by exonucleases. CircRNAs are expressed in different cells and have various functions. The function of circRNAs is done by sponging miRNAs, changing gene expression, and protein production. The expression of circRNAs changes in different types of cancers, which causes changes in cell growth, proliferation, differentiation, and apoptosis. Changes in the expression of circRNAs can cause the invasion and progression of tumors. Studies have shown that changes in the expression of circRNAs can be seen in acute lymphoid leukemia (ALL) and chronic lymphoid leukemia (CLL). The conducted studies aim to identify circRNAs whose expression has changed in these leukemias and their more precise function so that these circRNAs can be identified as biomarkers, prediction of patient prognosis, and treatment targets for ALL and CLL patients. In this study, we review the studies conducted on the role and function of circRNAs in ALL and CLL patients. The results of the studies show that there is a possibility of using circRNAs as biomarkers in the identification and treatment of patients in the future.

The Clinical Influence of Complete Remission With Incomplete Count Recovery (CRi) on Single-Unit Unrelated Cord Blood Transplantation in Patients With Acute Leukemia.

Recent evidence has indicated that measurable residual disease (MRD) markedly affects the prognosis of patients with acute leukemia post-transplantation. However, the prognostic relevance of complete remission with incomplete count recovery (CRi) before transplantation has not been extensively explored. In this single-center, longitudinal study, we assessed the outcomes of 466 MRD-negative acute leukemia patients who underwent single-unit unrelated cord blood transplantation (sUCBT), including 117 patients with CRi. We observed that acute myeloid leukemia (AML) patients with CRi had a significantly lower cumulative incidence of both neutrophil (90.8% versus 96.5%) and platelet engraftment (67.2% versus 85.3%) and experienced increased transplant-related mortality (TRM) (100-day TRM: 14.2% versus 5.3%; 1-year TRM: 20.6% versus 11.3%; P = .024 and .063, respectively), mainly due to infection-related deaths, compared to those in complete remission (CR). Multivariate analysis revealed that CRi was an independent adverse predictor of both neutrophil and platelet engraftment and increased 100-day TRM in AML patients. However, CRi status did not affect relapse or reduce 5-year overall survival (OS), leukemia-free survival (LFS), or GVHD-free relapse-free survival (GRFS) in the AML cohort. Conversely, for patients with acute lymphoblastic leukemia (ALL), CRi did not impact engraftment, TRM, relapse or survival after sUCBT. Our findings underscore that CRi status before sUCBT portends poorer engraftment outcomes and a greater TRM in AML patients, although it does not significantly affect the prognosis of ALL patients.

Exploring the role of pain on physical activity among youth with acute lymphoblastic leukemia using the biopsychosocial model.

BACKGROUND: Engaging in physical activity (PA) throughout cancer treatment offers many benefits, but may be challenging due to cancer-related pain. Pain research in pediatric cancer has primarily focused on procedural pain, with fewer studies exploring how pain affects PA. The current study qualitatively investigated the impact of pain on PA in youth with acute lymphoblastic leukemia (ALL) using a biopsychosocial framework. PROCEDURE: As part of a larger study, caregivers (N = 17) of a child diagnosed with ALL and on treatment for less than 1 year completed a semi-structured interview about perceptions of their child's health behaviors during ALL treatment. This secondary analysis focused specifically on discussions about pain and its impact on PA. We followed Braun and Clarke's (2006) six-step thematic analysis framework to identify themes of pain-related barriers to PA. RESULTS: Key pain-related barriers endorsed by caregivers included: interactions among pain and treatment effects, caregiver distress around seeing their child in pain, and fear of interfering with medical equipment. Despite these barriers, caregivers found creative solutions to adapt activities for their child. Caregivers were reassured by PA advice from their medical team; however, advice varied between teams. CONCLUSION: The relationship between pain and PA during ALL treatment is influenced by an intricate system of biological (e.g., treatment effects), psychological (e.g., parental distress), and social (e.g., communication among families and medical teams) factors. Future directions include identifying evidence-based PA recommendations and exploring family-team communication dynamics. This study also highlights a need to prioritize ALL pain management and involve caregivers in behavioral treatment protocols to improve PA.

Prediction of Response to FDA-Approved Targeted Therapy and Immunotherapy in Acute Lymphoblastic Leukemia (ALL).

OPINION STATEMENT: Acute lymphoblastic leukemia (ALL) represents the predominant cancer in pediatric populations, though its occurrence in adults is relatively rare. Pre-treatment risk stratification is crucial for predicting prognosis. Important factors for assessment include patient age, white blood cell (WBC) count at diagnosis, extramedullary involvement, immunophenotype, and cytogenetic aberrations. Minimal residual disease (MRD), primarily assessed by flow cytometry following remission, plays a substantial role in guiding management plans. Over the past decade, significant advancements in ALL outcomes have been witnessed. Conventional chemotherapy has remarkably reduced mortality rates; however, its intensive nature raises safety concerns and has led to the emergence of treatment-resistant cases with recurrence of relapses. Consequently, The U.S. Food and Drug Administration (FDA) has approved several novel treatments for relapsed/refractory ALL due to their demonstrated efficacy, as indicated by improved complete remission and survival rates. These treatments include tyrosine kinase inhibitors (TKIs), the anti-CD19 monoclonal antibody blinatumomab, anti-CD22 inotuzumab ozogamicin, anti-CD20 rituximab, and chimeric antigen receptor (CAR) T-cell therapy. Identifying the variables that influence treatment decisions is a pressing necessity for tailoring therapy based on heterogeneous patient characteristics. Key predictive factors identified in various observational studies and clinical trials include prelymphodepletion disease burden, complex genetic abnormalities, and MRD. Furthermore, the development of serious adverse events following treatment could be anticipated through predictive models, allowing for appropriate prophylactic measures to be considered. The ultimate aim is to incorporate the concept of precision medicine in the field of ALL through valid prediction platform to facilitate the selection of the most suitable treatment approach.

Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

PURPOSE: Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS: To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS: Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. CONCLUSION: Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

Allogeneic stem cell transplant with TBI-based myeloablative conditioning in adolescents and young adults with Philadelphia chromosome-negative ALL treated with pediatric protocols.

To investigate the safety of total body irradiation-based myeloablative conditioning (TBI-MAC) in adolescent and young adult (AYA) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) patients treated with pediatric protocols, treatment outcomes of 106 AYA patients aged 16-39 years old undergoing allogeneic stem cell transplant (allo-SCT) with TBI-MAC in the first remission were compared according to chemotherapy types before transplant. Pediatric and adult protocols were used in 56 and 50 of the patients, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) and the overall survival (OS) rates were not significantly different between the pediatric-protocol and adult-protocol group (NRM: 4 % vs. 14 % at five years post-transplant, respectively, p = 0.26; OS: 81 % vs. 66 %, respectively, p = 0.14). Multivariate analysis for NRM revealed that a performance status >0 (hazard ratio [HR] = 4.8) and transplant due to chemotherapy toxicities (HR = 3.5) were independent risk factors, but a pediatric protocol was not (HR = 0.48). The CI of NRM and the OS rates were also similar among patients aged over 24 years old. These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric protocols.

Survival Outcomes in Older Adult Acute Lymphoblastic Leukemia Patients Analyzed by Facility Volume and Type: A National Cancer Database Analysis.

BAKGROUND: It is important to understand the outcomes of adult acute lymphoblastic leukemia (ALL) patients at different facilities as treatment paradigms change. AIMS: Our primary objective was to determine adult ALL overall survival (OS) by facility volume and type. Secondary objectives included identifying sociodemographic factors that may have impacted outcomes and analyzing treatment patterns by facility volume and type. METHODS: This was a retrospective analysis of the National Cancer Database (NCDB) that included patients ≥40 years diagnosed with ALL between 2004 and 2016. RESULTS: A total of 14 593 patients were included in this study. Univariate OS was greatest at low volume (LV) and community programs (CPs) and the least at high volume (HV) and academic programs (AP). This difference was lost after multivariable Cox proportional hazards model analysis, which found no difference in survival by facility volume or type, however, survival was significantly influenced by age, race, Hispanic ethnicity, insurance, and residence location (p < 0.05). Patients treated at HV and APs compared to LV and CP received more anti-neoplastic directed therapy. CONCLUSION: Our results suggest treatment facility volume and type do not impact older adult ALL patient (≥40 years) survival, however confounding sociodemographic differences do impact survival outcomes, despite more aggressive and novel treatment approaches provided at HV and APs.

Long-Term Remission in T315I+ Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Blinatumomab and Allogeneic Stem Cell Transplantation: Two Case Studies.

BACKGROUND Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults has a poor prognosis with conventional chemotherapy. Treatment with tyrosine kinase inhibitors (TKIs) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved clinical outcomes; however, the relapse rate is still high. Therapeutic options for patients with relapsed/refractory (R/R) Ph+ ALL are scarce, with very few studies focusing on these patients. Blinatumomab is a novel bispecific T-cell engager antibody construct showing promising efficacy in R/R Ph+ ALL. CASE REPORT Here, we present 2 cases of relapsed Ph+ ALL with T315I mutation refractory to multiple TKIs and chemotherapy. Patient 1 was a 48-year-old woman who had increased leukocytes in her peripheral blood cells, with 90% abnormal cells and decreased platelets. Bone marrow (BM) smear showed 95% blasts. Patient 2 was a 20-year-old man who had leukocytosis with thrombocytopenia, while all other parameters were normal. BM aspirate showed 98% immature granulocytes/blasts. The immunophenotypic observations of both the patients on BM were consistent with the presence of ALL. Both patients were effectively treated with a combination of blinatumomab and allo-HSCT and achieved complete remission in 1 month with minimal residual disease negativity and remained in remission for a long period. CONCLUSIONS The findings suggest, that for patients with R/R Ph+ ALL with T315I mutation who respond poorly to TKIs, salvage therapy with blinatumomab is a potentially effective treatment for improving clinical outcomes. The treatment with blinatumomab can further act as a bridge to HSCT in these patients, helping them to attain deeper remission.

Advancements in the Regulatory Role of microRNAs in Childhood Acute Lymphoblastic Leukemia: Mechanisms and Clinical Implications.

microRNAs (miRNAs), tiny, non-coding RNA molecules, fine-tune the expression of target genes through interacting with mRNAs. These miRNAs are involved in a wide range of biological processes, encompassing cell division, death, blood cell production, and tumor development. When these miRNAs become dysfunctional, they can promote the invasion and spread of cancer cells in various human malignancies, including leukemia. Acute lymphoblastic leukemia (ALL), the preeminent malignancy affecting children, is a blood cancer marked by the uncontrollable growth of immature lymphoid cells that displace healthy blood precursors in the bone marrow. Despite a decline in ALL mortality rates over the past two decades, a significant proportion of deaths still results from a lack of effective diagnostic and prognostic markers that can guide treatment decisions and overcome drug resistance. The analysis of miRNA expression patterns in ALL could lead to more precise disease classification, earlier diagnosis, and better prognostic outcomes in the near future. The connection between miRNA dysfunction and the biology of ALL suggests that these molecules could represent promising therapeutic targets. Therefore, this review delves into the regulatory mechanisms of miRNAs in pediatric ALL, exploring how miRNA-based diagnostic, prognostic, and therapeutic strategies offer unique advantages and hold promise for clinical applications.