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Background: Previous studies have shown continuous improved overall survival (OS) up to 2015 for young adults with acute lymphoblastic leukaemia (ALL). However, recently several important advances have been made justifying a more contemporary analysis of outcomes in adult with ALL., Methods: In this nationwide population-based cohort study, we included patients above 18 years of age diagnosed with ALL between January 1, 1998, and December 31, 2020. Patients were followed until December 31, 2022. By employing flexible parametric survival models, we quantified progress in OS using the key endpoint of 2-year age standardized OS for all patients and clinical subgroups of interest., Findings: This study includes 657 patients and demonstrates a significant improvement in OS over time with the 2-year age standardized OS increasing from 36·4 % (95 % CI, 27·0-45·8 %) for patients diagnosed in 1998 to 68·6 % (95 % CI, 60·2-76·9)for patients diagnosed in 2020, corresponding to an absolute increase in 2-year OS of 32·2 % points (95 % CI, 19·1-45·2). Stratified analysis revealed improvements for both Philadelphia chromosome positive and negative ALL, across cytogenetic risk groups, and for B- and T-cell ALL, whereas the latter did not reach statistical significance. Improvements were seen across all ages; however, most pronounced for Philadelphia chromosome positive ALL and patients below 60 years of age., Interpretation: These results show a universal and continuous improvement in the treatment of adult ALL. Currently, novel treatment combination and advances in cellular therapy occur rapidly, and we expect even further improvements in the years to come., Funding: Northern Region of Denmark., Competing Interests: Declaration of Competing Interest D.T.K: Consulting/advisory board: AbbVie, Atheneum, Astellas Pharma (non-related, potential); A.S.R: Consulting fees: AbbVie. Travel grant; Jazz Pharmaceuticals (non-related, potential). Other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2024. The Author(s).)

Purpose of Review: The use of immunotherapy in recent years has changed the paradigm of treatment in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), improving outcomes in the relapsed/refractory setting. New strategies are incorporating immunotherapy into front-line regimens to reduce the toxicity of chemotherapy, prolong survival and increase the possibility of treating older patients. The aim of this review was to describe the new strategies, which have incorporated these drugs into front-line regimens for BCP-ALL patients., Recent Findings: Recent studies have demonstrated that immunotherapy can be included in front-line induction, consolidation and/or maintenance regimens for the treatment of BCP-ALL patients by its addition to chemotherapy, by substituting some chemotherapy cycles or even including immunotherapy in chemotherapy-free strategies., Summary: The implications of these relevant findings will allow treating older patients, reducing the toxicity of chemotherapy and increasing patient outcomes. In addition, these findings have raised the possibility of avoiding the need for hematologic stem cell transplant in some selected patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Acute lymphoblastic leukemia (ALL) relapsed after allogeneic hematopoietic cell transplantation (allo-HCT) has a catastrophic prognosis. Blinatumomab, a CD3/CD19-directed bispecific T cell engager, is reportedly effective for advanced B-cell ALL (B-ALL), even after allo-HCT. However, the efficacy of blinatumomab in extramedullary relapse (EMR) is controversial. Donor lymphocyte infusion (DLI) is another immunological treatment worth considering for ALL relapsed after allo-HCT. We report the case of a 56-year-old woman with B-ALL. Allo-HCT was performed during the second complete remission (CR). Thirteen months after allo-HCT, isolated EMR (iEMR) of B-ALL developed without bone marrow lesions. A third CR was achieved with 2 cycles of blinatumomab. An additional four cycles each of blinatumomab and DLI were then administered. The patient did not develop graft-versus-host disease and has confirmed 2-year treatment-free remission without a second allo-HCT. Therefore, blinatumomab was considered an effective salvage therapy for iEMR of B-ALL after allo-HCT, because iEMR could have a lower tumor burden than that seen in systemic relapse, and low tumor burden was a prognostic factor for response to blinatumomab. Furthermore, immunological consolidation therapies could only provoke graft-versus-leukemia effects if the imbalanced effector/target ratio was restored and the tumor burden was lowered through immunosurveillance., (© 2024. Japanese Society of Hematology.)

The optimal myeloablative conditioning regimen for ALL patients undergoing hematopoietic cell transplant (HCT) with an alternative donor is unknown. We analyzed HCT outcomes ALL patients (n = 269) who underwent HCT at our center from 2010 to 2020 in complete remission (CR) after FTBI-etoposide and CNI-based GvHD prophylaxis for matched donor HCT (ETOP-package; n = 196) or FTBI-Fludarabine and post-transplant cyclophosphamide (PTCy)-based prophylaxis for HLA- mismatched (related or unrelated) donors (FLU-package; n = 64). Patients in FLU-package showed a significant delay in engraftment (p < 0.001) and lower cumulative incidence (CI) of any and extensive chronic GVHD (p = 0.009 and 0.001, respectively). At the median follow up of 4.6 years (range 1-12 years); non-relapse mortality, overall or leukemia-free survival and GVHD-free/relapse-free survival were not significantly impacted by the choice of conditioning. However, in patients at CR2 or with measurable residual disease (MRD+), there was a trend towards higher relapse after FLU-package (p = 0.08 and p = 0.07, respectively), while patients at CR1 regardless of MRD status had similar outcomes despite the package/donor type (p = 0.9 and 0.7, respectively). Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL. Disease status and depth of remission at HCT were independent predictors for better outcomes., (© 2024. The Author(s).)

The one-year survival rate for patients experiencing a relapse of B-cell acute lymphocytic leukemia (B-ALL) following hematopoietic stem cell transplantation (HSCT) is approximately 30%. Patients experiencing a relapse after allogeneic HSCT frequently encounter difficulties in obtaining autologous CAR-T products. We conducted a study involving 14 patients who received donor-derived CAR-T therapy for relapsed B-ALL following HSCT between August 2019 and May 2023 in our center. The results revealed a CR/CRi rate of 78.6% (11/14), a GVHD rate of 21.4% (3/14), and a 1-year overall survival (OS) rate of 56%. Decreased bone marrow donor cell chimerism in 9 patients recovered after CAR-T therapy. The main causes of death were disease progression and infection. Further analysis showed that GVHD (HR 7.224, 95% CI 1.42-36.82, P = 0.017) and platelet recovery at 30 days (HR 6.807, 95% CI 1.61-28.83, P = 0.009) are significantly associated with OS after CAR-T therapy. Based on the findings, we conclude that donor-derived CAR-T cells are effective in treating relapsed B-ALL patients following HSCT. Additionally, GVHD and poor platelet recovery impact OS, but further verification with a larger sample size is needed., Competing Interests: Declaration of Competing Interest The authors of this manuscript declare that they have no conflicts of interest., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The Japan Children's Cancer Group Relapsed Acute Lymphoblastic Leukemia (ALL) Committee conducted a prospective observational study (ALL-R14) to explore promising reinduction therapy regimens for relapsed ALL to investigate in future trials. In Japan, clofarabine- and bortezomib-based regimens were of interest since they were newly introduced for ALL in the study period (2015-2018). Seventy-five pediatric patients were enrolled in total. The 2-year event-free/overall survival rates in patients with first (n = 59) or second (n = 11) relapse were 40.1% (95% confidence interval [CI]: 25.5-52.3%)/66.3% (95% CI 52.3-77.0%) and 34.1% (95% CI 9.1-61.6%)/62.3% (95% CI 27.7-84.0%), respectively. Clofarabine- or bortezomib-based regimens were used only in patients with high-risk disease. The first reinduction therapy used in the 41 patients with early or multiple relapsed B-cell precursor ALL was clofarabine in 7 patients and bortezomib in 9 patients. The odds ratio for reinduction failure risk with a clofarabine- or bortezomib-based regimen compared with other regimens was 9.0 (95% CI 0.9-86.4, P = 0.057) or 1.9 (95% CI 0.4-8.7, P = 0.42), respectively. Thus, clofarabine- or bortezomib-based regimens had no obvious advantage as reinduction therapy for relapsed ALL in children., (© 2024. Japanese Society of Hematology.)

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., (© 2024 Wiley Periodicals LLC.)

Objective: The present study aims to provide outcome data in children with relapsed acute lymphoblastic leukemia (ALL) over two decades and variables that impact survival., Method: This retrospective study included children who were diagnosed with ALL and treated at our center and relapsed between March 2002 and March 2021., Results: A total of 100 children (64 boys, 36 girls) were included; 80 had B-ALL, 20 had T-ALL. 50 children had a very early relapse, while 25 each had an early and late relapse. The site of relapse was bone marrow in 57, isolated central nervous system (CNS) in 10, isolated testicular in 1, and combined bone marrow and CNS relapse in 32 children. Thirty-six families opted for the best supportive care; 23 of these had very early relapse. Among the 35 who were in remission following induction chemotherapy, 32 (91%) underwent hematopoietic stem cell transplantation (HSCT); 17/32 (53%) were alive and disease-free. Overall survival (OS) was 19 (19%) with a median follow-up of 23.5 months with a significantly improved survival post-measurable risk of disease (MRD) based risk stratification (4% vs 35%, P = 0.02). The OS with very early, early, and late relapses were 8%, 28%, and 32% (P = 0.018), and 15%, 12.5%, and 50% with bone marrow, combined and isolated CNS relapses (P = 0.008)., Conclusion: Relapsed ALL remains a challenge, with OS of 19% and 53% among those who underwent HSCT. Abandonment after relapse continues to be prevalent, and we need to integrate social support for providing care and optimal treatment.

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.

Background: Hematopoietic cell transplantation (HCT) increases survival for acute leukemia. Outpatient allogeneic HCT reduces costs and increases transplant rates in developing countries. We report outcomes of outpatient HLA-identical and haploidentical HCT in acute leukemia., Methods: This single-center retrospective cohort study analyzed 121 adult patients with acute myeloblastic (AML) and acute lymphoblastic leukemia (ALL) receiving an outpatient allogeneic HCT with peripheral blood allografts after reduced-intensity conditioning (RIC) from 2012-2022., Results: There were 81 (67%) haploidentical and 40 (33%) HLA-identical transplants. Complete chimerism (CC) at day +100 was not different in HLA-identical compared to haploidentical HCT (32.5% and 38.2%, P =0.054). Post-HCT complications, including neutropenic fever (59.3% vs. 40%), acute graft-versus-host-disease (aGVHD) (46.9% vs. 25%), cytokine release syndrome (CRS) (18.5% vs. 2.5%), and hospitalization (71.6% vs 42.5%) were significantly more frequent in haploidentical HCT. Two-year overall survival (OS) was 60.6% vs. 46.9%, ( P =0.464) for HLA-identical and haplo-HCT, respectively. There was no difference in the 2-year disease-free-survival (DFS) (33.3% vs. 35%, P =0.924) between transplant types. In multivariate analysis, positive measurable residual disease (MRD) at 30 days (HR 8.8, P =0.018) and 100 days (HR 28.5, P =0.022) was associated with lower OS, but not with non-relapse mortality (NRM) ( P =0.252 and P =0.123, univariate). In univariate analysis, both 30-day and 100-day MRD were associated with lower DFS rates ( P =0.026 and P =0.006), but only day 30 MRD was significant in multivariate analysis ( P =0.050). In the case of relapse, only MRD at day 100 was associated with increased risk in the univariate and multivariate analyses (HR 4.48, P =0.003 and HR 4.67, P =0.008). Chronic graft-versus-host-disease (cGVHD) was protective for NRM (HR 0.38, P =0.015). There was no difference in cumulative incidence of relapse (CIR) between transplant types ( P =0.126). Forty-four (36.4%) patients died, with no difference between HCT type ( P =0.307). Septic shock was the most frequent cause of death with 17 cases, with no difference between transplant types., Conclusions: Outpatient peripheral blood allogenic HCT after RIC is a valid and effective alternative for adult patients suffering acute myeloblastic or lymphoblastic leukemia in low-income populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Jaime-Pérez, Valdespino-Valdes, Gómez-De León, Barragán-Longoria, Dominguez-Villanueva, Cantú-Rodríguez, Gutiérrez-Aguirre and Gómez-Almaguer.)

Background: Rearrangements of the histone-lysine-N-methyltransferase (KMT2A), previously referred to as mixed-lineage leukemia (MLL), are among the most common chromosomal abnormalities in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), involving numerous different fusion partners. KMT2A-rearranged (KMT2A-r) leukemia is characterized by a rapid onset, aggressive progression, and significantly worse prognosis compared to non-KMT2A-r leukemias. Even with contemporary chemotherapeutic treatments and hematopoietic stem cell transplantations (HSCT), patients with KMT2A-r leukemia typically experience poor outcomes and limited responses to these therapies., Objectives: This review aims to consolidate recent studies on the general gene characteristics and associated mechanisms of KMT2A-r acute leukemia, as well as the cytogenetics, immunophenotype, clinical presentation, and risk stratification of both KMT2A-r-AML and KMT2A-r-ALL. Particularly, the treatment targets in KMT2A-r acute leukemia are examined., Methods: A comprehensive review was carried out by systematically synthesizing existing literature on PubMed, using the combination of the keywords 'KMT2A-rearranged acute leukemia', 'lymphoblastic leukemia', 'myeloid leukemia', and 'therapy'. The available studies were screened for selection based on quality and relevance., Conclusions: Studies indicate that KMT2A rearrangements are present in over 70% of infant leukemia cases, approximately 10% of adult AML cases, and numerous instances of secondary acute leukemias, making it a disease of critical concern to clinicians and researchers alike. The future of KMT2A-r acute leukemia research is characterized by an expanding knowledge of the disease's biology, with an emphasis on personalized therapies, immunotherapies, genomic advancements, and innovative therapeutic combinations. The overarching aim is to enhance patient outcomes, lessen the disease burden, and elevate the quality of life for those affected. Ongoing research and clinical trials in this area continue to offer promising opportunities for refining treatment strategies and improving patient prognosis., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL) 1-3 , approximately 50% of patients relapse within the first year 4-6 , representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2 high CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2 low CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells., (© 2024. The Author(s).)

While outcomes for newly diagnosed children with acute lymphoblastic leukemia (ALL) have improved over the last few decades, 10-15% will relapse. Outcomes for those children with relapse remains a challenge, with 5-year overall survival of approximately 35-60%. Large cooperative group trials have identified factors associated with favorable (low risk, LR) outcome at relapse, including later relapse, B-cell phenotype, isolated extramedullary relapse and a good response to initial re-induction therapy. Contemporary therapeutic regimens are aimed at improving outcomes, while decreasing toxicity. A main focus of current research involves how immunotherapy can be best incorporated with cytotoxic chemotherapy to improve survival in relapsed ALL. Here we review therapeutic strategies for LR relapse, including review of recently completed and ongoing trials.

Background: Umbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients., Objective: To compare outcomes by social determinants of health., Study Design: We designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS)., Results: For 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults. Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes., Conclusions: OS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Chimeric antigen receptor cell therapy is a successful immunotherapy for the treatment of blood cancers. However, hurdles in their manufacturing remain including efficient isolation and purification of the T-cell starting material. Herein, we describe a one-step separation based on inertial spiral microfluidics for efficient enrichment of T-cells in B-cell acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia patient's samples. In healthy donors used to optimize the process, the lymphocyte purity was enriched from 65% (SD ± 0.2) to 91% (SD ± 0.06) and T-cell purity was enriched from 45% (SD ± 0.1) to 73% (SD ± 0.02). Leukemic samples had higher starting B-cells compared to the healthy donor samples. Efficient enrichment and recovery of lymphocytes and T-cells were achieved in ALL samples with B-cells, monocytes and leukemic blasts depleted by 80% (SD ± 0.09), 89% (SD ± 0.1) and 74% (SD ± 0.09), respectively, and a 70% (SD ± 0.1) T-cell recovery. Chronic lymphocytic leukemia samples had lower T-cell numbers, and the separation process was less efficient compared to the ALL. This study demonstrates the use of inertial microfluidics for T-cell enrichment and depletion of B-cell blasts in ALL, suggesting its potential to address a key bottleneck of the chimeric antigen receptor-T manufacturing workflow., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This nationwide study retrospectively examined the center effect on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia. The cohort analyses were separated into Philadelphia chromosome (Ph)-positive and -negative cases. The patients were divided into low- and high-volume groups according to the number of allo-HSCTs at each facility. The primary endpoint was 5-year overall survival (OS). This study included 1156 low-volume and 1329 high-volume Ph-negative and 855 low-volume and 926 high-volume Ph-positive cases. In Ph-negative cases, 5-year OS was significantly higher in the high-volume centers at 52.7% (95% confidence interval [CI]: 49.9-55.5) versus 46.8% (95% CI: 43.8-49.7) for the low-volume centers (P < 0.01). Multivariate analysis identified high volume as a favorable prognostic factor (hazard ratio [HR]: 0.81 [95% CI: 0.72-0.92], P < 0.01). Subgroup analysis in Ph-negative cases revealed that the center effects were more evident in patients aged ≥40 years (HR: 0.72, 95% CI: 0.61-0.86, P < 0.01) and those receiving cord blood transplantation (HR: 0.62, 95% CI: 0.48-0.79, P < 0.01). In Ph-positive cases, no significant difference was observed between the high and low-volume centers for 5-year OS (59.5% [95% CI: 56.2-62.7] vs. 54.9% [95% CI: 51.3-58.3], P = 0.054). In multivariate analysis, center volume did not emerge as a significant prognostic indicator. This study showed center effects on survival in Ph-negative but not in Ph-positive cases, highlighting the heterogeneity of the center effect in allo-HSCT for B-cell acute lymphoblastic leukemia. Collaborative efforts among transplant centers and further validation are essential to improve outcomes., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Several international centers have used and reported on pediatric-inspired regimens to treat adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data from the Chinese population. We performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) to treat adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27 years) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥40 years and persistent detectable minimal residual disease (MRD) after induction were independent prognostic factors. Traditional risk factors for adult patients combined with post-induction MRD had predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high-risk factors who can achieve a deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.

Reduced-toxicity conditioning (RTC) regimens aim to mitigate regimen-related toxicity while maintaining anti-leukemic efficacy in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed outcomes of RTC regimens utilizing melphalan versus intravenous busulfan combined with fludarabine in adult acute lymphoblastic leukemia (ALL) patients. A retrospective analysis was conducted with 149 consecutive adult ALL patients (median age 51, range 18-60) in remission undergoing allo-HSCT. Patients received either fludarabine 150 mg/BSA plus 2 days of melphalan 70 mg/BSA (FM140, n = 76) from 2009 to 2015 or fludarabine plus 3 days of busulfan 3.2 mg/kg (FB9.6, n = 73) from 2016 to 2021. At 5 years post-HSCT, FM140 demonstrated superior disease-free survival (53.4% vs. 30.5%, p = 0.007) and lower cumulative relapse (27.4% vs. 46.8%, p = 0.026) than FB9.6. Five-year overall survival and non-relapse mortality did not significantly differ. FM140 exhibited a higher incidence of acute graft-versus-host disease (GVHD) grades II-IV (49.3% vs. 30.3%, p = 0.016), though rates of acute GVHD grades III-IV and chronic GVHD were similar. Multivariate analysis identified Philadelphia chromosome and minimal residual disease positive status, and FB9.6 conditioning as predictors of increased relapse and poorer disease-free survival. FM140 RTC regimen displayed significantly reduced relapse and superior disease-free survival compared to FB9.6 in ALL patients undergoing allo-HSCT, highlighting its current clinical utility., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Zhao, Liu and Zhang.)

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.

Purpose: BCR::ABL1 quantification is widely regarded as the standard for monitoring measurable residual disease (MRD) in Philadelphia chromosome-positive (Ph+) ALL. However, recent evidence of BCR::ABL1 multilineage involvement questions the significance of BCR::ABL1 MRD. We aimed to define the prognostic role of MRD as assessed by BCR::ABL1 or lymphoid-specific immunoglobulin/T-cell receptor ( IG/TR ) gene markers., Patients and Methods: We conducted BCR::ABL1 and IG/TR quantification after each treatment cycle in 264 patients treated in the GRAAPH-2014 trial, which used four cycles of reduced-intensity chemotherapy with nilotinib, followed by hematopoietic stem-cell transplantation (HSCT)., Results: Comparing BCR::ABL1 and IG/TR MRD revealed residual BCR::ABL1 -positive non-ALL cells in 98 (43%) of 228 patients, defining multilineage Ph+ ALL. Despite poorer BCR::ABL1 responses, patients with multilineage Ph+ ALL had similar disease-free survival (DFS; hazard ratio [HR], 0.83 [95% CI, 0.49 to 1.41]; P = .50). Although BCR::ABL1 response failed to predict outcomes, IG/TR positivity (≥0.01%) was strongly associated with lower DFS (after cycle 2, HR, 2.49 [95% CI, 1.40 to 4.40]; P = .002; after cycle 4, HR, 4.13 [95% CI, 1.82 to 9.38]; P = .001). In multivariable analysis, both IG/TR positivity after cycle 2 and initial WBC count ≥30 × 10 9 /L predicted poorer DFS, enabling to define a high-risk group having a 4-year DFS of 56.5% compared with 87.6% (HR, 3.72 [95% CI, 1.93 to 7.15]; P < .001). Moreover, allogeneic HSCT significantly improved DFS in the high-risk group (HR, 0.33 [95% CI, 0.18 to 0.60]; P < .001), whereas the standard-risk group had favorable outcomes regardless of allogeneic HSCT., Conclusion: Our findings challenge the significance of BCR::ABL1 monitoring in adult Ph+ ALL and demonstrate the prognostic role of IG/TR MRD. This study provides a framework for using MRD to guide treatment strategies in adults with Ph+ ALL.

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., (©2024 American Association for Cancer Research.)

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., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Background: Allogeneic hematopoietic stem cell transplantation stands as a vital treatment for leukemia, yet its implementation poses considerable challenges and complications. A comprehensive understanding of these challenges is crucial for appreciating the significance of enhanced nursing care., Objective: To explore and summarise the nursing experience of allogeneic haematopoietic stem cell transplantation for acute lymphoblastic leukaemia. The significance of this objective lies in the potential transformative impact that enhanced nursing care can have on overall patient outcomes within the context of allogeneic hematopoietic stem cell transplantation., Methods: Patients with acute lymphoblastic leukaemia treated with allogeneic haematopoietic stem cell transplantation in our hospital between August 2020 and January 2022 were recruited for this study. A total of 50 patients who met the complete inclusion criteria were enrolled and included in this study. Patients in the traditional group were given traditional nursing interventions, while patients in the exploration group were offered individualized interventions according to their personalized plans. In the traditional group, standard nursing care involved routine health education, vital signs monitoring, and sterile care in a laminar flow ward. Post-transplantation changes were observed, and patients were encouraged to engage in suitable exercises. The exploration group received enhanced infection control measures, including regular disinfection and cleaning of patient wards. Individualized care plans, collaborative chemotherapy consultations, and extensive patient and family education were implemented. Clinical data of all patients were collected, and their nursing experience was summarized and analyzed by comparing the incidence of adverse reactions and evaluating nursing satisfaction., Results: The analysis group demonstrated a significantly lower incidence of adverse reactions compared to the traditional group. Specifically, the total adverse reaction rate in the analysis group was 8.00%, markedly lower than the traditional group's 48.00% (P < .05). Moreover, patient satisfaction in the exploration group was significantly higher than that observed in the traditional group (P < .05). In detail, the satisfaction level in the exploration group reached 92.67%, while the traditional group reported a satisfaction level of 77.56%., Conclusion: For patients with acute lymphoblastic leukaemia who received allogeneic haematopoietic stem cell transplantation, a personalized care intervention plan involving careful primary nursing, full protection and enhanced psychological care can It can effectively improve the adverse effects of sleep, thus increasing their satisfaction with nursing.

Outcomes of patients with B-acute lymphoblastic leukemia (B-ALL) have improved remarkably in the past decade. This has largely been due to the development and introduction of novel immunotherapies such as blinatumomab, inotuzumab ozogamicin, chimeric antigen receptor T (CAR-T) cells, highly potent tyrosine kinase inhibitors, and improved risk stratification, including better understanding of high risk genomic subgroups and better methods of measurable residual disease (MRD) detection. Historically, allogeneic stem cell transplant (allo-SCT) has been the consolidative treatment of choice in first complete remission for fit adults with B-ALL. However, allo-SCT is associated with significant treatment-related mortality and morbidity. Current research is directed at the incorporation of novel immunotherapies into frontline regimens to improve depth and durability of responses and ultimately increase cure rates. In this review, we will discuss the emerging role of novel immune-based treated strategies in both the frontline and relapsed/refractory settings. We present our approach to newly diagnosed patients with B-ALL and illustrate how the incorporation of novel agents and use of high-sensitivity MRD assays can abrogate the need for allo-SCT in most patients with B-ALL., Competing Interests: Disclosure N.J.S. has received consulting fees from Pfizer Inc., GSK, NKARTA, and Sanofi, research funding from Takeda Oncology, Astellas Pharma Inc., Xencor, Stemline Therapeutics, and NextCure, and honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer Inc., Astellas Pharma Inc., Sanofi and BeiGene. E.J. has received consulting fees and research funding from Abbvie, Pfizer Inc., BMS, Amgen, Takeda Oncology, and Adaptive Biotechnologies. H.K. has received research funding from AbbVie, Amgen, Ascentage Pharma, BMS, Daiichi Sankyo, ImmunoGen, Jazz Pharmaceuticals, and Novartis as well as honoraria from AbbVie, Amgen, Amphista Therapeutics, Ascentage Pharma, Astellas Pharma, Biologix, Curis, Ipsen, KAHR, Novartis, Pfizer, Precision Biosciences, Shenzhen TargetRx, and Takeda Oncology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Anti-T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM® and the impact of ATLG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing. Based on 121 patients and 812 samples for POPPK analysis, a two-compartmental model with parallel linear and non-linear clearance and bodyweight as covariate, best described the ATLG concentration-time data. The level of ATLG exposure (day active ATLG <1 AU/mL, median 16 days post-HSCT) was strongly associated with aGVHD grade II-IV, with a lower incidence in patients with prolonged active ATLG exposure (≤day 16 50% vs. >day 16 8.2%; P<0.001). When stratified for remission state, patients transplanted in complete remission (CR) 2 or 3 with prolonged ATLG exposure had a higher relapse risk, while this effect was not seen in CR1 patients (P=0.010). High level ATLG exposure was associated with delayed CD4 T-cell recovery at 4 and 8 weeks post-HSCT, but not at 12 weeks, and overall and relapse-free survival were not influenced by CD4 recovery at 12 weeks post-HSCT. This study underlines the importance of individualized ATLG exposure with the use of model-informed precision dosing in order to optimize the HSCT outcome in pediatric ALL.

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We retrospectively analyzed high-risk ALL patients in CR1 receiving total body irradiation based conditioning regimen with ATLG (n = 74) or PTCy (n = 73) for GVHD prophylaxis. The 3-year OS and LFS were similar in both groups: 65 and 60% in the ATLG group and 64 and 67% in the PTCy group (p = 0.9 and 0.5, respectively). CIR and NRM rate at three years was 12 and 21% after PTCy and 19 and 20% after ATLG (p = 0.4 and p = 0.9, respectively). Acute GvHD grades II-IV and grades III/IV at 100 days was 46 and 19% after PTCy and 33 and 10% after ATLG (p = 0.08 and p = 0.9, respectively). Chronic GvHD of all grade at two years was higher after PTCy: 55% versus 26% (p < 0.001). Based on the propensity score matching (PSM) analysis, aGvHD grades II-IV was trending higher in the PTCy group compared to the ATLG group (p = 0.07). In contrast to the PSM analysis, on multivariate analysis the receipt of PTCy compared with ATLG was associated with a reduced CIR (p = 0.026). Our retrospective single-center analysis shows a lower incidence of acute and chronic GvHD while displaying similar LFS and OS after ATLG compared to PTCy in TBI based allogeneic stem cell transplantation for high-risk ALL., (© 2024. The Author(s).)

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14-64, IQR 28-48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P < .0001) and overall survival (OS, 72% vs. 47%, P < .0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 10 9 /L and PLT count ≤ 154 × 10 9 /L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common., (© 2024 Wiley Periodicals LLC.)

Background: Total body irradiation (TBI) is a pivotal part of conditioning prior to hematopoietic stem cell transplantation (HSCT) for childhood acute lymphoblastic leukemia (ALL), yet evidence is sparse regarding the effect of TBI delivery techniques on acute and late toxicities., Design: In a national cohort of pediatric HSCT-recipients, we compared three TBI schedules; 12 Gray (Gy) delivered as (i) 4 Gy daily fractions from 2008 to 2011 (n = 12); (ii) 2 Gy fractions twice daily with two-dimensional (2D) planning technology from 2012 to 2015 (n = 16); and (iii) 2 Gy twice daily with three-dimensional (3D) planning intensity-modulated radiotherapy (IMRT) from 2016 to 2020 (n = 14)., Results: The 5-year event-free survival was 75.0%, 81.3%, and 81.3% in Cohorts 1, 2, and 3, respectively. Acute toxicity assessed as maximum ferritin and C-reactive protein during the first 3 months post HSCT did not differ between cohorts, nor did the time to first hospital discharge (median 28, 32, and 31 days, p = .25). The incidences of acute graft-versus-host disease (GvHD) (66%, 56%, 71%) and chronic GvHD (25%, 31%, 14%) were comparable. Pulmonary function assessed by spirometry did not differ significantly. The 5-year cataract-free survival was 33.3%, 79%, and 100% in Cohorts 1, 2, and 3, respectively. We found a nonsignificant tendency toward more endocrinopathies in Cohort 1 compared to Cohorts 2 and 3., Conclusion: The change of modality did not result in more relapses. More fractionation led to improvement with a lower incidence of cataract and a tendency toward fewer endocrinopathies. The effect of 3D-planning-IMRT technology requires further evaluation in larger studies., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

The present study aimed to investigate the real-world results of childhood acute lymphoblastic leukemia (cALL) cases in Fujian, China. The clinical data of 1414 patients with newly diagnosed cALL in Fujian were retrospectively analyzed. Patients were treated according to the Chinese Children Leukemia Group 2008 protocol (CCLG-ALL 2008 group) or Chinese Children's Cancer Group 2015 protocol (CCCG-ALL 2015 group). Cumulative incidence of treatment abandonment (TA) at 5 years was 4.2% ± 0.6% and significantly associated with treatment period and risk stratification. The 5-OS and EFS were significantly higher in the CCCG-ALL 2015 group than in the CCLG-ALL 2008 group. Patients treated with CCCG-ALL 2015 from Fujian Medical Union Hospital had a significantly higher 4-year OS and EFS than did those from the other four hospitals. Real-world TA of cALL greatly decreased, and its long-term survival significantly increased in Fujian, which may be related to optimizing programs, multi-center collaboration, and improving treatment compliance.

Epigenetic modifier (EM) genes play important roles in the occurrence and progression of acute lymphoblastic leukemia (ALL). However, the prognostic significance of EM mutations in ALL has not yet been thoroughly investigated. This retrospective study included 205 adult patients with ALL engaged in a pediatric-type regimen. Based on targeted next-generation sequencing, they were divided into EM mutation group (EM-mut, n = 75) and EM wild-type group (EM-wt, n = 130). The EM-mut group showed a higher positive rate of minimal residual disease (MRD) on treatment day24 and before consolidation therapy (P = 0.026, 0.020). Multivariate Cox regression analysis showed that EM-mut was an independent adverse factor for overall survival (OS) and event-free survival (EFS) (HR = 2.123, 1.742; P = 0.009, 0.007). Survival analysis revealed that the OS and EFS rates were significantly lower in the EM-mut group than in the EM-wt group (3-year OS rate, 45.8% vs. 65.0%, P = 0.0041; 3-year EFS rate, 36.7% vs. 53.2%, P = 0.011). In conclusion, EM was frequently mutated in adult ALL and was characterized by poor response to induction therapy and inferior clinical outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) constitutes a distinctive cytogenetic entity associated with challenging outcomes, particularly in adult patients. Current upfront chemotherapy-tyrosine kinase inhibitor (TKI)-based therapies include first, second and third-generation TKIs that have revolutionized patient outcomes including molecular remission and overall survival. Chemotherapy-free regimens such as blinatumomab-dasatinib or blinatumomab-ponatinib offer exciting possibilities, yet challenges arise, particularly in preventing central nervous system relapse. Monitoring measurable residual disease is now a cornerstone particularly using next-generation sequencing (NGS)-Clonoseq for accurate assessment. Controversy regarding the ability to omit consolidation with allogeneic stem cell transplantation, specifically for patients achieving early molecular remission, is related to the excellent survival achieved with novel combinations in the upfront setting, however challenged by the lower disease control when transplant is utilized beyond first remission. Post-transplant maintenance introduces new dilemmas: the optimal TKI, dosing, and duration of therapy are open questions. Meanwhile, a myriad of new combinations and cellular therapies are used for relapsed Ph+ ALL, prompting us to unravel the optimal sequencing of these promising regimen. In this review, we delve into the breakthroughs and controversies in Ph+ ALL with ten commonly asked questions., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

HLA matching is a critical factor in allogeneic unrelated hematopoietic cell transplantation (HCT) because of its impact on post-transplantation survival and quality of life. Umbilical cord blood transplantation (UCBT) offers unique advantages, but determining the optimal approach to graft selection and immunosuppression remains challenging. Unsupervised clustering, a machine learning technique, has potential for analyzing transplantation outcomes, but its application in investigating leukemia outcomes has been limited. This study aimed to identify optimal combinations of HLA/ killer immunoglobulin receptor (KIR) donor-patient pairing, conditioning, and immunosuppressive regimens in pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) undergoing UCBT. Outcome data for single, unmanipulated UCBT in pediatric AML (n = 708) and ALL (n = 1034) patients from the Eurocord/EBMT registry were analyzed using unsupervised clustering. Resulting clusters were used to inform post hoc competing risks and Kaplan-Meier analyses. In AML, single HLA-C mismatches with other loci fully matched (7/8) were associated with poorer relapse-free survival (RFS) (P = .039), but a second mismatch at any other locus counteracted this effect. In ALL, total body irradiation (TBI) effectively prevented relapse mortality (P = .007). KIR/HLA-C match status affected RFS in AML (P = .039) but not in ALL (P = .8). Administration of antithymocyte globulin (ATG) substantially increased relapse, with no relapses occurring in the 85 patients who did not receive ATG. Our unsupervised clustering analyses generate several key statistical and mechanistic hypotheses regarding the relationships between HLA matching, conditioning regimens, immunosuppressive therapies, and transplantation outcomes in pediatric AML and ALL patients. HLA-C and KIR combinations significantly impact RFS in pediatric AML but not in ALL. ATG use in fully matched pediatric patients is associated with late-stage relapse. TBI regimens appear to be beneficial in ALL, with efficacy largely independent of histocompatibility variables. These findings reflect the distinct genetic and biological profiles of AML and ALL., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Relapsed/refractory acute lymphoblastic leukemia (R/R ALL) continues to be a major cause of mortality in children worldwide, with around 15% of ALL patients experiencing relapse and approximately 10% eventually dying from the disease. Early identification of R/R ALL in children has posed a longstanding clinical challenge., Method: Genetic analysis of survival outcomes in pediatric patients with ALL from the TARGET-ALL dataset revealed five risk score factors identified through the intersection of differential genes (relapse/non-relapse) from the GSE17703 and GSE6092 databases. A risk score equation was formulated using these factors and validated against prognostic data from 46 ALL cases at our institution. Patients from multiple datasets were stratified into high and low-score groups based on this equation. Protein-protein interaction networks (PPI) were then constructed using the intersecting differential genes from all three datasets to identify hub nodes and predict interacting transcription factors. Additionally, genes related to cell pyroptosis with varying expression across these datasets were screened, and a multifactorial ROC curve (incorporating risk score and differential expression of pyroptosis-related genes) was generated. Furthermore, relationships among variables in the predictive model were depicted using a nomogram, and model efficacy was assessed through decision curve analysis (DCA)., Results: By analyzing the TARGET-ALL, GSE17703, and GSE6092 databases, we developed a prognostic risk assessment model for pediatric ALL incorporating BAG2, EPHA4, FBXO9, SNX10, and WNK1. Validation of this model was conducted using data from 46 pediatric ALL cases obtained from our institution. Following the identification of 27 differentially expressed genes, we constructed a PPI and identified the top 10 hub genes (PTPRC, BTK, LCK, PRKCQ, CD3D, CD27, CD3G, BLNK, RASGRP1, VPREB1). Using this network, we predicted the top 5 transcription factors (HOXB4, MYC, SOX2, E2F1, NANOG). ROC and DCA were conducted on pyroptosis-related genes exhibiting differential expression and risk scores. Subsequently, a nomogram was generated, demonstrating the effectiveness of the risk score in predicting prognosis for pediatric ALL patients., Conclusions: We have developed a risk prediction model for pediatric R/R ALL utilizing the genes BAG2, EPHA4, FBXO9, SNX10, and WNK1. This model provides a scientific foundation for early identification of R/R ALL in children.

Background: The diagnosis and treatment of childhood acute lymphoblastic leukemia (ALL) may impact mental health. We investigated the long-term risk of psychiatric disorders among survivors of ALL in a population-based cohort study., Methods: We identified patients diagnosed with ALL in Denmark and Sweden before age 20 during 1982-2008. Survivors of ALL (n = 2026), their siblings (n = 3027), and population comparison subjects (n = 9713) were followed for hospital contacts for psychiatric disorders from 5 years after ALL diagnosis (or corresponding index date) until 2017., Results: By age 30, the absolute risk of psychiatric hospital contacts was 19.9% (95% confidence interval [CI]: 17.9-22.1) for ALL survivors, 18.5% (95% CI: 16.9-20.2) for siblings, and 18.3% (95% CI: 17.3-19.2) for population comparison subjects. Overall, survivors were at higher risk of any psychiatric disorders than siblings (hazard ratio [HR] = 1.25; 95% CI: 1.04-1.50), and population comparison subjects (HR = 1.20; 95% CI: 1.06-1.35). The subgroup of survivors (n = 332) who received a hematopoietic stem cell transplantation (HSCT) and/or had a relapse were at highest risk of psychiatric disorders (HR = 2.07; 95% CI: 1.26-3.41 compared to siblings; HR = 1.67; 95% CI: 1.25-2.23 compared to population comparison subjects)., Conclusions: The overall absolute risk of psychiatric hospital contacts among ALL survivors was close to that in siblings and population comparison subjects. The modestly increased relative risk was mainly driven by the subgroup of survivors who received HSCT and/or had a relapse. Our findings are reassuring for the large subgroup of ALL survivors without HSCT or relapse, and provide novel insight on both absolute and relative risk of hospital contacts for psychiatric disorders., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background/objectives: The Berlin-Frankfurt-Münster (BFM)-S classification is a crucial prognostic indicator in children experiencing first-relapsed acute lymphoblastic leukemia (ALL). Early molecular response to therapy, evaluated by measurable/minimal residual disease (MRD), has a significant impact on the survival of patients with childhood ALL. Applying risk stratification based on the BFM-S classification and MRD response after induction, the first nationwide prospective multicenter study, ALL-R08, was conducted in children with first-relapsed ALL in Japan., Methods: The ALL-R08 study comprised two parts: ALL-R08-I, an observational study aimed at obtaining an overall picture of outcomes in first-relapsed childhood ALL, and ALL-R08-II, a clinical trial for the non-T-ALL S2 risk group. In ALL-R08-II, patients with an MRD level of ≥10 -3 at the end of induction therapy were assigned to undergo allogeneic hematopoietic stem cell transplantation (allo-HCT), whereas those with an MRD level less than 10 -3 and isolated extramedullary relapse continued to receive chemotherapy., Results: In total, 163 patients were enrolled in the ALL-R08 study, and 82 and 81 patients were enrolled in the ALL-R08-I and the ALL-R08-II, respectively. In ALL-R08-I, the probability of 3-year event-free survival (EFS) for patients with S1, S2, S3, S4, and post-HCT groups was 83% ± 15%, 37% ± 11%, 28% ± 8%, 14% ± 7%, and 0%, respectively. In the ALL-R08-II trial, 3-year EFS in patients with post-induction MRD less than 10 -3 and ≥10 -3 was 70% ± 9% (n = 27) and 68% ± 8% (n = 31) (p = .591), respectively., Conclusions: ALL-REZ BFM-type treatment is equally effective for children with first-relapsed ALL treated according to the Japanese frontline protocols and for children with first-relapsed ALL treated according to the BFM-type frontline protocols., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

The outcomes of relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant to new drugs such as tyrosine kinase inhibitors, inotuzumab ozogamicin (InO) and blinatumomab are dismal. We treated two cases of Ph+ALL resistant to these drugs that achieved long-term survival after treatment with chimeric antigen receptor (CAR)-T cell therapy or a second allogeneic hematopoietic stem cell transplantation (HCT) with a sequential conditioning regimen. Case 1: A 15-year-old boy was diagnosed with Ph+ALL. Despite the second HCT after the treatment of ponatinib and blinatumomab, hematological relapse occurred. InO was ineffective and he was transferred to a CAR-T center. After the CAR-T cell therapy, negative measurable residual disease (MRD) was achieved and maintained for 38 months without maintenance therapy. Case 2: A 21-year-old man was diagnosed with Ph+ALL. Hematological relapse occurred after the first HCT. Despite of the treatment with InO, ponatinib, and blinatumomab, hematological remission was not achieved. The second HCT was performed using a sequential conditioning regimen with clofarabine. Negative MRD was subsequently achieved and maintained for 42 months without maintenance therapy. These strategies are suggestive and helpful to treat Ph+ALL resistant to multiple immunotherapies.

Backgroud: Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear., Case Presentation: We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free., Conclusion: This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.

Acute lymphoblastic leukemia (ALL) survivors are at risk for developing subsequent neoplasms, but there is limited information on long-term risks and risk factors for both subsequent malignant neoplasms (SMNs) and subsequent non-malignant neoplasms (SNMNs). We analyzed long-term risk and risk factors for SMNs and SNMNs among 3291 5-year ALL survivors from the Dutch Childhood Cancer Survivor Study-LATER cohort (1963-2014). We calculated standardized incidence ratios (SIRs) and cumulative incidences and used multivariable Cox proportional hazard regression analyses for analyzing risk factors. A total of 97 survivors developed SMNs and 266 SNMNs. The 30-year cumulative incidence was 4.1% (95%CI: 3.5-5.3) for SMNs and 10.4%(95%CI: 8.9-12.1) for SNMNs. Risk of SMNs was elevated compared to the general population (SIR: 2.6, 95%CI: 2.1-3.1). Survivors treated with hematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI) (HR:4.2, 95%CI: 2.3-7.9), and without TBI (HR:4.0,95%CI: 1.2-13.7) showed increased SMN risk versus non-transplanted survivors. Cranial radiotherapy (CRT) was also a risk factor for SMNs (HR:2.1, 95%CI: 1.4-4.0). In conclusion, childhood ALL survivors have an increased SMN risk, especially after HSCT and CRT. A key finding is that even HSCT-treated survivors without TBI treatment showed an increased SMN risk, possibly due to accompanied chemotherapy treatment. This emphasizes the need for careful follow-up of HSCT and/or CRT-treated survivors., (© 2024. The Author(s).)