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Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial.

Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS) whole genome sequencing (WGS) (n 157) and bespoke targeted NGS (t-NGS) (n 175) (overlap n 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n 91), whereas PAX5 P80R mutations (n 11) defined a distinct PAX5 subtype. DUX4-r subtype (n 80) was defined by DUX4 rearrangements andor ERG deletions. These patients had a low relapse rate and excellent survival. ETV6RUNX1-like subtype (n 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.

How I Prevent and Treat Central Nervous System Disease in Adults with Acute Lymphoblastic Leukemia.

The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). While CNS disease is identified only in a minority of patients at the time of diagnosis, subsequent CNS relapses (either isolated or concurrent with other sites) will occur in some patients, even after delivery of prophylactic therapy targeted to the CNS. Historically, prophylaxis against CNS disease has included intrathecal (IT) chemotherapy and radiotherapy (RT), although the latter is being used with decreasing frequency. Treatment of a CNS relapse usually involves intensive systemic therapy and cranial or craniospinal RT along with IT therapy, and consideration of allogeneic hematopoietic cell transplant (HCT). However, short- and long-term toxicities can make these interventions prohibitively risky, particularly for older adults. As new antibody-based immunotherapy agents have been approved for relapsedrefractory B-cell ALL, their use specifically in patients with CNS disease is an area of keen interest, both because of the potential for efficacy but also concerns of unique toxicity to the CNS. In this review, we discuss data-driven approaches for these common and challenging clinical scenarios, as well as highlight how recent findings potentially support the use of novel immunotherapeutic strategies for CNS disease.

Abstracts of the Cell Therapy Transplant Canada 2022 Annual Conference.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2022 Annual Conference. The conference was held in-person 15-18 June 2022, in Niagara Falls, Ontario. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 16 June, and oral abstract authors were featured during the oral abstract session in the afternoon on Friday, 17 June 2022. Thirty-three (33) abstracts were selected for presentation as posters and six (6) as oral presentations. The top abstracts in each of four (4) categories, (1) BasicTranslational sciences, (2) Clinical TrialsObservations, (3) LaboratoryQuality, and (4) PharmacyNursingOther Transplant Support, received awards for both the oral and poster presentations. All of these were marked as Award Recipient with the relevant category. We congratulate all the presenters on their research and contribution to the field.

Acute Lymphoblastic Leukemia Developing in a Patient with 46, XY Pure Gonadal Dysgenesis (Swyer Syndrome) with Malignant Gonadal Germ Cell Tumor A Case Report and Literature Review.

A female phenotype with strip-like gonads, 46, XY pure gonadal dysgenesis (PGD) has a high tendency to develop into gonadal germ cell tumors. We described one patient with 46, XY PGD, who had a gonadal mixed germ cell tumor (GCT) and acute lymphoblastic leukemia (ALL). This is a unique case because two malignancies developed and relapsed in one person with chromosome abnormality, and the patient is the youngest reported so far. There is an association between her GCT and ALL, as the two malignancies may share a common clonal origin and the

A Case of Acute Myeloid Leukemia with Myelodysplasia-Related Changes, SET-NUP214 Fusion, and Complex Karyotype.

The SET-NUP214 fusion formed by cryptic t(99)(q34q34) or del(9)(q34.11q34.13) is a rare gene rearrangement. This rearrangement has been reported mostly in T-cell acute lymphoblastic leukemia, but only rarely in acute myeloid leukemia (AML). The acute leukemia cases with the SET-NUP214 fusion gene show typical immunophenotype, karyotype, and poor treatment response. However, the cytogenetic or genetic changes in AML with SET-NUP214 fusion are not well understood. The diagnosis was made based on a combination of the morphology, immunophenotyping, multiplex reverse transcriptase-polymerase chain reaction, FISH, karyotype, Sanger sequencing, next-generation sequencing, and microarray analysis. The author reports a rare case of AML with myelodysplasia-related changes, SET-NUP214 fusion gene, and complex karyotype that was resistant to induction chemotherapy, making diagnosis and treatment difficult. Further studies, including cytogenetic and molecular analyses, are needed to determine the pathophysiology and clinical significance for this rare gene rearrangement.

Loss of protective anti-HBs titers and seroconversion to hepatitis B vaccination in children during chemotherapy for acute lymphoblastic leukemia.

This study aimed to evaluate loss of protective anti-hepatitis B (HBs) titers and seroconversion to hepatitis B vaccine (HBV) during chemotherapy in children with acute lymphoblastic leukemia (ALL). Anti-HBs titers were done at diagnosis. Patients were divided into two groups. Group I (protective titers >10 mIUml) received single double dose of HBV as booster. Titers were repeated at three time points end of phase 1b, beginning of re-induction, and start of maintenance chemotherapy. Group II (nonprotective titers <10 mIUL) received hepatitis B immunoglobulin (HBIG), prior to start of chemotherapy, followed by three double doses of HBV as booster. Titers were repeated at two time points prior to first dose, and 4 weeks after third dose of vaccine. Total 125 patients were included 88 in group I 37 in group II. Among group I patients, 98.7%, 90%, and 84% retained protective titers at the three points, respectively. Subgroup analysis showed that those with initial titers greater than 100 mIUL retained protective titers better than those with titers between 11 and 100 mIUL (p .0001). Among group II patients, 62% and 64% attained protective titers at the two points, respectively. HBV boosters helped maintain protective titers during intensive ALL chemotherapy in immunized children having titers more than 10 mIUL, and more so if titer was more than 100 mIUL. Therefore, we propose that cut off for protective anti-HBs titers be changed to greater than or equal to 100 mIUL. Titers between 11 and 100 mIUL may require combined active and passive immunization. Around one-third of group II patients who fail to attain protective titers may need frequent doses of HBIG.

Childcare attendance and risk of childhood acute lymphoblastic leukaemia A register study based on the Danish childcare database.

Childhood acute lymphoblastic leukaemia (ALL) is suggested to result from a dysregulated immune response to infections in children with a preleukaemic state. Childcare in early life supposedly may protect against childhood ALL by facilitating sufficient exposure to infections to stimulate and ensure normal maturation of the immune system. We assessed the association between childcare attendance before age 2 years and risk of childhood ALL in a register-based cohort study, including all children aged 2 to 14 years born in Denmark during 1991 to 2014 with available childcare information recorded in the Danish Childcare Database (n 1 116 185). Cox regression was used to estimate hazard ratios (HRs) comparing children enrolled in childcare and children not enrolled before age 2 years. Further, we assessed the association according to age at enrolment, type of childcare facility and specific ALL subtypes. During 10 460 811 person-years of follow-up, 460 children developed ALL at ages 2 to 14 years. Of these, 57 (12.4%) never attended childcare before age 2 years compared with 10.6% in the total cohort. Compared with homecare, childcare attendance before age 2 years was associated with a statistically non-significantly, marginally decreased risk of childhood ALL with adjusted HR 0.87 (95% confidence interval CI 0.65-1.16). Risk estimates did neither vary statistically significantly by age at enrolment nor by type of childcare facility and also not between childhood ALL subtypes, including frequently prenatally initiated ALL subtypes. Results from this large, nationwide register-based study provided no evidence that childcare attendance in the first years of life protects against childhood ALL.

T-cell acute lymphoblastic leukemia promising experimental drugs in clinical development.

Despite advances in treatment approaches in acute lymphoblastic leukemia (ALL), the prognosis of adults with newly diagnosed T-ALL remains poor, as well as that of adults and children with relapsed disease. Novel targeted therapies are therefore needed. This review summarizes promising emerging strategies for the treatment of T-ALL. The recent molecular characterization of T-ALL has led to the identification of new therapeutic targets. Small-molecules inhibitors and other targeted therapies have therefore been recently developed and are currently under clinical investigations. Similarly, first studies involving monoclonal antibodies and chimeric antigen receptor (CAR) T cells have shown encouraging results. Improvement of outcome with these novel approaches, eventually combined with current standard chemotherapy, is therefore expected in a near future in T-ALL.

Effects of ABCB1 polymorphisms on the transport of ponatinib into the cerebrospinal fluid in Japanese Philadelphia chromosome-positive acute lymphoblastic leukaemia patients.

The effects of polymorphisms of ABCB1 and ABCG2 on the dose-adjusted plasma trough concentrations and cerebrospinal fluid (CSF)-to-plasma ratios of ponatinib were evaluated. Blood (C

B-cell Lymphoblastic Lymphoma of the Paranasal Sinuses A Case Study of a Rare Clinical Entity.

Lymphoblastic lymphoma is a rare and aggressive form of non-Hodgkin lymphoma (NHL). The tumor can derive from T-cell or B-cell and is clinically similar to acute lymphoblastic leukemia with minimal to no bone marrow involvement distinguishing the two. We present a rare case of lymphoblastic lymphoma originating from the paranasal sinuses. A 40-year-old male presented to the emergency department and was diagnosed with right-sided acute sinusitis complicated by pre-septal cellulitis. After failing medical management, he underwent endoscopic sinus surgery. Pathologic analysis of nasal contents stained for CD79a, CD34, and PAX5, suggesting a B-cell lymphoblastic lymphoma (B-LBL). He was referred to hematology-oncology and was treated with hyperfractionated cyclophosphamide, vincristine, Adriamycin, dexamethasone (Hyper-CVAD). Short-term follow-up has thus far demonstrated near-complete resolution of the tumor. Non-Hodgkin lymphomas of the paranasal sinuses are rare, and B-cell lymphoblastic lymphomas comprise just 0.3% of adults with NHL. Immunohistochemical phenotyping for B-LBL is typically positive for B-cell markers CD19, CD20, CD22 and CD79a. Classic treatment involves a chemotherapy regimen of Hyper-CVAD with an overall survival rate of 66%. B-cell lymphoblastic lymphoma is rarely reported in the paranasal sinuses. A thorough history and physical exam along with a complete workup, including biopsies with histopathological and immunohistochemical analysis, needs to be obtained. Little is known about its prognosis when the primary site is within the paranasal sinuses, and therefore, patients need prompt and aggressive treatment when the diagnosis is made.

ETS Fight Club on Microsatellite Enhancers.

In this issue of Blood Cancer Discovery, Kodgule, Goldman, Monovichet al. cleverly analyzed the transcription regulatory elements to investigate why the second copy of ETV6 is often lost in ETV6RUNX1-translocated in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). It turns out that ETV6 suppresses the enhancer activity of GGAA microsatellite repeats, preventing ERG from subverting them to activate aberrant oncogene transcription. See related article by Kodgule, Goldman, Monovich et al., p. 34 (5).

Allogeneic Chimeric Antigen Receptor T Cells for Hematologic Malignancies.

Autologous chimeric antigen receptor (CAR) T cell therapy has been extensively studied over the past decades. Currently, autologous CAR T products are FDA-approved to treat B cell acute lymphoblastic leukemia (B-ALL), large B cell, mantle cell, and follicular lymphomas, and multiple myeloma. However, this therapy has drawbacks including higher cost, production lead time, logistical complexity, and higher risk of manufacturing failure. Alternatively, allogeneic CAR T cell therapy, currently under clinical trial, has inherent disadvantages, including cell rejection, graft versus host disease, and undetermined safety and efficacy profiles. Different strategies, including modifying HLA and T cell receptor expression using different effector cells, are under investigation to circumvent these issues. Early allogeneic CAR T therapy results for B-ALL and B-NHL have been promising. Large sample clinical trials are ongoing. Here, we discuss the pros and cons of allo-CAR T for hematologic malignancies and review the latest data on this scalable approach.

CAR-T cell Therapies for B-cell Lymphoid Malignancies Identifying Targets Beyond CD19.

Chimeric antigen receptors (CARs) are synthetic engineered receptors with an antigen recognition domain derived from a high-specificity monoclonal antibody that can target surface molecules on tumor cells. T cells are genetically engineered to express CARs, thereby harnessing the antigen-recognition ability of antibodies and effector function of T cells. Target surface molecule selection is crucial for manufacturing CARs. Ideally, a target surface molecule should be restricted to tumor cells and minimally expressed or absent on normal tissues. Different CD19-targeted CAR-T cell therapies have been approved for the treatment of B-cell lymphoid malignancies that are refractory to other therapies, including indolent and aggressive B-cell non-Hodgkin lymphomas (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). Despite impressive results, many patients with aggressive and refractory B-cell malignancies do not respond to or relapse after CD19 CAR-T cell therapies. Thus, several additional strategies are currently being evaluated to overcome these limitations. This review discusses studies on other promising CAR-T cell targets, including CD20, CD22, BAFF-R, ROR1, CD70, BCR complex, kappalambda light chains, multitargeted CAR-T cells, and combinations of CAR-T cell therapy with different drugs.

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia.

This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimalmeasurable residual disease (MRD) and recently identified tumor genetic subtypes. Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase-polymerase chain reaction, multiplex ligation-dependent probe amplification, and RNA-sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG-ALL-2013 study enrolled patients who received MRD-directed therapy. The 5-year event-free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD-guided therapy, those with ETV6-RUNX1 fusion and high hyperdiploidy had the highest 5-year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR-ABL1 ALL. Recently identified subtypes like DUX4-rearranged, ZNF384-rearranged, MEF2D-rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high-risk or very-high-risk subtypes, the TPOG-ALL-2013 regimen did not confer significant improvements compared to TPOG-ALL-2002, and the outcomes of BCR-ABL1-like, MEF2D-rearranged, and KMT2A-rearranged ALL subtypes (in addition to those of T-cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients. The TPOG-ALL-2013 study yielded outcomes superior to those of patients treated in the preceding TPOG-ALL-2002 study. This study provides important data to inform the design of future clinical trials in Taiwan. MRD-directed therapy improved the outcomes for pediatric ALL, especially standard-risk patients. Genomic analyses and MRD might be used together for risk-directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan.

RNA-binding protein PUM2 promotes T-cell acute lymphoblastic leukemia via competitively binding to RBM5 3UTR with miR-28-5p.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, and T-ALL patients are prone to early disease relapse and suffer from poor outcomes. The crucial function of RNA-binding proteins (RBPs) has been reported in the progression of cancers by regulating the expression of transcripts. This study aimed to reveal the role and molecular regulatory mechanism of RBP Pumilio2 (PUM2) in T-ALL. The expression of genes was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The viability, proliferation, and apoptosis of T-ALL cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2-deoxyuridine, and flow cytometry analysis. Luciferase reporter, RNA pulldown, and RNA immunoprecipitation assays were performed to confirm the binding of PUM2 to RBM5. The combination between RNA-binding motif protein 5 (RBM5) and microRNA (miR)-28-5p was validated using luciferase reporter assay. Our data revealed that PUM2 was highly expressed in T-ALL blood samples and cell lines. PUM2 knockdown suppressed the proliferation but accelerated the apoptosis of T-ALL cells in vitro. Additionally, RBM5 exhibited a low expression level in T-ALL samples and cells. PUM2 negatively regulated RBM5 via targeting its 3untranslated region (3UTR). Moreover, PUM2 competitively bound to RBM5 3UTR with miR-28-5p. Rescue experiments showed that RBM5 knockdown reversed the anti-tumor effects mediated by PUM2 knockdown in T-ALL cells. PUM2 plays as a novel oncogenic RBP in T-ALL by competitively binding to RBM5 mRNA with miR-28-5p.

Prognostic impact of total body irradiation dose in pediatric acute lymphoblastic leukemia patients treated with allogeneic hematopoietic stem cell transplantation in second complete remission.

Allogeneic HSCT may improve survival in pediatric ALL patients who relapse. In this study, we analyzed the outcome and prognostic factors of 62 ALL patients (35 male, 56.5%) who received allogeneic HSCT in second complete remission (CR) at our institution between April 1st 2009 and December 31st 2019. The median time from diagnosis to relapse was 35.1 months (range, 6.0‒113.6 mo). Fifty-three patients (85.5%) experienced bone marrow relapse only. The number of patients who received transplant according to each donor type was as follows HLA matched family donor 17 (27.4%), matched unrelated donor (UD) 22 (35.5%), mismatched donor 23 (37.1%). All patients received HSCT with a myeloablative conditioning, 58 patients (93.5%) with the incorporation of TBI 31 patients 12 Gray (Gy), 24 patients 13.2 Gy, 3 patients 8 Gy. The 5-year event-free survival (EFS), and overall survival of the study group was 41.3±6.3% (2662), and 42.3±6.6% (2762), respectively. The cumulative incidence of relapse and transplant-related mortality was 57.1±6.4% and 1.6±1.6%, respectively. Infant ALL, shorter time from diagnosis to relapse, and TBI dose of 12 Gy, rather than 13.2 Gy, resulted in significantly worse EFS. In multivariate analysis, infant ALL and TBI dose of 12 Gy during conditioning predicted significantly lower EFS. In our study group, treatment with a higher dose of TBI during conditioning resulted in better EFS for ALL patients who underwent HSCT in second CR. Further study is needed to determine potential long-term complications associated with a higher TBI dose.

CXCR4 antagonists disrupt leukaemia-meningeal cell adhesion and attenuate chemoresistance.

The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge. Developing novel and more effective CNS-directed therapies has been hampered, in part, by our limited understanding of the leukaemia niche in the CNS relative to the bone marrow. Accordingly, defining the molecular and cellular components critical for the establishment and maintenance of the CNS leukaemia niche may lead to new therapeutic opportunities. In prior work we showed that direct intercellular interactions between leukaemia and meningeal cells enhance leukaemia chemoresistance in the CNS. Herein, we show that the CXCR4CXCL12 chemokine axis contributes to leukaemia-meningeal cell adhesion. Importantly, clinically tested CXCR4 antagonists, which are likely to cross the blood-brain and blood-cerebral spinal fluid barriers and penetrate the CNS, effectively disrupted leukaemia-meningeal cell adhesion. Moreover, by disrupting these intercellular interactions, CXCR4 antagonists attenuated leukaemia chemoresistance in leukaemia-meningeal cell co-culture experiments and enhanced the efficacy of cytarabine in targeting leukaemia cells in the meninges in vivo. This work identifies the CXCR4CXCL12 axis as an important regulator of intercellular interactions within the CNS leukaemia niche and supports further testing of the therapeutic efficacy of CXCR4 antagonists in overcoming CNS niche-mediated chemoresistance.

Association between high-dose methotrexate-induced toxicity and polymorphisms within methotrexate pathway genes in acute lymphoblastic leukemia.

Methotrexate (MTX) is a folic acid antagonist, the mechanism of action is to inhibit DNA synthesis, repair and cell proliferation by decreasing the activities of several folate-dependent enzymes. It is widely used as a chemotherapy drug for children and adults with malignant tumors. High-dose methotrexate (HD-MTX) is an effective treatment for extramedullary infiltration and systemic consolidation in children with acute lymphoblastic leukemia (ALL). However, significant toxicity results in most patients treated with HD-MTX, which limits its use. HD-MTX-induced toxicity is heterogeneous, and this heterogeneity may be related to gene polymorphisms in related enzymes of the MTX intracellular metabolic pathway. To gain a deeper understanding of the differences in toxicity induced by HD-MTX in individuals, the present review examines the correlation between HD-MTX-induced toxicity and the gene polymorphisms of related enzymes in the MTX metabolic pathway in ALL. In this review, we conclude that only the association of SLCO1B1 and ARID5B gene polymorphisms with plasma levels of MTX and MTX-related toxicity is clearly described. These results suggest that SLCO1B1 and ARID5B gene polymorphisms should be evaluated before HD-MTX treatment. In addition, considering factors such as age and race, the other exact predictor of MTX induced toxicity in ALL needs to be further determined.

Single-cell profiling of T cells uncovers a tissue-resident memory-like T-cell subset associated with bidirectional prognosis for B-cell acute lymphoblastic leukemia.

The character and composition of leukemia-related T cells are closely related to the treatment response and prognosis for patients. Though B cell-acute lymphoblastic leukemia (B-ALL) patients have benefited from immune-based approaches, such as chimeric antigen receptor T cells therapy, some of them still end with poor prognosis, especially for adult patients. Therefore, deep understanding of the developmental relationship between T cell subtypes in relation to B-ALL patient prognosis is urgently needed. We analyzed the peripheral blood T cell single-cell RNA sequencing data of three B-ALL patients, using data from 11 healthy individuals as controls. In total, 16,143 and 53,701 T cells from B-ALL patients and healthy adults, respectively, were objectively analyzed for detailed delineation of 13 distinct T cell clusters. Cluster-specific genes were used as marker genes to annotate each T cell subtype. Unbiased analysis enabled the discovery of circulating CD103 T cell (CD3CD103MKI67), also defined as tissue-resident memory-like T (Trm-like) cell, populations were elevated in B-ALL patients, which expressed high level of cell proliferation and exhaustion related genes. In addition, cell fate trajectory analysis showed these Trm-like cells, which shared T-cell receptor (TCR) clonotypes with exhausted T (Tex) cells and effector T (Teff) cells, were supposed to transition into Teff cells however, mainly transformed into Tex cells in leukemia environment. More importantly, Trm-like cells transformation into Teff cells and Tex cells potentially led to favorable or poor prognosis for B-ALL patients, respectively. In sum, a circulating Trm-like cell subset with high level expression of cell proliferation and exhaustion related genes was elevated in B-ALL patients. The bidirectional developmental potential of these T cells into Teff or Tex is closely associated with favorable or poor prognosis, respectively. Together, our study provided a unique insight of alteration of leukemia related T cells, also showed a potential immunotherapy direction and prognosis assessment model for B-ALL patients.

Triple-hit explanation for the worse prognosis of pediatric acute lymphoblastic leukemia among Mexican and Hispanic children.

Acute lymphoblastic leukemia (ALL) is the most common malignancy among Mexican and Hispanic children and the first cause of death by disease in Mexico. We propose a triple-hit explanation for the survival gap affecting this population. The first hit can be attributed to epidemiology and social, cultural, and economic burdens. The second hit refers to cancer biology, with a high incidence of unfavorable genetic characteristics associated with an unfavorable response to treatment and, subsequently, poor survival. Finally, the third hit relates to sub-optimal treatment and support. Society and culture, leukemia biology, and treatment approach limitations are key factors that should not be seen apart and must be considered comprehensively in any strategy to improve the prognosis of Mexican and Hispanic children with ALL.

Glutathione levels are associated with methotrexate resistance in acute lymphoblastic leukemia cell lines.

Methotrexate (MTX), a folic acid antagonist and nucleotide synthesis inhibitor, is a cornerstone drug used against acute lymphoblastic leukemia (ALL), but its mechanism of action and resistance continues to be unraveled even after decades of clinical use. To better understand the mechanisms of this drug, we accessed the intracellular metabolic content of 13 ALL cell lines treated with MTX by 1H-NMR, and correlated metabolome data with cell proliferation and gene expression. Further, we validated these findings by inhibiting the cellular antioxidant system of the cells in vitro and in vivo in the presence of MTX. MTX altered the concentration of 31 out of 70 metabolites analyzed, suggesting inhibition of the glycine cleavage system, the pentose phosphate pathway, purine and pyrimidine synthesis, phospholipid metabolism, and bile acid uptake. We found that glutathione (GSH) levels were associated with MTX resistance in both treated and untreated cells, suggesting a new constitutive metabolic-based mechanism of resistance to the drug. Gene expression analyses showed that eight genes involved in GSH metabolism were correlated to GSH concentrations, 2 of which (gamma-glutamyltransferase 1 GGT1 and thioredoxin reductase 3 TXNRD3) were also correlated to MTX resistance. Gene set enrichment analysis (GSEA) confirmed the association between GSH metabolism and MTX resistance. Pharmacological inhibition or stimulation of the main antioxidant systems of the cell, GSH and thioredoxin, confirmed their importance in MTX resistance. Arsenic trioxide (ATO), a thioredoxin inhibitor used against acute promyelocytic leukemia, potentiated MTX cytotoxicity in vitro in some of the ALL cell lines tested. Likewise, the ATOMTX combination decreased tumor burden and extended the survival of NOD scid gamma (NSG) mice transplanted with patient-derived ALL xenograft, but only in one of four ALLs tested. Altogether, our results show that the cellular antioxidant defense systems contribute to leukemia resistance to MTX, and targeting these pathways, especially the thioredoxin antioxidant system, may be a promising strategy for resensitizing ALL to MTX.

Label-free testing strategy to evaluate packed red blood cell quality before transfusion to leukemia patients.

Patients worldwide require therapeutic transfusions of packed red blood cells (pRBCs), which is applied to the high-risk patients who need periodic transfusions due to leukemia, lymphoma, myeloma and other blood diseases or disorders. Contrary to the general hospital population where the transfusions are carried out mainly for healthy trauma patients, in case of high-risk patients the proper quality of pRBCs is crucial. This leads to an increased demand for efficient technology providing information on the pRBCs alterations deteriorating their quality. Here we present the design of an innovative, label-free, noninvasive, rapid Raman spectroscopy-based method for pRBCs quality evaluation, starting with the description of sample measurement and data analysis, through correlation of spectroscopic results with reference techniques outcomes, and finishing with methodology verification and its application in clinical conditions. We have shown that Raman spectra collected from the pRBCs supernatant mixture with a proper chemometric analysis conducted for a minimum one ratio of integral intensities of the chosen Raman marker bands within the spectrum allow evaluation of the pRBC quality in a rapid, noninvasive, and free-label manner, without unsealing the pRBCs bag. Subsequently, spectroscopic data were compared with predefined reference values, either from pRBCs expiration or those defining the pRBCs quality, allowing to assess their utility for transfusion to patients with acute myeloid leukemia (AML) and lymphoblastic leukemia (ALL).

The Interplay of Cesarean-Section Delivery and First-Birth Order as Risk Factors in Acute Lymphoblastic Leukemia.

Childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been associated with early-life exposures, including birth by cesarean section (C-section), and a deficit of social exposure (first child). These exposures as proxies for microbiome acquisition in infancy are essential to prime the immune system and restrain later dysregulated immune responses that can trigger ALL in susceptible individuals. We tested risk factors pertaining to immune stimulation that may impact BCP-ALL development. Cases comprised 1,126 children (0-12 years) with ALL (BCP-ALL 78.5%) from the EMiLI study group in Brazil (2002-2020). Age- and sex-matched controls (n 2,252) were randomly selected from healthy children whose mothers participated in the National Placental and Umbilical Cord Blood Bank donation. Multiple logistic regression was run fitted and adjusted for selected covariates models. C-section delivery was associated with increased risk for ALL odds ratio (OR) ALL 1.10 95% confidence intervals (CI), 1.04-1.15 ORBCP-ALL 1.09 95% CI, 1.03-1.14, as well as being the firstborn child. Interaction analysis showed a significant effect of first birth on the observed C-section associations (P < 0.0001). Indeed, high-risk children, namely, firstborn children delivered via C-section were at increased risk for ALL (OR 2.33 95% CI, 2.40-4.84) compared with non-first, vaginally born children. An increased risk was found for firstborn children delivered by C-section and non-breastfed with ALL (ORALL 2.32 95% CI, 1.27-4.24 ORBCP-ALL 2.37 95% CI, 1.18-4.76). Our observations are in accord with the prediction that exposures determining microbiome composition and adrenal pathway in infancy contribute to the risk of BCP-ALL. These findings encourage the exploration of potential preventive interventions. See related commentary by Wiemels and Gallant, p. 292.

Chimeric antigen receptor T-cell therapy for T-ALL and AML.

Non-B-cell acute leukemia is a term that encompasses T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Currently, the therapeutic effectiveness of existing treatments for refractory or relapsed (RR) non-B-cell acute leukemia is limited. In such situations, chimeric antigen receptor (CAR)-T cell therapy may be a promising approach to treat non-B-cell acute leukemia, given its promising results in B-cell acute lymphoblastic leukemia (B-ALL). Nevertheless, fratricide, malignant contamination, T cell aplasia for T-ALL, and specific antigen selection and complex microenvironment for AML remain significant challenges in the implementation of CAR-T therapy for T-ALL and AML patients in the clinic. Therefore, designs of CAR-T cells targeting CD5 and CD7 for T-ALL and CD123, CD33, and CLL1 for AML show promising efficacy and safety profiles in clinical trials. In this review, we summarize the characteristics of non-B-cell acute leukemia, the development of CARs, the CAR targets, and their efficacy for treating non-B-cell acute leukemia.

Antibiotic prophylaxis in acute childhood leukemia What is known so far

The treatment of acute lymphoblastic leukemia (ALL) has evolved in recent decades, reaching an overall survival rate close to 90%. Currently, approximately 4% of patients with ALL die from secondary complications of chemotherapy. Among these complications, the most frequent is febrile neutropenia (FN). The treatment of acute myeloid leukemias (AMLs) is even more aggressive, being consequently related to a considerable amount of treatment-related toxicity with a high risk of severe infection and death. In order to reduce the infection-related risks in these groups of patients, systemic antibacterial prophylaxis has emerged as a possible approach. Antibiotic prophylaxis during neutropenia periods in those undergoing chemotherapy have .already been proven in adults with acute leukemias (ALs). Among the possible available therapeutic options for bacterial prophylaxis in children with cancer, fluoroquinolones emerged with the most amount of evidence. Within this class, levofloxacin became the best choice. Therefore, the use of levofloxacin seems to be indicated in very specific situations in children who are known to be neutropenic for a long time, secondary to intensive chemotherapy in children with AL undergoing chemotherapy to induce remission or in children undergoing hematopoietic stem cell transplantation (HSCT). This article aims to describe recent evidence focusing on antibiotic prophylaxis in children with ALs.

Malignant hypercalcemia as the debut of acute lymphoblastic leukemia in a pediatric patient-a diagnostic and therapeutic approach Case report.

Hypercalcemia is a rare metabolic disorder in the pediatric population, with several differential diagnoses that resemble hematologic malignancies. In cases of severe hypercalcemia, therapeutic strategies other than hyperhydration, such as the use of bisphosphonates, have been described. We present the case of a previously healthy 12-year-old boy who was admitted to the emergency department due to fatigue, hypo-responsiveness, and progressively worsening poor appetite for the previous 19 days. Initial laboratory tests revealed severe hypercalcemia (total calcium 19 mgdl), hyperphosphatemia, elevated creatinine, and hyperuricemia. Management with hyperhydration and xanthine oxidase inhibitor (allopurinol) was provided. The patient was transferred to the pediatric intensive care unit where treatment with furosemide, systemic corticosteroid, and zoledronic acid was started. Metabolic, infectious, renal, and endocrinological causes were excluded. Follow-up paraclinical studies showed a progressive hematologic involvement with heterogeneous hypochromic microcytic anemia, thrombocytopenia, and elevated lactic dehydrogenase. Bone marrow aspiration and biopsy were performed, which confirmed the diagnosis of B-precursor acute lymphoblastic leukemia. Hypercalcemia was resolved 72 h after the application of bisphosphonates. Hypercalcemia as an oncological metabolic emergency in the onset of acute lymphoblastic leukemia is uncommon in children. The use of intravenous bisphosphonates is an effective therapy in the early resolution of the condition. We present the case of a 12-year-old patient with malignant hypercalcemia who responded favorably to the use of a single dose of bisphosphonates.

Comprehensive view on genetic features, therapeutic modalities and prognostic models in adult T-cell lymphoblastic lymphoma.

Adult T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive subtype of non-Hodgkins lymphoma that differs from pediatric T-LBL and has a worse prognosis. Due to its rarity, little is known about the genetic and molecular characteristics, optimal treatment modalities, and prognostic factors of adult T-LBL. Therefore, we summarized the existing studies to comprehensively discuss the above issues in this review. Genetic mutations of

A typical bedside-to-bench investigation of leukemogenic driver MEF2D fusion reveals new targeted therapy in B-cell acute lymphoblastic leukemia.

B-cell acute lymphoblastic leukemia (B-ALL) is a malignant tumor originating from B-lineage lymphoid precursor cells. The incidence of B-ALL is about 80% in childhood acute leukemia and 20% in adults. In recent years, with standardized treatment guided by risk stratification, the long-term disease-free survival rate of children is about 80%, while that of adults is less than 40%. However, the specific pathogenesis of the newly identified B-ALL and the targeted therapy strategies have not been vigorously investigated. In this review, we highlight the recent breakthroughs in mechanistic studies and novel therapeutic options in DUX4- and MEF2D-subtype B-ALLs.

A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1.

A significant proportion of infant B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene expression, gene fusions, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 87 fusions with significant allele frequency across patients and shared functional impacts, suggesting common mechanisms across fusions. We further identified a gene expression signature that predicts high risk independently of the gene fusion background and includes the upregulation of the splicing factor

Costs associated with adverse events from remission induction for children with Acute Lymphoblastic Leukemia (ALL).

ALL is the most frequent hematological tumor in children, so during remission induction chemotherapy protocol (RICP) adverse events (AEs) may appear. The public program in Mexico in charge of financial support to oncologic children without social security delivered a fix amount for ALL chemotherapy, but additional money needed to treat any other unexpected condition should be taken from the budget of the oncologic healthcare providers. So the purpose of our study was to estimate and evaluate the direct medical costs associated to EAs during RICP in children with ALL. This study was retrospective, longitudinal, and observational based on medical records review of patients in RICP. The CTCAE was used to identify and classify AEs according to a SOC category. We focused on extracting resources data that were consumed both for inpatients and outpatients AEs. A micro-costing approach was adopted which involve quantification of each healthcare resource consumed by the hospital multiplying them by unit cost. The probability distributions of data were evaluated to identify the appropriated statistical tests to be used for comparisons between groups that were performed with Wilcoxon rank sum test. Generalized linear models (GLM) were adjusted to evaluate the effects of patient characteristics on total cost. Forty patients accumulated 204 inpatient and 81 outpatient AEs during RICP. Comparison of total costs between groups showed an incremental cost of $7,460.23 likewise attributable to AEs. The total cost of a pediatric patient undergoing RICP without adverse events was $3,078.36 and the total cost of a patient with AEs exceeds it threefold. The costs associated with AEs during RICP in Mexican children with ALL representing a high burden for the healthcare provider. Generalized linear models showed that variables such as sex, risk category and alive status are associated with the total costs of AEs. This is the first study aiming to analyze the effect of ALL-related AEs on health care costs in pediatric population, so our results may help not only to local decision making but also it may contribute to the research agenda in this field.

MicroRNA composition of plasma extracellular vesicles a harbinger of late cardiotoxicity of doxorubicin.

The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies. We have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 acute lymphoblastic leukemia (ALL) survivors and 61 healthy controls (254 samples in total). We then analyzed processes regulated by differentially expressed circulating miRNAs and cross-validated results with the data of patients with clinically manifested cardiomyopathies. We found that especially miRNAs contained within EVs may be informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin signaling, transforming growth factor beta (TGFβ) or epidermal growth factor receptors (ErbB). We identified vesicular miR-144-3p and miR-423-3p as the most variable between groups and significantly correlated with echocardiographic parameters and, respectively, for plasma let-7g-5p and miR-16-2-3p. Moreover, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is differentially expressed in the circulation of patients with dilated cardiomyopathy. We also found that distribution of particular miRNAs between of plasma and EVs (proportion between compartments) e.g., miR-184 in ALL, is altered, suggesting changes within secretory and miRNA sorting mechanisms. Our results show that transcriptomic changes resulting from doxorubicin induced myocardial injury are reflected in circulating miRNA levels and precede development of the late onset cardiomyopathy phenotype. Among miRNAs related to cardiac function, we found vesicular miR-144-3p and miR-423-3p, as well as let-7g-5p and miR-16-2-3p contained in the total plasma. Selection of source for such studies (plasma or EVs) is of critical importance, as distribution of some miRNA between plasma and EVs is altered in ALL survivors, in comparison to healthy people, which suggests that doxorubicin-induced changes include miRNA sorting and export to extracellular space.

FIP1L1-PDGFRA fusion gene in T-lymphoblastic lymphoma A case report.

T-lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of T-lymphoid precursors, rarely co-occurring with myeloidlymphoid neoplasms with eosinophilia (MLNs-Eo), with consequent rearrangement of tyrosine kinase (TK)-related genes. The FIP1L1-PDGFRA fusion gene is the most frequent molecular abnormality seen in eosinophilia-associated myeloproliferative disorders, but is also present in acute myeloid leukemia (AML), T-lymphoblastic leukemialymphoma (TLL), or both simultaneously. T-LBL mainly affects children and young adults, involving lymph node, bone marrow, and thymus. It represents about 85% of all immature lymphoblastic lymphomas, whereas immature B-cell lymphomas comprise approximately 15% of all cases of LBL. In this case report, we present an example of T cell lymphoblastic lymphoma with coexistent eosinophelia, treated successfully with a tyrosine-kinase inhibitor (TKI). FIP1L1-PDGFRA-positive T-LBL and myeloproliferative disorders have excellent response to low-dose treatment with (TKI) imatinib. Most patients achieve rapid and complete hematologic and molecular remission within weeks.

Measurable residual disease in acute lymphoblastic leukemia How low is low enough

Quantification of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) is a well-established clinical tool used to risk stratify patients during the course of chemotherapy, immunotherapy, andor transplant therapy. As technologies evolve, the sensitivity for quantifying exceptionally low disease burden using either next generation sequencing (NGS) or next generation flow cytometry (NGF) has improved. It is now possible to detect MRD and quantify it precisely in patients who would previously have been deemed MRD negative by older, lower sensitivity methods. Persistence or recurrence of ALL disease burden above 10

Recent progress in acute leukemia and myelodysplasia.

The advances and progress in the understanding and management of acute leukemia and myelodysplasia continue to occur at an exponential rate. While this has led to more therapy options, clinicians and researchers are now facing more challenges in terms of clinical decision-making and more unanswered questions. This paper has outlined some conundrums in acute leukemia and myelodysplasia, and the efforts that are underway to address these.

Should all CAR-T therapy for acute lymphoblastic leukemia Be consolidated with allogeneic stem cell transplant

Autologous T cells genetically modified with a CD19 chimeric antigen receptor are an effective therapy for children and adults with relapsed or refractory acute lymphoblastic leukemia with initial response rates ranging from 70 to 85%. Unfortunately, about half of these responding patients will subsequently relapse raising the question of whether allogeneic hemopoietic stem cell transplant should be considered as a consolidative therapy. Currently efforts are focused on defining risk factors for relapse to try and develop algorithms predicting which patients may benefit from allogenic transplant.

When will chemotherapy be replaced in upfront induction therapy for adult acute lymphoblastic leukemia (ALL)

The treatment of acute lymphoblastic leukemia (ALL) has changed significantly over the last decade. With the approval of novel antibody based therapies in the relapsedrefractory setting, many of these agents are starting to be used in the upfront setting in clinical trials for older patients. These results have been impressive, and further trials are underway. Other targeted therapies (i.e. BCL inhibitors) are being explored. This article will discuss the incorporation of novel agents to replace chemotherapy in induction.

What are the long-term complications of pediatric ALL treatments and how can they be mitigated Perspectives on long-term consequences of curative treatment in childhood ALL.

Despite cure rates approaching 100% for some subsets of patients, survivors of childhood acute lymphoblastic leukemia (ALL) report a multitude of short- and long-term side effects. Indeed, the long-term complications of pediatric ALL treatment regimens can be associated with significant morbidity and mortality. Identifying mitigation strategies and developing more effective, less toxic therapies is a central goal of current research.

Quantifying imbalanced classification methods for leukemia detection.

Uncontrolled proliferation of B-lymphoblast cells is a common characterization of Acute Lymphoblastic Leukemia (ALL). B-lymphoblasts are found in large numbers in peripheral blood in malignant cases. Early detection of the cell in bone marrow is essential as the disease progresses rapidly if left untreated. However, automated classification of the cell is challenging, owing to its fine-grained variability with B-lymphoid precursor cells and imbalanced data points. Deep learning algorithms demonstrate potential for such fine-grained classification as well as suffer from the imbalanced class problem. In this paper, we explore different deep learning-based State-Of-The-Art (SOTA) approaches to tackle imbalanced classification problems. Our experiment includes input, GAN (Generative Adversarial Networks), and loss-based methods to mitigate the issue of imbalanced class on the challenging C-NMC and ALLIDB-2 dataset for leukemia detection. We have shown empirical evidence that loss-based methods outperform GAN-based and input-based methods in imbalanced classification scenarios.

PAX5 epigenetically orchestrates CD58 transcription and modulates blinatumomab response in acute lymphoblastic leukemia.

Blinatumomab is an efficacious immunotherapeutic agent in B cell acute lymphoblastic leukemia (B-ALL). However, the pharmacogenomic basis of leukemia response to blinatumomab is unclear. Using genome-wide CRISPR, we comprehensively identified leukemia intrinsic factors of blinatumomab sensitivity, i.e., the loss of

Evaluation of cell collection efficiency in non-mobilized adult donors for autologous chimeric antigen receptor T-cell manufacturing.

Data about collection efficiency 1 (CE1), which takes into account blood cell counts before and after collection, thus providing a more accurate estimate, in the collection of autologous T lymphocytes by apheresis for chimeric antigen receptor (CAR) T-cells remain scarce. We evaluated donor- and procedure-related characteristics that might influence the CE1 of lymphocytes. We retrospectively reviewed all mononuclear cell (MNC) collections) performed for CAR T-cell manufacturing in our institution from May 2017 to June 2021 in adult patients. Age, gender, weight, total blood volume (TBV), prior haematopoietic cell transplant, diagnosis, days between last treatment and apheresis, pre-collection cell counts, duration of apheresis, TBV processed, vascular access, inlet flow and device type were analysed as potential factors affecting CE1 of lymphocytes. A total of 127 autologous MNC collections were performed on 118 patients diagnosed with acute lymphoblastic leukaemia (n 53, 45%), non-Hodgkin lymphoma (n 40, 34%), multiple myeloma (n 19, 16%), and chronic lymphocytic leukaemia (n 6, 5%). The median CE1 of lymphocytes was 47% (interquartile range 32%-65%). In multiple regression analysis, Amicus device was associated with higher CE1 of lymphocytes (p 0.01) and lower CE1 of platelets (p < 0.01) when compared with Optia device. The knowledge of the MNC and lymphocyte CE1 of each apheresis device used to collect cells for CAR T therapy, together with the goal of the number of cells required, is essential to define the volume to be processed and to ensure the success of the collection.

Vena caval filters remain as a useful tool in patients with deep vein thrombosis and contraindications to anticoagulation. Although they are rarely used in paediatric patients, they have been shown to be safe and effective when used in the inferior vena cava.In this case report, we describe the

Accounting for treatment during the development or validation of prediction models.

Clinical prediction models are widely used to predict adverse outcomes in patients, and are often employed to guide clinical decision-making. Clinical data typically consist of patients who received different treatments. Many prediction modeling studies fail to account for differences in patient treatment appropriately, which results in the development of prediction models that show poor accuracy and generalizability. In this paper, we list the most common methods used to handle patient treatments and discuss certain caveats associated with each method. We believe that proper handling of differences in patient treatment is crucial for the development of accurate and generalizable models. As different treatment strategies are employed for different diseases, the best approach to properly handle differences in patient treatment is specific to each individual situation. We use the Ma-Spore acute lymphoblastic leukemia data set as a case study to demonstrate the complexities associated with differences in patient treatment, and offer suggestions on incorporating treatment information during evaluation of prediction models. In clinical data, patients are typically treated on a case by case basis, with unique cases occurring more frequently than expected. Hence, there are many subtleties to consider during the analysis and evaluation of clinical prediction models.

Trends of Vancomycin-Resistant Enterococcus Infections in Cancer Patients.

Objective Vancomycin-resistant

Fatigue trajectories during pediatric ALL therapy are associated with fatigue after treatment a national longitudinal cohort study.

Fatigue is one of the most prevalent and distressing symptoms reported by survivors of childhood cancer. There is currently a lack of longitudinal studies on cancer-related fatigue, and especially on the relationship between the course of fatigue during treatment and fatigue at follow-up. The purpose of the current study was therefore to investigate if the course of fatigue during treatment, treatment intensity, serious adverse events, sex, or age at diagnosis are associated with cancer-related fatigue after treatment. Participants were 92 children and adolescents diagnosed with acute lymphoblastic leukemia (mean age at diagnosis was 6.26 years). Fatigue was measured with PedsQL multidimensional fatigue scale proxy reports 5 months after diagnosis, 12 months after diagnosis, 24 months after diagnosis, and at follow-up 12 months after end of treatment. The effect of patient and treatment characteristics on fatigue reported at follow-up was tested through logistic regression analyses. The course of fatigue during treatment significantly predicted fatigue reported at follow-up for general fatigue (p .038, OR 9.20), sleeprest fatigue (p .011, OR 15.48), and cognitive fatigue (p < .001, OR 10.78). None of the other variables were associated with fatigue at follow-up for any of the subscales. The findings demonstrate that fatigue reported during treatment can predict fatigue at follow-up. These results stress the need for longitudinal assessments. Healthcare professionals need to be aware that pediatric patients who are fatigued during treatment need to receive additional attention and timely interventions since cancer-related fatigue will not resolve by itself in the first year after end of treatment.

Novel coronavirus infection (COVID-19) in a 12-year-old boy with acute lymphoblastic leukemia.

Pediatric acute lymphoblastic leukemia (ALL) with COVID-19 might still have a risk of severe infection due to immunocompromised condition. The clinical features in oncology population are quite similar to those of previous reports in general pediatric cases. Chemotherapy should be arranged individually to balance the risk between leukemia progressivity itself and COVID-19 complications. Interruptions of therapy must be thought in cases with severe or symptomatic infection of severe acute respiratory syndrome-CoV-2. In this case report, chemotherapy will be started 1 week after the improvement of general condition. Chemotherapy should not be postponed for >14 days.

Transformation of diffuse large B-cell lymphoma to lymphoblastic lymphoma.

Transformations in diffuse large B-cell lymphoma (DLBCL) are extremely rare. Here, we are presenting a very rare case of DLBCL transforming into lymphoblastic lymphoma (LBL) diagnosed by fine-needle aspiration cytology (FNAC) and flow cytometry. A 31-year old male on antiretroviral therapy and a known case of diffuse large B-cell lymphoma diagnosed 1 year back on cervical lymphadenopathy, presented with left axillary swelling for 3 months. FNAC and Flow cytometry were performed from the left axillary swelling which confirmed the diagnosis of LBL.

Semisynthetic aurones A14 protects against T-cell acute lymphoblastic leukemia via suppressing proliferation and inducing cell cycle arrest with apoptosis.

Acute lymphoblastic leukemia is an aggressive neoplasm and seriously threatens human health. A14 is one kind of semisynthetic aurone that exhibits the capability to inhibit prostate cancer, but little is known about the role of A14 on T-cell acute lymphoblastic leukemia. Firstly, the effects of A14 on the ability of leukemia cells to proliferate were measured by Vi-cell counter. Then, we detected the cell cycle and apoptosis by flow cytometry and characterized the related protein expression using immunoblotting. In addition, we constructed stable luciferase expressing cell lines for use in a cell derived xenograft mouse model to measure the effect of A14 on T-cell acute lymphoblastic leukemia. Results exhibited that A14 markedly suppressed cell proliferation and induced G2M phase arrest along with cell cycles regulating proteins changes. A14 led to apoptosis in leukemia cells, at least partly, through the cytochrome c signaling pathway. Experiments in cell derived xenograft mouse model also showed that A14 markedly ameliorated the survival rate. The present study revealed that semisynthetic aurones A14 can effectively protect against T-cell acute lymphoblastic leukemia progression both in vitro and in vivo, indicating the capability of A14 as a promising drug for the treatment of T-cell acute lymphoblastic leukemia.

Central Nervous System Prophylaxis and Treatment in Acute Leukemias.

Improvements in systemic therapy in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) have improved patient outcomes and reduced the incidence of CNS relapse. However, management of patients with CNS disease remains challenging, and relapses in the CNS can be difficult to salvage. In addition to treatment with CNS-penetrant systemic therapy (high-dose methotrexate and cytarabine), intrathecal prophylaxis is indicated in all patients with ALL, however is not uniformly administered in patients with AML without high-risk features. There is a limited role for radiation treatment in CNS prophylaxis however, radiation should be considered for consolidative treatment in patients with CNS disease, or as an option for palliation of symptoms. Re-examining the role of established treatment paradigms and investigating the role of radiation as bridging therapy in the era of cellular therapy, particularly in chemotherapy refractory patients, is warranted.

Invasive fungal diseases impact on outcome of childhood ALL - an analysis of the international trial AIEOP-BFM ALL 2009.

In children with acute lymphoblastic leukemia (ALL), risk groups for invasive fungal disease (IFD) with need for antifungal prophylaxis are not well characterized, and with the advent of new antifungal compounds, current data on outcome are scarce. Prospectively captured serious adverse event reports of children enrolled in the international, multi-center clinical trial AIEOP-BFM ALL2009 were screened for provenprobable IFD, defined according to the updated EORTCMSG consensus definitions. In a total of 6136 children (median age 5.2 years), 224 provenprobable IFDs (65 yeast and 159 mold) were reported. By logistic regression, the risk for provenprobable IFDs was significantly increased in children ≥12 years and those with a blast count ≥10% in the bone marrow on day 15 (P < 0.0001 each). Provenprobable IFDs had a 6-week and 12-week mortality of 10.7% and 11.2%, respectively. In the multivariate analysis, the hazard ratio for event-free and overall survival was significantly increased for provenprobable IFD, age ≥12 years, and insufficient response to therapy (P < 0.001, each). Our data define older children with ALL and those with insufficient treatment-response at high risk for IFD. As we show that IFD is an independent risk factor for event-free and overall survival, these patients may benefit from targeted antifungal prophylaxis.

Association of Minimal Residual Disease by a Single-Tube 8-Color Flow Cytometric Analysis With Clinical Outcome in Adult B-Cell Acute Lymphoblastic Leukemia.

Minimalmeasurable residual disease (MRD) measured by molecular and multiparametric flow cytometry (MFC) has been proven to be predictive of relapse and survival in patients with B-cell acute lymphoblastic leukemia (B-ALL). A universally applicable antibody panel at a low cost but without compromising sensitivity and power of prognosis prediction in adult B-ALL remains unestablished. To report our experience of using a single-tube 8-color MFC panel to measure the MRD status as a prognostic indicator in adult B-ALL patients. We retrospectively analyzed the characteristics, MRD status, and prognosis of adult B-ALL based on a large real-world cohort of 486 patients during a 10-year period. MRD assessed by MFC and polymerase chain reaction (PCR) assays for BCR-ABL patients showed concordant results in 74.2% of cases. MRD- status by our MFC panel could clearly predict a favorable relapse-free survival (RFS) and overall survival (OS) both at the end of induction and at the end of 1 consolidation course. Patients with continuous MRD- and with at least 1 MRD- result showed a favorable RFS and OS compared with those with at least 1 MRD result and continuous MRD, respectively. The single-tube 8-color MFC panel demonstrated a low cost, decent sensitivity, and comparability with polymerase chain reaction-MRD but an excellent performance in predicting RFS and OS, and thus could potentially be taken as a routine indicator in the evaluation of the treatment response for adult patients with B-ALL.

Nelarabine Combination Therapy for Relapsed or Refractory T-cell Acute Lymphoblastic LymphomaLeukemia.

Nelarabine, an anti-metabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (RR T-ALLLBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with RR T-ALLLBL 29 were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69) with 18 children (< 18 years) included. After a median of 1 (range 1-3) cycle of treatment, 24 patients (55%) achieved CR 62% with combination therapy and 40% with monotherapy (p 0.21). Most responders (21, 88%) pursued allogeneic stem cell transplant (alloSCT). Overall survival (OS) was 12.8 months (CI 95% 6.93-not reached) in the entire cohort and was higher in the combination therapy vs. monotherapy group (24-month OS 53% vs. 8%, p 0.003). The rate of neurotoxicity was similar between groups (27% vs. 17%, p 0.46) while grade IIIIV anemia and thrombocytopenia were more frequent in the combination group (76 vs. 20%, p<0.001 and 66% vs. 27%, p 0.014, respectively). In a multivariable analysis, nelarabine combination therapy and alloSCT post nelarabine were associated with improved OS (HR 0.41, p 0.04 and HR 0.25, p 0.008). In conclusion, compared to monotherapy, nelarabine combination therapy was well tolerated and associated with improved survival in pediatric and adult patients with RR T-ALLLBL.

Enhancing CD19 Chimeric Antigen Receptor T Cells Through Memory-Enriched T Cells.

Chimeric antigen receptor T (CAR-T) cells directed against CD19 have transformed the therapy of relapsedrefractory B-cell acute lymphoblastic leukemia (RR B-ALL). A recent study reports promising activity and safety of CD19 CAR-T cells generated from naïve, stem, and central memory T cells in adults with RR B-ALL. See related article by Aldoss et al., p. 742.

An efficient computer vision-based approach for acute lymphoblastic leukemia prediction.

Leukemia (blood cancer) diseases arise when the number of White blood cells (WBCs) is imbalanced in the human body. When the bone marrow produces many immature WBCs that kill healthy cells, acute lymphocytic leukemia (ALL) impacts people of all ages. Thus, timely predicting this disease can increase the chance of survival, and the patient can get his therapy early. Manual prediction is very expensive and time-consuming. Therefore, automated prediction techniques are essential. In this research, we propose an ensemble automated prediction approach that uses four machine learning algorithms K-Nearest Neighbor (KNN), Support Vector Machine (SVM), Random Forest (RF), and Naive Bayes (NB). The C-NMC leukemia dataset is used from the Kaggle repository to predict leukemia. Dataset is divided into two classes cancer and healthy cells. We perform data preprocessing steps, such as the first images being cropped using minimum and maximum points. Feature extraction is performed to extract the feature using pre-trained Convolutional Neural Network-based Deep Neural Network (DNN) architectures (VGG19, ResNet50, or ResNet101). Data scaling is performed by using the MinMaxScaler normalization technique. Analysis of Variance (ANOVA), Recursive Feature Elimination (RFE), and Random Forest (RF) as feature Selection techniques. Classification machine learning algorithms and ensemble voting are applied to selected features. Results reveal that SVM with 90.0% accuracy outperforms compared to other algorithms.

Anti-CD19 chimeric antigen receptor T-cell followed by interferon-α therapy induces durable complete remission in donor cell-derived acute lymphoblastic leukemia A case report.

Donor cell-derived leukemia (DCL) is a special type of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with DCL generally have a poor prognosis due to resistance to conventional chemotherapy. Here, we report a case of donor cell-derived acute lymphoblastic leukemia after umbilical cord blood transplantation. The patient didnt respond to induction chemotherapy. She then received anti-CD19 CAR-T cell therapy and achieved MRD-negative complete remission (CR). However, MRD levels rose from negative to 0.05% at 5 months after CAR-T cell therapy. Higher MRD levels were significantly associated with an increased risk of leukemia recurrence. Afterward, preemptive interferon-α treatment was administrated to prevent disease recurrence. To date, the patient has maintained MRD-negative CR for 41 months. Our results suggested that anti-CD19 CAR-T cells followed by interferon-α therapy are effective in treating donor cell-derived acute lymphoblastic leukemia. This report provides a novel strategy for the treatment of DCL.

Severe coronavirus HCoV-NL63 pneumonia in a patient receiving blinatumomab with secondary antibody deficiency in COVID-19 times.

Human coronavirus NL63 (HCoV-NL63) is one of four common human respiratory coronaviruses. It causes lower respiratory tract infections in young children, elderly and immunosuppressed people, which could result in fatal outcomes. In this time of pandemic, we want to highlight the importance of other coronaviruses infection besides SARS-CoV-2, especially in a patient with underlying conditions like acute lymphoblastic leukemia, receiving immunosuppressive therapy that could result in humoral secondary immunodeficiencies. We present the case of a 44-year-old Colombian man with acute lymphoblastic leukemia who developed HCoV-NL63 pulmonary infection after the first month of treatment with blinatumomab complicated with severe secondary hypogammaglobulinemia. HCoV-NL63 was detected by multiplex PCR, and HCoV-NL63 viral pneumonia was diagnosed. Hypogammaglobulinemia was studied by determining serum immunoglobulins levels and protein electrophoresis. The treatment consisted of supportive therapy and replacement with intravenous immunoglobulins. After therapy, the patient improved his oxygenation, and the infection was resolved in a few days. This case highlights the relevance of other coronaviruses infections besides SARS-CoV-2 in patients receiving immunosuppressive therapy who develop secondary antibody deficiency, and the importance of replacement therapy with intravenous immunoglobulins at early stage of infection with HCoV-NL63.

How should childhood acute lymphoblastic leukemia relapses in low-income and middle-income countries be managed The AHOPCA-ALL study group experience.

Children with relapsed acute lymphoblastic leukemia (ALL) in low-income and middle-income countries rarely survive. The Pediatric Hematology-Oncology Association of Central America (AHOPCA) developed the AHOPCA-ALL REC 2014 protocol to improve outcomes in resource-constrained settings without access to stem cell transplantation. The AHOPCA-ALL REC 2014 protocol was based on a modified frontline induction phase 1A, a consolidation therapy with six modified R-blocks derived from the ALL-Berlin-Frankfurt-Munster REZ 2002 protocol and intermittent maintenance therapy. Children with B-lineage ALL were eligible after a late medullary relapse, an early or late combined relapse, or any extramedullary relapses. Those with T-lineage ALL were eligible after early and late extramedullary relapses, as were those with both B-lineage and T-lineage relapses occurring at least 3 months after therapy abandonment. The study population included 190 patients with T-lineage (n 3) and B-lineage (n 187) ALL. Of those with B-lineage ALL, 25 patients had a very early extramedullary relapse, 40 had an early relapse (32 extramedullary and 8 combined), and 125 had a late relapse (34 extramedullary, 19 combined, and 72 medullary). The main cause of treatment failure was second relapse (52.1%). The 3-year event-free survival rate (± standard error) was 25.9% ± 3.5%, and the 3-year overall survival rate was 36.7% ± 3.8%. The 3-year event-free survival rate was 47.2% ± 4.7% for late relapses. The most frequently reported toxicity was grade 3 or 4 infection. Mortality during treatment occurred in 17 patients (8.9%), in most cases because of infectious complications. Selected children with relapsed ALL in Central America can be cured with second-line regimens even without access to consolidation with stem cell transplantation. Children in low-income and middle-income countries who have lower risk relapses of ALL should be treated with curative intent.

IL-7 and IL-7R in health and disease An update through COVID times.

The role of IL-7 and IL-7R for normal lymphoid development and an adequately functioning immune system has been recognized for long, with severe immune deficiency and lymphoid leukemia as extreme examples of the consequences of deregulation of the IL-7-IL-7R axis. In this review, we provide an update (focusing on the past couple of years) on IL-7 and IL-7R in health and disease. We highlight the findings on IL-7IL-7R signaling mechanisms and the, sometimes controversial, impact of IL-7 and its receptor on leukocyte biology, COVID-19, acute lymphoblastic leukemia, and different solid tumors, as well as their relevance as therapeutic tools or targets.

Chimeric Antigen Receptor T Cells in Large B-Cell Lymphoma Analysis of Overall Survival Based on Reconstructed Patient-Level Data.

Chimeric antigen receptor (CAR) T-cell products (eg, tisagenlecleucel tisa, axicabtagene ciloleucel axi) have been used in patients with relapsedrefractory large B-cell lymphoma (LBCL) and in adult patients with acute lymphoblastic leukemia (ALL). After the recent publication of long-term follow-up data in LBCL, reviewing the evidence on this topic is worthwhile. The aim of the present work was to study the pattern of overall survival (OS) reported for CAR T-cell products in LBLC and ALL. A standard literature search was performed. OS was studied through an artificial intelligence technique (the Shiny method) that reconstructs individual patient data from published Kaplan-Meier curves. Standard statistics along with indirect comparisons were performed on these reconstructed data. Indirect comparisons focused on CAR T cells versus chemotherapy in LBCL and ALL tisa and axi were further indirectly compared in LBCL. Seven trials were included (4 for LBCL, 3 for ALL). Other populations were selected as control groups. The main results of our analysis were (1) the survival advantage of CAR T cells is greater in adult patients with ALL than in patients with LBCL and (2) for LBCL, the survival gain is more substantial for axi compared with tisa. Our results are helpful to define the place in therapy of CAR T cells in these 2 disease conditions and also suggest preliminary estimates of cost-effectiveness. One strength of our analysis is that extensive information was available for the treatment options included in indirect comparisons. The main weakness is the inability of the Shiny method to perform multivariate analyses.

Gene Expression Network and Circ0008012 Promote Progression in MLLAF4 Positive Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia with MLLAF4 rearrangement remains a major hurdle to improving outcomes. Gene network and circRNAs have been found to participate in tumorigenesis, while their roles in leukemia still need to be explored. Recent patents have shown that circRNAs exhibit the markers for the children ALL, although the target and related mechanism remain to be elucidated. This study aims to explore the possible targets and mechanisms of ALL with MLL-AF4 rearrangement. We first generated a gene network focusing on MLL-AF4 rearrangement. Cell viability was determined with Cell Counting Kit-8 assay. The cell apoptosis was tested by the Annexin VPI assay. The RNA-protein complexes were analyzed by qRT-PCR, and the pathway proteins were analyzed by western blot. This gene network was associated with biological processes, such as nucleic acid metabolism and immunity, indicating its key role in inflammation. We found that circ0008012 was upregulated in MLLAF4 ALL cells and regulated cell proliferation and apoptosis. Further computed simulation and RIP showed that IKKβ was the strongest protein in the NF-κB pathway binding with circ0008012. As a result, possible regulation of circ0008012 is suggested by binding IKKβ in the IKKαIKKβIKKγ compound, which then phosphorylates IκB and activates NF-κBp65p300 compound in nuclear factor, thereby leading to leukemia. We identified a gene network for MLLAF4 ALL. Moreover, circ0008012 may be a therapeutic target for this subtype of ALL.

The Role of Genetics and Synergistic Effect of Targeting Common Genetic Mutations in Acute Lymphoblastic Leukemia (ALL).

Increasing concern regarding non-treatment and relapse in Acute Lymphoblastic Leukemia (ALL) among children and adults has attracted the attention of researchers to investigate the genetic factors of ALL and discover new treatments with a better prognosis. Nevertheless, the survival rate in children is more than in adults therefore, it is necessary to find new potential molecular targets with better therapeutic results. Genomic analysis has enabled the detection of different genetic defects that are serious for driving leukemogenesis. The study of genetic translocation provides a better understanding of the function of genes involved in disease progression. This paper presents an overview of the main genetic translocations and dysregulations in the signaling pathways of ALL. We also report the inhibitors of these main translocations and evaluate the synergistic effect of chemical inhibitors and gamma-ray irradiation on ALL.

Graph4Med a web application and a graph database for visualizing and analyzing medical databases.

Medical databases normally contain large amounts of data in a variety of forms. Although they grant significant insights into diagnosis and treatment, implementing data exploration into current medical databases is challenging since these are often based on a relational schema and cannot be used to easily extract information for cohort analysis and visualization. As a consequence, valuable information regarding cohort distribution or patient similarity may be missed. With the rapid advancement of biomedical technologies, new forms of data from methods such as Next Generation Sequencing (NGS) or chromosome microarray (array CGH) are constantly being generated hence it can be expected that the amount and complexity of medical data will rise and bring relational database systems to a limit. We present Graph4Med, a web application that relies on a graph database obtained by transforming a relational database. Graph4Med provides a straightforward visualization and analysis of a selected patient cohort. Our use case is a database of pediatric Acute Lymphoblastic Leukemia (ALL). Along routine patients health records it also contains results of latest technologies such as NGS data. We developed a suitable graph data schema to convert the relational data into a graph data structure and store it in Neo4j. We used NeoDash to build a dashboard for querying and displaying patients cohort analysis. This way our tool (1) quickly displays the overview of patients cohort information such as distributions of gender, age, mutations (fusions), diagnosis (2) provides mutation (fusion) based similarity search and display in a maneuverable graph (3) generates an interactive graph of any selected patient and facilitates the identification of interesting patterns among patients. We demonstrate the feasibility and advantages of a graph database for storing and querying medical databases. Our dashboard allows a fast and interactive analysis and visualization of complex medical data. It is especially useful for patients similarity search based on mutations (fusions), of which vast amounts of data have been generated by NGS in recent years. It can discover relationships and patterns in patients cohorts that are normally hard to grasp. Expanding Graph4Med to more medical databases will bring novel insights into diagnostic and research.

B-Cell Acute Lymphoblastic Leukemia with iAMP21 in a Patient with Constitutional Ring Chromosome 21.

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is associated with various specific cytogenetic and molecular markers that significantly influence treatment and prognosis. Intrachromosomal amplification of chromosome 21 (iAMP21) defines a rare distinct cytogenetic subgroup of childhood B-ALL, which is characterized by amplification of region 21q22.12 comprising the RUNX1 gene. Constitutional structural chromosomal abnormalities involving chromosome 21 confer an increased risk for B-ALL with iAMP21. Here, we report the development of B-ALL with iAMP21 in a 9-year-old child with a constitutional ring chromosome 21, r(21)c, uncovered after B-ALL diagnosis. Cytogenetic and microarray analysis of the post-therapy sample revealed an abnormal chromosome 21 lacking a satellite and having a deletion of the terminal 22q22.3 region, consistent with a constitutional ring chromosome 21, r(21)(p11.2q22). On a retrospective analysis, this ring chromosome was observed in the normal cells in the pre-treatment diagnostic specimen. Constitutional ring chromosome 21 may remain undetected in patients with mild or no neurodevelopmental phenotype, posing an unknown lifelong risk of developing B-ALL with iAMP21. Individuals with constitutional structural chromosome 21 rearrangements such as ring 21 require a close surveillance and long-term follow-up studies to establish their risk of B-ALL relapse and possibility of developing other malignancies. Germline analysis is recommended to all pediatric patients with iAMP21-related B-ALL to rule out structural chromosome 21 rearrangements and to elucidate molecular mechanisms of iAMP21 formation.

In Vitro Study of Cytotoxic Mechanisms of Alkylphospholipids and Alkyltriazoles in Acute Lymphoblastic Leukemia Models.

This study investigates the efficacy of miltefosine, alkylphospholipid, and alkyltriazolederivative compounds against leukemia lineages. The cytotoxic effects and cellular and molecular mechanisms of the compounds were investigated. The inhibitory potential and mechanism of inhibition of cathepsins B and L, molecular docking simulation, molecular dynamics and binding free energy evaluation were performed to determine the interaction of cathepsins and compounds. Among the 21 compounds tested,

Immune Ablation and Stem Cell Rescue in Two Pediatric Patients with Progressive Severe Chronic Graft-Versus-Host Disease.

Transplantation of allogeneic hematopoietic stem cells represents an established treatment for children with high-risk leukemia. However, steroid-refractory chronic graft-versus-host disease (SR-cGvHD) represents a severe life-threatening complication, for which there is no standard therapy. After failing several lines of immunosuppressive and biological treatment, we applied an immunoablative therapy with re-transplantation of purified CD34

A Dual Role for FADD in Human Precursor T-Cell Neoplasms.

A reduction in

Autoimmune Neutropenia and Immune-Dysregulation in a Patient Carrying a

In recent years, the knowledge about the immune-mediated impairment of bone marrow precursors in immune-dysregulation and autoimmune disorders has increased. In addition, immune-dysregulation, secondary to marrow failure, has been reported as being, in some cases, the most evident and early sign of the disease and making the diagnosis of both groups of disorders challenging. Dyskeratosis congenita is a disorder characterized by premature telomere erosion, typically showing marrow failure, nail dystrophy and leukoplakia, although incomplete genetic penetrance and phenotypes with immune-dysregulation features have been described. We report on a previously healthy 17-year-old girl, with a cousin successfully treated for acute lymphoblastic leukemia, who presented with leukopenia and neutropenia. The diagnostic work-up showed positive anti-neutrophil antibodies, leading to the diagnosis of autoimmune neutropenia, a slightly low NK count and high TCR-αβ-double-negative T-cells. A next-generation sequencing (NGS) analysis showed the 734C>A variant on exon 6 of the TINF2 gene, leading to the p.Ser245Tyr. The telomere length was short on the lymphocytes and granulocytes, suggesting the diagnosis of an atypical telomeropathy showing with immune-dysregulation. This case underlines the importance of an accurate diagnostic work-up of patients with immune-dysregulation, who should undergo NGS or whole exome sequencing to identify specific disorders that deserve targeted follow-up and treatment.

Identification of a Novel Curcumin Derivative Influencing Notch Pathway and DNA Damage as a Potential Therapeutic Agent in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy considered curable by modern clinical management. Nevertheless, the prognosis for T-ALL high-risk cases or patients with relapsed and refractory disease is still dismal. Therefore, there is a keen interest in developing more efficient and less toxic therapeutic approaches. T-ALL pathogenesis is associated with Notch signaling alterations, making this pathway a highly promising target in the fight against T-ALL. Here, by exploring the anti-leukemic capacity of the natural polyphenol curcumin and its derivatives, we found that curcumin exposure impacts T-ALL cell line viability and decreases Notch signaling in a dose- and time-dependent fashion. However, our findings indicated that curcumin-mediated cell outcomes did not depend exclusively on Notch signaling inhibition, but might be mainly related to compound-induced DNA-damage-associated cell death. Furthermore, we identified a novel curcumin-based compound named CD2066, endowed with potentiated anti-proliferative activity in T-ALL compared to the parent molecule curcumin. At nanomolar concentrations, CD2066 antagonized Notch signaling, favored DNA damage, and acted synergistically with the CDK1 inhibitor Ro3306 in T-ALL cells, thus representing a promising novel candidate for developing therapeutic agents against Notch-dependent T-ALL.

Carvedilol exhibits anti-acute T lymphoblastic leukemia effect in vitro and in vivo via inhibiting β-ARs signaling pathway.

An increasing number of studies have focus upon β-adrenergic receptor blockers and their anti-tumor effects. However, the use of Carvedilol (CVD), the third generation β-AR blocker, has not been explored for use against T-ALL. In this study, the level of β-ARs was explored in pediatric T-ALL patients. Moreover, the antitumor effects of CVD against T-ALL were assessed in vitro and in vivo, and the underlying mechanisms were investigated. The viability of T-ALL cells following CVD treatment was detected using a CCK-8 assay, and the apoptotic and cell cycle effects were measured using flow cytometry. The protein levels of β-ARs, cAMP, Epac, JAK2, STAT3, p-STAT3, PI3K, p-PI3K, AKT, p-AKT, mTOR, cyclin D1, PCNA, and cleaved caspase-3 were assessed by Western blotting. In vivo experiments were used to investigate the effect of CVD on T-ALL growth in mice. The results indicated that β-ARs were highly expressed in the newly diagnosed T-ALL cells when compared to those in the control group (P < 0.05). In vitro, CVD significantly inhibited T-ALL cell viability, promoted apoptosis and blocked the G0G1 phase of cell cycle. After CVD treatment, the protein levels of β-ARs, cAMP, Epac, PI3K, p-PI3K, AKT, p-AKT, mTOR, JAK2, STAT3, p-STAT3, cyclin D1 and PCNA were significantly downregulated (P < 0.05) whereas cleaved caspase-3 was significantly upregulated (P < 0.05). In vivo, the volume and weight of the xenograft tumors were significantly decreased in the CVD group (P < 0.05). CVD promoted xenograft tumor apoptosis and reduced the proportion of CEM-C1 cells in murine peripheral blood and bone marrow (P < 0.05). Our results demonstrate that β-ARs are expressed in T-ALL. CVD has a strong antitumor effect against T-ALL and inhibits β-AR associated signaling pathways. Therefore, CVD may provide a potential therapy for T-ALL.

The prognostic significance of hematogones in childhood B-cell acute lymphoblastic leukemia.

Recent studies have demonstrated hematogones (HGs) expansion to be associated with favorable outcomes in hematological diseases, especially in patients with acute myeloid leukemia and patients undergoing hematopoietic stem cell transplantation. Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. As of now, minimal residual disease (MRD) remains the most compelling independent prognostic factor in childhood ALL. There is need for more prognostic tools for evaluating relapse risk. The goal of this study was to assess the prognostic value of HGs on relapse-free survival (RFS) and overall survival (OS) in childhood ALL. In this prospective cohort study, a total of 122 subjects with definitive diagnosis of precursor B lymphoblastic leukemia were evaluated. Flow cytometric HG detection was performed in bone marrow aspirates after induction and consolidation therapy. The median follow-up period of patients was 35.5 ± 9.4 (SD) months. Patients who had at least 1.0% HGs had a significantly better RFS (p .023). Moreover, univariate and multivariate analyses confirmed that positive HGs were independently associated with longer RFS (unadjusted model hazard ratio 0.33, 95% CI 0.12-0.91, p .031 adjusted model hazard ratio 0.30, 95% CI 0.11-0.82, p .020). Along with the role of MRD, our study shows the significance of HGs as an independent prognostic factor. The results indicate the independent prognostic value of HGs on RFS after adjustment for other prognostic factors, and can be beneficial for risk stratification and treatment modifications amongst pediatric B-cell ALL patients.

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study.

Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (RR B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. Adults with RR B-ALL received a single infusion of KTE-X19 (1 × 10 After 26.8-months median follow-up, the overall complete remission (CR) rate (CR CR with incomplete hematological recovery) among treated patients (N 55) in phase 2 was 71% (56% CR rate) medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N 49) and matched historical controls (N 40) was 25.4 and 5.5 months, respectively. These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult RR B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. NCT02614066.

Oncogenic deubiquitination controls tyrosine kinase signaling and therapy response in acute lymphoblastic leukemia.

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL.

Clinical screening for Ph-like ALL and the developing role of TKIs.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a common subtype of B-lineage acute lymphoblastic leukemia (B-ALL) with increasing frequency across the age spectrum. Characterized by a kinase-activated gene expression profile and driven by a variety of genetic alterations involving cytokine receptors and kinases, Ph-like ALL is associated with high rates of residual disease and relapse in patients treated with conventional chemotherapy. In this case-based review, we describe the biology of the 2 major ABL-class and JAK pathway genetic subtypes of Ph-like ALL, discuss current diagnostic testing methodologies, and highlight targeted inhibitor and chemoimmunotherapy approaches under clinical investigation in children, adolescents, and adults with these high-risk leukemias.

Updates in infant acute lymphoblastic leukemia and the potential for targeted therapy.

Outcomes for infants diagnosed under 1 year of age with KMT2A-rearranged acute lymphoblastic leukemia (ALL) have remained stagnant over the past 20 years. Successive treatment protocols have previously focused on intensification of conventional chemotherapy, but increased treatment-related toxicity and chemoresistance have led to a plateau in survival. We have now entered an era of immunotherapy with integration of agents, such as blinatumomab or chimeric antigen receptor T-cell therapy, into the standard chemotherapy backbone, showing significant promise for improving the dismal outcomes for this disease. There remains much optimism for the future as a wealth of preclinical studies have identified additional novel targeted agents, such as venetoclax or menin inhibitors, ready for incorporation into treatment, providing further ammunition to combat this aggressive disease. In contrast, infants with KMT2A-germline ALL have demonstrated excellent survival outcomes with current therapy, but there remains a high burden of treatment-related morbidity. Greater understanding of the underlying blast genetics for infants with KMT2A-germline ALL and incorporation of immunotherapeutic approaches may enable a reduction in the intensity of chemotherapy while maintaining the excellent outcomes.

Leukemogenesis in infants and young children with trisomy 21.

Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of acute lymphoblastic leukemia (ALL) before their fifth birthday. ML-DS originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as transient abnormal myelopoiesis (TAM) that is caused by cooperation between trisomy 21-associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor GATA1. Around 10% of neonates with DS have clinical signs of TAM, although the frequency of hematologically silent GATA1 mutations in DS neonates is much higher (25%). While most cases of TAMsilent TAM resolve without treatment within 3 to 4 months, in 10% to 20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. By contrast, DS-ALL, which is almost always B-lineage, presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene (60%), often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.

New developments in ALL in AYA.

The outcome for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved, mostly based on the use of pediatric-inspired intensive protocols. Due to increasing disease resistance and treatment-related toxicity with age, further improvements are now expected from the expanding knowledge of ALL biology, more accurate risk stratification, and the early introduction of targeted small molecules and immunotherapy. In the last decade, the rate of AYA with B-cell precursor ALL with undetermined genetic drivers (B-other) has shrunk from 40% to fewer than 10%. The high-risk subgroup of Philadelphia-like ALL is the most frequent entity diagnosed in this age range, offering a multitude of potentially actionable targets. The timely and accurate identification of these targets remains challenging, however. Early minimal residual disease (MRD) monitoring has become a standard of care for the risk stratification and identification of patients likely to benefit from an allogeneic hematopoietic stem cell transplantation. Recently approved immunotherapies are moving frontline to eradicate MRD, to improve the outcome of high-risk patients, and, eventually, to reduce treatment burden. Comprehensive care programs dedicated to AYA with cancer aim at improving inclusion in specific clinical trials and at giving access to appropriate psychosocial support, fertility preservation, and survivorship programs.

Optimal approach to T-cell ALL.

T-lineage acute lymphoblastic leukemia (T-ALL) is curable for most children and adolescent and young adult patients with contemporary frontline chemotherapy regimens. During the past decade, improved survival rates have resulted from the optimization of frontline chemotherapy regimens, the use of minimal residual disease (MRD) assessment for evaluating a patients risk for relapse, and the intensification of treatment based on the persistence of MRD. Optimization of initial therapy is critical because relapsed T-ALL after initial intensive chemotherapy is incurable for most adult patients. Current T-ALL salvage chemotherapy regimens are minimally effective, and unlike in B-cell ALL, there are no approved antibody therapies or chimeric antigen receptor T-cell therapies for relapsed disease. Immunotherapy and small-molecule inhibitors are beginning to be tested in relapsed T-ALL and have the potential to advance the treatment. Until effective salvage strategies are discovered, however, intensive frontline therapy is required for cure. In this article I review the current frontline chemotherapy regimens for adult patients with T-ALL, summarize the novel targeted and immune therapeutics currently in early-phase clinical trials, and outline how these therapies are helping to define an optimal approach for T-ALL.

Ph ALL in 2022 is there an optimal approach

Philadelphia chromosome-positive (Ph) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein. With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph ALL.

Evidence-Based Minireview What is the optimal tyrosine kinase inhibitor for adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia

The incorporation of BCRABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy significantly improved the outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). This was first shown with the addition of the first-generation TKI imatinib, which allowed more patients to be bridged to an allogeneic stem cell transplant (SCT) and led to superior long-term outcomes compared with chemotherapy alone. The use of second-generation TKIs (eg, dasatinib and nilotinib) has led to further improvement in outcomes of patients with Ph- positive ALL, with a long-term survival of 40% to 60% in several studies. Ponatinib is a third-generation, more potent TKI that results in high rates of molecular response and promising long-term survival even when allogeneic SCT is not routinely performed. While randomized data to support the TKI selection in Ph-positive ALL are lacking, data from single-arm studies suggest deeper molecular responses and superior survival outcomes with each successive generation of TKI. More recently, chemotherapy-free regimens with blinatumomab and TKIs have shown excellent results in the frontline setting and may represent an emerging paradigm shift in the treatment of Ph-positive ALL.

Risk factors and screening for neurocognitive impacts of therapy.

Long-term survivors of pediatric hematologic malignancies are at elevated risk for neurocognitive impairment. Such impairment manifests in different ways at different times during survivorship, with deficits in processing speed, attention, and memory often appearing before deficits in executive function, intelligence, and academics. Survivors exposed to therapies that directly target the central nervous system (CNS), as is the case in acute lymphoblastic leukemia, may demonstrate subtle deficits during frontline therapy, and these deficits may grow and evolve over time. Survivors who do not receive CNS-directed therapies (eg, Hodgkin lymphoma) are also at elevated risk for neurocognitive impairment, although the influence on brain function is indirect through cancer therapy impact on systemic organ function vital to brain health (eg, cardiopulmonary morbidity). Over the course of the survivors life span, the presence and impact of neurocognitive deficits will be determined by a complex interaction between premorbid development and environment, cancer therapy and clinical care, and posttreatment recovery and health. The timing and type of these treatment and health events will dictate the approach to screening and monitoring for neurocognitive impairment.

Ponatinib-Associated Cutaneous Eruptions-A Case Series and Review of Clinicopathologic Findings.

Ponatinib is a third-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia. Cutaneous toxicities are a commonly reported side effect of ponatinib treatment with rash being one of the most common. Specific subtypes are infrequently reported, but include hyperkeratotic, folliculocentric, ichthyosiform, and pityriasis rubra pilaris-like eruptions. Herein, we highlight the clinicopathologic features of 2 cases of ponatinib-induced pityriasis rubra pilaris-like eruptions. We also classify the clinical and histopathologic features of all previously reported ponatinib-associated eruptions in the literature and discuss treatment and potential diagnostic pitfalls.

Severe, life-threatening, and fatal chronic health conditions after allogeneic blood or marrow transplantation in childhood.

A comprehensive assessment of morbidity after allogeneic bone marrow transplantation (BMT) performed in childhood remains understudied. Seven hundred eighty-nine allogeneic BMT recipients who had survived ≥2 years after BMT performed between 1974 and 2014 at age <22 years and 690 siblings completed a 255-item survey self-reporting sociodemographics and chronic health conditions. A severity score (grade 3 severe, 4 life-threatening, or 5 fatal) was assigned to the conditions using Common Terminology Criteria for Adverse Events, version 5.0. For the BMT cohort, the cumulative incidence of chronic health conditions was calculated as a function of time from BMT. Proportional subdistribution hazards models were used to determine predictors of grade 3-5 conditions. Logistic regression was used to estimate the risk of grade 3-4 conditions in BMT recipients who were alive at the time of this study compared with siblings. The median age at transplantation was 11.3 years (range, 0.4-22.0 years), and the median length of follow-up was 11.7 years (range, 2.0-45.3 years). The most prevalent primary diagnoses were acute lymphoblastic leukemia (30.7%), and acute myeloid leukemiamyelodysplastic syndrome (26.9%). At age 35 years, the cumulative incidence of a grade 3-4 condition was 53.8% (95% CI, 46.7%-60.3%). The adjusted odds ratio of a grade 3-4 condition was 15.1 in survivors (95% CI, 9.5-24.0) compared with siblings. The risk of a grade 3-5 condition increased with age at BMT (hazard ratio HR, 1.03 95% CI, 1.01-1.05) and was higher among females (HR, 1.27 95% CI, 1.02-1.59), patients who received total body irradiation (HR, 1.71 95% CI, 1.27-2.31), and those reporting chronic graft-versus-host disease (HR, 1.38 95% CI, 1.09-1.74). Two-year survivors of allogeneic BMT in childhood have an increased risk of grade 3-4 chronic health conditions compared with siblings, suggesting the need for long-term follow-up.

USP44 accelerates the growth of T-cell acute lymphoblastic leukemia through interacting with WDR5 and repressing its ubiquitination.

T-cell acute lymphoblastic leukemia (T-ALL) is a common hematologic malignancy. Based on the data from GSE66638 and GSE141140, T-ALL patients depicted a higher USP44 level. However, its role in T-ALL is still unclear. In the present study, we investigated the role of USP44 in T-ALL growth. USP44 overexpression elevated the proliferation of CCRF-CEM cells, while USP44 knockdown suppressed the proliferation of Jurkat and MOLT-4 cells. In addition, USP44 accelerated the cell cycle progression, with boosted cyclinD and PCNA levels. However, USP44 knockdown induced apoptosis in Jurkat and MOLT-4 cells, with an upheaval among cleaved caspase-3 and PARP levels. Mechanistically, USP44 co-localized and interacted with WDR5, leading to the repression of its ubiquitination and degradation. Interestingly, WDR5 overexpression abolished the apoptosis induced by USP44 knockdown. Consistently, the

Commercial DURAClone panels for extending the repertoire of multicolour immunophenotypic panels in an academic flow cytometry laboratory in South Africa.

Commercial multicolour fixed immunophenotyping panels can improve flow cytometric diagnostic immunophenotyping repertoire. This study validated the commercially available, standardised Beckman Coulter lyophilised DURAClone RE panels to discriminate specific haematolymphoid subtypes. We compared the diagnostic capability of the DURAClone acute leukaemia B (ALB), chronic leukaemia B (CLB), and plasma cells (PC) panels to the predicate second-line panels in Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa, from April to August 2020. Clinical diagnostic concordance between the in-house second-line immunophenotyping (the predicate method) and DURAClone was established. The ALB panels tested for precursor B-cell acute lymphoblastic leukaemia ( There was 100% clinical diagnostic concordance between the predicate and the test panels for second-line diagnostic investigation of B-ALL (with additional CD56), mature B-LPD (with additional discernment of CD81, ROR-1, CD79b and CD43) and PCD. The DURAClone CLB exceeded the predicate second-line performance, offering extended second-line diagnostic discernment of mature B-LPD subtypes and discernment of CD5 B-LPD from other non-CD5 (or CD5-) B-LPD likewise, the PC panels enabled discovery of PCD. While ALB testing offered no additional diagnostic advantage over existing predicate investigation, CD58 did offer additional information to discern haematogones from B-ALL.

Effect of Testicular Boost in Children With Leukemia Receiving Total Body Irradiation and Stem Cell Transplant A Single-Institution Experience.

Children with leukemia who receive fractionated total body irradiation (fTBI) with 12 to 13.2 Gy as part of conditioning for hematopoietic stem cell transplant are frequently treated with an additional 4 Gy testicular boost to reduce the risk of testicular relapse. While institutional practices vary, limited data exists regarding whether the 4-Gy testicular boost reduces the risk of relapse and whether it causes toxicity beyond that imparted by TBI. This study compared the survival and endocrine outcomes among the patients who were treated with and without a testicular boost as part of fTBI from 1990 to 2019 at our center. We retrospectively reviewed charts of male children with leukemia treated with fTBI as part of a conditioning regimen for stem cell transplant from 1990 to 2019. Reported outcomes included progression-free survival, testicular relapse rate, and overall survival. Gonadal dysfunction and fertility were assessed by comparing the rate of abnormally low testosterone or high luteinizing hormone or follicular stimulating hormone, number of offspring, fertility service use, and abnormal sperm count in the subsequent follow-up period between the testicular boost and nonboost subset. Ninety-three male patients (63 acute lymphoblastic leukemia, 30 acute myeloid leukemia) with a median age of 9 years (range, 1-22) and follow-up of 3.3 years were included. In addition to 12- to 13.2-Gy fTBI, 51 male patients (54%) received a testicular boost to 4 Gy. There was 1 testicular relapse in the boost subset and none in the nonboost subset. Five-year progression-free survival for the boost and nonboost subset was 74% and 66%, respectively ( Omission of testicular boost may be associated with comparable oncologic but improved gonadal endocrine outcomes and should be further studied.

Mutational analysis of ribosomal proteins in a cohort of pediatric patients with T-cell acute lymphoblastic leukemia reveals Q123R, a novel mutation in RPL10.

T-cell acute lymphoblastic leukemia (T-ALL) is a subtype of ALL involving the malignant expansion of T-cell progenitors. It is driven by a number of different possible genetic lesions, including mutations in genes encoding for ribosomal proteins (RPs). These are structural constituents of ribosomes, ubiquitous effectors of protein synthesis. Albeit the R98S mutation in RPL10, recurring with a higher frequency among RP mutations, has been extensively studied, less is known about the contribution of mutations occurring in other RPs. Alterations affecting translational machinery may not be well tolerated by cells, and there may be a selective pressure that determines the emergence of mutations with a compensatory effect. To explore this hypothesis, we sequenced the exomes of a cohort of 37 pediatric patients affected by T-ALL, and analyzed them to explore the co-occurrence of mutations in genes involved in ribosome biogenesis (including RPs) and translational control, and in known T-ALL driver genes. We found that some of the mutations in these sub-classes of genes tend to cluster together in different patients, indicating that their co-occurrence may confer some kind of advantage to leukemia cells. In addition, our sequencing highlighted the presence of a novel mutation in RPL10, namely the Q123R, which we found associated with a defect in protein synthesis. Our findings indicate that genetic alterations involving ribosome biogenesis and translational control should be carefully considered in the context of precision medicine in T-ALL.

Physical fitness throughout chemotherapy in children with acute lymphoblastic leukaemia and lymphoma.

Acute lymphoblastic leukaemialymphoma (ALLLBL) and its treatment interfere with normal physical functioning. However, it remains unclear how physical fitness (PF) is affected throughout treatment for ALLLBL. Sixty-two patients (2.1 to 18.3 years) treated for ALLLBL underwent four physical tests at nine timepoints from baseline up to 6 months post-treatment. We assessed muscle strength of the quadriceps and tibialis anterior, standing broad jump test (SBJ) for functional mobility and six-minute walk test (6MWT) for endurance. One-sample t-tests were used to compare our results to the norm at each timepoint. Norm-referenced Z-scores were predicted based on time, risk group and age at diagnosis, using linear mixed models. Quadriceps strength, SBJ and 6MWT scores were significantly lower than norm values at all timepoints from diagnosis up to 6 months after maintenance therapy. Significant decreases over time were encountered for quadriceps strength and SBJ, mainly occurring after induction therapy (F 3.568, p < 0.001 and F 2.699, p 0.008, respectively). Age at diagnosis was a significant predictor for tibialis anterior strength (F 5.266, p 0.025), SBJ (F 70.422, p < 0.001) and 6MWT (F 15.890, p < 0.001) performances, with lower results in adolescents at all timepoints. Six months after treatment, quadriceps strength, 6MWT and SBJ scores remained below expected levels. The decreased quadriceps strength, functional mobility and endurance at all timepoints, with a large deterioration following induction therapy, suggest the need for early interventions, specifically in the adolescent population. The continued low results 6 months after therapy emphasise the importance of long-term rehabilitation. •Acute lymphoblastic leukaemia is the most common type of cancer among children, with increasing survival rates due to therapeutic improvements. •Acute lymphoblastic leukaemialymphoma and its treatment can cause muscle weakness, neuromuscular toxicity and a decreased cardiopulmonary fitness. Together with physical inactivity, this can result in a decreased physical fitness. •Quadriceps strength, functional mobility and endurance are decreased during treatment for acute lymphoblastic leukaemialymphoma. The lowest measurements are observed after induction therapy, suggesting the need for early interventions. •We observed continued lower results for quadriceps strength, functional mobility and endurance at the end of treatment, up to 6 months after therapy, supporting the need for long-term rehabilitation.

The demands of caregivers of children with acute lymphoblastic leukaemia in different therapy stages and the exploration of possible interventions A longitudinal investigation survey at a Tertiary Medical Institution.

To describe the demands of family caregivers of children with ALL at different therapy stages and explore the possible interventions to address their care demands. A longitudinal investigation study. A total of 157 family caregivers of children treated in the Haematological oncology ward of a tertiary medical hospital in China between March and December in 2020 were included in this study. The Comprehensive Needs of Caregivers of Cancer Patients and Families Taking Care of Children Scale was used to investigate the family caregivers of children with ALL. The family caregivers completed the questionnaire accompanied by a researcher within two weeks of each therapy stage, which included the induction, consolidation and continuation stages. Family caregivers of children with ALL had many demands that varied based on the stage of therapy. Family caregivers in the induction therapy stage needed more information about their childrens disease, having the highest score in information demands (35.60 ± 5.85). The family caregivers in the consolidation therapy stage needed more information on symptom management and socio-economic support, having the highest score in care and support demands (36.14 ± 5.12). The family caregivers in the continuation therapy stage (including interim and maintenance therapy stages) focused more on their own and the childrens social adaptation, so they scored the highest for psychosocial demands (35.96 ± 5.69). Family caregivers of children with ALL had different demands that varied based on the stage of therapy. Medical personnel should be aware of the primary needs of family caregivers at different therapy stages to provide early interventions and support based on their demands, ultimately improving the physical and mental condition of family caregivers and the quality of care.

Silencing of IRF8 Mediated by m6A Modification Promotes the Progression of T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a poor prognosis, urging for novel therapeutic targets and treatment strategies. N6-methyladenosine (m6A) is a crucial methylation modification that affects the pathogenesis of leukemia by regulating the mRNA of key genes. Interferon regulatory factor 8 (IRF8) is a crucial transcription factor for hematological lineage commitment, but its role in T-ALL is unclear. Here, IRF8 is shown to suppress T-ALL. The expression of IRF8 is abnormally silenced in patients with T-ALL. Knockout of Irf8 significantly hastens the progression of Notch1-induced T-ALL in vivo. Overexpression of IRF8 suppresses the proliferation and invasion of T-ALL cells by inhibiting the phosphatidylinositol 3-kinaseAKT signaling pathway. The fat mass- and obesity-associated protein (FTO), an m6A demethylase, is responsible for directly binding to m6A sites in 3 untranslated region of IRF8 messenger RNA (mRNA) and inducing mRNA degradation via m6A modification. Targeting the FTO-IRF8 axis is used as a proof of concept therapy inhibition of FTOs demethylase activity drastically alleviates the proliferation of leukemic cells and prolongs the survival of T-ALL mice by restoring IRF8 expression. This study elucidates the pathogenesis of T-ALL from the perspective of epitranscriptomics and provides new insight into the genetic mechanisms and targeted therapy of T-ALL.

The Mechanism of Resveratrol on Acute T-Lymphocyte Leukemia through IL-7-Mediated JAK STAT Signaling Pathway.

To explore the roles and relative mechanism of resveratrol against T-ALL through detecting the signaling molecules in IL-7 and JAKSTAT pathway. In vitro experiments, Molt4 cells were divided into 3 groups, including the control group, the DMSO group and resveratrol-treated group (Res group). The control group cells without any treatment, the DMSO group cells treated with 0.05% DMSO for 48 hours, the Res group cells treated with 200 μmolL resveratrol for 48 hours. In vivo experiments, female C57BL6J mice (6-8 weeks) were randomly divided into the control group, the T-ALL model group (T-ALL group), and Res treatment group (Res group). The control group mice treated with 0.05% DMSO by intragastric treatment, the T-ALL group mice treated with 0.05% DMSO by intragastric treatment, and the Res group mice treated with 10 mgml resveratrol. Expression of Resveratrol could inhibit the proliferation ability of Molt4 cells, decrease the relative levels of p-JAK1, p-JAK3, p-STAT5, Pim1 protein, and the expression levels of Resveratrol may inhibite IL-7-medicated JAKSTAT signaling pathway to reduce the expression of target protein Pim1 to further exert its anti-T-ALL effects. IL-7介导的JAKSTAT信号通路在白藜芦醇抗急性T淋巴细胞白血病中的作用研究. 观察T-ALL细胞株和小鼠模型中IL-7及JAKSTAT通路中信号分子的变化，探讨白藜芦醇抗T-ALL的作用机制. 将T-ALL 细胞株Molt4分成对照、DMSO处理和白藜芦醇处理（Res）共3组，其中对照组不做任何处理，DMSO组用0.05% DMSO处理48 h，Res组用200 μmolL白藜芦醇处理48 h。将15只6-8周龄健康雌性C57BL6J小鼠随机分为正常对照、T-ALL模型（T-ALL）和白藜芦醇处理（Res）共3组，其中对照和T-ALL组均以 0.05% DMSO灌胃处理，Res组以10 mgml白藜芦醇灌胃处理。采用RT-qPCR法检测各组细胞和小鼠脾脏组织中 Res抑制Molt4细胞增殖，下调Molt4细胞及T-ALL小鼠脾脏中p-JAK1、p-JAK3、p-STAT5、Pim1蛋白相对表达量以及 白藜芦醇可能通过下调IL-7和IL-7R的表达水平，抑制其介导的JAKSTAT信号通路，进而降低靶蛋白Pim1表达发挥抗T-ALL的作用.

The Application of RNA-Sequencing in Pediatric B-Cell Acute Lymphoblastic Leukemia.

To explore the molecular genetic characteristics of children with B-cell acute lymphoblastic leukemia (B-ALL) and the application value of RNA-sequencing (RNA-seq). The clinical and laboratory examination data of newly diagnosed B-ALL children who were given treatment in the Department of Hematology, Childrens Hospital of Chongqing Medical University from May 2015 to April 2020 were collected and analyzed. All children were confirmed by bone marrow morphology, histochemical staining and flow cytometry, and the karyotype analysis, FISH, RT-PCR and RNA-seq detection were conducted. There were 71 males and 58 females with a median age of 50(8-190) months in 129 newly diagnosed children with B-ALL. The fusion gene was positive in 99 children (76.7%). A total of 86 leukemia related or possibly related gene mutations were detected, with a positive rate of 66.7%. There was no significant difference in the detection rates of RNA-seq can not only detect known fusion genes, but also discover new or rare fusion genes and gene mutations. The application of RNA-seq has important guiding significance for risk classification and precise targeted therapy of pediatric B-ALL. 全转录组测序在儿童急性B淋巴细胞白血病中的应用. 探索儿童急性B淋巴细胞白血病（B-ALL）的分子遗传学特点及全转录组测序（RNA-seq）在儿童B-ALL中的应用价值. 收集并分析2015年5月-2020年4月重庆医科大学附属儿童医院血液肿瘤中心收治的初诊B-ALL患儿的临床及实验室检查资料，所有患儿均经骨髓形态学及组织化学染色、流式细胞术确诊，且完善染色体核型分析、荧光原位杂交（FISH）、逆转录聚合酶链反应（RT-PCR）及RNA-seq检测. 129例初诊B-ALL患儿中男71例，女58例，中位年龄50(8-190)个月，99例患儿检出融合基因阳性，阳性率76.7%，86例检测出白血病相关及可能相关基因突变阳性，阳性率约为66.7%。 全转录组测序不仅能检测出已知的融合基因，同时能发现新的及罕见的融合基因及基因突变，其应用对B-ALL患儿危险度分级及精准靶向治疗有重要指导意义.

Detection of Fusion Gene and Prognosis Analysis in Children with Acute Lymphoblastic Leukemia of Different Immunophenotypes.

To observe the detection of fusion gene in children with acute lymphoblastic leukemia (ALL) of different immunophenotypes, and analyze the relationship between fusion gene and prognosis. The clinical data of 86 children with ALL treated in the hospital from May 2015 to May 2020 were retrospectively analyzed, the immunophenotypes and the prognosis of children were recorded, the detection of fusion gene in ALL children with different immunophenotypes was compared, the relationship between detection of fusion gene and prognosis was analyzed. The results of bone marrow immunophenotype showed that there were 13 cases of T cell type and 73 cases of B cell type in 86 children with ALL. The detection rate of fusion gene There are differences in fusion genes among ALL children with different immunophenotypes, minimal residual disease, extramedullary infiltration, and fusion gene are associated with prognosis of ALL children. Fusion gene detection can be used as new method to predict the prognosis of children with ALL. 不同免疫分型急性淋巴细胞白血病患儿融合基因检测及预后分析. 观察不同免疫分型急性淋巴细胞白血病（ALL）患儿的融合基因检出情况，并分析融合基因与预后的关系. 回顾性分析本院2015年5月-2020年5月收治的86例ALL患儿的临床资料，记录患儿免疫分型及预后情况，比较不同免疫分型患儿的融合基因检出情况，并分析融合基因检测与预后的关系. 骨髓免疫分型结果显示，86例ALL患儿中有13例T细胞型，73例B细胞型。T细胞型患儿融合基因 不同免疫分型的ALL患儿融合基因存在差异，微小残留病、髓外浸润、融合基因均与患儿预后有关，检测融合基因可作为预测患儿预后的新手段.

To investigate the regulatory effect of miRNA-29a-3p ( Thirty-five patients with ALL treated in our hospital from January 2017 to January 2019 were selected as research objects, and 35 adults who underwent physical examination in the same period were selected as healthy control group. The Compared with healthy control group, HDGF was highly expressed in serum of patients with ALL and leukemia cells HuT 78, E6-1, CCRF-CEM, while Overexpression of 探讨miRNA-29a-3p（ 选择2017年1月-2019年1月在本院就诊的急性淋巴细胞白血病患者35例，同期进行健康体检的成人35例为健康对照组。将 与健康对照组相比，急性淋巴细胞白血病患者血清及细胞HuT 78、E6-1、CCRF-CEM中HDGF高表达，

Application of genome editing technology for the validation of pharmacogenomics in acute lymphoblastic leukemia.

Therapeutic outcome in childhood acute lymphocytic leukemia has been dramatically improved by recent developments in treatment. However, disease relapse is still observed in approximately 10-15% of the patients. Moreover, adverse effects associated with intensified chemotherapy and hematopoietic stem cell transplantation remain important clinical issues for some survivors. Personalized medicine is valuable, under these circumstances, to reduce adverse effects and further improve the therapeutic outcome. Thus, identifying pharmacogenomic backgrounds associated with individual variation in drug sensitivity of leukemia cells and chemotherapy-induced adverse effects is important for precision medicine development. Recent advances in genome-editing technologies, such as CRISPRCas9 system, enable direct confirmation of associations between drug sensitivities and genetic backgrounds, such as polymorphisms and mutations, in the intrinsic genes of leukemia cells. Consequently, genome-editing systems are an ideal tool to develop in vitro and in vivo experimental models of drug sensitivity or resistance. The usefulness of the CRISPRCas9 system for the validation of pharmacogenomics in the selection of chemotherapeutic agents for acute lymphocytic leukemia has been discussed with specific examples in this review.

Acute lymphoblastic leukemia with masked Philadelphia chromosome.

A 76-year-old woman with leukocytosis and thrombocytopenia was admitted to our hospital. A bone marrow examination showed a composition of 82.0% blasts, i.e., positive for TdT, CD10, CD19, CD34, and HLA-DR and negative for cyCD3, CD13, CD33, MPO, and cyµ. The reverse transcription-polymerase chain reaction analysis revealed a minor BCR-ABL1 fusion gene, leading to a diagnosis of acute lymphocytic leukemia (ALL) with a BCR-ABL1 fusion gene. G-band assay was negative for Philadelphia (Ph) chromosome and also revealed add (21) (q22. 1) and del (20) (q11. 2q13.3). Fluorescence in situ hybridization (FISH) assaying revealed a positive BCR-ABL1 fusion signal. Thus, this patient was diagnosed as Ph chromosome-negative and BCR-ABL1-positive fusion gene ALL, which suggested the presence of ALL with the masked Ph chromosome found in approximately 1% of chronic myeloid leukemia. Therefore, the FISH analysis may complement cytogenetic analysis when cytogenetic and molecular genetic findings are contradictory in ALL.

A Case of Methotrexate-induced Subacute Encephalopathy that Showed no Abnormalities on Magnetic Resonance Imaging Soon After Symptom Appearance.

A 21-year-old woman was diagnosed with acute lymphoblastic leukemia. After the administration of intrathecal methotrexate (MTX), the patient experienced dysarthria and paralysis for one hour. Magnetic resonance imaging (MRI) performed one hour from the onset and just before symptoms disappeared revealed no abnormalities. The next day, the symptoms appeared again, and diffusion-weighed MRI revealed a high-intensity area in the left frontal lobe. The patient was diagnosed with MTX-induced encephalopathy. This case suggested that MRI performed as soon as symptoms appear might show normal findings in MTX-induced encephalopathy.

Lineage switch in a pediatric patient with KMT2A-MLLT3 from acute megakaryoblastic leukemia to T cell acute lymphoblastic leukemia at the fourth relapse after allo-HSCT with literature review.

We present a patient with acute megakaryoblastic leukemia (AMKL) harboring KMT2A-MLLT3 that converted to T cell acute lymphoblastic leukemia (T-ALL) at her fourth relapse. A 4-year-old girl developed AMKL with multiple swollen lymph nodes. She exhibited several recurrences in the bone marrow and died of septic shock after her fourth relapse. Bone marrow cells at the initial diagnosis and at all four relapses had the same KMT2A-MLLT3 fusion transcript. She also developed a somatic mutation (c.7177C > T p.Q2393X) of NOTCH1 at the fourth relapse. This sequential phenotypic and cytogenetic study may yield valuable insights into the mechanism of AMKL to T-ALL lineage switch and possible implications for treatment selection.

Cerebrovascular accident in a child with precursor B-cell acute lymphoblastic leukemia and coronavirus disease 2019 a case report.

Coronavirus disease 2019 can lead to rare but severe and life-threatening diseases in susceptible high-risk populations, including patients with immunodeficiency. A rare event in this report is stroke following COVID-19 disease in a patient with an immunocompromised background due to leukemia and anti-cancer treatments. A 6-year-old iranian girl with precursor B-cell leukemia receiving vincristine therapy presented with fever and absolute neutrophil count < 500. Her severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test was positive. During hospitalization, she had abrupt onset tachypnea, reduced O Owing to the link between coronavirus disease 2019 and hematologic cancers with hypercoagulopathy and the tendency of patients with leukemia to have coronavirus disease 2019 complications, children with leukemia as well as suspected coronavirus disease 2019 must be hospitalized to prevent blood clot formation.

A CRLF2 Rearrangement in a Pediatric Patient with B-ALL Detected by FISH Within the Context of a Complex Abnormal Karyotype.

B-cell acute lymphoblastic leukemia (B-ALL) is one of the prevalent pediatric leukemias, accounting for 26% of cancers diagnosed in children 0-14 years of age. We present a case report of an 11-year-old girl with B-ALL. The patient was in complete remission nine months after diagnosis but passed away a month later from chemotherapy-induced hepatic failure, renal failure, and febrile neutropenia. Conventional cytogenetics showed a karyotype of 46,XX,del(5)(q31q35),add(6)(q23),del(7)(q32q36),add(11)(q23),ider(21)(q10)add(21) (q22),inc20. DNA FISH analysis performed on the bone marrow showed variant rearrangement of CRLF2, as well as loss of ETV6 signals and gain of RUNX1 signals. The presence of CRLF2 rearrangements within the context of a complex karyotype is often associated with CRLF2 overexpression and poor prognosis. The heterogeneity of B-ALL and the variability in the outcomes of patients that lack characteristic genetic abnormalities highlight the importance of profiling unusual genetic cases such as this one and continuing research to understand the molecular mechanisms of rarer mutations.

Elucidation of the Reaction Mechanism of

The l-asparaginase (l-ASNase) enzyme catalyzes the conversion of the non-essential amino acid l-asparagine into l-aspartic acid and ammonia. Importantly, the l-ASNases are used as a key part of the treatment of acute lymphoblastic leukemia (ALL) however, despite their benefits, they trigger severe side effects because they have their origin in bacterial species (

Successful treatment of disseminated amphotericin-resistant fusariosis in a paediatric patient with acute lymphoblastic leukaemia a case report and literature review.

Disseminated fusariosis is a rare and fatal infection in immunocompromised patients. We report a case of disseminated amphotericin-resistant fusariosis in a paediatric patient with acute lymphoblastic leukaemia and review the features of reported disseminated fusariosis in China. Case reports of disseminated fusariosis were searched from the Chinese literature over the last two decades. The presented case is a 15-year-old female who developed fever and multiple painful purple plaques with black necrotic centres and blood blisters. Fusarium was detected in blood and skin lesions with a high minimum inhibitory concentration (MIC) of amphotericin B (AMB) (>32 μgmL) and a low MIC of voriconazole (VRC) (0.25 μgmL). The Fusarium fujikuroi species complex was finally identified by rRNA gene analysis. Combination therapy of VRC and terbinafine (TRF) successfully resolved the disease after more than four months of treatment. Based on the review, the most common manifestations of disseminated fusariosis were fever, skin lesions and positive blood cultures, comprising nine cases (64.3%). Other sites of infection, including the lungs, eyes, sinuses or bone marrow, occurred in eight cases (57.1%). Seven patients (50%) were cured after monotherapy or combination therapy with AMB and VRC. In view of this case and the review of the literature, early identification of Fusarium infection and the appropriate antifungal drugs are critical for successful treatment. Primary therapy should consist of VRC or liposomal amphotericin B (L-AMB), with salvage therapy consisting of posaconazole (PSC). The combination of antifungals is probably necessary and more effective.