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Multiple Asparaginase Infusions Cause Increasingly Severe Acute Hyperammonemia.

Adverse reactions during and shortly after infusing asparaginase for the treatment of acute lymphoblastic leukemia can increase in severity with later doses, limiting further use and increasing relapse risk. Although asparaginase is associated with hyperammonemia, the magnitude of the increase in serum ammonia immediately after the infusion and in response to multiple infusions has not been examined. The concurrence of hyperammonemia and infusion reactions was studied using weaned juvenile pigs that received 12 infusions of Erwinia asparaginase (Erwinase 1250 Ukg) over 28 days, with two 5-day recovery periods without asparaginase after the eighth and eleventh doses. Infusion reactions and prolonged hyperammonemia (>50 µM ammonia 48 h after the infusion) began after the fourth dose and increased with later doses. Dense sampling for 60 min revealed an acute phase of hyperammonemia that peaked within 20 min after starting the first infusion (298 62 µM) and lasted less than 1 h, without apparent symptoms. A pronounced acute hyperammonemia after the final infusion (1260 250 µM) coincided with severe symptoms and one mortality during the infusion. The previously unrecognized acute phase of hyperammonemia associated with asparaginase infusion coincides with infusion reactions. The juvenile pig is a translational animal model for understanding the causes of acute and chronic hyperammonemia, differentiating from hypersensitivity reactions, and for improving infusion protocols to reduce acute hyperammonemia and to allow the continued use of asparaginase.

Recurrent massive hemoptysis from distal pulmonary pseudoaneurysms complicating invasive aspergillosis in a teenager.

Invasive pulmonary aspergillosis in children rarely complicates life-threatening massive hemoptysis. Here, we report the case of a 15-year-old girl with acute lymphoblastic leukemia who was hospitalized for fever and medullary aplasia 1 month after beginning chemotherapy for invasive pulmonary aspergillosis. Despite voriconazole and caspofungine treatment, excavation of some lesions caused a unilateral small pneumothorax and bilateral pleural effusion, justifying intensive care management. The massive hemoptysis that occurred on day 23 was complicated with heart failure, and the patient was promptly resuscitated. Fibroscopy and computed tomography angiography (CTA) did not reveal the origin or cause of the bleeding. A second massive bleeding event occurred on day 32, and heart failure resolved after 10min of low flow. A new CTA showed 2 pseudoaneurysms of the subsegmental pulmonary arteries that were treated with embolization. Sedation was gradually decreased owing to improvement in respiratory status, but the patient did not regain consciousness because of deep brain sequelae. A limitation of care was decided upon, and the patient died in the following weeks. Massive hemoptysis is a rare life-threatening complication of invasive pulmonary aspergillosis, especially in children. Pulmonary artery pseudoaneurysms are unusual and should be detected as soon as possible to guide therapy. Intensive care management should be followed by embolization if the patient is stable otherwise, surgery is indicated, ideally after identifying the source of bleeding by CTA or bronchoscopy. Early CTA follow-up can be proposed if the source of bleeding is still unknown as pseudoaneurysms can appear or grow rapidly.

Multiparametric flow cytometry directing the evaluation of CRLF2 rearrangements and JAK2 status in pediatric B cell precursor acute lymphoblastic leukemia.

This study aimed to determine whether cytokine receptor-like factor 2 (CRLF2) antigen expression evaluated using multiparametric flow cytometry (MFC) could predict the genotype of CRLF2 and Janus kinase 2 (JAK2) status for application in the diagnosis of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). A total of 321 BCP-ALL bone marrow samples were collected, 291 at diagnosis and 13 at first relapse, while 17 samples were excluded due to low cellular viability. The CRLF2 antigen expression was evaluated using flow cytometry (percentage of positivity and median fluorescence intensity MFI). The CRLF2 transcript levels were assessed via quantitative reverse transcription polymerase chain reaction using SYBR Green. The CRLF2 rearrangements (CRLF2-r) were identified using the CRLF2 break-apart probe via fluorescence in situ hybridization. Sanger sequencing was performed to identify the JAK2 exon 16 mutations. We observed that 60 of the 291 cases (20.6%) presented CRLF2 antigen positivity, whereas the CRLF2 transcript overexpression was found in 19 of 113 cases (16.8%). The JAK2 mutation was found in four out of 116 cases (3.4%), all of which had CRLF2 ≥10% of positive cells and intermediate or high MFI (p < 0.0001). In addition, in the 13 cases with the CRLF2-r, a positive correlation was found with the CRLF2 antigen intermediate (61.5%) MFI (p 0.017). Finally, the CRLF2-positive antigen was identified in the BCP-ALL subclones. The identification of the CRLF2 antigen using the MFC, based on the percentage of positivity and MFI values, is a useful tool for predicting JAK2 mutations and CRLF2-r.

CAR-T therapy as a consolidation in remission B-ALL patients with poor prognosis.

To date, almost all studies regarding chimeric antigen receptor (CAR)-T cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) were performed in refractoryrelapsed (rr) or minimal residual disease-positive patients. CAR-T therapy in remission patients has not been reported. To observe the treatment outcome of CAR-T cells for remission B-ALL patients with poor prognosis. CAR-T treatment was applied to two B-ALL patients in remission status who had poor prognostic factors and refused transplantation, and one case was unable to accept standard chemotherapy owing to multiple complications. The procedure of CAR-T therapy in these two remission patients was the same as that in rr B-ALL patients. Lentiviral vectors encoding second generation CARs composed of CD3ζ and 4-1BB were used to produce CAR-T cells. Lymphodepleting agents fludarabine and cyclophosphamide were administered prior to cell infusion. Grade I cytokine release syndrome occurred after each T-cell infusion and there was no neurotoxicity. CAR-T treatment followed by non-intensive maintenance chemotherapy and targeted drugs allowed both patients to obtain a long-term event-free survival of more than three and a half years without transplantation. CAR-T therapy could be used in high-risk B-ALL patients as a consolidation to avoid transplantation, the combination of CAR-T and following maintenance therapy may be better than CAR-T alone for durable remission.

Clinicopathologic and genetic evaluation of B-lymphoblastic leukemia with intrachromosomal amplification of chromosome 21 (iAMP21) in adult patients.

Intrachromosomal amplification of chromosome 21 (iAMP21) defines a rare provisional entity of B-cell acute lymphoblastic leukemia (B-ALL) in the current WHO classification and has been described as specific for pediatric patients with a median age at diagnosis of 9-10 years. We report two adult cases of B-ALL with iAMP21, one 31-year-old woman and one 40-year-old man, identified by karyotyping and next generation sequencing (NGS), with fluorescence

Pneumocystis jirovecii pneumonia PJP An unrecognized concern in AML patients on Venetoclax.

Pneumocystis jirovecii pneumonia (PJP) is infrequently found in patients with acute myeloid leukemia (AML) whereas its more commonly found in lymphoid malignancies like acute lymphoblastic leukemia and various lymphomas. AML patients are conventionally treated with intensive chemotherapeutic regimen which includes Daunorubicin, Idarubicin, Cytarabine and various other drugs. TrimethoprimSulfamethoxazole prophylaxis is not routinely administered to such patients. In recent years, targeted therapies like Venetoclax which is a Bcl-2 inhibitor have been introduced for AML treatment which is given in combination with other chemotherapy and targeted molecules. There is tremendous use of Venetoclax for AML recently specially in unfit and elderly population. We are witnessing this uncommon infection more commonly in those patients treated with Venetoclax based therapy. We report the case series of five patients of AML who were treated with Venetoclax based therapy and had subsequently developed PJP leading to death in four of them. The incidence of PJP was 13.2% among the patients treated with Venetoclax based treatment at our institution in that timeframe. The low index of suspicion led to delay in diagnosis and thereby treatment. Such an association of Venetoclax and Pneumocystis jirovecii pneumonia has not been reported till date, so this prompts for early detection and treatment of this potentially life threatening but treatable infection. So the role of routine prophylaxis with TrimethoprimSulfamethoxazole in those receiving Venetoclax based therapy in AML patients merits a thought.

Development of a Therapeutic Video Game With the MDA Framework to Decrease Anxiety in Preschool-Aged Children With Acute Lymphoblastic Leukemia Mixed Methods Approach.

Preschool-aged children with acute lymphoblastic leukemia (ALL) receive long-term treatment according to the Taiwan Pediatric Oncology Group (TPOG)-ALL 2013 protocol. Severe anxiety and noncompliance ahead of frequent invasive therapies leads to an increase in health care costs. Previous studies have shown that therapeutic video games (TVGs) can decrease the anxiety experienced by children who are ill. To our knowledge, no existing TVG has been designed specifically for preschool-aged children with ALL in Taiwan. The purpose of this study was to develop a TVG using the popular Mechanics, Dynamics, and Aesthetics (MDA) framework for game design and to investigate the effect of this TVG on the reduction of therapy-related anxiety among preschool-aged children with ALL. This study used a mixed methods approach over three phases (1) develop a TVG using the MDA framework, (2) test the reliability of the TVG among three certified childrens art therapists, and (3) evaluate the reduction of therapy-related anxiety among participants after using the TVG for 6 weeks, using a two-group, stratified randomized controlled trial at a medical center in northern Taiwan. Eligible preschool-aged children with ALL were randomly assigned 11 into an experimental group or a control group. The two groups of subjects received the same usual care, and only the experimental group had access to and used the TVG. The childrens anxiety responses were reported by their family caregivers using the face rating scale (FRS). Descriptive analyses, the Fisher exact test, the Pearson chi-square test, and the Mann-Whitney U test were used to statistically analyze the variables. Six mechanics rules supported the dynamics of the TVG using four main features-character, nursery, tasks, and market-in order to complete all of the therapy-related anxiety reduction scenarios and to achieve eight aesthetics goals. The results of reliability test showed that participants found the TVG to be useful and trustworthy for preschool-aged children with ALL (Cronbach α.98). A total of 15 participants were enrolled and randomly allocated to the experimental group (n7) or the control group (n8). The average number of TVG log-ins was 37.9 (SD 15.30, range 14-62) in the experimental group. The demographic data showed homogeneity across the two groups regarding age (3 to 5 years), sex (male), risk classification (standard risk), and treatment status (continuation therapy). The mean FRS score was 6.16 (SD 3.31) for the experimental group as compared to 7.45 (SD 2.71) for the control group (P.04), which represented a significant difference between the groups at the 6-week follow-up. This research provides evidence that using a TVG can decrease anxiety in preschool-aged children with ALL in Taiwan. The TVG could be used to support clinical professionals before they perform invasive therapies. However, it is recommended to increase the statistical power for inference. ClinicalTrials.gov NCT04199637 httpswww.clinicaltrials.govct2showNCT04199637.

Prognostic significance of copy number variation in B-cell acute lymphoblastic leukemia.

Copy number variations (CNVs) are widespread in both pediatric and adult cases of B-cell acute lymphoblastic leukemia (B-ALL) however, their clinical significance remains unclear. This review primarily discusses the most prevalent CNVs in B-ALL to elucidate their clinical value and further personalized management of this population. The discovery of the molecular mechanism of gene deletion and the development of targeted drugs will further enhance the clinical prognosis of B-ALL.

Cerebral sinuses thrombosis prior to the diagnosis of acute lymphoblastic leukemia in a child A case report.

Acute lymphoblastic leukemia is the most common malignancy in children. In children, venous thromboembolism is relatively common. In most cases, venous thromboembolism manifests in patients who are diagnosed with acute lymphoblastic leukemia. Several risk factors associated with acute lymphoblastic leukemia predispose patients to the development of venous thromboembolism. Unlike most reported cases of venous thromboembolism, herein we report a child who developed cerebral venous sinus thrombosis prior to the diagnosis of acute lymphoblastic leukemia. The patient recovered from an attack of acute gastroenteritis with sepsis, pancytopenia, and disseminated intravascular coagulation 2 weeks before the development of thrombosis. Her laboratory workup for coagulopathy and disseminated intravascular coagulation was normal at the time of diagnosis of cerebral sinus thrombosis. The genetic workup for thrombophilia risk identified several genetic thrombophilia mutations the homozygous factor XIII V34L and MTHFR A1298C mutations and heterozygous factor V Leiden mutation. Three weeks later, the patient was diagnosed with acute lymphoblastic leukemia. However, it remains questionable whether the thrombotic event was caused by the previous infection of gastroenteritis, sepsis, and disseminated intravascular coagulation picture (which was augmented by her genetic thrombophilia risk), or was it caused by acute lymphoblastic leukemia (that was not detected at early stages with its associated hypercoagulable state), or was it caused by a type of paraneoplastic syndrome. A multifactorial etiology is proposed.

Chimeric Antigen Receptor T Cells Targeting Cell Surface GRP78 to Eradicate Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a serious, life-threatening hematological malignancy. The treatment outcome of relapsed or refractory AML patients remains dismal, and new treatment options are needed. Chimeric antigen receptor (CAR) T cells have been successful in improving the prognosis for B-lineage acute lymphoblastic leukemia and lymphoma by targeting CD19. However, CAR T-cell therapy for AML is still elusive, owing to the lack of a tumor-specific cell surface antigen and spare hematopoietic stem cells (HSCs). This study generated a novel CAR construction that targets the cell surface protein glucose-regulated protein 78 (GRP78) (csGRP78). We confirmed that GRP78-CAR T cells demonstrate an anti-tumor effect against human AML cells

Relapse Mechanism and Treatment Strategy After Chimeric Antigen Receptor T-Cell Therapy in Treating B-Cell Hematological Malignancies.

Over the past few decades, immunotherapy has revolutionized the modern medical oncology field. Chimeric antigen receptor (CAR)-T cell therapy has a promising curative effect in the treatment of hematological malignancies. Anti-CD19 CAR-T cells are the most mature CAR-T cells recently studied and in recent years it has achieved a complete remission rate of approximately 90% in the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Although CAR-T cell therapy has greatly alleviated the disease in patients with leukemia or lymphoma, some of them still relapse after treatment. Therefore, in this article, we discuss the factors that may contribute to disease relapse following CAR-T cell therapy and summarize potential strategies to overcome these obstacles, thus providing the possibility of improving standard treatment regimens.

Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR).

Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trials primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100 mgm

Outcome of adolescents and young adults with acute lymphoblastic leukemia in a single center in Brazil.

Acute lymphoblastic leukemia (ALL) presents a poor prognosis in adults. The adoption of pediatric protocols has been changing this scenario, especially for adolescents and young adults (AYA). We aimed to evaluate a consecutive series of patients treated at the State Institute of Hematology of Rio de Janeiro between 2012 and 2020, focusing on the AYA subgroup. The B-ALL was the most frequent subtype (81.6%) and AYA, the predominant age group (57.7%). The median overall survival (OS) was 9.4 months. High early mortality was observed and sepsis was the main cause of death. Better OS results were noted in AYA, in comparison to over 39y (13.3 × 6.2 months, respectively), the Berlin-Frankfurt-Münster (BFM) being the protocol of choice in this group. The use of the pediatric protocol seems to improve the OS of AYA, however, high rates of deaths from infection were observed, demonstrating the need for advances in the Brazilian public system clinical support.

Prevention and management of pegaspargase associated-toxicities (excluding coagulation abnormalities). Recommendations of the French Society of Children and Adolescent Cancers (Leukemia committee).

Pegaspargase (Oncaspar®), a pegylated form of native Escherichia Coli-derived L-asparaginase is an essential component chemotherapy used in the treatment of acute lymphoblastic leukemia (ALL) in pediatric and adult patients. Its particular toxicity profile requires a specific management to improve safety and tolerability and optimize treatment outcome and therefore survival. Within the framework of workshops of practice harmonization of the French Society of Children and Adolescent Cancers, diagnostic and management of the most commonly occuring toxicities (excluding coagulation abnormalities) during Pegaspargase treatment were reviewed according to the analysis of published studies.

Allogeneic CD34-selected stem cell boost as salvage treatment of life-threatening infection and severe cytopenias after CAR-T cell therapy.

A variable incidence of profound cytopenia has been described in patients receiving chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory (RR) B-cell acute lymphoblastic leukemia (ALL). This complication leads to severe infection in some cases, especially those who present additional risk factors including prior hematopoietic stem cell transplantation (HSCT). We report a case of breakthrough invasive fungal infection in a patient with prolonged neutropenia after CAR-T cell therapy administered for relapsed B-cell ALL after allogeneic haploidentical HSCT. After disease progression was discarded, therapy with antifungal agents, G-CSF and thrombopoietin analogue was started. However, no sign of haematological recovery or infection improvement was observed. A fresh mobilized selected CD34-stem cell boost from her haploidentical transplant donor was infused without further conditioning. Within 15 days of mobilized CD34-boost administration the patient showed complete resolution of both the aplasia and fungal infection. This case illustrates as proof-of-concept the efficacy and safety of selected CD34-stem cell boost from prior donor as salvage treatment of prolonged cytopenias after CAR-T cell therapy.

Longitudinal investigation of suicidal ideation and associated factors during pediatric acute lymphoblastic leukemia chemotherapy.

This study describes the prevalence of suicidal ideation (SI) during acute lymphoblastic leukemia (ALL) therapy and investigates the influence of clinical factors and physical symptoms on SI. The Childrens Depressive Inventory (CDI-2) was administered to ALL patients (diagnosed 2012-2017) at start of consolidation, delayed intensification (DI), maintenance cycle 1 (MC1), and maintenance cycle 2 (MC2) in a multi-site study. SI was present if patients endorsed the item I want to kill myself. Logistic regression models evaluated associations between SI and sociodemographic factors depressive symptoms and below average, average, and above average symptom clusters identified using latent class analysis of pain, nausea, fatigue, and sleep. Participants (n 175) were 51% male, 75% high-very high-risk disease, with a median age of 11.2 years at diagnosis (range 7-18 years). Overall, 14.9% of patients (75% under age 12 years) endorsed SI during treatment, including 4% at start of consolidation, 9% at DI, 8% at MC1, and 4% at MC2. Non-Hispanic Other patients were 10.9-times (95% CI 2.30-53.40) more likely than non-Hispanic Whites to endorse SI (p 0.003). The frequency of SI was higher in patients experiencing above average (53.3%) compared to below average (4.1%, p 0.003) symptoms. Depressive symptoms were consistently associated with SI. SI during the initial year of childhood ALL was more prevalent in children under the age of 12 years, from ethnic groups not typically associated with increased risk, and who endorsed increased physical and depressive symptoms. Findings highlight the need for improved screening of mental health problems to mitigate symptoms of distress.

Ku70 affects the frequency of chromosome translocation in human lymphocytes after radiation and T-cell acute lymphoblastic leukemia.

As one of the most common chromosomal causes, chromosome translocation leads to T-cell acute lymphoblastic leukemia (T-ALL). Ku70 is one of the key factors of error-prone DNA repair and it may end in translocation. So far, the direct correlation between Ku70 and translocation has not been assessed. This study aimed to investigate the association between Ku70 and translocation in human lymphocytes after radiation and T-ALL. Peripheral blood lymphocytes (PBLs) from volunteers and human lymphocyte cell line AHH-1 were irradiated with X-rays to form the chromosome translocations. Phytohemagglutinin (PHA) was used to stimulate lymphocytes. The frequency of translocation was detected by fluorescence in situ hybridization (FISH). Meanwhile, the expression of Ku70 was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Furthermore, Ku70 interference, overexpression and chemical inhibition were used in AHH-1 cell lines to confirm the correlation. Finally, the expression of Ku70 in T-ALL samples with or without translocation was detected. The expression of Ku70 and frequencies of translocation were both significantly increased in PBLs after being irradiated by X-rays, and a positive correlation between the expression (both mRNA and protein level) of Ku70 and the frequency of translocation was detected (r 0.4877, P 0.004 r 0.3038, P 0.0358 respectively). Moreover, Ku70 interference decreased the frequency of translocations, while the frequency of translocations was not significantly affected after Ku70 overexpression. The expression of Ku70 and frequencies of translocation were both significantly increased in cells after irradiation, combined with chemical inhibition (P < 0.01). The protein level and mRNA level of Ku70 in T-ALL with translocation were obviously higher than T-ALL with normal karyotype (P 0.009, P 0.049 respectively). Ku70 is closely associated with the frequency of chromosome translocation in human lymphocytes after radiation and T-ALL. Ku70 might be a radiation damage biomarker and a potential tumor therapy target.

Preclinical validation and treatment of volumetric modulated arc therapy based total bone marrow irradiation in Halcyon™ ring gantry linear accelerator.

This study aims​ to report preclinical validation, and the first clinical treatment of total bone marrow irradiation (TMI) and total bone marrow and lymph nodal irradiation (TMLI) using Volumetric modulated arc therapy in Halcyon-E ring gantry linear accelerator. Preclinical validation includes simulation, planning, patient-specific QA, and dry run. Four patients, two female and two male, with body weights of 116 kg, 52 kg, 64 kg, and 62 kg with two with chronic myeloid leukemia, one each with acute lymphoblastic leukemia and acute myeloid leukemia (AML) were simulated and planned for TMITMLI. Patients were immobilized with a full-body vacuum bag. Head first supine (HFS) and Feet first supine (FFS) CT scans were acquired from head to knee and knee to toe. Planning target volume (PTV) was created with a uniform margin of 6 mm over the total bone marrowbone marrow lymph nodes. HFS and FFS PTVs were optimized independently using 6MV unflatten energy for 12 Gy in 6 fractions. Plans were merged to create the resultant dose distribution using a junction bias dose matching technique. The total number of isocenters was ≤ 10 per CT set, and two to four full arcs were used for each isocenter. A junction dose gradient technique was used for dose feathering between arcs between adjacent isocenters. Only one female patient diagnosed as AML received the TMLI treatment, while the other three patients dropped out due to clinical complications and comorbidities that developed in the time between simulation and treatment. The result presented has been averaged over all four patients. For PTV, 95% dose was normalised to 95% volume, PTVV107% receiving 3.3 ± 3.1%. Total lung mean and V12Gy were 1048.6 ± 107.1 cGy and 19.5 ± 12.1%. Maximum lens doses were 489.5 ± 35.5 cGy (left L) and 497 ± 69.2 cGy (right R). The mean cardiac and bilateral kidney doses were 921.75 ± 89.2 cGy, 917.9 ± 63.2 cGy (L), and 805.9 ± 9.7 cGy (R). Average Monitor Unit was 7738.25 ± 1056.6. The median number of isocenters was 17(HFSFFS), average MUDose (cGy) ratio per isocenter was 2.28 ± 0.3. Halcyon-E ring gantry linear accelerator capable of planning and delivering TMITMLI.​​.

Anlotinib exerts potent antileukemic activities in Ph chromosome negative and positive B-cell acute lymphoblastic leukemia via perturbation of PI3KAKTmTOR pathway.

Despite advances in the development of novel targeted therapies, the need for B-ALL alternative treatments has not been met. Anlotinib could blunt the proangiogenic activity of VEGFR, PDGFR, and FGFR, and has shown strong antitumor activities across multiple tumors. However, anlotinib cytotoxicity against B-ALL has not ever been evaluated, thus prompting us to initiate this study. Expression2Kinases program was used to identify potential treatment targets. Cell viability and apoptosis were determined by CCK-8 and Annexin VPI staining kit, respectively. qRT-PCR and Western blotting were utilized to investigate the molecular mechanisms. In vivo antileukemia activity of Anlotinib was evaluated in a Ph Compared with treatment-naive B-ALL cases, RR B-ALL patients had higher activities in the VEGFVEGFR signaling and the PI3KAKTmTOR pathway. Exposure of Ph This work provides impressive preclinical evidence of anlotinib against Ph

PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120.

Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies to target poor prognosis subgroups, like PAX5 translocated. We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes. We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features. Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone. This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group. Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazione Cariparo.

Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia.

Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse. Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL. This article is highlighted in the In This Issue feature, p. 2483.

Energy balance in cancer survivors at risk of weight gain a review.

The study of energy balance i.e., energy intake (EI) and energy expenditure (EE) is a powerful tool for understanding body weight regulation and may contribute to our understanding of rapid weight gain risk in certain cancer survivors post-diagnosis. The purpose of this review was to summarize studies that assessed longitudinal, prospective changes in components of energy balance from diagnosisstart of treatment to any duration of follow-up in cancer survivors with prior evidence of weight gain (breast, prostate, thyroid, gynecologic, testicular, and acute lymphoblastic leukemia) RESULTS The available literature suggests that energy balance components may be altered in cancer survivors who have a heightened risk of weight gain post-diagnosis. The evidence for EI was overall inconsistent. Conversely, decreases in resting and physical activity EE during the active phases of treatment (e.g., chemotherapy, hypothyroid state) were commonly noted, which then slowly rebounded towards baseline levels at the end of treatment and during follow-up assessments. Much of this evidence is based on data collected from breast cancer survivors, which highlights a paucity of data currently available on other cancer types. While there is growing acknowledgement that weight management interventions in cancer survivors are needed, it is important to recognize that changes in both behavioral (EI, physical activity EE) and passive (resting EE, thermic effect of food) components of energy balance may occur post-diagnosis. This information can help to inform weight management interventions which often entail modifications in diet andor physical activity.

FDA Approval Summary Brexucabtagene Autoleucel for Treatment of Adults With Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.

In October 2021, the FDA approved brexucabtagene autoleucel (brexu-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (B-ALL). Approval was based on the phase II portion of ZUMA-3, a single-arm, open-label, multicenter trial that evaluated a single infusion of brexu-cel, preceded by lymphodepleting chemotherapy with cyclophosphamide and fludarabine, in this population. Efficacy was established on the basis of complete remission (CR) within 3 months after infusion and the duration of CR (DOCR). Among 54 patients in the efficacy analysis population, the CR rate was 52% (95% CI 38, 66) with a median time-to-response of 56 days. With a median follow-up for responders of 7.1 months, the median DOCR was not reached. For all leukapheresed patients in the phase II portion of this trial (n 71), the CR rate was 41% (95% CI 29, 53). Among the 78 patients treated with the approved dose of brexu-cel, serious adverse reactions occurred in 79% and fatal adverse reactions occurred in 5% and included cerebral edema and infections. Cytokine release syndrome occurred in 92% (grade ≥3, 26%) and neurologic toxicities occurred in 87% (grade ≥3, 35%), leading to implementation of a risk evaluation and mitigation strategy (REMS). Postmarketing study with 15 years of follow-up will further evaluate long-term safety in adult patients with relapsed or refractory B-ALL.

Low Expression of CD5 and CD6 Is Associated with Poor Overall Survival for Patients with T-Cell Malignancies.

T-cell malignancies (TCMs), including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), are highly aggressive and have a poor prognosis. To further understand prognostic stratifications and to design targeted therapies, this study aims to explore novel, potential biomarkers based on alterations in immune costimulatory molecules (CMs) for TCMs. Peripheral blood from 25 Seven CMs were associated with overall survival (OS). Among these CMs, CD5 and CD6 had the highest pairwise positive correlation ( Low expression of CD5 and CD6 was associated with poor OS for TCM patients, and this may be a potential immune biomarker panel for prognostic stratification of TCM patients.

Case report Successful allogeneic stem cell transplantation in a child with novel GATA2 defect associated B-cell acute lymphoblastic leukemia.

GATA-binding protein 2 (

Endothelial cell-leukemia interactions remodel drug responses, uncovering T-ALL vulnerabilities.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and often incurable disease. To uncover therapeutic vulnerabilities, we first developed T-ALL patient-derived tumor xenografts (PDXs) and exposed PDX cells to a library of 433 clinical-stage compounds in vitro. We identified 39 broadly active drugs with antileukemia activity. Because endothelial cells (ECs) can alter drug responses in T-ALL, we developed an ECT-ALL coculture system. We found that ECs provide protumorigenic signals and mitigate drug responses in T-ALL PDXs. Whereas ECs broadly rescued several compounds in most models, for some drugs the rescue was restricted to individual PDXs, suggesting unique crosstalk interactions andor intrinsic tumor features. Mechanistically, cocultured T-ALL cells and ECs underwent bidirectional transcriptomic changes at the single-cell level, highlighting distinct education signatures. These changes were linked to bidirectional regulation of multiple pathways in T-ALL cells as well as in ECs. Remarkably, in vitro EC-educated T-ALL cells transcriptionally mirrored ex vivo splenic T-ALL at single-cell resolution. Last, 5 effective drugs from the 2 drug screenings were tested in vivo and shown to effectively delay tumor growth and dissemination thus prolonging overall survival. In sum, we developed a T-ALLEC platform that elucidated leukemia-microenvironment interactions and identified effective compounds and therapeutic vulnerabilities.

A novel CD19CD22CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL.

The bispecific T-cell engager (BiTE) blinatumomab against CD19 and CD3 has emerged as the most successful bispecific antibody (bsAb) to date however, a significant proportion of patients do not respond to the treatments or eventually experience relapse after an initial response, and the recurrence rate increases significantly due to escape or downregulation of the CD19 antigen. To enhance antitumor efficacy and overcome potential immune escape, we developed a novel approach to design a CD19CD22CD3 trispecific antibody (tsAb) by site-specifically fusing anti-CD19 scFv (FMC63) and anti-CD22 nanobody (Nb25) to the defined sites of the CD3 antigen-binding fragment (Fab, SP34). This strategy allows for the optimal formation of immune synapses mediated by CD19CD22CD3 between target cells and T cells. Optimized tsAb can be superior for inducing T-cell-specific cytotoxicity and cytokine production against CD19 andor CD22 tumor cells compared to other tsAb formats, and demonstrated significantly enhanced antitumor efficacy and the ability to overcome immune escape compared with the corresponding bsAbs alone or in combination, as well as with blinatumomab. In addition, tsAb treatment can lead to the long-term elimination of primary B-ALL patient samples in the PDX model and significantly prolong survival. This novel approach provides unique insight into the structural optimization of T-cell-redirected multispecific antibodies using site-specific recombination, and may be broadly applicable to heterogeneous and resistant tumor populations as well as solid tumors.

Clinical Characteristic, Diagnosis and Treatment of Acute Lymphoblastic Leukemia Combined with Pneumocystis Carinii Pneumonia in Children.

To investigate the clinical characteristics and treatment of pneumocystis carinii pneumonia (PCP) in children with acute lymphoblastic leukemia (ALL), in order to improve the early diagnosis and effective treatment. Clinical data of five children with ALL developing PCP in the post-chemotherapy granulocyte deficiency phase were analyzed retrospectively. The clinical manifestations, laboratory tests, imaging findings, treatment methods and effect were summarized. The male-to-female ratio of the five children was 1∶4, and the median age was 5.5 (2.9-8) years old. All patients developed PCP during granulocyte deficiency phase after induction remission chemotherapy. The clinical manifestations were generally non-specific, including high fever, tachypnea, dyspnea, non-severe cough, and rare rales in two lungs (wet rales in two patients). Laboratory tests showed elevated C-reactive protein (CRP), serum procalcitonin (PCT), (1,3)-β-D-glucan (BDG), lactate dehydrogenase (LDH) and inflammatory factors including IL-2R, IL-6 and IL-8. Chest CT showed diffuse bilateral infiltrates with patchy hyperdense shadows. Pneumocystis carinii(PC) was detected in bronchoalveolar lavage fluid (BALF) or induced sputum by high-throughput sequencing in all patients. When PCP was suspected, chemotherapy was discontinued immediately, treatment of trimethoprim-sulfame thoxazole (TMP-SMX) combined with caspofungin against PC was started, and adjunctive methylprednisolone was used. Meanwhile, granulocyte-stimulating factor and gammaglobulin were given as the supportive treatment. All patients were transferred to PICU receiving mechanical ventilation due to respiratory distress during treatment. Four children were cured and one died. PCP should be highly suspected in ALL children with high fever, dyspnea, increased LDH and BDG, and diffuse patchy hyperdense shadow or solid changes in lung CT. The pathogen detection of respiratory specimens should be improved as soon as possible. TMPSMZ is the first-line drug against PCP, and the combination of Caspofungin and TMPSMZ treatment for NH-PCP may have a better efficacy. Patients with moderate and severe NH-PCP may benefit from glucocorticoid. 儿童急性淋巴细胞白血病合并卡氏肺孢子虫肺炎的临床特点和诊治分析. 探讨儿童急性淋巴细胞白血病（ALL）化疗后骨髓抑制期并发卡氏肺孢子虫肺炎(PCP)的临床特点和治疗对策，为临床医生进行早期诊断和有效治疗提供参考. 回顾性分析5例儿童ALL化疗后粒细胞缺乏期发生PCP的临床表现、实验室检查、影像学结果以及治疗和转归. 5例患儿男女比例为1∶4，中位年龄5.5（2.9-8）岁。5例患儿均为诱导缓解化疗后粒细胞缺乏期间出现PCP，临床表现缺乏特异性，主要表现为高热、气促、呼吸费力，咳嗽不剧烈，2例出现肺部湿啰音，3例双肺无啰音。实验室检查结果提示，C反应蛋白（CRP）、血清降钙素原（PCT）、（1，3）-β-D-葡聚糖(BDG)、乳酸脱氢酶(LDH)以及炎症因子IL-2R、IL-6、IL-8均升高；胸部CT表现为双肺弥漫多发斑片状密度增高影；均通过高通量测序技术在肺泡灌洗液或深部痰中检出卡氏肺孢子虫。所有患儿疑诊PCP即停化疗，并予复方磺胺甲恶唑片联合卡泊芬净抗卡氏肺孢子虫治疗和甲基强的松龙抗炎，同时予粒细胞刺激因子、丙种球蛋白等支持治疗；期间所有儿童均因呼吸窘迫转入PICU，予无创或有创机械通气治疗。4例患儿治愈，1例患儿死亡. ALL患儿出现高热、呼吸困难、LDH及BDG升高，肺部弥漫斑片影或实变时，应高度怀疑PCP，尽快完善呼吸道标本的病原体检测。TMPSMZ是抗PCP的一线用药，卡泊芬净静滴联合TMPSMZ口服治疗NH-PCP可能有更好的疗效，糖皮质激素辅助治疗中重度NH-PCP可能使患者获益.

Effect of Netrin-1 on VEGFA Expression in T-ALL Cells and Its Related Mechanism.

AbstractObjective To investigate the effect of the axon guidance factor Netrin-1 on the expression of VEGFA in T cell acute lymphoblastic leukemia(T-ALL) and its related mechanism. ELISA assays were applied to detect the levels of Netrin-1 and VEGFA in the bone marrow (BM) samples from children in the T-ALL and control group. The level of Netrin-1 and VEGFA were compared between control children and patients, and the liner correlation between Netrin-1 and VEGFA was analyzed. The T-ALL cells Jurkat and Molt-4 were culture in vitro, and the cells were treated with different concentration of Netrin-1 (0, 25, 50, 100 ngml) for 24 h, quantitative RT-PCR (qRT-PCR) and Western blot were used to detect the VEGFA expression in Jurkat, Molt-4 cells. The expression of Netrin-1 receptors in T-ALL cells was detected by qRT-PCR and the interaction between Netrin-1 and receptor in each cells was detected by co-IP. Furthermore, Western blot was used to detect the phosphorylation level of key prateins of AKT signal transduction pathway including Akt and mTOR in T-ALL cells treated with Netrin-1 (100 ngml). The expression of VEGFA and phosphorylation of AKT pathway transducers were detected by Western blot, after T-ALL cells treated with Netrin-1 (100 ngml) combined with inhibitors specific to Akt or mTOR. The expression level of Netrin-1 and VEGFA in T-ALL patients BM samples were both signi-ficantly higher than that of control group. And the expression level of Netrin-1 was positively correlated with that of VEGFA（r20974). With the increase of Netrin-1 concentration, the expression level of VEGFA also increased(P<0.05）. Netrin-1 interacted with its receptor, integrin-β4 at the Netrin-1 concentration of 100 ngml. Further, the treatment of Netrin-1 could increase the phosphorylation of Akt and mTOR, which were the key transducers of AKT pathway. After treatment of T-ALL cells with Netrin-1 (100 ngmL) and Akt inhibitor, the expression of VEGFA and phosphorylation of Akt or mTOR decreased. When the cells were treated with Netrin-1(100 ngml) and mTOR inbititor, the phosphorylation level of mTOR and the expression of VEGFA decreased, the phosphorylation level of Akt increased. The expression of Netrin-1 and VEGFA in bone marrow of childred with T-ALL were abnormal, and there was a linear relationship between them. Netrin-1 can interact with its receptor, integrin-β4 and activate AKT transduction pathway to elevate the expression of VEGFA in T-ALL cells. Netrin-1对T-ALL细胞中VEGFA表达的影响及相关机制研究. 探讨Netrin-1对急性T淋巴细胞白血病（T Cell Acute Lymphoblastic Leukemia, T-ALL）细胞中VEGFA水平的影响及可能的作用机制. 采用ELISA法检测10例T-ALL患儿和23例非恶性血液系统疾病患儿骨髓中Netrin-1、VEGFA的水平并进行比较，分析疾病组和对照组患儿骨髓中Netrin-1与VEGFA水平的相关性。体外培养T-ALL细胞株Jurkat、Molt-4，用不同浓度的Netrin-1（0，25，50，100 ngml）处理细胞24 h后，qRT-PCR及Western blot检测不同浓度下各细胞中VEGFA的表达量；qRT-PCR检测两种细胞中Netrin-1受体的表达,并采用co-IP检测Netrin-1与T-ALL细胞中受体的结合；Western blot检测各组细胞中Akt-mTOR通路中关键蛋白的磷酸化水平。使用AktmTOR抑制剂与Netrin-1（100 ngml）联合处理T-ALL细胞后，采用Western blot检测各组细胞中VEGFA的表达量以及AktmTOR通路中关键分子的磷酸化水平. T-ALL患儿骨髓中Netrin-1及VEGFA表达水平显著高于对照组（P<0.05），且在T-ALL患者中两者表达水平呈线性相关（r20.974）。随着Netrin-1浓度的升高，VEGFA的表达水平也升高（P<0.05）。当Netrin-1浓度为100 ngml时，Netrin-1与Integrin-β4受体结合。Netrin-1浓度为100 ngml处理细胞24 h后，Akt、mTOR通路关键分子的磷酸化水平均提高；当Netrin-1（100 ngml）与Akt抑制剂联合处理T-ALL细胞后，VEGFA的表达量下降，Akt、mTOR的磷酸化水平也下降；而与mTOR抑制剂联合处理细胞后，Akt的磷酸化水平升高，mTOR的磷酸化水平降低，VEGFA的表达量也下降. T-ALL患儿骨髓中Netrin-1及VEGFA表达量存在异常且两者存在线性关系；Netrin-1通过Integrin-β4受体，激活AktmTOR通路诱导T-ALL细胞表达VEGFA.

The Effect of KRAS on Proliferation and Apoptosis of T-ALL Cell Lines.

To investigate the function of RAS protein on the progression of the T-ALL cell lines in vitro. The DNA of the T-ALL cells was purified then amplified the coding regions of three RAS genes (KRAS, NRAS, HRAS) by PCR reaction. After T-A cloning, the coding regions of KRAS, NRAS and HRAS were sequenced by Sanger Sequencing. The siRNA oligonucleotides were cloned into the pSEH-361 vector, which were then packaged into retroviral together with pAMPHO and pVSVG in the HEK-293T cells. The T-ALL cells were infected with the retrovirus. The gene expressions were detected by qRT-PCR and Western blot. The T-ALL cells were stained with Annexin V-PE7-AAD and the apoptotic cells were detected by flow cytometry. The T-ALL cells were stained with Hoechst 33258, and the cell cycle distribution was determined by flow cytometry. The expression of cleaved-Caspase 3 was stained with antibody and observed with fluorescence microscope. For RAS genes, beside the Loucy and the P12-ICH cells harbored KRAS c.6187G>A (p.KRAS The KRAS protein is vital for the progression of the T-ALL cells in vitro, it is a potential therapeutic target for T-ALL patients. KRAS对T-ALL细胞株增殖及凋亡的影响. 探讨RAS蛋白家族在维持T-ALL细胞株体外生长中的功能. 纯化T-ALL细胞株DNA，利用PCR法扩增3个RAS基因（KRAS、NRAS、HRAS）的编码区。经T-A克隆后，Sanger法对KRAS、NRAS、HRAS基因编码区测序。将siRNA克隆到pSEH-361载体，在HEK-293T细胞中与pAMPHO和pVSVG一起包装成逆转录病毒，随后感染T-ALL细胞。qRT-PCR和Western blot检测基因表达情况。利用Annexin V-PE7-AAD染色T-ALL细胞，流式细胞术检测细胞凋亡情况。利用Hoechst 33258染色T-ALL细胞，流式细胞术检测细胞周期分布情况。经抗体染色，荧光显微镜观察cleaved-Caspase 3蛋白的表达. 在T-ALL细胞株中，除Loucy和P12-ICH细胞KRAS基因发生c.6187G>A(p.KRAS KRAS蛋白维持T-ALL细胞株体外生长，是治疗T-ALL的潜在药物靶点.

Effect of Chemotherapy Course Delay on the Relapse of Paediatric B-cell Acute Lymphoblastic Leukemia.

To investigate the effect of course delay of CCLG-ALL-2008 regimen on the relapse of paediatric B-cell acute lymphoblastic leukemia (B-ALL) patients. Paediatric B-ALL patients newly diagnosed and treated with CCLG-ALL-2008 regimen in the Childrens Hospital of Soochow University from January 2011 to December 2014 were retrospectively analyzed to clarify the relationship between chemotherapy course delay and relapse, and explore the causes of course delay which led to relapse. Patients were followed up until July 2019. The correlation between treatment delay (number of weeks) and relapse rate was statistically significant (P0.034), and hazard ratio indicated that longer than 4 weeks had a significant effect. The effect of positive minimal residual disease (MRD) (1×10 Treatment delay exceeding 4 weeks, positive MRD at the 12th week, and myelosuppression are independent prognostic factors for relapse. 疗程拖延对儿童急性B淋巴细胞白血病复发的影响. 探讨急性B淋巴细胞白血病患儿采用CCLG-ALL-2008方案疗程拖延对疾病复发的影响。. 对2011年1月至2014年12月在苏州大学附属儿童医院初诊并接受CCLG-ALL-2008方案治疗的急性B淋巴细胞白血病患儿进行回顾性分析，明确化疗疗程拖延与复发的关系，并探究导致疗程拖延引起复发的原因，随访至2019年7月。. 疗程拖延周数对复发率的影响具有统计学意义（P0.034），风险率比提示大于4周影响显著。第12周微小残留病阳性（1×10-4≤微小残留病≤1×10-2）对复发率的影响亦有统计学意义（P0.041）。在疗程拖延原因中，单纯骨髓抑制对复发率的影响有统计学意义（P0.01）。. 疗程拖延4周以上、第12周微小残留病阳性和单纯骨髓抑制是影响复发的独立预后因素。.

Observation of Nutritional Status Changes in Patients with Acute Leukemia During Chemotherapy.

To assess changes of nutritional status by comprehensive nutrition assessment including nutritional risk screening, dietary assessment, blood biochemical index, and body composition in acute leukemia patients who had undergone chemotherapy. A total of 169 patients with acute leukemia treated at The First Affiliated Hospital of Soochow University from June 2018 to August 2019 were recruited for this study. Before and after chemotherapy, the NRS-2002 and PG-SGA scales, dietary intake, blood biochemical index and body composition were evaluated to compare the changes of nutritional status. NRS-2002 score and PG-SGA score after chemotherapy were significantly increased than those before chemotherapy (P<0.001). Many patients had insufficient nutritional intake during chemotherapy, and the dietary intake score of patients with induction chemotherapy was significantly lower than that of patients with consolidation chemotherapy (P0.043). The results of multivariate analysis showed that induction chemotherapy was the independent risk factor for the increase of PG-SGA scores and the decrease of dietary intake (all P<0.05). After chemotherapy, the white blood cell count, hemoglobin, and platelet count were significantly decreased (P<0.001), the prealbumin was significantly increased (P<0.001), and the blood glucose was increased (P0.04), but albumin was not significantly changed. The weight, body mass index, fat-free mass, skeletal muscle mass and intracellular water were all significantly decreased (P<0.001), and visceral fat area was increased significantly after chemotherapy (P<0.05), especially in newly-diagnosed acute lymphoblastic leukemia patients after the induction of chemotherapy. The nutritional status of patients with acute leukemia has undergone significant changes after chemotherapy. A single indicator has limited significance for nutritional status assessment. Comprehensive assessment of nutritional status by multiple tools is worthy of clinical application. 急性白血病患者化疗期间营养状况变化的观察研究. 针对接受诱导及巩固化疗的急性白血病患者进行包含营养风险筛查、膳食评价、血生化指标监测、人体成分分析的综合营养评估，分析化疗期间营养状况变化。. 纳入2018年6月至2019年8月于苏州大学附属第一医院就诊的169例急性白血病患者，化疗前后分别进行NRS-2002及PG-SGA量表评估，评估化疗过程中膳食摄入量，测定患者血常规、血生化指标，监测人体成分，从多个维度比较化疗前后营养状况的变化。. 化疗后患者NRS-2002评分、PG-SGA评分较化疗前明显升高（P<0.001）；化疗期间许多患者存在营养摄入不足情况，初治化疗患者膳食摄入评分明显低于巩固化疗患者（P0.043）；多因素分析结果显示，初治诱导化疗为患者PG-SGA评分升高、膳食摄入减少的独立危险因素( 均P<0.05)；患者接受化疗后，白细胞计数、血红蛋白、血小板计数较化疗前明显下降（P<0.001），前白蛋白明显升高（P<0.001），血糖升高（P0.04），白蛋白水平改变不明显；患者化疗后体重、身体质量指数、去脂体重、骨骼肌质量、细胞内水分均明显下降（P<0.001），内脏脂肪面积明显升高（P<0.05）。这一变化在初治急性淋系白血病患者中更明显。. 急性白血病患者化疗后营养状况发生了明显变化，单一指标对营养状态评估意义有限，多种工具综合评估营养状况值得在临床中推广应用。.

MiR-27a downregulates 14-3-3θ, RUNX1, AF4, and MLL-AF4, crucial drivers of blast transformation in t(411) leukemia cells.

The chromosomal translocation t(411)(q21q23), a hallmark of an aggressive form of acute lymphoblastic leukemia (ALL), encodes mixed-lineage leukemia (MLL)-AF4 oncogenic chimera that triggers aberrant transcription of genes involved in lymphocyte differentiation, including HOXA9 and MEIS1. The scaffold protein 14-3-3θ, which promotes the binding of MLL-AF4 to the HOXA9 promoter, is a target of MiR-27a, a tumor suppressor in different human leukemia cell types. We herein study the role of MiR-27a in the pathogenesis of t(411) ALL. Reverse transcription quantitative PCR (qPCR) reveals that MiR-27a and 14-3-3θ expression is inversely correlated in t(411) ALL cell lines interestingly, MiR-27a relative expression is significantly lower in patients affected by t(411) ALL than in patients affected by the less severe t(1221) leukemia. In t(411) leukemia cells, ectopic expression of MiR-27a decreases protein level of 14-3-3θ and of the key transcription factor RUNX1. We show for the first time that MiR-27a also targets AF4 and MLL-AF4 in agreement, MiR-27a overexpression strongly reduces AF4 and MLL-AF4 protein levels in RS411 cells. Consequent to AF4 and MLL-AF4 downregulation, MiR-27a overexpression negatively affects transcription of HOXA9 and MEIS1 in different t(411) leukemia cell lines. In agreement, we show through chromatin immunoprecipitation experiments that MiR-27a overexpression impairs the binding of MLL-AF4 to the HOXA9 promoter. Lastly, we found that MiR-27a overexpression decreases viability, proliferation, and clonogenicity of t(411) cells, whereas it enhances their apoptotic rate. Overall, our study identifies the first microRNAthat strikes in one hit four crucial drivers of blast transformation in t(411) leukemia. Therefore, MiR-27a emerges as a new promising therapeutic target for this aggressive and poorly curable form of leukemia.

Extracellular expression of

L-asparaginase (ASNase) is an efficient inhibitor of tumor development, used in chemotherapy sessions against acute lymphoblastic leukemia (ALL) tumor cells its use results in 80% complete remission of the disease in treated patients.

A Case of Central Nervous System Post-Transplant Lymphoproliferative Disorder Following Haploidentical Stem Cell Transplantation in a Patient With Acute Lymphoblastic Leukemia.

We present a differential diagnosis of an intracranial lesion following haploidentical stem cell transplantation (haplo-SCT) in a female patient with acute lymphoblastic leukemia (ALL). This patient received an anti-CD19-chimeric antigen receptor (CAR) T-cell therapy for refractory B-cell ALL and obtained minimal residual disease (MRD)-positive (0.03%) complete remission (CR). Then the patient received a bridging therapy of haplo-SCT. After bridging therapy, the patient maintained MRD-negative and full donor chimerism in bone marrow (BM) and was negative for Epstein-Barr virus (EBV)-DNA copy in peripheral blood. At 91 days after haplo-SCT, the patient presented with dizziness and fatigue and magnetic resonance imaging (MRI) demonstrated an intracranial lesion. The diagnosis of isolated extramedullary relapse (IEMR) was temporarily considered. Then next-generation sequencing (NGS) identified positive EBV-DNA in the cerebrospinal fluid, although EBV-DNA in the peripheral blood was negative. Furthermore, the positive EBV-DNA by NGS and complete donor chimerism in the brain tissue confirmed the diagnosis of central nervous system post-transplant lymphoproliferative disorder (CNS-PTLD). However, the EBV-encoded small RNAs (EBERs)

Asparagine is a non-essential amino acid since it can either be taken up via the diet or synthesized by asparagine synthetase. Acute lymphoblastic leukemia (ALL) cells do not express asparagine synthetase or express it only minimally, which makes them completely dependent on extracellular asparagine for their growth and survival. This dependency makes ALL cells vulnerable to treatment with L-asparaginase, an enzyme that hydrolyzes asparagine. To date, all clinically approved L-asparaginases have significant L-glutaminase co-activity, associated with non-immune related toxic side effects observed during therapy. Therefore, reduction of L-glutaminase co-activity with concomitant maintenance of its anticancer L-asparaginase effect may effectively improve the tolerability of this unique drug. Previously, we designed a new alternative variant of Erwinia chrysanthemi (ErA Erwinaze) with decreased L-glutaminase co-activity, while maintaining its L-asparaginase activity, by the introduction of three key mutations around the active site (ErA-TM). However, Erwinaze and our ErA-TM variant have very short half-lives in vivo. Here, we show that the fusion of ErA-TM with an albumin binding domain (ABD)-tag significantly increases its in vivo persistence. In addition, we evaluated the in vivo therapeutic efficacy of ABD-ErA-TM in a B-ALL xenograft model of SUP-B15. Our results show a comparable long-lasting durable antileukemic effect between the standard-of-care pegylated-asparaginase and ABD-ErA-TM L-asparaginase, but with fewer co-glutaminase-related acute side effects. Since the toxic side effects of current L-asparaginases often result in treatment discontinuation in ALL patients, this novel ErA-TM variant with ultra-low L-glutaminase co-activity and long in vivo persistence may have great clinical potential.

The use of ICU resources in CAR-T cell recipients a hospital-wide study.

CAR-T cell (chimeric antigen receptor T) therapy has emerged as an effective treatment of refractory hematological malignancies. Intensive care management is intrinsic to CAR-T cell therapy. We aim to describe and to assess outcomes in critically ill CAR-T cell recipients. Hospital-wide retrospective study. Consecutive CAR-T cell recipients requiring ICU admission from July 2017 and December 2020 were included. 71 patients (median age 60 years 37-68) were admitted to the ICU 6 days 4-7 after CAR-T cell infusion. Underlying malignancies included diffuse large B cell lymphoma (n 53, 75%), acute lymphoblastic leukemia (17 patients, 24%) and multiple myeloma (n 1, 1.45%). Performance status (PS) was 1 1-2. Shock was the main reason for ICU admission (n 40, 48%). Isolated cytokine release syndrome (CRS) was the most common complication (n 33, 46%), while 21 patients (30%) had microbiologically documented bacterial infection (chiefly catheter-related infection). Immune effector cell-associated neurotoxicity syndrome was reported in 26 (37%) patients. At ICU admission, vasopressors were required in 18 patients (25%) and invasive mechanical ventilation in two. Overall, 49 (69%) and 40 patients (56%) received tocilizumab or steroids, respectively. Determinant of mortality were the reason for ICU admission (disease progression vs. sepsis or CRS (HR 4.02 95%CI 1.10-14.65), Performance status (HR 1.97point 95%CI 1.14-3.41) and SOFA score (HR 1.16point 95%CI 1.01-1.33). Meaningful survival could be achieved in up to half the CAR-T cell recipients. The severity of organ dysfunction is a major determinant of death, especially in patients with altered performance status or disease progression.

Unconventional Oil and Gas Development Exposure and Risk of Childhood Acute Lymphoblastic Leukemia A Case-Control Study in Pennsylvania, 2009-2017.

Unconventional oil and gas development (UOGD) releases chemicals that have been linked to cancer and childhood leukemia. Studies of UOGD exposure and childhood leukemia are extremely limited. The objective of this study was to evaluate potential associations between residential proximity to UOGD and risk of acute lymphoblastic leukemia (ALL), the most common form of childhood leukemia, in a large regional sample using UOGD-specific metrics, including a novel metric to represent the water pathway. We conducted a registry-based case-control study of 405 children ages 2-7 y diagnosed with ALL in Pennsylvania between 2009-2017, and 2,080 controls matched on birth year. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between residential proximity to UOGD (including a new water pathway-specific proximity metric) and ALL in two exposure windows a primary window (3 months preconception to 1 y prior to diagnosisreference date) and a perinatal window (preconception to birth). Children with at least one UOG well within Our study including a novel UOGD metric found UOGD to be a risk factor for childhood ALL. This work adds to mounting evidence of UOGDs impacts on childrens health, providing additional support for limiting UOGD near residences. httpsdoi.org10.1289EHP11092.

A Comparison of Dexamethasone Plus Vincristine versus Standard Regimen in Induction Therapy of Adult Acute Lymphoblastic Leukemia Patients Undergoing Hematopoietic Stem Cell Transplantation.

Netrin-1 induces the anti-apoptotic and pro-survival effects of B-ALL cells through the Unc5b-MAPK axis.

B-cell acute lymphoblastic leukemia (B-ALL) comprises over 85% of all acute lymphoblastic leukemia (ALL) cases and is the most common childhood malignancy. Although the 5 year overall survival of patients with B-ALL exceeds 90%, patients with relapsed or refractory B-ALL may suffer from poor prognosis and adverse events. The axon guidance factor netrin-1 has been reported to be involved in the tumorigenesis of many types of cancers. However, the impact of netrin-1 on B-ALL remains unknown. The expression level of netrin-1 in peripheral blood samples of children with B-ALL and children without neoplasia was measured by enzyme-linked immunosorbent assay (ELISA) kits. Then, CCK-8 cell proliferation assays and flow cytometric analysis were performed to detect the viability and apoptosis of B-ALL cells (Reh and Sup B15) treated with exogenous recombinant netrin-1 at concentrations of 0, 25, 50, and 100 ngml. Furthermore, co-immunoprecipitation(co-IP) was performed to detect the receptor of netrin-1. UNC5B expression interference was induced in B-ALL cells with recombinant lentivirus, and then CCK-8 assays, flow cytometry assays and western blotting assays were performed to verify that netrin-1 might act on B-ALL cells via the receptor Unc5b. Finally, western blotting and kinase inhibitor treatment were applied to detect the downstream signaling pathway. Netrin-1 expression was increased in B-ALL, and netrin-1 expression was upregulated in patients with high- and intermediate-risk stratification group of patients. Then, we found that netrin-1 induced an anti-apoptotic effect in B-ALL cells, implying that netrin-1 plays an oncogenic role in B-ALL. co-IP results showed that netrin-1 interacted with the receptor Unc5b in B-ALL cells. Interference with UNC5B was performed in B-ALL cells and abolished the antiapoptotic effects of netrin-1. Further western blotting was applied to detect the phosphorylation levels of key molecules in common signaling transduction pathways in B-ALL cells treated with recombinant netrin-1, and the FAK-MAPK signaling pathway was found to be activated. The anti-apoptotic effect of netrin-1 and FAK-MAPK phosphorylation was abrogated by UNC5B interference. FAK inhibitor treatment and ERK inhibitor treatment were applied and verified that the FAK-MAPK pathway may be downstream of Unc5b. Taken together, our findings suggested that netrin-1 induced the anti-apoptotic effect of B-ALL cells through activation of the FAK-MAPK signaling pathway by binding to the receptor Unc5b. Video Abstract.

Chromothripsis is a frequent event and underlies typical genetic changes in early T-cell precursor lymphoblastic leukemia in adults.

Chromothripsis is a mitotic catastrophe that arises from multiple double strand breaks and incorrect re-joining of one or a few chromosomes. We report on incidence, distribution, and features of chromothriptic events in T-cell acute lymphoblastic leukemias (T-ALL). SNP array was performed in 103 T-ALL (39 ETPnear ETP, 59 non-ETP, and 5 with unknown stage of differentiation), including 38 children and 65 adults. Chromothripsis was detected in 11.6% of all T-ALL and occurred only in adult cases with an immature phenotype (1239 cases 30%). It affected 1 to 4 chromosomes, and recurrently involved chromosomes 1, 6, 7, and 17. Abnormalities of genes typically associated with T-ALL were found at breakpoints of chromothripsis. In addition, it gave rise to newrare alterations, such as, the SFPQZFP36L2 fusion, reported in pediatric T-ALL, deletions of putative suppressors, such as IKZF2 and CSMD1, and amplification of the BCL2 gene. Compared to negative cases, chromothripsis positive T-ALL had a significantly higher level of MYCN expression, and a significant downregulation of RGCC, which is typically induced by TP53 in response to DNA damage. Furthermore we identified mutations andor deletions of DNA repairgenome stability genes in all cases, and an association with NUP214 rearrangements in 33% of cases.

Polo-like Kinase 4 the Variation During Therapy and its Relation to Treatment Response and Prognostic Risk Stratification in Childhood Acute Lymphoblastic Leukemia Patients.

Polo-like kinase 4 (PLK4) plays an essential role in the tumorigenesis of some blood malignancies consequently, we hypothesized that PLK4 might serve as a potential biomarker in childhood acute lymphoblastic leukemia (ALL) patients. Therefore, this study investigated the expression of PLK4 and its clinical relevance in childhood ALL patients. Bone marrow specimens were collected from 95 childhood ALL patients and 20 primary immune thrombocytopenia patients (as controls), and their PLK4 expression (reverse transcription-quantitative polymerase chain reaction) was measured after enrollment. Besides, the PLK4 expression in childhood ALL patients was also determined at day 15 after the initiation of induction therapy (D15). PLK4 was increased in childhood ALL patients compared with controls (2.830 (interquartile range (IQR) 1.890-3.660) versus 0.976 (IQR 0.670-1.288), P≤0.001). PLK4 at diagnosis was elevated in T cell acute lymphoblastic leukemia patients than in B cell acute lymphoblastic leukemia patients (P0.027). Besides, PLK4 at diagnosis was positively linked with the Chinese Medical Association risk stratification (P0.016), but not with prednisone response (P0.077) or bone marrow response (P0.083). In addition, PLK4 was decreased at D15 after treatment compared with at diagnosis (P≤0.001). Interestingly, PLK4 at D15 (P0.033) was elevated in T cell acute lymphoblastic leukemia patients than in B cell acute lymphoblastic leukemia patients. Furthermore, increased PLK4 at D15 was associated with poor prednisone response (P0.018), poor bone marrow response (P0.034), and increased the Chinese Medical Association risk stratification (P0.015). In terms of prognosis, high PLK4 was associated with shorter event-free survival (P0.020), whereas it was not related to the overall survival (P0.135). In conclusion, PLK4 has the potential as a biomarker for treatment response and prognostic risk stratification of childhood ALL patients.

Optimum Methotrexate Exposure in Patients With Suspected or Confirmed CNS Invasive Hematological Malignancies A Systematic Critical Review.

The present review aims to evaluate the current state-of-the-art dosing regimens of high-dose (HD) and intrathecal methotrexate (MTX) using therapeutic drug monitoring (TDM) to optimize its therapeutic response and minimize associated toxicity, particularly in the central nervous system (CNS). MTX is administered systemically in a HD regimen (>1 gm 2 ) for the treatment of various hematological neoplasms. HD-MTX treatment becomes complicated by marked interindividual drug elimination variability. TDM is specified to manage this high variability. Approximately 3%-7% of adults with acute lymphoblastic leukemia are diagnosed with CNS involvement, and the incidence of CNS relapse in patients, despite receiving prophylaxis, ranges from 5% to 10%. HD-MTX penetrates the blood-brain barrier and can be administered intrathecally, making this drug an important component of chemotherapy regimens for patients with hematologic malignancies involving the CNS or those at high risk of CNS relapse. The major evidence found was that an MTX area under the curve target between 1000 and 1100 μmol hour -1 L is associated with better clinical outcomes. However, there seems to be a clinical gap in the prospective validation of HD and IT MTX management to optimize clinical outcomes and minimize toxicity, using the relationship between exposure level (area under the curve MTX) and optimal response to MTX, at systemic and CNS exposure.

Three cases of hemodiafiltration for the treatment of CAR-T related grade 3 - 4 cytokine release syndrome after ineffective treatment with IL-6 receptor inhibitors.

Clinical study of mesenchymal stem cells from third-party donors in the treatment of refractory late onset hemorrhagic cystitis after allogeneic hematopoietic stem cell transplanation.

Renal Lymphoma Diagnosed on Kidney Biopsy Presenting as Acute Kidney Injury.

Renal manifestations associated with hematolymphoid malignancies are known. Primary or secondary involvement of the kidney by lymphomatous infiltration has various clinical presentations. Acute kidney injury is not an uncommon finding in relation to lymphomatous interstitial infiltration proven on kidney biopsy. However, diagnosing it solely on renal biopsy remains a challenge and needs expertise and aid of immunohistochemistry as the prognosis is dismal. This is a retrospective study of kidney biopsy-proven cases of renal lymphoma presenting with acute kidney injury. The study included 12 patients with ages ranging from 4 to 50 years who presented with serum creatinine ranging 2.1-9.6 mg%. Renal biopsy findings showed interstitial lymphomatous infiltrate. Two cases were diagnosed as primary lymphoma and the other 10 as secondary lymphomas. Among the 12 cases, nine were B-cell non-Hodgkin lymphoma, of which diffuse large B-cell lymphoma was diagnosed in six (50%), low-grade B-cell type in two (16.6%), chronic lymphocytic leukemia in one (8.3%), and three were T-cell-type. Two were acute T-cell lymphoblastic lymphoma and one other was a high-grade T-cell lymphoma. Four patients succumbed. The other four patients are alive one is on chemotherapy, while two of them are on hemodialysis. Acute kidney injury as a presenting feature with lymphomatous infiltration of renal parenchyma is not uncommon. The patchy involvement makes it challenging on kidney biopsy with definitive diagnosis being made with the help of immunohistochemistry. Appropriate multidisciplinary involvement improves patient outcome.

Therapeutic potential of an anti-CCR9 mAb evidenced in xenografts of human CCR9

Relapsed or refractory T acute lymphoblastic leukemia (T-ALL) still carries poor prognosis. Aiming to improve outcomes, the therapeutic potential of an anti-CCR9 monoclonal antibody (mAb 92R), targeting the human chemokine-receptor CCR9 is analyzed on orthotopic xenotransplants. 92R mAb treatment of mice carrying human CCR9

Systematic Oxidative Stress Indexes Associated with the Prognosis in Patients with T Lymphoblastic LymphomaLeukemia.

T lymphoblastic lymphomaleukemia (T-LBLALL) is an aggressive malignant tumor with 5-year overall survival (OS) rate reached 80% after high-dose chemotherapy. Due to the relatively low incidence of T-LBLALL, only a few risk factors have been identified. The occurrence and prognosis of malignant tumors are closely related to oxidative stress, but the prognostic relationship between T-LBLALL and systematic oxidative stress indexes has not been reported yet. A total of 258 T-LBLALL patients were retrospectively analyzed. The relationship between systematic oxidative stress indexes, such as creatinine (CRE), gamma-glutamyl transpeptidase ( Higher CRE, CRP, and lower ALB were associated with poorer OS in T-LBLALL patients. The OSRG established by CRE, ALB, and CRP was an independent prognostic factor for OS of T-LBLALL patients. Patients in the high-risk group were more likely to be patients older than 14 years old and patients with superior vena cava obstruction syndrome (SVCS), pleural effusion, pericardial effusion, and mediastinal mass. For OS in T-LBLALL patients, OSRG was observed as an independent prognostic factor, which provided a new idea for accurate prognostic prediction.

Umbilical cord blood A promising source for allogeneic CAR-T cells.

Chimeric antigen receptor T (CAR-T) cell therapy is an effective treatment for relapsed and refractory acute lymphoblastic leukemia (RR ALL). However, autologous CAR-T cells derived from patients with B-ALL often show poor amplification ability, exhaustion, and anergy. To overcome these limitations, allogeneic CAR-T cells may be used as effective substitutes however, which source would be the best substitute is unclear. In this study, we compared the immunophenotype and antitumor efficacy of anti-CD19 CAR-T cells derived from healthy donor cord blood (CB), healthy donor peripheral blood (PB), and PB of B-ALL patients PB (patient)

Central nervous system mucormycosis in a patient with hematological malignancy A case report and review of the literature.

Invasive mucormycosis is a refractory fungal infection. Central nervous system (CNS) mucormycosis is a rare complication caused by infiltration from the paranasal sinuses or hematogenous dissemination. Here, we present a case of a brain abscess, due to mucormycosis, diagnosed using burr craniotomy. A 25-year-old Japanese woman with relapsed-refractory acute lymphoblastic leukemia underwent cord blood transplantation (CBT). The patient experienced prolonged and profound neutropenia, and oral voriconazole was administered as primary antifungal prophylaxis. The patient received a conditioning regimen on day -11 and complained of aphasia and right hemiparesis on day -6. Magnetic resonance imaging (MRI) revealed a T2-weighted high-intensity area in the left frontal cortex. A brain abscess was suspected, and liposomal amphotericin B (L-AMB) administration was started. The patient underwent CBT as scheduled and underwent neutrophil engraftment on day 14. Although the patient achieved complete remission on day 28, her consciousness level gradually deteriorated. MRI revealed an enlarged brain lesion with a midline shift sign, suggesting brain herniation. Craniotomy was performed to relieve intracranial pressure and drain the abscess on day 38, and a diagnosis of cerebral mucormycosis was confirmed. The L-AMB dose was increased to 10 mgkg on day 43. Although the patients consciousness level improved, she died of hemorrhagic cystitis and aspiration pneumonia. Cerebral mucormycosis should be suspected if neurological symptoms are observed in stem cell transplant recipients. Prompt commencement of antifungal therapy and debridement are crucial because mucormycosis has a poor prognosis.

Sequential Approach to Improve the Molecular Classification of Childhood Acute Lymphoblastic Leukemia.

Identification of specific leukemia subtypes is a key to successful risk-directed therapy in childhood acute lymphoblastic leukemia (ALL). Although RNA sequencing (RNA-seq) is the best approach to identify virtually all specific leukemia subtypes, the routine use of this method is too costly for patients in resource-limited countries. This study enrolled 295 patients with pediatric ALL from 2010 to 2020. Routine screening could identify major cytogenetic alterations in approximately 69% of B-cell ALL (B-ALL) cases by RT-PCR, DNA index, and multiplex ligation-dependent probe amplification. STIL-TAL1 was present in 33% of T-cell ALL (T-ALL) cases. The remaining samples were submitted for RNA-seq. More than 96% of B-ALL cases and 74% of T-ALL cases could be identified based on the current molecular classification using this sequential approach. Patients with Philadelphia chromosome-like ALL constituted only 2.4% of the entire cohort, a rate even lower than those with ZNF384-rearranged (4.8%), DUX4-rearranged (6%), and Philadelphia chromosome-positive (4.4%) ALL. Patients with ETV6-RUNX1, high hyperdiploidy, PAX5 alteration, and DUX4 rearrangement had favorable prognosis, whereas those with hypodiploid and KMT2A and MEF2D rearrangement ALL had unfavorable outcomes. With the use of multiplex ligation-dependent probe amplification, DNA index, and RT-PCR in B-ALL and RT-PCR in T-ALL followed by RNA-seq, childhood ALL can be better classified to improve clinical assessments.

Prominence of NUDT15 genetic variation associated with 6-mercaptopurine tolerance in a genome-wide association study of Japanese children with acute lymphoblastic leukaemia.

Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Childrens Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, β -10.99, p 3.7 × 10

BRD4 Inhibitor GNE-987 Exerts Anticancer Effects by Targeting Super-Enhancer-Related Gene LYL1 in Acute Myeloid Leukemia.

AML (acute myeloid leukemia) is a common hematological malignancy in children with poor treatment effects and poor prognosis. Recent studies have shown that as a novel BRD4 (bromodomain containing 4) PROTACs (proteolysis targeting chimeras) degrader, GNE-987 can slow down the growth of various tumors and increase apoptosis, with promising clinical prospects. However, the function and molecular mechanism of GNE-987 in AML remain unclear. This study is aimed at investigating the therapeutic effect of GNE-987 on AML and its underlying mechanism. The association between BRD4 and AML was assessed by studying public databases. After GNE-987 was added to AML cells, cell proliferation slowed down, the cycle was disturbed, and apoptosis increased. Western blotting was used to detect BRD2 (bromodomain containing 2), BRD3 (bromodomain containing 3), BRD4, and PARP (poly ADP-ribose polymerase) proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq (RNA sequencing) and ChIP-seq (chromatin immunoprecipitation sequencing) validated the function and molecular pathways of GNE-987 in processing AML. BRD4 expression was significantly elevated in pediatric AML samples compared with healthy donors. GNE-987 inhibited AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3, and BRD4 were consistent with decreased VHL (Von Hippel Lindau) expression in AML cells. In an AML xenograft model, GNE-987 significantly reduced the hepatosplenic infiltration of leukemia cells and increased the mouse survival time. Based on analysis of RNA-seq and ChIP-seq analyses, GNE-987 could target multiple SE- (super-enhancer-) related genes, including LYL1 (lymphoblastic leukemia 1), to inhibit AML. GNE-987 had strong antitumor activity in AML. GNE-987 could effectively inhibit the expression of SE-related oncogenes including LYL1 in AML. Our results suggested that GNE-987 had broad prospects in the treatment of AML.

The Effect of Chemotherapy Induction Therapy on the Pancreas in Patients with Acute Lymphoblastic Leukemia.

The effect of chemotherapy induction on the pancreatic in patients with acute lymphoblastic leukemia is not described in Ethiopia. The study determined the chemotherapy drug-induced pancreatitis in patients with acute lymphoblastic leukemia. A preexperimental study (pretest and posttests) was conducted in forty patients with acute lymphoblastic leukemia. For some skewed data, a log transformation was computed. The back transformation was then calculated. Descriptive statistics and a mixed-model ANOVA were used to analyze the data. A post hoc Bonferroni test was used. A In this study, no clinically significant acute pancreatitis occurred. Elevated amylase and lipase levels, indicating grade 2 acute pancreatitis, were observed in 25% and 17.5% of patients, respectively. Amylase enzyme levels in children differed significantly from preinduction to the second week of induction ( Clinically significant acute pancreatitis did not occur, but patients experienced mild (grade 2) acute pancreatitis. Amylase and lipase enzymes responded significantly to chemotherapy induction in children. Chemotherapy drugs should be given without altering pancreatic enzymes, specifically in children.

Effect of CB2 Stimulation on Gene Expression in Pediatric B-Acute Lymphoblastic Leukemia New Possible Targets.

Acute lymphoblastic leukemia type B (B-ALL) is the most common kind of pediatric leukemia, characterized by the clonal proliferation of type B lymphoid stem cells. Important progress in ALL treatments led to improvements in long-term survival nevertheless, many adverse long-term consequences still concern the medical community. Molecular and cellular target therapies, together with immunotherapy, are promising strategies to overcome these concerns. Cannabinoids, enzymes involved in their metabolism, and cannabinoid receptors type 1 (CB1) and type 2 (CB2) constitute the endocannabinoid system, involved in inflammation, immune response, and cancer. CB2 receptor stimulation exerts anti-proliferative and anti-invasive effects in many tumors. In this study, we evaluated the effects of CB2 stimulation on B-ALL cell lines, SUP-B15, by RNA sequencing, Western blotting, and ELISA. We observe a lower expression of CB2 in SUP-B15 cells compared to lymphocytes from healthy subjects, hypothesizing its involvement in B-ALL pathogenesis. CB2 stimulation reduces the expression of

A Bright Horizon Immunotherapy for Pediatric T-Cell Malignancies.

Immunotherapy has transformed the treatment of hematologic malignancies in the past two decades. The treatment of acute lymphoblastic leukemia (ALL), in particular, has been highly impacted by multiple novel immunotherapies. For pediatric patients with T-cell malignancies, translating immunotherapies has proved more challenging due to the complexities of fratricide, risk of product contamination with malignant cells, and concerns over T-cell aplasia. Despite these hurdles, many creative and promising strategies are on the horizon. We review challenges in the development of immunotherapy for T-cell malignancies, strategies to overcome these challenges, as well as therapies currently being investigated and starting to reach the clinic. Immunotherapy will hopefully successfully treat patients with relapsed and refractory T-cell malignancies and may someday be incorporated in up-front protocols in order to prevent relapses.

COVID-19 and Adult Acute Leukemia Our Knowledge in Progress.

The majority of publications regarding SARS-CoV-2 infections in adult patients with acute leukemia (AL) refer to hematological patients in general and are not focused on acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). We herein report a review of the current literature on adult AL patients infected with SARS-CoV-2. Overall, SARS-CoV-2-associated mortality ranges from 20-52% in patients with adult AL. AML patients have a particularly high COVID-19-related mortality. Of note, most of the available data relate to the pre-vaccination era and to variants before Omicron. The impact of COVID-19 infections on AL treatment is rarely reported. Based on the few studies available, treatment delay does not appear to be associated with an increased risk of relapse, whereas therapy discontinuation was associated with worse outcomes in AML patients. Therefore, the current recommendations suggest delaying systemic AL treatment in SARS-CoV-2-positive patients until SARS-CoV-2 negativity, if immediate AL treatment is not required. It is recommended to offer vaccination to all AL patients the reported antibody responses are around 80-96%. Seronegative patients should additionally receive prophylactic administration of anti-SARS-CoV-2 monoclonal antibodies. Patients with AL infected with SARS-CoV-2 should be treated early with antiviral therapy to prevent disease progression and enable the rapid elimination of the virus.

Potent preclinical activity of FLT3-directed chimeric antigen receptor T-cell immunotherapy against

Chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 or CD22 induce remissions in the majority of patients with relapsedrefractory B-cell acute lymphoblastic leukemia (ALL), although relapse due to target antigen loss or downregulation has emerged as a major clinical dilemma. Accordingly, great interest exists in developing CAR T cells directed against alternative leukemia cell surface antigens that may help to overcome immunotherapeutic resistance. The fms-like tyrosine kinase 3 receptor (FLT3) is constitutively activated via FLT3 mutation in acute myeloid leukemia (AML) or wild-type FLT3 overexpression in KMT2A (lysine-specific methyltransferase 2A)-rearranged ALL, which are associated with poor clinical outcomes in children and adults. We developed monovalent FLT3-targeted CAR T cells (FLT3CART) and bispecific CD19xFLT3CART and assessed their anti-leukemia activity in preclinical models of FLT3-mutant AML and KMT2A-rearranged infant ALL. We report robust in vitro FLT3CART-induced cytokine production and cytotoxicity against AML and ALL cell lines with minimal cross-reactivity against normal hematopoietic and non-hematopoietic tissues. We also observed potent in vivo inhibition of leukemia proliferation in xenograft models of both FLT3-mutant AML and KMT2A-rearranged ALL, including a post-tisagenlecleucel ALL-to-AML lineage switch patient-derived xenograft model pairing. We further demonstrate significant in vitro and in vivo activity of bispecific CD19xFLT3CART against KMT2Arearranged ALL and posit that this additional approach might also diminish potential antigen escape in these high-risk leukemias. Our preclinical data credential FLT3CART as a highly effective immunotherapeutic strategy for both FLT3- mutant AML and KMT2A-rearranged ALL which is poised for further investigation and clinical translation.

Invasive Fungal Rhinosinusitis Due to Co-infection with Mucormycosis and

Invasive fungal infections remain an important cause of complication and morbidity in the management of acute leukemias. Here we report the case of a 27-year-old patient from French Polynesia who was diagnosed with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia. After induction chemotherapy, she developed rhinosinusitis with extensive bone lysis. The context and clinical presentation quickly made us suspect an invasive mucormycosis infection. However, a multidisciplinary investigation including mass spectrometry techniques also revealed the presence of

Immunotherapy and Allogeneic Bone Marrow Transplantation in B Acute Lymphoblastic Leukemia How to Sequence

Long-term disease control is achieved in 80-90% of patients with acute lymphoblastic leukemia of B origin (B-ALL). About half of adult and 10% of pediatric patients develop refractory or relapsed disease, whereas survival after relapse accounts about 10% in adults and 30-50% in children. Allogeneic bone marrow transplantation offers remarkable benefit in cases with unfavorable outcome. Nevertheless, novel immunotherapeutic options have been approved for patients with adverse prognosis. Immunotherapeutic agents, nowadays, are preferred over standard chemotherapy for patients with relapsed or refractory B-ALL The mode of action, efficacy and safety data of immunotherapeutic agents released, indications and sequence of those therapies over the course of treatment, are herein reviewed.

Endothelial nitric oxide synthase gene polymorphism (786TC) in childhood acute lymphoblastic leukemia survivors.

To detect eNOS gene polymorphism and its relation to cardiovascular complications in pediatric acute lymphoblastic leukemia (ALL) survivors. CBC, renal and liver function tests, lipid profile, Carotid artery Intima Media Thickness (CIMT), and Brachial artery Intima Media Thickness (BIMT). eNOS gene polymorphism was done in 40 childhood ALL survivors and 40 controls. There was no significant difference between survivors and control groups regarding 786 TC polymorphism. There was a significant increase in serum cholesterol, TGs, LDL, VLDL, and HbA1c in the TC and CC group more than in the TT group, while there was a significant decrease in serum HDL in the TC and CC group more than in the TT group. There was no significant difference as regards echocardiography findings between different polymorphisms of 786 TC, but there was a significant difference between 786 TC groups with regard to the carotid and brachial arteries intima media thickness (IMT) measurements being significantly higher in the TC and CC group more than in the TT group. Carotid and brachial arteries intima media thickness measurements were higher in the survivors when compared to healthy controls. eNOS gene polymorphism may play a role in modifying or developing CVD in pediatric ALL survivors.

Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety.

Development of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL oncogene constitutes an effective approach for the treatment of chronic myeloid leukemia (CML) andor acute lymphoblastic leukemia. However, currently available inhibitors are limited by drug resistance and toxicity. Ponatinib, a third-generation inhibitor, has demonstrated excellent efficacy against both wild type and mutant BCR-ABL kinase, including the gatekeeper T315I mutation that is resistant to all other currently available TKIs. However, it is one of the most cardiotoxic of the FDA-approved TKIs. Herein, we report the structure-guided design of a novel series of potent BCR-ABL inhibitors, particularly for the T315I mutation. Our drug design paradigm was coupled to iPSC-cardiomyocyte models. Systematic structure-activity relationship studies identified two compounds,

Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing.

Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1). The significance of these two anti-ferroptosis pathways is still poorly understood in cancers from hematopoietic origin. Here, we report that blood-derived cancer cells are selectively sensitive to compounds that block the GSH-dependent anti-ferroptosis axis. In T- and B- acute lymphoblastic leukemia (ALL) cell lines and patient biopsies, the promoter of the gene coding for FSP1 is hypermethylated, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression also favors ALL-tumor growth in an in vivo chick chorioallantoic membrane (CAM) model. Hence, our results reveal a metabolic vulnerability of ALL that might be of therapeutic interest.

Assessment of adrenal function in pediatric cancer survivors.

Oncological therapy can temporarily or permanently disrupt adrenal gland function. The aim of our study was to assess the function of adrenal glands in cancer survivors and to find the best diagnostic tools for it. Sixty patients aged 1.2-14.9 years (mean 8.3 ±3.5) with diagnosed malignancies and 45 healthy children as controls were recruited to the study. Patients were assessed 0-8 years (mean 2.4 ±2.0 years) after the oncological therapy. In all patients fasting blood samples were collected to measure glucose, sodium, potassium, cortisol, aldosterone, plasma renin activity (PRA), dehydroepiandrostenedione-sulphate (DHEA-S), adrenocorticotropic hormone (ACTH) and antibodies against the adrenal cortex (AAA). Moreover, 24-hour urinary free cortisol (UFC) was assessed. Test with synthetic ACTH was carried out with 250 µg in neuroblastoma and nephroblastoma patients and with 1 µg in other oncological patients. The levels of morning cortisol and sodium were significantly lower and blood glucose were higher in cancer survivors than in controls (p 0.006, p 0.043, p 0.008). Basal laboratory tests confirmed adrenal insufficiency (AI) in 1 patient with neuroblastoma. Low-dose ACTH revealed AI in 3 patients with acute lymphoblastic leukemia. In the study group, UFC correlated with evening and midnight cortisol (p 0.001, p 0.006). In the control group UFC correlated with DHEA-S (r 0.623, p 0.0001). None of assessed parameters correlated with the time since the completion of oncological therapy. The study confirmed possibility of developing asymptomatic AI in cancer survivors even several years after therapy. Instead of morning cortisol, classical diagnostic low-dose ACTH test seems to be an optimal tool for adrenal functions assessment. Leczenie onkologiczne może przejściowo lub trwale zakłócić funkcjonowanie nadnerczy. Celem badania była ocena funkcji nadnerczy u dzieci po leczeniu onkologicznym. Do badania zrekrutowano sześćdziesięciu pacjentów w wieku 1,2–14,9 roku, średnio 8,3 ±3,5 ze zdiagnozowanymi nowotworami i 45 zdrowych dzieci jako grupa kontrolna. Pacjentów oceniano 0–8 lat, średnio 2,4 ±2,0 lat po leczeniu onkologicznym. U wszystkich uczestników badania pobrano na czczo próbki krwi dla oceny glukozy, sodu, potasu, kortyzolu, aldosteronu, aktywności reninowej osocza, siarczanu dehydroepiandrostendionu (DHEA-S), hormonu adrenokortykotropowego (ACTH) i przeciwciał przeciwko korze nadnerczy. Ponadto oceniono wydalanie kortyzolu w 24-godzinnej zbiórce moczu (UFC). U pacjentów z neuroblastomą i nefroblastomą przeprowadzono test z 250 µg syntetycznego ACTH, u pozostałych pacjentów onkologicznych zastosowano test z 1 µg ACTH. Stężenia porannego kortyzolu i sodu były znacznie mniejsze, a stężenia glukozy we krwi większe u pacjentów onkologicznych niż w grupie kontrolnej (p 0,006, p 0,043, p 0,008). Badania hormonalne potwierdziły niewydolność nadnerczy (AI) u 1 pacjenta z nerwiakiem zarodkowym. Test z 1 µg ACTH ujawnił AI u 3 pacjentów z ostrą białaczką limfoblastyczną. W grupie pacjentów onkologicznych UFC korelowało z wieczornym i nocnym kortyzolem (p 0,001, p 0,006). W grupie kontrolnej UFC korelowało z DHEA-S (r 0,623, p 0,0001). Żaden z ocenianych parametrów nie korelował z czasem od zakończenia terapii onkologicznej. Badanie potwierdziło ryzyko rozwoju bezobjawowej AI u pacjentów pediatrycznych nawet kilka lat po terapii onkologicznej. Test z 1 µg ACTH wydaje się bardziej optymalnym narzędziem dla oceny czynności nadnerczy niż stężenie porannego kortyzolu.

Does transitory steroid-induced central hypothyroidism in children treated for haematological malignancies warrant clinical intervention

Steroid-induced central hypothyroidism (CH) is a frequent but under-diagnosed hormonal disturbance in children treated for acute lymphoblastic leukaemia (ALL) and lymphoma. To determine the occurrence, frequency of symptoms, replacement therapy administration, and association of CH with glucocorticoid therapy in children treated for haematological malignancies. A prospective clinical survey was conducted on 21 patients (61.9% male, mean age 9.1 years) treated in the Childrens Hospital Zagreb during 2019, of whom 12 were treated for for ALL and 6 for Hodgkin lymphoma (HL), based on clinical (signs and symptoms) and laboratory data (hormonal status). Overt CH was verified in 15 (71.4%) and mild CH in 3 patients (14.2%). The most common symptoms and signs were fatigue, apathy, and electrolyte imbalance, observed in 50% of CH cases. Hormonal substitutional therapy was initiated in 44.4% of affected patients, during a mean of 2.08 months, with significant clinical improvement. Overt CH was more prevalent in patients with ALL than in those with HL (p 0.025). Among children with ALL there was no difference in CH occurrence between the prednisone and dexamethasone groups however, dexamethasone-induced CH was more frequently symptomatic (p 0.03). The prednisone dosage played no role in CH incidence in patients with HL. Further studies are needed to determine the real incidence of thyroid dysfunction during intensive chemotherapy treatment in children with ALL and lymphoma. Recommendations for optimal hormonal replacement therapy and a follow-up plan for paediatric oncology patients with CH are also urgently required. Centralna niedoczynność tarczycy wywołana przez steroidy (CH) jest raczej częstym, ale jednocześnie niezdiagnozowanym wystarczająco czynnikiem zaburzeń hormonalnych u dzieci leczonych na ostrą białaczkę limfoblastyczną (ALL) i chłoniaka. Określenie występowania, częstotliwości objawów, podawanie terapii zastępczej i powiązania CH z leczeniem glikokortykosteroidami u dzieci leczonych z powodu złośliwych nowotworów hematologicznych. Perspektywiczne badanie kliniczne zostało przeprowadzone na 21 chorych (61,9% chłopców, średni wiek 9,1 roku), leczonych w Szpitalu Dziecięcym w Zagrzebiu w 2019 r., z czego 12 na ALL, a 6 na chłoniaka Hodgkina (HL), w oparciu o dane kliniczne (objawy) i laboratoryjne (stan hormonów). Wyraźna CH została potwierdzona w 15 przypadkach (71,4%), a łagodna CH u 3 pacjentów (14,2%). Najczęstszymi objawami było zmęczenie, apatia i brak równowagi elektrolitowej, obserwowane w 50% przypadków CH. Leczenie zastępczo-hormonalne wprowadzono u 44,4% chorych, średnio przez 2,08 miesiąca, z uzyskaniem istotnej poprawy klinicznej. Wyraźna CH była znacznie częstsza u pacjentów z ALL niż tylko z HL (p 0,025). Wśród dzieci z ALL nie było różnicy w występowaniu CH między grupą prednizonu i deksametazonu, jednak częściej występowała objawowa CH wywołana przez deksametazon (p 0,03). Dawka prednizonu nie odgrywała żadnej roli w zachorowaniu na CH u pacjentów z HL. Potrzebne są dalsze badania w celu określenia rzeczywistego występowania dysfunkcji tarczycy podczas leczenia z zastosowaniem chemioterapii u dzieci z ALL oraz z chłoniakiem. Pilne są również zalecenia dotyczące optymalnej, zastępczej terapii hormonalnej oraz planu monitorowania pacjentów onkologicznych dziecięcych z CH.

The magnitude and perceived reasons for childhood cancer treatment abandonment in Ethiopia from health care providers perspective.

Treatment abandonment is one of major reasons for childhood cancer treatment failure and low survival rate in low- and middle-income countries. Ethiopia plans to reduce abandonment rate by 60% (2019-2023), but baseline data and information about the contextual risk factors that influence treatment abandonment are scarce. This cross-sectional study was conducted from September 5 to 22, 2021, on the three major pediatric oncology centers in Ethiopia. Data on the incidence and reasons for treatment abandonment were obtained from healthcare professionals. We were unable to obtain data about the patients or guardians perspective because the information available in the cancer registry was incomplete to contact adequate number of respondents. We used a validated, semi-structured questionnaire developed by the International Society of Pediatric Oncology Abandonment Technical Working Group. We included all (N 38) health care professionals (physicians, nurses, and social workers) working at these centers who had more than one year of experience in childhood cancer service provision (a universal sampling and 100% response rate). The perceived mean abandonment rate in Ethiopia is 34% (SE 2.5%). The risk of treatment abandonment is dependent on the type of cancer (high for bone sarcoma and brain tumor), the phase of treatment and treatment outcome. The highest risk is during maintenance and treatment failure or relapse for acute lymphoblastic leukemia, and during pre- or post-surgical phase for Wilms tumor and bone sarcoma. The major influencing risk factors in Ethiopia includes high cost of care, low economic status, long travel time to treatment centers, long waiting time, belief in the incurability of cancer and poor public awareness about childhood cancer. The perceived abandonment rate in Ethiopia is high, and the risk of abandonment varies according to the type of cancer, phase of treatment or treatment outcome. Therefore, mitigation strategies to reduce the abandonment rate should include identifying specific risk factors and prioritizing strategies based on their level of influence, effectiveness, feasibility, and affordability.

SOHO State of the Art Updates and Next Questions Novel Approaches to Pediatric T-cell ALL and T-Lymphoblastic Lymphoma.

While outcomes for children with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) have improved significantly with contemporary therapy, outcomes for patients with relapsed or refractory (rr) disease remain dismal. Improved risk stratification and the incorporation of novel therapeutics have the potential to improve outcomes further in T-ALLT-LL by limiting relapse risk and improving salvage rates for those with rr disease. In this review we will discuss the challenges and new opportunities for improved risk stratification in T-ALL and T-LL. We will further discuss the recent incorporation of the novel therapeutics nelarabine and bortezomib into front-line therapy for children with T-ALL and T-LL. Finally, we will address new classes of targeted small molecule inhibitors, immunotherapeutics, and chimeric antigen receptor T-cell therapies under investigation in rr T-ALL and T-LL.

ALNett A cluster layer deep convolutional neural network for acute lymphoblastic leukemia classification.

Acute Lymphoblastic Leukemia (ALL) is cancer in which bone marrow overproduces undeveloped lymphocytes. Over 6500 cases of ALL are diagnosed every year in the United States in both adults and children, accounting for around 25% of pediatric cancers, and the trend continues to rise. With the advancements of AI and big data analytics, early diagnosis of ALL can be used to aid the clinical decisions of physicians and radiologists. This research proposes a deep neural network-based (ALNett) model that employs depth-wise convolution with different dilation rates to classify microscopic white blood cell images. Specifically, the cluster layers encompass convolution and max-pooling followed by a normalization process that provides enriched structural and contextual details to extract robust local and global features from the microscopic images for the accurate prediction of ALL. The performance of the model was compared with various pre-trained models, including VGG16, ResNet-50, GoogleNet, and AlexNet, based on precision, recall, accuracy, F1 score, loss accuracy, and receiver operating characteristic (ROC) curves. Experimental results showed that the proposed ALNett model yielded the highest classification accuracy of 91.13% and an F1 score of 0.96 with less computational complexity. ALNett demonstrated promising ALL categorization and outperformed the other pre-trained models.

Maternal obesity and acute lymphoblastic leukemia risk in offspring A summary of trends, epidemiological evidence, and possible biological mechanisms.

Acute lymphoblastic leukemia, a heterogenous malignancy characterized by uncontrolled proliferation of lymphoid progenitors and generally initiated in utero, is the most common pediatric cancer. Although incidence of ALL has been steadily increasing in recent decades, no clear reason for this trend has been identified. Rising concurrently with ALL incidence, increasing maternal obesity rates may be partially contributing to increasing ALL prevelance. Epidemiological studies, including a recent meta-analysis, have found an association between maternal obesity and leukemogenesis in offspring, although mechanisms underlying this association remain unknown. Therefore, the purpose of this review is to propose possible mechanisms connecting maternal obesity to ALL risk in offspring, including changes to fetalneonatal epigenetics, altered insulin-like growth factor profiles and insulin resistance, modified adipokine production and secretion, changes to immune cell populations, and impacts on birthweight and childhood obesityadiposity. We describe how each proposed mechanism is biologically plausible due to their connection with maternal obesity, presence in neonatal andor fetal tissue, observation in pediatric ALL patients at diagnosis, and association with leukemogenesis, A description of ALL and maternal obesity trends, a summary of epidemiological evidence, a discussion of the pathway from intrauterine environment to subsequent malignancy, and propositions for future directions are also presented.

Efficacy of ruxolitinib in acute lymphoblastic leukemia A systematic review.

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk molecular subtype with a gene expression profile similar to Philadelphia-positive ALL, but not harboring the BCR-ABL1 gene fusion. We aimed to investigate the efficacy of target therapy with the Janus kinase inhibitor, ruxolitinib, in patients with Ph-like ALL and molecular signature of JAK-STAT signaling pathway. A systematic search of the literature was performed to identify reports concerning administration of ruxolitinib in Ph-like ALL patients. Additionally, Polish Pediatric ALL registries were searched for patients with Ph-like ALL treated with ruxolitinib. Extracted information included epidemiological background, somatic aberrations, treatment response, and patient outcome. After PubMed database search, twelve patients were identified, and one was identified in the Polish Pediatric ALL registry. In nine patients gene fusions affecting JAK2 (n 7) and EPOR (n 2) were detected. Surface overexpression of CRLF2 and IKZF1 deletions were observed in two and three patients, respectively. Induction failure occurred in all the patients. Therapy with ruxolitinib led to complete (n 7) and partial (n 2) remission, in three individuals no information was found. Based on the limited number of studies describing the efficacy of ruxolitinib as an additional compound administrated with standard ALL therapy, we conclude that this approach can be considered in patients with aberrations activating JAK-STAT pathway.

The impact of race, ethnicity, and obesity on CAR T-cell therapy outcomes.

Cancer outcomes with chemotherapy are inferior in patients of minority racialethnic groups and those with obesity. Chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for relapsedrefractory hematologic malignancies, but whether its benefits extend commensurately to racialethnic minorities and patients with obesity is poorly understood. With a primary focus on patients with B-cell acute lymphoblastic leukemia (B-ALL), we retrospectively evaluated the impact of demographics and obesity on CAR T-cell therapy outcomes in adult and pediatric patients with hematologic malignancies treated with CAR T-cell therapy across 5 phase 1 clinical trials at the National Cancer Institute from 2012 to 2021. Among 139 B-ALL CAR T-cell infusions, 28.8% of patients were Hispanic, 3.6% were Black, and 29.5% were overweightobese. No significant associations were found between race, ethnicity, or body mass index (BMI) and complete remission rates, neurotoxicity, or overall survival. Hispanic patients were more likely to experience severe cytokine release syndrome compared with White non-Hispanic patients even after adjusting for leukemia disease burden and age (odds ratio, 4.5 P .001). A descriptive analysis of patients with multiple myeloma (n 24) and non-Hodgkin lymphoma (n 23) displayed a similar pattern to the B-ALL cohort. Our findings suggest CAR T-cell therapy may provide substantial benefit across a range of demographics characteristics, including for those populations who are at higher risk for chemotherapy resistance and relapse. However, toxicity profiles may vary. Therefore, efforts to improve access to CAR therapy for underrepresented populations and elucidate mechanisms of differential toxicity among demographic groups should be prioritized.

Higher doses of tisagenlecleucel are associated with improved outcomes a report from the pediatric real-world CAR consortium.

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractoryrelapsed B-cell acute lymphoblastic leukemia it is US Food and Drug Administration approved for this indication. Currently, patients receive a single dose of tisagenlecleucel across a wide dose range of 0.2 to 5.0 × 106 and 0.1 to 2.5 × 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7 × 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles 0.134 to 1.300 × 106 (n 48 27%), 1.301 to 1.700 × 106 (n 46 26%), 1.701 to 2.400 × 106 (n 43 24%), and 2.401 to 5.100 × 106 (n 43 24%). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard to targeting higher cell doses, within the approved dose range, to optimize patients potential for long-standing remission.

Ocular findings in children with acute leukemia at a tertiary care center in South America.

The purpose of this study was to evaluate ophthalmological findings in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in a Latin American population. This was a single-center, retrospective study. The observational analysis was conducted in AML and ALL patients seen as a routine examination at the department of ophthalmology of tertiary care center in Argentina between March 1, 2017, and February 28, 2018. Overall, 137 patients with acute leukemia were included. The mean age was 7.9 ± 5.2 years (0-18), and 55% were male ( Our results show that ocular involvement occurs in a high percentage of patients with leukemia with a clear clinical, humoral, and sometimes prognostic correlation, suggesting routine ophthalmologic evaluation in these patients.

Initial ultrasound evaluation of an anterior mediastinal mass ultimately diagnosed as T-cell acute lymphoblastic leukemia a report of three cases in children.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) in the anterior mediastinum has an acute onset and requires early treatment. The diagnostic strategy for anterior mediastinal masses in pediatric patients usually involves imaging evaluation, surgical biopsy, or resection for diagnosis and treatment. Thereafter, appropriate chemotherapy regimen selection is based on the pathological diagnosis. In some cases, general anesthesia is avoided to prevent complications such as airway compression and circulatory collapse. We present 3 cases with T-ALL where ultrasound was used for the first evaluation of the anterior mediastinal mass. A 5-year-old girl had lymph node swelling at the supraclavicular fossa. Ultrasound examination showed a huge anterior mediastinal mass with an abnormal thymus, surrounding the proximal main trachea in the mediastinum. These sonographic findings indicated a possibility for tracheal compression during general anesthesia. A 12-year-old boy had dyspnea. Ultrasound examination showed a massive pericardial effusion and stenosis of the right pulmonary artery. These sonographic findings indicated a risk of circulation collapse. An 8-year-old boy had cervical swelling and dyspnea. Ultrasound examination showed a huge mass on the anterior mediastinum and a huge thrombus in the left atrium. This sonographic finding indicated a risk of thromboembolism. Ultrasonography is useful in pediatric patients with anterior mediastinal masses due to T-ALL. By focusing on the thymus, a diagnosis of T-ALL might be recommended. To avoid catastrophic circulation collapse, tracheal and vascular compression should be evaluated. Direct invasion may also be detectable.

The Effect of

Our study was performed in 2020 on sixty-two cases of childhood aged 3-16 (year) with ALL disease who were selected by convenience sampling from the two hospitals of Tabriz, Iran. RFLPPCR method was used for genotyping the promoter region of the Based on the result of log-logistic model along with frailty gamma, the proportional odds (standard error) of survival for a CC allele of With controlling unmeasured factors affecting, the

Fabrication of AuFe

Due to their high sensitivity, simplicity, portability, self-contained, and low cost, the development of electrochemical biosensors is a beneficial way to diagnose and anticipate many types of cancers. An electrochemical nanocomposite-based aptasensor is fabricated for the determination of miRNA-128 concentration as the acute lymphoblastic leukemia (ALL) biomarker for the first time. The aptamer chains were immobilized on the surface of the glassy carbon electrode (GCE) through gold nanoparticlesmagnetitereduced graphene oxide (AuNPsFe

The safety of blinatumomab in pediatric patients with acute lymphoblastic leukemia A systematic review and meta-analysis.

Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that has proven efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Despite its efficacy, it has also been associated with the development of potentially serious adverse events such as the cytokine release syndrome (CRS) and neurologic events. The present meta-analysis aimed to assess the safety profile of blinatumomab in terms of serious adverse events, CRS, and neurologic events (such as seizure and encephalopathy) in pediatric patients with B-cell ALL. A systematic review was conducted in Pubmed up to December 10, 2021 to retain pediatric clinical trials on blinatumomab. A random effect meta-analysis approach was used. This study followed the PRISMA statement. Four out of the 255 initial references were selected, of which 2 were phase 12 clinical trials and 2 phase 3 clinical trials. Blinatumomab was associated with a lower risk of serious adverse events (Risk ratio RR, 0.56 95% CI, 0.32-0.99), febrile neutropenia (RR, 0.13 95% CI, 0.06-0.26), infection (RR, 0.40 95% CI, 0.29-0.56), and grade ≥ 3 adverse events (RR, 0.79 95% CI, 0.67-0.93) compared to chemotherapy. No difference in the risk of CRS (RR, 8.37 95% CI, 0.27-260.97) and seizure (RR, 6.43 95% CI, 0.79-53.08) was observed between groups, while for encephalopathy a higher risk was associated with blinatumomab compared to chemotherapy (RR, 8.90 95% CI, 1.08-73.29). Our data support the good safety profile of bliantumomab in treating pediatric patients with B-ALL.

Apoptin Overexpression Efficiently Amplified Cytotoxic Effects of PI3K Inhibition Using BKM120 in Lymphoblastic Leukemia Cell Lines.

Minimal residual disease in BCRABL1-positive acute lymphoblastic leukemia different significance in typical ALL and in CML-like disease.

Recently, we defined CML-like subtype of BCRABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCRABL1-positive ALL (diagnosed I2000-IV2021, treated according to EsPhALL (n 133) or other (n 14) protocols), using DNA-based monitoring of BCRABL1 genomic breakpoint and clonal immunoglobulinT-cell receptor gene rearrangements. Although overall prognosis of CML-like (n 48) and typical ALL (n 99) was similar (5-year-EFS 60% and 49%, respectively 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCRABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far.

Early T-cell precursor lymphoblastic leukemia accompanied by prominent blastic plasmacytoid dendritic cell proliferation mimicking blastic plasmacytoid dendritic cell neoplasm an exceptional case report and literature review.

Plasmacytoid dendritic cells (pDCs) are commonly associated with myeloid malignancies. The association between lymphoblastic leukemia and pDCs has been little explored. Here, we report a novel case of early T-cell precursor lymphoblastic leukemia (ETP-ALL) accompanied by prominent proliferation of blastic pDCs mimicking BPDCN. The diagnosis was established based on a comprehensive analysis of morphology, immunophenotype and clinical implications. We also present a literature review and discussion on the differential expression of reactive and neoplastic pDCs, the functional role of pDCs in lymphoblastic leukemia, and the etiological association of normal pDCs and BPDCN. The current case demonstrates for the first time that prominent pDC proliferation can be associated with lymphoid neoplasms and can exhibit blastic morphology and immunophenotype. The underlying mechanism of the coexistence of these two blastic populations remains unknown. Further genetic profiling may be required to denote the progressive development of tumor stem cells to the lymphoid, myeloid or dendritic cell lineage. Moreover, the prognostic value of pDCs in hematological neoplasms needs further investigation.

Poor treatment responses were related to poor outcomes in pediatric B cell acute lymphoblastic leukemia with KMT2A rearrangements.

The KMT2A gene, formerly named the MLL gene, is rearranged (KMT2Ar) in 70-75% of infants, 5-6% of children and 10-15% of adult patients with B cell acute lymphoblastic leukemia (B-ALL). The outcome after chemotherapy of pediatric cases remains poor, and only a few studies have investigated the clinical and laboratory features, treatment response and prognosis in Chinese populations. A total of 48 B-ALL children with KMT2Ar were enrolled in the study, and clinical and laboratory data were collected and analyzed by age group. The relationship between prognosis and traditional risk factors and treatment response was investigated for these patients who received chemotherapy. The 48 enrolled patients included 28 males and 20 females 18 (37.50%) or 30 (62.50%) patients were an age of < 12 m (infant B-ALL) or of > 12 m at onset. An initial WBC count of 300 × 10

Acute myeloid leukaemia following direct acting antiviral drugs in HCV-infected patients A 10 years retrospective single-center study.

After several cases of peculiar hematological malignancies following introduction of new oral anti-hepatitis C virus (HCV) treatments in our recent practice, we aimed to systematically identify all cases of hematological malignancies (HM) in patients with chronic HCV infection and to compare them according to the prescription of oral anti-HCV Direct Acting Antivirals (DAA) treatment or not. In this single-center retrospective observational study, we included all patients with confirmed HM and chronic HCV infection managed between 2010 and 2019 in the Pitié-Salpêtrière hospital, Paris. Non-inclusion criteria were a benign hematological disorder, an HM preceding chronic HCV infection and HCV acute infection. We compared characteristics of patients who received DAA before HM diagnosis to those with no DAA before HM. Over the 10 years, 61 cases of HM among HCV infected patients were identified (female 29%, median age of 58.0 years IQR 17). Twenty-one received DAA before the onset of HM (Group DAA) and 40 did not (Group DAA-) including 22 having received DAA after HM. In the DAA group, oral NS5B, NS5A and NS3A inhibitors were used in 90, 76 and 29% respectively. HM developed in the two years following DAA initiation in 76%. Eight (38%) had Non-Hodgkin Lymphoma, 5 (24%) had an Acute Myeloid Leukaemia (AML) including two with a mixed phenotype, 2 each had Hodgkin Lymphoma, Multiple Myeloma or a myeloproliferative disorder and one each had a chronic Lymphocytic Leukaemia or AL Amyloidosis. In the Group DAA-, HM were NHL in 20(50%) patients, Myeloproliferative neoplasms in 7 (17%), Multiple Myeloma in 5, Hodgkin Lymphoma in 3, Myelodysplastic syndrome and AML in 2 (5%) each and Acute Lymphoblastic Leukaemia in one. No significant difference between the groups DAA and - was found according to age, sex, HCV genotype, viral load, co-infection or type and exposition of previous HCV treatments. AML, liver transplantation and cirrhosis were significantly more frequent in the DAA group (p 0.020, 0.045 and 0.032, respectively). AML seemed more frequent after using DAA treatments, notably in severe HCV patients including cirrhotic andor liver transplanted patients. A multicentric observational study is ongoing to confirm and explore the results.

Association of IKZF1 and CDKN2A gene polymorphisms with childhood acute lymphoblastic leukemia a high-resolution melting analysis.

Acute lymphoblastic leukemia is the most prevailing pediatric hematologic malignancy, and various factors such as environmental exposures and genetic variation affect ALL susceptibility and patients outcome. According to genome-wide association studies, several single nucleotide polymorphisms (SNPs) in IKZF1 (rs4132601) and CDKN2A (rs3731249 and rs3731217) genes are associated with ALL susceptibility. Hereupon, this study aimed to discover the association between these SNPs and the risk of childhood ALL among a sample of the Iranian population. A total of fifty children with ALL were included in this case-control study, along with an additional fifty healthy children, matched for age and gender. High-resolution melting (HRM) analysis was employed to genotyping rs4132601, rs3731249, and rs3731217. In the patient group, the CT genotype and T allele frequency of rs3731249 were significantly greater than controls (p 0.01 and p 0.005, respectively). Moreover, the positive association of CT and dominant model (CT TT) genotypes and T allele at rs3731249 with the risk of ALL was confirmed (OR 9.56, OR 10.76 and OR 11.00, respectively). There was no significant relation between rs4132601 (IKZF1), rs3731217 (CDKN2A), and childhood ALL. The present study indicates that CT genotype and T allele at rs3731249 (CDKN2A) can significantly increase the risk of ALL among children.

Single-cell analysis of acute lymphoblastic and lineage-ambiguous leukemia approaches and molecular insights.

Despite recent progress in identifying the genetic drivers of acute lymphoblastic leukemia (ALL), prognosis remains poor for those individuals who experience disease recurrence. Moreover, acute leukemias of ambiguous lineage lack a biologically informed framework to guide classification and therapy. These needs have driven the adoption of multiple complementary single-cell sequencing approaches to explore key issues in the biology of these leukemias, including cell of origin, developmental hierarchy and ontogeny, and the molecular heterogeneity driving pathogenesis, progression, and therapeutic responsiveness. There are multiple single-cell techniques for profiling a specific modality, including RNA, DNA, chromatin accessibility and methylation and an expanding range of approaches for simultaneous analysis of multiple modalities. Single-cell sequencing approaches have also enabled characterization of cell-intrinsic and -extrinsic features of ALL biology. In this review we describe these approaches and highlight the extensive heterogeneity that underpins ALL gene expression, cellular differentiation, and clonal architecture throughout disease pathogenesis and treatment resistance. In addition, we discuss the importance of the dynamic interactions that occur between leukemia cells and the nonleukemia microenvironment. We discuss potential opportunities and limitations of single-cell sequencing for the study of ALL biology and treatment responsiveness.

Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5S100A4-S100A9 Pathway in Acute Lymphoblastic Leukemia.

Purple sweet potato is considered an abundant, inexpensive, and ideal source of anthocyanins. Purple sweet potato anthocyanins (PSPAs) have been shown to possess high antimutagenicity and antitumor effects due to the abundance of acylated anthocyanins. However, the effect and underlying mechanism of PSPA effects in acute lymphoblastic leukemia (ALL), especially T-cell acute lymphoblastic leukemia (T-ALL), remain unclear. In this study, the antileukemic effects of PSPAs and the underlying molecular mechanisms were evaluated by in vitro and in silico assays. PSPAs extracted from ten cultivars were analyzed and quantified. Anthocyanins from Nanzi 018, which showed the best antileukemic effect, were selected to analyze the underlying mechanism. First, the PSPAs potently reduced cell viability and induced apoptosis. Additionally, the PSPAs sharply increased intracellular Ca

There is growing evidence for an inherited basis of susceptibility to childhood acute lymphoblastic leukemia. Genomewide association studies by us and others have identified non-coding acute lymphoblastic leukemia risk variants at the ARID5B gene locus, but the molecular mechanisms linking ARID5B to normal and malignant hematopoiesis remain largely unknown. Using a Vav1-driven transgenic mouse model, we characterized the role of Arid5b in hematopoiesis in vivo. Arid5b overexpression resulted in a dramatic reduction in the proportion of circulating B cells, immature, and mature Bcell fractions in the peripheral blood and the bone marrow, and also a decrease of follicular B cells in the spleen. There were significant defects in B-cell activation upon Arid5b overexpression in vitro with hyperactivation of B-cell receptor signaling at baseline. In addition, increased mitochondrial oxygen consumption rate of naïve or stimulated B cells of Arid5b-overexpressing mice was observed, compared to the rate of wild-type counterparts. Taken together, our results indicate that ARID5B may play an important role in B-cell development and function.

Early Growth Response Factor 1 in Aging Hematopoietic Stem Cells and Leukemia.

Aging is associated with various hematological disorders and a higher risk of myeloproliferative disorders. An aged hematopoietic system can be characterized by decreased immune function and increased myeloid cell production. Hematopoietic stem cells (HSCs) regulate the production of blood cells throughout life. The self-renewal and regenerative potential of HSCs determine the quality and quantity of the peripheral blood cells. External signals from the microenvironment under different conditions determine the fate of the HSCs to proliferate, self-renew, differentiate, or remain quiescent. HSCs respond impromptu to a vast array of extracellular signaling cascades such as cytokines, growth factors, or nutrients, which are crucial in the regulation of HSCs. Early growth response factor 1 (EGR1) is one of the key transcription factors controlling HSC proliferation and their localization in the bone marrow (BM) niche. Downregulation of

Treatment strategy for acute lymphoblastic leukemia in adolescent and young adults.

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is a relatively new concept that refers to patients aged 15-39 years with unique pathophysiology and requiring specific clinical care. Many clinical studies have revealed that treatment with the pediatric protocol has better disease-free and overall survival than the adult protocol for AYA-ALL. AYA-ALL survival was significantly improved from 30% with the adult regimen to 60-70% with the pediatric regimen. Two types of strategies are available to adapt pediatric regimens to AYA-ALL, a pediatric-inspired and a fully pediatric regimen. Determining the recommended strategy from these two strategies is difficult at this time. New knowledge of AYA-ALL-specific genetic characteristics provides new strategies for targetable ALL, especially Ph-like ALL. New immunotherapy has been approved for refractory and recurrent ALL however, treatment results of AYA-ALL were improved by introducing the first line of immunotherapy in BCP-ALL, which may have a poor prognosis such as residual MRD. Pediatric and adult hematologists must work together to improve the prognosis of AYA-ALL.

Treatment strategy for B cell precursor acute lymphoblastic leukemia in children.

Over the last 60 years, treatment outcomes for pediatric B cell precursor acute lymphoblastic leukemia have improved dramatically, resulting in long-term survival in approximately 90% of cases. These advancements are the results findings of Biological studies, their acceptance as prognostic factors for treatment responses, including MRD, and the accumulation of clinical trials including many randomized controlled trials. Further improvements in the cure rate and reduction of short-term and long-term complications will be issued in the future. To address such issues, new drugs such as immunotherapy and molecular targeted therapy, as well as more precise stratification, are required, and it is expected that progress will be made by promoting clinical trials in the future.

Treatment strategy for T-cell acute lymphoblastic leukemia in children.

T-cell acute lymphoblastic leukemia (T-ALL) accounted for approximately 10-15% of pediatric ALL and has often been treated within the same framework as B-cell precursor ALL (BCP-ALL). T-ALL has a poorer prognosis than BCP-ALL. However, improvements have been achieved through treatment intensification strategies using dexamethasone, L-asparaginase, and nelarabine, thereby reducing cranial irradiation. Furthermore, T-ALL-specific treatment protocols have been introduced based on these advancements. The JPLSG ALL-T11JALSG T-ALL-211-U trial in Japan has been conducted from 2011 to 2017 for newly diagnosed patients with T-ALL under the age of 25 years. The trial included minimal residual disease-based treatment stratification and treatment intensification as described above and has shown excellent outcomes. Recently, new therapeutic agents have been actively developed for T-ALL. Thus, targeted therapy development based on new findings is expected in the future.

Treatment strategy for Philadelphia chromosome-positive acute lymphoblastic leukemia in children.

Tyrosine kinase inhibitor (TKI)-combined chemotherapy has become the standard option in pediatric Philadelphia chromosome-positive acute lymphocytic leukemia (PhALL) treatment. Additionally, hematopoietic cell transplantation (HCT) in the first remission is no longer an absolute indication. However, pediatric PhALL remains refractory leukemia, with a disease-free survival rate of approximately 60% for patients without HCT in the first remission due to treatment-related death or relapse after chemotherapy. Further outcome improvement will require an intensified targeted therapy with second- or third-generation TKIs or less toxic immunotherapies, as well as improved safety, with reduced conventional chemotherapy. Continuous attention to these issues in clinical trials will change pediatric PhALL from intractable to manageable leukemia in the future.

Treatment strategy for infant acute lymphoblastic leukemia.

Infant acute lymphoblastic leukemia (ALL), which develops in the first year of life, is a rare disease with approximately 20 cases per year in Japan. In particular, KMT2A (MLL) gene rearranged ALL (KMT2A-rALL) has a dismal prognosis, with a 5-year event-free survival rate of <50%. Moreover, acute and late severe toxicities from infants intensive treatment remain an issue. Although outcomes of domestic and international clinical trials appear to improve gradually, the problem remains intractable. Therefore, introducing more appropriate risk stratification and less toxic and more effective novel treatment strategies is urgently required to improve the prognosis and long-term survival of infants with ALL. To achieve these goals, establishing new treatment strategies using novel agents through international collaborative studies is warranted in the future.

A survey on thromboprophylaxis and coagulation assessment in children and young adults with acute lymphoblastic leukaemia (ALL) in the Nordic and Baltic countries Different practices of assessment and management.

Patients undergoing treatment for acute lymphoblastic leukaemia (ALL) are at risk of coagulopathy, especially thromboembolism. We conducted a survey on practices in the assessment and management of coagulopathy during the new ALLTogether protocol in 29 (17 paediatric, 12 adult) Nordic and Baltic cancer centres. While 92% of adult centres used thromboprophylaxis with low-molecular-weight heparin, no paediatric centre did. Almost all providers performed baseline coagulation studies, but only 59% continued the assessment. Fibrinogen replacement was conducted in 59%, and antithrombin replacement in 28% of the centres. The survey highlights the need for guidelines in the management of coagulopathy during ALL therapy.

Zinc finger protein 384 (

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous malignancy and consists of several genetic abnormalities. Some of these abnormalities are used in clinics for risk calculation and treatment decisions. Patients with

Tcf-1 promotes genomic instability and T cell transformation in response to aberrant β-catenin activation.

Understanding the mechanisms promoting chromosomal translocations of the rearranging receptor loci in leukemia and lymphoma remains incomplete. Here we show that leukemias induced by aberrant activation of β-catenin in thymocytes, which bear recurrent

Mcm2 hypomorph leads to acute leukemia or hematopoietic stem cell failure, dependent on genetic context.

Minichromosome maintenance proteins (Mcm2-7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3UTR of the Mcm2 gene (designated Mcm2

Clinical application of next-generation sequencing-based monitoring of minimal residual disease in childhood acute lymphoblastic leukemia.

Next-generation sequencing (NGS) is an emerging technology that can comprehensively assess the diversity of the immune system. We explored the feasibility of NGS in detecting minimal residual disease (MRD) in childhood acute lymphoblastic leukemia (ALL) based on immunoglobulin and T cell receptor. Bone marrow samples were collected pre- and post-treatment with pediatric ALL admitted to Shenzhen Childrens Hospital from February 1st, 2020 to January 31st, 2021. We analyzed the MRD detected by NGS, multiparametric flow cytometry (MFC) and real-time quantitative PCR (RQ-PCR), and analyzed risk factors of positive NGS-MRD at the end of B-ALL induction chemotherapy. A total of paired 236 bone marrow samples were collected from 64 children with ALL (58 B-ALL and 6 T-ALL). The decrease in the clonal rearrangement frequency of IGH, IGK, and IGL was generally consistent after treatment. Positive MRD was detected in 57.5% (77134) of B-ALL and 80% (1215) of T-ALL by NGS after chemotherapy, which was higher than those detected by MFC and RQ-PCR. In B-ALL patients, MRD results detected by NGS were consistent with MFC (r 0.708, p < 0.001) and RQ-PCR (r 0.618, p < 0.001). At the end of induction, NGS-MRD of 40.4% B-ALL was > 0.01% and multivariate analysis indicated that ≧2 clonal rearrangement sequences before treatment were an independent factor of negative NGS-MRD. NGS is more sensitive than MFC and RQ-PCR for MRD measurement. B-ALL children with ≧2 clonal rearrangements detected by NGS before treatment are difficult to switch to negative MRD after chemotherapy.

Evaluation of liver function tests to identify hepatotoxicity among acute lymphoblastic leukemia patients who are receiving chemotherapy induction.

The effect of induction chemotherapy on liver function in patients with acute lymphoblastic leukemia is not well documented in Ethiopia. This study assessed hepatotoxicity in patients with acute lymphoblastic leukemia who were undergoing induction chemotherapy in Ethiopia. A 1-month cohort study was undertaken in forty patients with acute lymphoblastic leukemia, with measurements taken at the baseline, second, and fourth weeks. A Log 10 transformation was done because of the skewed distribution of liver function tests. Descriptive statistics such as mean and proportion were calculated. A mixed model ANOVA and Bonferroni post hoc test were computed. A p value < 0.05 was declared to determine statistical significance. Clinically significant hepatotoxicity was observed in 15% of patients. Mild liver injury occurred in 5% of patients. The mean of all liver function tests increased significantly from pre-induction to post-induction. ALT levels were significantly higher in patients who received blood transfusions, but not in those who did not. Regardless of other factors, ALP level in children is significantly higher than in adults, although total bilirubin in adults is higher than in children. A significant proportion of patients had hepatotoxicity. During chemotherapy induction, the mean of all liver function tests rose significantly, but this elevation of serum liver function tests may be transient. Chemotherapy drugs should be given without causing a significant alteration in serum liver function tests. Continuous monitoring of patients should be required.

BET bromodomain inhibition rescues PD-1-mediated T-cell exhaustion in acute myeloid leukemia.

Sustained expression of programmed cell death receptor-1 (PD-1) is correlated with the exhaustion of T cells, and blockade of the PD-1 pathway is an effective immunotherapeutic strategy for treating various cancers. However, response rates are limited, and many patients do not achieve durable responses. Thus, it is important to seek additional strategies that can improve anticancer immunity. Here, we report that the bromodomain and extraterminal domain (BET) inhibitor JQ1 inhibits PD-1 expression in Jurkat T cells, primary T cells, and T-cell exhaustion models. Furthermore, JQ1 dramatically impaired the expression of PD-1 and T-cell immunoglobulin mucin-domain-containing-3 (Tim-3) and promoted the secretion of cytokines in T cells from patients with acute myeloid leukemia (AML). In line with that, BET inhibitor-treated CD19-CAR T and CD123-CAR T cells have enhanced anti-leukemia potency and resistant to exhaustion. Mechanistically, BRD4 binds to the NFAT2 and PDCD1 (encoding PD-1) promoters, and NFAT2 binds to the PDCD1 and HAVCR2 (encoding Tim-3) promoters. JQ1-treated T cells showed downregulated NFAT2, PD-1, and Tim-3 expression. In addition, BET inhibitor suppressed programmed death-ligand 1 (PD-L1) expression and cell growth in AML cell lines and in primary AML cells. We also demonstrated that JQ1 treatment led to inhibition of leukemia progression, reduced T-cell PD-1Tim-3 expression, and prolonged survival in MLL-AF9 AML mouse model and Nalm6 (B-cell acute lymphoblastic leukemia cell)-bearing mouse leukemia model. Taken together, BET inhibition improved anti-leukemia immunity by regulating PD-1PD-L1 expression, and also directly suppressed AML cells, which provides novel insights on the multiple effects of BET inhibition for cancer therapy.

Adaptable Leukemia Cells Resisting CAR T-cell Attack via B-cell Activation.

Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable milestones in the treatment of B-cell malignancies. However, cancer cells frequently survive CAR T-cell killing in a large cohort of patients. Relapse oftentimes is associated with antigen loss. In this issue, Im and colleagues report a new mechanism of leukemic-cell resistance to anti-CD19 CAR T cells Leukemic cells can enable a B-cell activation and germinal center reaction signature, which causes CD19 transcriptional downregulation and survival from CAR exposure. See related article by Im et al., p. 1055 (5).