Treatment Of Acute Lymphoblastic Leukemia Research Articles

Substrate Affinity Is Not Crucial for Therapeutic L-Asparaginases: Antileukemic Activity of Novel Bacterial Enzymes

L-asparaginases are used in the treatment of acute lymphoblastic leukemia. The aim of this work was to compare the antiproliferative potential and proapoptotic properties of novel L-asparaginases from different structural classes, viz. EcAIII and KpAIII (class 2), as well as ReAIV and ReAV (class 3). The EcAII (class 1) enzyme served as a reference. The proapoptotic and antiproliferative effects were tested using four human leukemia cell models: MOLT-4, RAJI, THP-1, and HL-60. The antiproliferative assay with the MOLT-4 cell line indicated the inhibitory properties of all tested L-asparaginases. The results from the THP-1 cell models showed a similar antiproliferative effect in the presence of EcAII, EcAIII, and KpAIII. In the case of HL-60 cells, the inhibition of proliferation was observed in the presence of EcAII and KpAIII, whereas the proliferation of RAJI cells was inhibited only by EcAII. The results of the proapoptotic assays showed individual effects of the enzymes toward specific cell lines, suggesting a selective (time-dependent and dose-dependent) action of the tested L-asparaginases. We have, thus, demonstrated that novel L-asparaginases, with a lower substrate affinity than EcAII, also exhibit significant antileukemic properties in vitro, which makes them interesting new drug candidates for the treatment of hematological malignancies. For all enzymes, the kinetic parameters (Km and kcat) and thermal stability (Tm) were determined. Structural and catalytic properties of L-asparaginases from different classes are also summarized.

From niche to blockbuster: a greater role for allopurinol in maintenance treatment of acute lymphoblastic leukemia.

Not available.

The dynamic changes of ghrelin and anandamide during the treatment of acute lymphoblastic leukemia in the pediatric population

The dynamic changes of ghrelin and anandamide during the treatment of acute lymphoblastic leukemia in the pediatric population

Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.

Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T-cell acute lymphoblastic leukaemia.

T-cell acute lymphoblastic leukaemia (T-ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T-ALL cases. Ubiquitin-specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T-ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T-ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T-ALL with or without mutant NOTCH1.

Quality of life in children and adolescents after treatment for acute lymphoblastic leukemia according to the NOPHO ALL2008 protocol.

The improved outcome of childhood acute lymphoblastic leukemia (ALL) over the last decades has increased the importance of assessing late effects and health-related quality of life (HRQoL), particularly when evaluating and comparing outcomes in clinical trials. This study aimed to assess HRQoL in children treated for ALL according to the NOPHO ALL2008 protocol. Children, aged 1 to less than 18years at diagnosis, alive in first remission, and their parents, were asked to complete PedsQL 4.0 Generic Core Scales (self- and proxy-report) at ≥6months after end of therapy. Data on socioeconomic factors and parent-reported toxicity were collected through a study-specific questionnaire, and the NOPHO ALL2008 database was used to identify eligible families and add additional disease- and treatment-related data. HRQoL data were collected during 2013-2019 in Sweden, Finland, and Denmark. A total of 299 children were included. The older children (8years and older) reported similar HRQoL scores compared to Finnish reference data, except lower scores for School Functioning in high-risk patients. Scores from the parent-proxy and self-reports from 5-7-year olds were notably lower than reference. Parent-reported toxicity was associated with lower total and physical HRQoL scores in adjusted models for younger as well as older children in the self-report and parent-proxy versions, and also with lower psychosocial score in the parent-proxy. Self-reported HRQoL was similar to reference population. The most important determinant for HRQoL after end of ALL treatment was parent-reported toxicity during treatment. Thus, minimizing complications is an obvious focus for future treatment protocols.

T-Cell Engagers-The Structure and Functional Principle and Application in Hematological Malignancies.

Recent advancements in cancer immunotherapy have made directing the cellular immune response onto cancer cells a promising strategy for the treatment of hematological malignancies. The introduction of monoclonal antibody-based (mAbs) targeted therapy has significantly improved the prognosis for hematological patients. Facing the issues of mAb-based therapies, a novel bispecific antibody (BsAb) format was developed. T-cell engagers (TCEs) are BsAbs, which simultaneously target tumor-associated antigens on tumor cells and CD3 molecules present on T-cells. This mechanism allows for the direct activation of T-cells and their anti-tumor features, ultimately resulting in the lysis of tumor cells. In 2014, the FDA approved blinatumomab, a TCE directed to CD3 and CD19 for treatment of acute lymphoblastic leukemia. Since then, numerous TCEs have been developed, allowing for treating different hematological malignancies such as acute myeloid leukemia, multiple myeloma, and non-Hodgkin lymphoma and Hodgkin lymphoma. As of November 2023, seven clinically approved TCE therapies are on the market. TCE-based therapies still have their limitations; however, improving the properties of TCEs, as well as combining TCE-based therapies with other forms of treatment, give hope to find the cures for currently terminal diseases. In this paper, we summarized the technical basis of the TCE technology, its application in hematology, and its current issues and prospects.

The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats.

Methotrexate (MTX) is an essential part of therapy in the treatment of acute lymphoblastic leukemia (ALL) in children, and inferior intellectual outcomes have been reported in children who are leukemia survivors. Although several studies have demonstrated that the interaction between gut microbiota changes and the brain plays a vital role in the pathogenesis of chemotherapy-induced brain injury, preexisting studies on the effect of MTX on gut microbiota changes focused on gastrointestinal toxicity only. Based on our previous studies, which revealed that MTX treatment resulted in inferior neurocognitive function in developing young rats, we built a young rat model mimicking MTX treatment in a child ALL protocol, trying to investigate the interactions between the gut and brain in response to MTX treatment. We found an association between gut microbiota changes and neurogenesis/repair processes in response to MTX treatment, which suggest that MTX treatment results in gut dysbiosis, which is considered to be related to MTX neurotoxicity through an alteration in gut-brain axis communication.

Dual targeting of glutamine and serine metabolism in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by disrupted blood cell production and function. Recent investigations have highlighted the potential of targeting glutamine metabolism as a promising therapeutic approach for AML. Asparaginases, enzymes that deplete circulating glutamine and asparagine, are approved for the treatment of acute lymphoblastic leukemia, but are also under investigation in AML, with promising results. We previously reported an elevation in plasma serine levels following treatment with Erwinia-derived asparaginase (also called crisantaspase). This led us to hypothesize that AML cells initiate the de novo serine biosynthesis pathway in response to crisantaspase treatment and that inhibiting this pathway in combination with crisantaspase would enhance AML cell death. Here we report that in AML cell lines, treatment with the clinically available crisantaspase, Rylaze, upregulates the serine biosynthesis enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) through activation of the Amino Acid Response (AAR) pathway, a cellular stress response mechanism that regulates amino acid metabolism and protein synthesis under conditions of nutrient limitation. Inhibition of serine biosynthesis through CRISPR-Cas9-mediated knockout of PHGDH resulted in a ~250-fold reduction in the half-maximal inhibitory concentration (IC50) for Rylaze, indicating heightened sensitivity to crisantaspase therapy. Treatment of AML cells with a combination of Rylaze and a small molecule inhibitor of PHGDH (BI4916) revealed synergistic anti-proliferative effects in both cell lines and primary AML patient samples. Rylaze-BI4916 treatment in AML cell lines led to the inhibition of cap-dependent mRNA translation and protein synthesis, as well as a marked decrease in intracellular glutathione levels, a critical cellular antioxidant. Collectively, our results highlight the clinical potential of targeting serine biosynthesis in combination with crisantaspase as a novel therapeutic strategy for AML.

[Advances on treatment of pediatric acute lymphoblastic leukemia with blinatumomab].

[Advances on treatment of pediatric acute lymphoblastic leukemia with blinatumomab].

Caregiver perceptions of child heath behaviors and weight during treatment for acute lymphoblastic leukemia.

Changes in health behaviors and weight are common during the early phases of pediatric acute lymphoblastic leukemia treatment, and may negatively impact treatment tolerability.. Given that ALL is most prevalent in children, caregivers play an essential role in shaping health behaviors during treatment. This study presents a qualitative analysis of semi-structured interviews with caregivers of youth in the early phases of ALL treatment. Caregivers (N=17, 95% female) of a child (M age=6.76years) diagnosed with ALL and on treatment for less than 1year (M=8.7months since diagnosis) completed a semi-structured interview about perceptions of their child's nutrition, physical activity, sedentary time, and weight during ALL treatment. Thematic analysis followed Braun and Clark's six-step framework (2006). Two coders established reliability (alpha=.88) and used a multi-pass coding system to extract themes. Caregivers' concerns around their child's weight during ALL treatment primarily centered around avoiding malnutrition. Weight gain during treatment was less of a concern and often viewed as protective. Caregivers reported encouraging their child to eat palatable, calorie-dense foods to mitigate risk for weight loss. Caregivers also expressed concern that children were less active and more sedentary due to treatment-related pain. Caregivers discussed health behaviors during treatment as being child-directed, rather than parent- or provider-directed. Future interventions may consider strategies to engage in joint parent-child decisions and caregiver education around risks of excessive weight gain during treatment. Interventions should include anticipatory guidance and aim to support parents in developing skills to support their child's health behaviors during treatment.

Calaspargase Pegol (Asparlas)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses calaspargase pegol (Asparlas), 3,750 units/5 mL (750 units/mL), concentrate for solution for IV infusion
 Indication : As a component of a multiagent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) in pediatric and young adult patients aged 1 year to 21 years

Genetic polymorphisms as predictors of methotrexate toxicity: literature review

Background. A significant advancement in the treatment of high-grade aggressive non-Hodgkin’s lymphomas and acute lymphoblastic leukemia is the inclusion of high-dose (1000–5000 mg/m2) methotrexate in the treatment protocol. This approach has significantly increased the long-term survival rate, but it has been associated with toxicity, requiring supportive care. Factors that predict toxicity were identified, including genes involved in the metabolism (MTHFR) or transport (SLCO1B1) of methotrexate. The analysis of methotrexate metabolism has identified additional genes responsible for the elimination of this drug, allowing for more effective prevention and treatment of methotrexate-associated toxicity.Aim. To study the genetic polymorphisms of enzymes involved in the methotrexate metabolism and associated toxicity in the treatment of pediatric acute lymphoblastic leukemia and non-Hodgkin’s lymphomas.Materials and methods. Data were analyzed in specialized medical databases such as Pubmed, Scopus, Web of Science, Frontiers, and Google Scholar from 2001 to 2024.Results. The main predictors of high-dose methotrexate-associated toxicity are gene polymorphisms in MTHFR, SLCO1B1, ARID5B.Conclusion. Despite the contradictory data presented in the literature, it is important to consider the detection of polymorphisms during high-dose methotrexate treatment in order to administer timely supportive care and prevent significant toxicity.

Work Disability and Return to Work After Treatment for Acute Lymphoblastic Leukemia: A Danish Nationwide Cohort Study [Letter].

Work Disability and Return to Work After Treatment for Acute Lymphoblastic Leukemia: A Danish Nationwide Cohort Study [Letter].

Unveiling the anticancer potential of L-Asparaginase (ASNase) from novel Streptomyces isolate HB2AG: Purification and characterization study

L-asparaginase (ASNase) obtained from microbial origins is a significant enzyme in the commercial sphere, crucial for the treatment of acute lymphoblastic leukemia. In the current investigation, we isolated ASNase through techniques involving ammonium sulfate precipitation and DEAE sepharose anion exchange column chromatography, revealing a molecular weight of 35kDa. The enzyme exhibited its peak activity at pH 8 and 40°C, maintaining approximately 99% of its enzymatic effectiveness. The Michaelis constant (Km) and maximum velocity (Vmax) were determined to be 0.0021M and 714.3µM/min, respectively. ASNase was found to be non-toxic on HEK293 cells and selectively effective against breast cancer, hepatocellular carcinoma cells, colorectal adenocarcinoma cells, Human lung cancer cell line, Neck squamous cells, and Human head carcinoma cells. Hepatocellular carcinoma cells exhibited remarkable responsiveness to ASNase, displaying an IC50 of 23µg/mL. This led to observable changes in nuclear morphology indicative of apoptosis, as evidenced by DAPI and Annexin V-FITC staining. ASNase also showed cell migration potential on HEK293 cells. Streptomyces HB2AG ASNase’s dynamic functioning across pH and temperature ranges, as well as its stability at 40°C and cytotoxic potential, make it a promising pharmaceutical candidate for various applications.

Expert recommendations for pancreatitis/pancreatic necrosis treatment after L-asparaginase in children with acute lymphoblastic leukemia

L-asparaginase is one of the most effective drugs in pediatric and adult acute lymphoblastic leukemia treatment. But drug side effects are an important problem. pancreatitis and pancreatic necrosis are not common (2–18 %) complication, but high chance of severe disease with fatal outcome make to bring in careful attention of pediatric oncologists-hematologists, surgeons, intensivists, radiologists. Recognizing multidisciplinary importance of this problem, at June 21st, 2023 at Morozov Children’s Clinical hospital a Round table on pancreatitis/pancreatic necrosis after L-asparaginase use was organized. This article presents expert recommendations from federal and regional clinics in diagnosis and treatment of such severe complication.

Prophylaxis with enoxaparin and antithrombin III in drug-induced coagulation alterations in childhood leukemia: a retrospective experience of 20 years

BackgroundThromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a possible prophylaxis of thromboembolic events during intensive therapy. Only the administration of enoxaparin was able to achieve evidence in the literature to date.MethodsIn this retrospective study, 173 childhood leukemia patients were treated over 20 years with a thromboembolic prophylaxis including enoxaparin and AT III during induction therapy with L-asparaginase and cortisone.ResultsWe here report the effectiveness of administration of enoxaparin and AT III in childhood leukemia, showing a strikingly low prevalence of deep vein thrombosis (2.9%). Especially in adolescent patients, a particularly great need for AT III was demonstrated.ConclusionsWe recommend thromboembolic prophylaxis with enoxaparin and AT III substitution during induction/reinduction therapy with L-asparaginase and glucocorticosteroids, especially from adolescence onwards.

Chemotherapy-initiated cysteine-rich protein 61 decreases acute B-lymphoblastic leukemia chemosensitivity

PurposeChemoresistance is a major challenge for acute lymphoblastic leukemia (ALL) treatment. Cysteine-rich protein 61 (Cyr61) plays an important role in drug resistance modulation of tumor cells, and Cyr61 levels are increased in the bone marrow of patients with ALL and contribute to ALL cell survival. However, the effect of Cyr61 on B cell acute lymphoblastic leukemia (B-ALL) cell chemosensitivity and the regulatory mechanisms underlying Cyr61 production in bone marrow remain unknown.MethodsNalm-6 and Reh human B-ALL cell lines were used in this study. Cyr61 levels were assessed using quantitative real-time PCR (qRT-PCR), western blot analysis, and enzyme-linked immunosorbent assay. The effect of Cyr61 on B-ALL cell chemosensitivity to daunorubicin (DNR) was evaluated using cell viability and flow cytometry analyses. The regulatory mechanisms of Cyr61 production in bone marrow were examined using qRT-PCR and western blot analysis.ResultsCyr61 knockdown and overexpression increased and decreased the chemosensitivity of B-ALL cells to DNR, respectively. Cyr61 attenuated chemotherapeutic drug-induced apoptosis by upregulating B cell lymphoma-2. Notably, DNR induced DNA damage response and increased Cyr61 secretion in B-ALL cells through the ataxia telangiectasia mutated (ATM)-dependent nuclear factor kappa B pathway.ConclusionDNR induces Cyr61 production in B-ALL cells, and increased Cyr61 levels reduce the chemosensitivity of B-ALL cells. Consequently, targeting Cyr61 or related ATM signaling pathway may present a promising treatment strategy to enhance the chemosensitivity of patients with B-ALL.

Fatigue in children who have recently completed treatment for acute lymphoblastic leukemia: a longitudinal study

BackgroundThis study examined fatigue in patients treated for childhood acute lymphoblastic leukemia (ALL) over a 2-year period (3- to 27-months post-treatment completion), from the perspective of children and parent caregivers, compared to a healthy comparison group.MethodsEighty-three patients (4–16 years at enrolment) and their parents, reported on the child’s fatigue using the Pediatric Quality of Life Inventory– Multidimensional Fatigue Scale (PedsQL-MFS), at 3- 15- and 27-months post-treatment completion, and 53 healthy children and their parents reported on fatigue across the same timepoints.ResultsParent proxy-reporting showed that parents of ALL patients reported more total fatigue than parents of the comparison group at all time points, with all subscales elevated (general, cognitive, and sleep/rest fatigue). In contrast, patient self-report of fatigue over this period differed from the comparison children for the general fatigue subscale only. Self-reported total fatigue was worse than the comparison group at the 27-month timepoint, with cognitive and sleep/rest fatigue symptoms contributing to this difference. Expected improvements in fatigue over time were not evident in either patient or parent report and no demographic risk factors were identified. Parents and children from both groups reported significantly more fatigue at all time points compared to commonly utilised normative population data.ConclusionsPatients treated for childhood ALL are impacted by fatigue symptoms in the post-treatment and early survivorship period. These findings highlight that patients in the 2-years following treatment require increased symptom surveillance and may benefit particularly from interventions that target cognitive and sleep/rest fatigue.

Abstract 7444: Hepatotoxicity from L-asparaginase is associated with lipid changes in a mouse model

Abstract L-asparaginase (Calaspargase-pegol, PEG) is currently an important component of acute lymphoblastic leukemia (ALL) treatment in children, adolescents, and young adults. Despite its high efficacy, toxicities including hepatotoxicity limit its use. Asparaginase-associated hepatotoxicity is often associated with obesity and fatty liver, highlighting lipid metabolism as a potential contributor to fatty liver. Therefore, we performed lipidomic analyses of plasma and liver from control and obese mice treated with one dose of PEG, to determine whether specific lipid moieties or classes may be associated with the hepatotoxicity produced by PEG. Control and obese 18-week-old male C57Bl6/J mice were treated with one dose of 3000 IU/kg PEG or vehicle (n = 6 per group). Hepatotoxicity was assessed one week later by liver histopathology and plasma alanine transaminase (ALT) and albumin levels. Liver and plasma lipidomic profiles were also analyzed by UHPLC-QTRAP-MS/MS. One week post Veh vs. PEG were compared using two-sided, unpaired t-tests. PEG increased liver steatosis scores in both control (Veh: 0.5±0.2, PEG: 3.7±0.3, p<0.001) and obese mice (Veh: 4.0±0.6, PEG: 6.7±0.2, p<0.01). While ALT levels did not show a clear pattern with PEG treatment, albumin level decreased in both control (Veh: 3.6±0.1, PEG: 2.7±0.2, p<0.01) and obese mice (Veh: 4.1±0.2, PEG: 2.8±0.1, p<0.01). Lipidomics analysis showed that plasma lipids generally decreased with PEG treatment in control (not shown) and more significantly in obese mice (Phosphatidylcholines [PC]: Veh 3000.0±381.1, PEG 507.2±71.5, p<0.001; Phosphatidylethanolamine [PE]: Veh 604.7±128.1, PEG 295.3±75.0, p<0.001; triglycerides [TG]: Veh 649.7±89.7, PEG 150.6±49.3, p<0.001). Similar patterns were observed in control (not shown) and obese livers for PC (Veh 11.1±0.8, PEG 5.7±0.8, p<0.001) and PE (Veh 6.7±0.8, PEG 3.5±0.5, p<0.001), whereas liver TG increased with treatment (Veh 220.1±113.5, PEG 586.6±113.4, p<0.001). Interestingly, there were strong negative correlations between steatosis score and liver PC (r2=0.46, p<0.001) and PE (r2=0.62, p<0.001). As low PC has been shown to induce fatty liver, this finding implies that PEG might induce steatosis via reduction in PC and its precursor, PE. Future work will investigate the mechanisms by which PEG reduces liver PE and PC levels, and whether this is causally related to steatosis and hepatotoxicity. Citation Format: Veronica Ruiz-Torres, Jennifer J. Chia, Michael Cohen, Jia Tan, Praveen Bandaru, Austin Brown, Van Huynh, Etan Orgel, Steven D. Mittelman. Hepatotoxicity from L-asparaginase is associated with lipid changes in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7444.