Medicine › Public Health, Environmental and Occupational Health

Acute Lymphoblastic Leukemia research

Works Count: 54983

Wikipedia

Description

This cluster of papers focuses on the epidemiology, genetic basis, treatment, and outcomes of childhood acute lymphoblastic leukemia (ALL). It covers topics such as genetic alterations, minimal residual disease, pharmacogenomics, prognostic factors, and relapse risk. The papers also discuss the challenges and advancements in pediatric oncology for the treatment of childhood leukemia.

Keywords

Childhood Cancer; Acute Lymphoblastic Leukemia; Genetic Alterations; Treatment Outcome; Minimal Residual Disease; Pharmacogenomics; Prognostic Factors; Thiopurine Therapy; Relapse Risk; Pediatric Oncology

Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity.

1980-09-01

Richard M. Weinshilboum , S. L. Sladek

Acute Lymphoblastic Leukemia in Children

2015-10-14

Stephen P. Hunger , Charles G. Mullighan

The most common cancer in childhood is now curable in 90% of patients. Current efforts are focused on devising molecular-based therapy for the subsets of acute lymphoblastic leukemia that are … The most common cancer in childhood is now curable in 90% of patients. Current efforts are focused on devising molecular-based therapy for the subsets of acute lymphoblastic leukemia that are most resistant to current therapy.

Results of Treatment With Hyper-CVAD, a Dose-Intensive Regimen, in Adult Acute Lymphocytic Leukemia

2000-02-01

Hagop M. Kantarjian , Susan O’Brien , Terry L. Smith +7 more

PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults with newly … PURPOSE: To evaluate the efficacy and toxicity of Hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), a dose-intensive regimen, in adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Adults with newly diagnosed ALL referred since 1992 were entered onto the study; treatment was initiated in 204 patients between 1992 and January 1998. No exclusions were made because of older age, poor performance status, organ dysfunction, or active infection. Median age was 39.5 years; 37% were at least 50 years old. Mature B-cell disease (Burkitt type) was present in 9%, T-cell disease in 17%. Leukocytosis of more than 30 × 10 9 /L was found in 26%, Philadelphia chromosome–positive disease in 16% (20% of patients with assessable metaphases), CNS leukemia at the time of diagnosis in 7%, and a mediastinal mass in 7%. Treatment consisted of four cycles of Hyper-CVAD alternating with four cycles of high-dose methotrexate (MTX) and cytarabine therapy, together with intrathecal CNS prophylaxis and supportive care with antibiotic prophylaxis and granulocyte colony-stimulating factor therapy. Maintenance in patients with nonmature B-cell ALL included 2 years of treatment with mercaptopurine, MTX, vincristine, and prednisone (POMP). RESULTS: Overall, 185 patients (91%) achieved complete remission (CR) and 12 (6%) died during induction therapy. Estimated 5-year survival and 5-year CR rates were 39% and 38%, respectively. The incidence of CNS relapse was low (4%). Compared with 222 patients treated with vincristine, doxorubicin, and dexamethasone (VAD) regimens, our patients had a better CR rate (91% v 75%, P < .01) and CR rate after one course (74% v 55%, P < .01) and better survival (P < .01), and a smaller percentage had more than 5% day 14 blasts (34% v 48%, P = .01). Previous prognostic models remained predictive for outcome with Hyper-CVAD therapy. CONCLUSION: Hyper-CVAD therapy is superior to our previous regimens and should be compared with established regimens in adult ALL.

The Pharmacology and Clinical Use of Methotrexate

1983-11-03

Jacques Jolivet , Kenneth H. Cowan , Gregory A. Curt +2 more

METHOTREXATE, the most widely used antimetabolite in cancer chemotherapy, has an essential role in the treatment of such diverse diseases as acute lymphocytic leukemia, non-Hodgkin's lymphoma, osteosarcoma, choriocarcinoma, head and … METHOTREXATE, the most widely used antimetabolite in cancer chemotherapy, has an essential role in the treatment of such diverse diseases as acute lymphocytic leukemia, non-Hodgkin's lymphoma, osteosarcoma, choriocarcinoma, head and neck cancer, and breast cancer.1 It has also become an important therapeutic alternative in the treatment of severe psoriasis2 and in the suppression of graft-versus-host disease after bone-marrow transplantation,3 as well as in the experimental treatment of various rheumatic diseases after primary therapy has failed.4 Through pharmacologic research we have gained an understanding of the basic steps in the action of methotrexate, including its transport across cell membranes, its intracellular . . .

Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study

2006-10-10

Adele K. Fielding , Susan Richards , Rajesh Chopra +7 more

View PDF Chat

Molecular Diagnosis of Thiopurine S-Methyltransferase Deficiency: Genetic Basis for Azathioprine and Mercaptopurine Intolerance

1997-04-15

Charles R. Yates , Eugene Y. Krynetski , Thrina Loennechen +5 more

Background: Thiopurine S-methyltransferase (TPM) catalyzes the S-methylation (that is, inactivation) of mercaptopurine, azathioprine, and thioguanine and exhibits genetic polymorphism. About 10% of patients have intermediate TPM activity because of heterozygosity, … Background: Thiopurine S-methyltransferase (TPM) catalyzes the S-methylation (that is, inactivation) of mercaptopurine, azathioprine, and thioguanine and exhibits genetic polymorphism. About 10% of patients have intermediate TPM activity because of heterozygosity, and about 1 in 300 inherit TPM deficiency as an autosomal recessive trait. If they receive standard doses of thiopurine medications (for example, 75 mg/m2 body surface area per day), TPM-deficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, which leads to severe and possibly fatal myelosuppression. Objective: To elucidate the genetic basis and develop molecular methods for the diagnosis of TPM deficiency and heterozygosity. Design: Diagnostic test evaluation. Setting: Research hospital. Patients: The TPM phenotype was determined in 282 unrelated white persons, and TPM genotype was determined in all persons who had intermediate TPM activity (heterozygotes) and a randomly selected, equal number of persons who had high activity. In addition, genotype was determined in 6 TPM-deficient patients. Measurements: Polymerase chain reaction (PCR) assays were developed to detect the G238C transversion in TPM*2 and the G460A and A719G transitions in TPM*3 alleles. Radiochemical assay was used to measure TPM activity. Mutations of TPM were identified in genomic DNA, and the concordance of TPM genotype and phenotype was determined. Results: 21 patients who had a heterozygous phenotype were identified (7.4% of sample [95% CI, 4.7% to 11.2%]). TPM*3A was the most prevalent mutant allele (18 of 21 mutant alleles in heterozygotes; 85%); TPM*2 and TPM*3C were more rare (about 5% each). All 6 patients who had TPM deficiency had two mutant alleles, 20 of 21 patients (95% [CI, 76% to 99.9%]) who had intermediate TPM activity had one mutant allele, and 21 of 21 patients (100% [CI, 83% to 100%]) who had high activity had no known TPM mutation. Detection of TPM mutations in genomic DNA by PCR coincided perfectly with genotypes detected by complementary DNA sequencing. Conclusions: The major inactivating mutations at the human TPM locus have been identified and can be reliably detected by PCR-based methods, which show an excellent concordance between genotype and phenotype. The detection of TPM mutations provides a molecular diagnostic method for prospectively identifying TPM-deficient and heterozygous patients.

Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia

2004-10-07

Andrew P. Weng , Adolfo A. Ferrando , Woojoong Lee +6 more

Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, … Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1, a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes, have activating mutations that involve the extracellular heterodimerization domain and/or the C-terminal PEST domain of NOTCH1. These findings greatly expand the role of activated NOTCH1 in the molecular pathogenesis of human T-ALL and provide a strong rationale for targeted therapies that interfere with NOTCH signaling.

Continuous culture of human lymphoblasts from peripheral blood of a child with acute leukemia

1965-04-01

George E. Foley , Herbert Lazarus , Sidney Farber +3 more

H blood buffy coat specimens derived from leukemic and non-leukemic patients have been studied extensively by various methods of cell culture with and without "feeder layers."l,4, 6 , 1 6 … H blood buffy coat specimens derived from leukemic and non-leukemic patients have been studied extensively by various methods of cell culture with and without "feeder layers."l,4, 6 , 1 6 , 2 1 Recent studies employing modifications of these methods of stationary or monolayer cell culture have resulted in the derivation of a line of monocytic cells from the buffy coat of an adult leukemic patient.11In these laboratories (and ekewhere, so far as is known at this time) experience with a variety of stationary or monolayer cultures initiated with cells obtained from bone marrow and peripheral blood buffy coat of children with acute leukemia during the past 10 or more years has been unsuccessful.The studies reported by Osgood and Brooke17 indicating that the derivation of monolayer cultures from the peripheral blood of adult patients with leukemia did not require the participation of "fixed tissue" elements provided by the usual "feeder layer"together with more recent observations in these laboratories and elsewhere29 3 that mononuclear cells occasionally detach from such monolayers and "grow" for varying periods of time in the fluid portion of the culturessuggested that, given appropriate experimental conditions, such cells might be isolated directly in suspension culture.This, together with consideration of the phenomenon of population

View PDF Chat

The international incidence of childhood cancer

1988-10-15

D M Parkin , Charles Stiller , G J Draper +1 more

The International Agency for Research on Cancer has coordinated a worldwide study of the incidence of cancer in childhood. Contributors from over 50 countries have provided data. This paper presents … The International Agency for Research on Cancer has coordinated a worldwide study of the incidence of cancer in childhood. Contributors from over 50 countries have provided data. This paper presents a summary of some of the major results. The incidence rates and relative frequencies of childhood cancers are described according to 12 diagnostic groups, defined mainly in terms of tumour morphology. Variations in the risk of those tumours between different countries and different ethnic groups provide important information on the relative importance of environmental and genetic factors in their aetiology.

Treatment of Acute Lymphoblastic Leukemia

2006-01-11

Ching‐Hon Pui , William E. Evans

Although the overall cure rate of acute lymphoblastic leukemia (ALL) in children is about 80 percent, affected adults fare less well. This review considers recent advances in the treatment of … Although the overall cure rate of acute lymphoblastic leukemia (ALL) in children is about 80 percent, affected adults fare less well. This review considers recent advances in the treatment of ALL, emphasizing issues that need to be addressed if treatment outcome is to improve further.

Azathioprine and 6-Mercaptopurine in Crohn Disease

1995-07-15

David C. Pearson

Purpose: To assess the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn disease and the effectiveness of azathioprine in maintaining remission of quiescent disease. Data Sources: Pertinent … Purpose: To assess the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active Crohn disease and the effectiveness of azathioprine in maintaining remission of quiescent disease. Data Sources: Pertinent studies were selected from the MEDLINE database (1966 to May 1994), abstracts from major gastrointestinal meetings, and references from published articles and reviews. Study Selection: Nine randomized, placebo-controlled trials of azathioprine or 6-mercaptopurine therapy were identified: Four addressed active disease, two addressed quiescent disease, and three had multiple therapeutic arms. Data Extraction: Data were extracted by three independent observers on the basis of the intention-to-treat principle and were analyzed with logistic regression. Each study was given a quality score on the basis of predetermined criteria. Data Synthesis: Compared with placebo, azathioprine or 6-mercaptopurine therapy had an odds ratio of response of 3.09 (95% CI, 2.45 to 3.91) in patients with active Crohn disease. When the single trial that used 6-mercaptopurine in active disease was excluded from the analysis, the odds ratio of response was 1.45 (CI, 1.12 to 1.87). No trials of quiescent disease used 6-mercaptopurine; the odds ratio of response in these trials of quiescent disease was 2.27 (CI, 1.76 to 2.93). For active disease, continuation of therapy for at least 17 weeks improved response (P = 0.03). For quiescent disease, a higher dose improved response (P = 0.008). Increased cumulative dose improved response in both groups (P < 0.001 for active disease and P = 0.01 for quiescent disease). A steroid-sparing effect was seen in active disease (odds ratio, 3.69 [CI, 2.12 to 6.42] and in quiescent disease (odds ratio, 4.64 [CI, 1.00 to 21.54]). Fistulae improved with therapy (odds ratio, 4.44 [CI, 1.50 to 13.20]). Adverse events requiring withdrawal from a trial, primarily allergy, leukopenia, pancreatitis, and nausea, were increased with therapy (odds ratio, 5.26 [CI, 2.20 to 12.60]). Conclusions: Azathioprine and 6-mercaptopurine are effective in treating active Crohn disease and in maintaining remission. Cumulative dose was an important factor in predicting response. Adverse effects were more common among patients receiving therapy.

Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium

2008-10-01

Melissa L. Bondy , Michael E. Scheurer , Beatrice Malmer +7 more

Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent … Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the group's consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address.

View PDF Chat

Genetic variegation of clonal architecture and propagating cells in leukaemia

2010-12-15

Kristina Anderson , Christoph Lutz , Frederik W. van Delft +7 more

In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993)

2007-11-30

Anthony H. Goldstone , Susan Richards , Hillard M. Lazarus +7 more

View PDF Chat

Deletion ofIKZF1and Prognosis in Acute Lymphoblastic Leukemia

2009-01-08

Charles G. Mullighan , Xiaoping Su , Jinghui Zhang +7 more

Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities … Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined.We studied a cohort of 221 children with high-risk B-cell-progenitor ALL with the use of single-nucleotide-polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1-positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell-progenitor ALL.More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell-lineage genes, and it was similar to the signature of BCR-ABL1-positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion.Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell-progenitor ALL.

View PDF Chat

The ikaros gene is required for the development of all lymphoid lineages

1994-10-01

Katia Georgopoulos , Michael Bigby , Jinhong Wang +4 more

Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation

2009-06-24

Ching-Hon Pui , Dario Campana , Deqing Pei +7 more

Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse.We conducted a clinical trial … Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse.We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it.The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection.With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

View PDF Chat

Genomic Analysis of the Clonal Origins of Relapsed Acute Lymphoblastic Leukemia

2008-11-27

Charles G. Mullighan , Letha A. Phillips , Xiaoping Su +4 more

Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for the minority of patients who relapse after treatment. To explore the genetic basis of … Most children with acute lymphoblastic leukemia (ALL) can be cured, but the prognosis is dismal for the minority of patients who relapse after treatment. To explore the genetic basis of relapse, we performed genome-wide DNA copy number analyses on matched diagnosis and relapse samples from 61 pediatric patients with ALL. The diagnosis and relapse samples typically showed different patterns of genomic copy number abnormalities (CNAs), with the CNAs acquired at relapse preferentially affecting genes implicated in cell cycle regulation and B cell development. Most relapse samples lacked some of the CNAs present at diagnosis, which suggests that the cells responsible for relapse are ancestral to the primary leukemia cells. Backtracking studies revealed that cells corresponding to the relapse clone were often present as minor subpopulations at diagnosis. These data suggest that genomic abnormalities contributing to ALL relapse are selected for during treatment, and they point to new targets for therapeutic intervention.

View PDF Chat

The genetic basis of early T-cell precursor acute lymphoblastic leukaemia

2012-01-01

Jinghui Zhang , Li Ding , Linda Holmfeldt +7 more

Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of … Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL. This work shows that treatments used for acute myeloid leukaemia and targeted therapies could be used for early T-cell precursor acute lymphoblastic leukaemia. The early T-cell precursor (ETP) subtype of childhood acute lymphoblastic leukaemia (ALL) has a poor prognosis when treated with standard chemotherapy. Whole genome sequencing is used here to gain insights into the genetic basis of the condition. The results reveal a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, lesions that disrupt haemopoiesis (many of which arise from chromosomal rearrangements that generate novel chimeric in-frame fusion genes), and inactivating mutations in histone modifying genes. This mutation pattern resembles that of myeloid malignancies, suggesting that myeloid-directed therapies such as high-dose cytarabine, or targeted therapies that inhibit cytokine receptor and JAK signalling, might be effective in ETP ALL.

View PDF Chat

Epidemiology of childhood cancer

2010-03-17

Peter Kaatsch

A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study

2009-01-09

Monique L. den Boer , Marjon van Slegtenhorst , Renée X. de Menezes +7 more

View PDF Chat

Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study

2008-04-03

Michael J. Borowitz , Meenakshi Devidas , Stephen P. Hunger +7 more

View PDF Chat

International Classification of Childhood Cancer, third edition

2005-02-14

E. Steliarova-Foucher , Charles Stiller , Brigitte Lacour +1 more

Abstract BACKGROUND The third edition of the International Classification of Diseases for Oncology (ICD‐O‐3), which was published in 2000, introduced major changes in coding and classification of neoplasms, notably for … Abstract BACKGROUND The third edition of the International Classification of Diseases for Oncology (ICD‐O‐3), which was published in 2000, introduced major changes in coding and classification of neoplasms, notably for leukemias and lymphomas, which are important groups of cancer types that occur in childhood. This necessitated a third revision of the 1996 International Classification of Childhood Cancer (ICCC‐3). METHODS The tumor categories for the ICCC‐3 were designed to respect several principles: agreement with current international standards, integration of the entities defined by newly developed diagnostic techniques, continuity with previous childhood classifications, and exhaustiveness. RESULTS The ICCC‐3 classifies tumors coded according to the ICD‐O‐3 into 12 main groups, which are split further into 47 subgroups. These 2 levels of the ICCC‐3 allow standardized comparisons of the broad categories of childhood neoplasms in continuity with the previous classifications. The 16 most heterogeneous subgroups are broken down further into 2–11 divisions to allow study of important entities or homogeneous collections of tumors characterized at the cytogenetic or molecular level. Some divisions may be combined across the higher‐level categories, such as the B‐cell neoplasms within leukemias and lymphomas. CONCLUSIONS The ICCC‐3 respects currently existing international standards and was designed for use in international, population‐based, epidemiological studies and cancer registries. The use of an international classification system is especially important in the field of pediatric oncology, in which the low frequency of cases requires rigorous procedures to ensure data comparability. Cancer 2005. © 2005 American Cancer Society.

View PDF Chat

Shrinkage necrosis: A distinct mode of cellular death

1971-09-01

J. F. R. Kerr

Acute lymphoblastic leukaemia

2008-03-01

Ching‐Hon Pui , Leslie L. Robison , A. Thomas Look

Acute lymphoblastic leukaemia

2013-03-22

Hiroto Inaba , Mel Greaves , Charles G. Mullighan

View PDF Chat

Targeted Therapy With the T-Cell–Engaging Antibody Blinatumomab of Chemotherapy-Refractory Minimal Residual Disease in B-Lineage Acute Lymphoblastic Leukemia Patients Results in High Response Rate and Prolonged Leukemia-Free Survival

2011-05-17

Max S. Topp , Peter Kufer , Nicola Gökbuget +7 more

Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute … Blinatumomab, a bispecific single-chain antibody targeting the CD19 antigen, is a member of a novel class of antibodies that redirect T cells for selective lysis of tumor cells. In acute lymphoblastic leukemia (ALL), persistence or relapse of minimal residual disease (MRD) after chemotherapy indicates resistance to chemotherapy and results in hematologic relapse. A phase II clinical study was conducted to determine the efficacy of blinatumomab in MRD-positive B-lineage ALL.Patients with MRD persistence or relapse after induction and consolidation therapy were included. MRD was assessed by quantitative reverse transcriptase polymerase chain reaction for either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours.Twenty-one patients were treated, of whom 16 patients became MRD negative. One patient was not evaluable due to a grade 3 adverse event leading to treatment discontinuation. Among the 16 responders, 12 patients had been molecularly refractory to previous chemotherapy. Probability for relapse-free survival is 78% at a median follow-up of 405 days. The most frequent grade 3 and 4 adverse event was lymphopenia, which was completely reversible like most other adverse events.Blinatumomab is an efficacious and well-tolerated treatment in patients with MRD-positive B-lineage ALL after intensive chemotherapy. T cells engaged by blinatumomab seem capable of eradicating chemotherapy-resistant tumor cells that otherwise cause clinical relapse.

View PDF Chat

Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia.

1996-01-01

Malcolm A. Smith , D Arthur , Bruce M. Camitta +7 more

PURPOSE To define more uniform criteria for risk-based treatment assignment for children with acute lymphoblastic leukemia (ALL), the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) sponsored … PURPOSE To define more uniform criteria for risk-based treatment assignment for children with acute lymphoblastic leukemia (ALL), the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) sponsored a workshop in September 1993. Participants included representatives from the Childrens Cancer Group (CCG), Pediatric Oncology Group (POG), Dana-Farber Cancer Institute (DFCI), St Jude Children's Research Hospital (SJCRH), and the CTEP. METHODS Workshop participants presented and reviewed data from ALL clinical trials, using weighted averages to combine outcome data from different groups. RESULTS For patients with B-precursor (ie, non-T, non-B) ALL, the standard-risk category (4-year event-free survival [EFS] rate, approximately 80%) will include patients 1 to 9 years of age with a WBC count at diagnosis less than 50,000/microL. The remaining patients will be classified as having high-risk ALL (4-year EFS rate, approximately 65%). For patients with T-cell ALL, different treatment strategies have yielded different conclusions concerning the prognostic significance of T-cell immunophenotype. Therefore, some groups/institutions will classify patients with T-cell ALL as high risk, while others will assign risk for patients with T-cell ALL based on the uniform age/WBC count criteria. Workshop participants agreed that the risk category of a patient may be modified by prognostic factors in addition to age and WBC count criteria, and that a common set of prognostic factors should be uniformly obtained, including DNA index (DI), cytogenetics, early response to treatment (eg, day-14 bone marrow), immunophenotype, and CNS status. CONCLUSIONS The more uniform approach to risk-based treatment assignment and to collection of specific prognostic factors should increase the efficiency of future ALL clinical research.

BCR–ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros

2008-04-13

Charles G. Mullighan , Christopher B. Miller , Ina Radtke +7 more

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration

2015-08-25

Ching‐Hon Pui , Jun J. Yang , Stephen P. Hunger +7 more

To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents.A review of English literature on childhood ALL … To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents.A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups.With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome-positive, and Philadelphia chromosome-like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL.The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.

View PDF Chat

Improved Survival for Children and Adolescents With Acute Lymphoblastic Leukemia Between 1990 and 2005: A Report From the Children's Oncology Group

2012-03-13

Stephen P. Hunger , Xiaomin Lu , Meenakshi Devidas +5 more

Purpose To examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's Oncology Group (COG) … Purpose To examine population-based improvements in survival and the impact of clinical covariates on outcome among children and adolescents with acute lymphoblastic leukemia (ALL) enrolled onto Children's Oncology Group (COG) clinical trials between 1990 and 2005. Patients and Methods In total, 21,626 persons age 0 to 22 years were enrolled onto COG ALL clinical trials from 1990 to 2005, representing 55.8% of ALL cases estimated to occur among US persons younger than age 20 years during this period. This period was divided into three eras (1990-1994, 1995-1999, and 2000-2005) that included similar patient numbers to examine changes in 5- and 10-year survival over time and the relationship of those changes in survival to clinical covariates, with additional analyses of cause of death. Results Five-year survival rates increased from 83.7% in 1990-1994 to 90.4% in 2000-2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with National Cancer Institute (NCI) standard- or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased. Conclusion This study documents ongoing survival improvements for children and adolescents with ALL. Thirty-six percent of deaths occurred among children with NCI standard-risk features emphasizing that efforts to further improve survival must be directed at both high-risk subsets and at those children predicted to have an excellent chance for cure.

View PDF Chat

Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling

2002-03-01

Allen Eng Juh Yeoh , Mary Elizabeth Ross , Sheila Shurtleff +7 more

View PDF Chat

Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update

2011-01-11

Ching‐Hon Pui , William L. Carroll , Soheil Meshinchi +1 more

We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of … We review recent advances in the biologic understanding and treatment of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), identify therapeutically challenging subgroups, and suggest future directions of research.A review of English literature on childhood acute leukemias from the past 5 years was performed.Contemporary treatments have resulted in 5-year event-free survival rates of approximately 80% for childhood ALL and almost 60% for pediatric AML. The advent of high-resolution genome-wide analyses has provided new insights into leukemogenesis and identified many novel subtypes of leukemia. Virtually all ALL and the vast majority of AML cases can be classified according to specific genetic abnormalities. Cooperative mutations involved in cell differentiation, cell cycle regulation, tumor suppression, drug responsiveness, and apoptosis have also been identified in many cases. The development of new formulations of existing drugs, molecularly targeted therapy, and immunotherapies promises to further advance the cure rates and improve quality of life of patients.The application of new high-throughput sequencing techniques to define the complete DNA sequence of leukemia and host normal cells and the development of new agents targeted to leukemogenic pathways promise to further improve outcome in the coming decade.

View PDF Chat

Outcomes for Children and Adolescents With Cancer: Challenges for the Twenty-First Century

2010-04-20

Malcolm A. Smith , Nita L. Seibel , Sean F. Altekruse +5 more

This report provides an overview of current childhood cancer statistics to facilitate analysis of the impact of past research discoveries on outcome and provide essential information for prioritizing future research … This report provides an overview of current childhood cancer statistics to facilitate analysis of the impact of past research discoveries on outcome and provide essential information for prioritizing future research directions.Incidence and survival data for childhood cancers came from the Surveillance, Epidemiology, and End Results 9 (SEER 9) registries, and mortality data were based on deaths in the United States that were reported by states to the Centers for Disease Control and Prevention by underlying cause.Childhood cancer incidence rates increased significantly from 1975 through 2006, with increasing rates for acute lymphoblastic leukemia being most notable. Childhood cancer mortality rates declined by more than 50% between 1975 and 2006. For leukemias and lymphomas, significantly decreasing mortality rates were observed throughout the 32-year period, though the rate of decline slowed somewhat after 1998. For remaining childhood cancers, significantly decreasing mortality rates were observed from 1975 to 1996, with stable rates from 1996 through 2006. Increased survival rates were observed for all categories of childhood cancers studied, with the extent and temporal pace of the increases varying by diagnosis.When 1975 age-specific death rates for children are used as a baseline, approximately 38,000 childhood malignant cancer deaths were averted in the United States from 1975 through 2006 as a result of more effective treatments identified and applied during this period. Continued success in reducing childhood cancer mortality will require new treatment paradigms building on an increased understanding of the molecular processes that promote growth and survival of specific childhood cancers.

View PDF Chat

Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease

2000-04-01

Marla C. Dubinsky , Stéphanie Lamothe , Hui Ying Yang +4 more

View PDF Chat

Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia

2014-09-11

Kathryn G. Roberts , Yongjin Li , Debbie Payne-Turner +7 more

Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR–ABL1–positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The … Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR–ABL1–positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.

View PDF Chat

Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study

2010-02-13

Valentino Conter , Claus R. Bartram , Maria Grazia Valsecchi +7 more

View PDF Chat

Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood

1998-11-01

Jacques J. M. van Dongen , Taku Seriu , E. Renate Panzer-Grümayer +7 more

Natalizumab Induction and Maintenance Therapy for Crohn's Disease

2005-11-02

William J. Sandborn , Jean–Fréderic Colombel , Roberts Enns +7 more

Natalizumab, a humanized monoclonal antibody against alpha4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients … Natalizumab, a humanized monoclonal antibody against alpha4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue.We conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150).In the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respectively; P=0.05) and remission (37 percent and 30 percent, respectively; P=0.12) at 10 weeks. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 percent vs. 28 percent, P<0.001) and remission (44 percent vs. 26 percent, P=0.003) through week 36 than did switching to placebo. Serious adverse events occurred in 7 percent of each group in the first trial and in 10 percent of the placebo group and 8 percent of the natalizumab group in the second trial. In an open-label extension study, a patient treated with natalizumab died from progressive multifocal leukoencephalopathy, associated with the JC virus, a human polyomavirus.Induction therapy with natalizumab for Crohn's disease resulted in small, nonsignificant improvements in response and remission rates. Patients who had a response had significantly increased rates of sustained response and remission if natalizumab was continued every four weeks. The benefit of natalizumab will need to be weighed against the risk of serious adverse events, including progressive multifocal leukoencephalopathy. (ClinicalTrials.gov numbers, NCT00032786 and NCT00032799.)

View PDF Chat

Risks of leukaemia and solid tumours in individuals with Down's syndrome

2000-01-01

Henrik Hasle , Inge Clemmensen , Margareta Mikkelsen

Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia

2009-01-14

Elaine Coustan‐Smith , Charles G. Mullighan , Mihaela Onciu +7 more

View PDF Chat

Second Malignant Neoplasms in Five-Year Survivors of Childhood Cancer: Childhood Cancer Survivor Study

2001-04-18

Joseph P. Neglia , Debra L. Friedman , Yutaka Yasui +6 more

Background: Because survival rates among childhood cancer patients are increasing, assessing the risk of second and subsequent malignant neoplasms (SMNs) is ever more important. Using the Childhood Cancer Survivor Study … Background: Because survival rates among childhood cancer patients are increasing, assessing the risk of second and subsequent malignant neoplasms (SMNs) is ever more important. Using the Childhood Cancer Survivor Study cohort, we identified the risk of SMNs. Methods: A retrospective cohort of 13 581 children diagnosed with common cancers before age 21 years and surviving at least 5 years was constructed with the use of data from patients treated at 25 U.S. and Canadian institutions. SMNs were ascertained through self-administered questionnaires and verified by pathology reports. Information on therapeutic exposures was abstracted from medical records. The risk of SMN was evaluated by standardized incidence ratios (SIRs) and excess absolute risk. Poisson multiple regression models were used to assess the impact of host and therapy factors on the risk of developing SMNs. All statistical tests were two-sided. Results: In 298 individuals, 314 SMNs were identified (SIR = 6.38; 95% confidence interval [CI] = 5.69 to 7.13). The largest observed excess SMNs were bone and breast cancers (SIR = 19.14 [95% CI = 12.72 to 27.67] and SIR = 16.18 [95% CI = 12.35 to 20.83], respectively). A statistically significant excess of SMNs followed all childhood cancers. In multivariate regression models adjusted for therapeutic radiation exposure, SMNs of any type were independently associated with female sex (P<.001), childhood cancer at a younger age (P for trend <.001), childhood Hodgkin's disease or soft-tissue sarcoma (P<.001 and P = .01, respectively), and exposure to alkylating agents (P for trend = .02). Twenty years after the childhood cancer diagnosis, the cumulative estimated SMN incidence was 3.2%. However, only 1.88 excess malignancies occurred per 1000 years of patient follow-up. Conclusions: Success in treating children with cancer should not be overshadowed by the incidence of SMNs. However, patients and health-care providers must be aware of risk factors for SMNs so that surveillance is focused and early prevention strategies are implemented.

View PDF Chat

Covariance Analysis of Censored Survival Data

1974-03-01

N. E. Breslow

The use of regression models for making covariance adjustments in the comparsion of survival curves is illustrated by application to a clinical trial of maintenance therapy for childhood leukemia. Three … The use of regression models for making covariance adjustments in the comparsion of survival curves is illustrated by application to a clinical trial of maintenance therapy for childhood leukemia. Three models are considered: the log linear exponential (Glasser [1967]); Cox's [1972] nonparametric generalization of this; and the linear exponential (Feigl and Zelen [1965]). Age and white blood count at diagnosis are both shown to be important for prognosis; adjustment for the latter variable has marked effects on the treatment comparisons. Both advantages and disadvantages with the regression approach are noted.

Clinical Significance of Minimal Residual Disease in Childhood Acute Lymphoblastic Leukemia

1998-08-27

Hélène Cavé , Jutte van der Werff ten Bosch , Stefan Suciu +7 more

The implications of the detection of residual disease after treatment of acute lymphoblastic leukemia (ALL) are unclear. We conducted a prospective study at 11 centers to determine the predictive value … The implications of the detection of residual disease after treatment of acute lymphoblastic leukemia (ALL) are unclear. We conducted a prospective study at 11 centers to determine the predictive value of the presence or absence of detectable residual disease at several points in time during the first six months after complete remission of childhood ALL had been induced. Junctional sequences of T-cell–receptor or immunoglobulin gene rearrangements were used as clonal markers of leukemic cells. Residual disease was quantitated with a competitive polymerase-chain-reaction (PCR) assay. Of 246 patients enrolled at diagnosis and treated with a uniform chemotherapy protocol, 178 were monitored for residual disease with one clone-specific probe (in 74 percent) or more than one probe (in 26 percent). The median follow-up period was 38 months.

View PDF Chat

Treatment of Crohn's Disease with 6-Mercaptopurine

1980-05-01

Daniel H. Present , Burton I. Korelitz , Nathaniel Wisch +3 more

To test the effectiveness of 6-mercaptopurine (6-MP) in the treatment of Crohn's disease, we entered 83 chronically ill patients into a two-year double-blind study comparing 6-MP with placebo. Crossover data … To test the effectiveness of 6-mercaptopurine (6-MP) in the treatment of Crohn's disease, we entered 83 chronically ill patients into a two-year double-blind study comparing 6-MP with placebo. Crossover data showed that improvement occurred in 26 of 39 courses of 6-MP (67%) as compared with three of 39 courses of placebo (8%) (P less than 0.001). Non-crossover data likewise confirmed the superiority of 6-MP. The drug was more effective than placebo in closing fistulas (31 vs 6%) and in permitting discontinuation or reduction of steroid dosage (75 vs. 36%) (P less than 0.001). The onset of response to 6-MP was often delayed, with 32% of patients taking longer than three months to respond, and 19% taking longer than four months. Adverse side effects to 6-MP occurred in 10% of patients and were uniformly reversible. We conclude that 6-MP is an effective and useful agent in the management of Crohn's disease.

International incidence of childhood cancer, 2001–10: a population-based registry study

2017-04-11

Eva Steliarova‐Foucher , Murielle Colombet , Lynn A. G. Ries +7 more

Cancer is a major cause of death in children worldwide, and the recorded incidence tends to increase with time. Internationally comparable data on childhood cancer incidence in the past two … Cancer is a major cause of death in children worldwide, and the recorded incidence tends to increase with time. Internationally comparable data on childhood cancer incidence in the past two decades are scarce. This study aimed to provide internationally comparable local data on the incidence of childhood cancer to promote research of causes and implementation of childhood cancer control.

View PDF Chat

Acute lymphoblastic leukemia: a comprehensive review and 2017 update

2017-06-30

T Terwilliger , Maher Abdul‐Hay

Abstract Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark … Abstract Acute lymphoblastic leukemia (ALL) is the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States alone. The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in differentiation and proliferation of lymphoid precursor cells. In adults, 75% of cases develop from precursors of the B-cell lineage, with the remainder of cases consisting of malignant T-cell precursors. Traditionally, risk stratification has been based on clinical factors such age, white blood cell count and response to chemotherapy; however, the identification of recurrent genetic alterations has helped refine individual prognosis and guide management. Despite advances in management, the backbone of therapy remains multi-agent chemotherapy with vincristine, corticosteroids and an anthracycline with allogeneic stem cell transplantation for eligible candidates. Elderly patients are often unable to tolerate such regimens and carry a particularly poor prognosis. Here, we review the major recent advances in the treatment of ALL.

View PDF Chat

The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia

2017-07-03

Yu Liu , John Easton , Ying Shao +7 more

View PDF Chat

Acute Lymphoblastic Leukemia

2004-04-07

Ching‐Hon Pui , Mary V. Relling , James R. Downing

This comprehensive survey emphasizes how recent advances in the knowledge of molecular mechanisms involved in acute lymphoblastic leukemia have influenced diagnosis, prognosis, and treatment. This comprehensive survey emphasizes how recent advances in the knowledge of molecular mechanisms involved in acute lymphoblastic leukemia have influenced diagnosis, prognosis, and treatment.

Acute Lymphoblastic Leukemia

1998-08-27

Ching‐Hon Pui , William E. Evans

Acute lymphoblastic leukemia (ALL) is diagnosed in 3000 to 4000 persons in the United States each year; two thirds of them are children.1,2 The current rate of cure of nearly … Acute lymphoblastic leukemia (ALL) is diagnosed in 3000 to 4000 persons in the United States each year; two thirds of them are children.1,2 The current rate of cure of nearly 80 percent in children attests to remarkable progress in the development of effective treatments for resistant subtypes of the disease. Progress has been incremental, from the introduction of combination chemotherapy and central nervous system treatment for presymptomatic leukemia to newer, intensive treatment regimens for patients at high risk for relapse (Figure 1). In contrast, only 30 to 40 percent of adults with ALL are cured.2,3 This discrepancy can . . .

Methotrexate toxicity: the need for vigilance in prescribing and monitoring

2025-06-24

K. M. Shivakumar , Joanne Young , Pratheepan Puvanakumar +2 more | Internal Medicine Journal

Critical roles of IKAROS and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

2025-06-24

Yali Ding , Bing He , Daniel Bogush +7 more | Leukemia

Abstract The IKZF1 gene encodes IKAROS – a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor … Abstract The IKZF1 gene encodes IKAROS – a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which IKAROS exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and IKZF 1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of IKAROS and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel IKAROS and HDAC1 functions in T-ALL: Both IKAROS and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by IKAROS is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and IKAROS-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of IKAROS and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.

Treatment of Philadelphia positive acute lymphoblastic leukemia

2025-06-24

Anna Torrent , Josep‐María Ribera | Acta Haematologica

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has historically been associated with poor prognosis and limited therapeutic options. Over the past two decades, however, the treatment paradigm has markedly shifted. … Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has historically been associated with poor prognosis and limited therapeutic options. Over the past two decades, however, the treatment paradigm has markedly shifted. The introduction of tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and ponatinib, has revolutionized frontline therapy, significantly improving remission rates and long-term survival. These agents, when combined with reduced-intensity chemotherapy or even with corticosteroids, have enabled less toxic regimens, particularly beneficial for older or unfit patients. The implementation of measurable residual disease (MRD) monitoring has emerged as a pivotal tool for risk stratification and therapeutic decision-making. Consequently, the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), considered a cornerstone of curative treatment, is being re-evaluated in patients achieving sustained deep molecular responses. More recently, immunotherapeutic strategies-including the bispecific T-cell engager blinatumomab and chimeric antigen receptor (CAR) T-cell therapies-have emerged as effective alternatives to conventional chemotherapy and TKIs. This review outlines the major advances in the management of Ph+ ALL, emphasizing the move toward more personalized, targeted, and less toxic treatment approaches.

Iohexol Clearance and Biomarker Analysis to Predict Toxicity in Patients With Acute Lymphoblastic Leukemia and Lymphoma Receiving High-Dose Methotrexate

2025-06-23

Amy L. Walz , Masha Kocherginsky , Monica Newmark +2 more | Journal of Pediatric Hematology/Oncology

High-dose methotrexate (HDMTX) remains integral to acute lymphoblastic leukemia/lymphoma (ALL) treatment. However, high MTX concentrations can lead to acute kidney injury (KI) and other toxicities. We investigated whether measured GFR … High-dose methotrexate (HDMTX) remains integral to acute lymphoblastic leukemia/lymphoma (ALL) treatment. However, high MTX concentrations can lead to acute kidney injury (KI) and other toxicities. We investigated whether measured GFR (mGFR) by iohexol clearance better predicts delayed MTX excretion and/or toxicity compared with standard of care using an estimated GFR (eGFR). We also examined if KI biomarkers (urine KIM-1 and clusterin, serum cystatin C, and plasma FGF23) identify KI more frequently than serum creatinine (sCr) alone. ALL patients receive 4 doses of HDMTX with alkalinized IV fluids, leucovorin rescue, and MTX clearance per the standard of care. We obtained mGFRs before HDMTX doses 1 and 4. eGFR was calculated using the Schwartz formula and biomarkers of KI were collected around each HDMTX dose. Overall, there were some associations between the mGFR/biomarkers with KI and other toxicities, but mGFR was not found to be a better predictor of delayed MTX clearance or toxicity than eGFR. The biomarkers did not predict KI development more frequently than sCr alone. On the basis of this study, there is no evidence that the current standard of care for determining the GFR in advance of HDMTX administration, nor postadministration management, should be adjusted.

Late Onset Blinatumomab‐Related Neurotoxicity in a Child With B‐Cell Acute Lymphoblastic Leukemia

2025-06-23

Krunal Shah , Harish Tandra , Ulrike Loebel +7 more | Pediatric Blood & Cancer

Changes in the Outcome of Pediatric Patients with Acute Lymphoblastic Leukemia—Single Center, Real-Life Experience

2025-06-23

Letiţia Elena Radu , Andra Marcu , Ana Maria Bică +7 more | Medicina

Background and Objectives: Due to the progress made in all areas of research, pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) now have an average overall survival rate of 90%. … Background and Objectives: Due to the progress made in all areas of research, pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) now have an average overall survival rate of 90%. There are still discrepancies between high-income countries and limited-resource centers. The aim of this study was to analyze prognostic factors and outcome parameters in a 223-patient cohort from a single center in Romania, treated with two adapted BFM protocols. Materials and Methods: The patients diagnosed with ALL in our center were enrolled in this study from January 2016 to December 2022 and subsequently followed up until December 2024. The patients were treated first according to the ALL IC BFM 2009 protocol until June 2019 and afterwards with the ALL AIEOP BFM 2017 protocol starting with July 2019. The prognostic factors were analyzed in both subgroups and the outcomes were measured: event-free survival (EFS), overall survival (OS), cumulative incidence of relapse (CIR), relapse-free survival (RFS) and non-relapse mortality (NRM). Results: The comparison between the two subgroups revealed that every parameter improved over time: complete remission after induction (87.75% vs. 80.7%), early deaths (3.92% vs. 5.78%), deaths in remission (4.08% vs. 5.26%), 5-year EFS (73.79% vs. 70.22%), 5-year CIR (18.36% vs. 19.04%), 5-year RFS (81.76% vs. 80.97%), 5-year NRM (7.85% vs. 10.77%), and 5-year OS (88.18% vs. 82.54%). Whereas for the standard-risk group, events such as relapse or death were isolated, for intermediate-risk patients, the events were limited to a small number and did not significantly influence the overall results, and for high-risk children, the results improved significantly between the two subgroups. The worst outcomes were observed in patients with the BCR::ABL1 fusion gene, T-cell phenotype, and in teenagers, compared to the ETV6::RUNX1 fusion gene, B precursor ALL, and in smaller children, respectively. Conclusions: The 5-year OS increased in our center from 82.54% to almost 90%, with the most substantial finding being the survival rate for high-risk patients, now reaching up to 80%. The prognostic factors were age at diagnosis, genetic characteristics, and response to treatment, especially prednisone sensibility.

Clinical Utility and Cost‐Effectiveness of Pretreatment NUDT15 Pharmacogenetic Testing to Prevent Thiopurine‐Induced Myelosuppression: A Genotype‐First Reverse Phenotyping Cohort Study Within the <scp>UK NIHR</scp> Inflammatory Bowel Disease Bioresource

2025-06-23

Christopher Roberts , Jaime Peters , Aleksejs Sazonvos +7 more | Alimentary Pharmacology & Therapeutics

The clinical utility and cost-effectiveness of pre-thiopurine NUDT15 pharmacogenetic testing in European and admixed populations are unknown. To report the prevalence, penetrance, expressivity, and pathogenicity of NUDT15 variant allele carriage … The clinical utility and cost-effectiveness of pre-thiopurine NUDT15 pharmacogenetic testing in European and admixed populations are unknown. To report the prevalence, penetrance, expressivity, and pathogenicity of NUDT15 variant allele carriage and the diagnostic accuracy and cost-effectiveness of an inexpensive loop-mediated isothermal amplification (LAMP) test. Retrospective case-matched cohort study of rates of severe myelosuppression in patients with and without loss-of-function NUDT15 variant allele(s) treated with a thiopurine. Overall, 1.3% of Europeans and 11.7% of South Asians carried a variant allele. Severe myelosuppression was associated with NUDT15 variant allele carriage (11.3% vs 0.95%; p < 0.001). Carriage of a single *3, *6 or *9 variant allele was associated with a shorter time to severe myelosuppression. Numbers needed to genotype to prevent myelosuppression in Europeans and South Asians were 786 and 23. Variant calling using the LAMP assay was fully concordant with Sanger sequencing (n = 154). It improved the safety of thiopurine dosing and was cost-effective when used to reduce the frequency and cost of thiopurine blood monitoring for patients without risk variants. We recommend TPMT and NUDT15 genetic testing in patients of Asian and admixed ancestry. In Europeans, reflex NUDT15 testing should be considered in patients with reduced TPMT activity or loss-of-function genotype. Thiopurines should be avoided in patients with > 1 NUDT15 variant allele and in patients with both NUDT15 and TPMT variant alleles. In patients with a single NUDT15 variant allele, we recommend thiopurine dose reduction (< 1 mg/kg/day) and intensified blood test monitoring.

Neo-antigen specific cancer vaccines for acute lymphoblastic leukemia—challenges, opportunities, and future directions

2025-06-23

Victoria Bloch Blytt Sandstad , Signe Modvig , Morten Orebo Holmström | Cancer Immunology Immunotherapy

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with standard treatment consisting of intensive chemotherapy and corticosteroids. While curative in most cases, this regimen leads to significant toxicity … Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, with standard treatment consisting of intensive chemotherapy and corticosteroids. While curative in most cases, this regimen leads to significant toxicity and long-term sequelae. Recent advancements in cancer immunotherapy, including chimeric antigen receptor T cells and bispecific T cell engagers, have improved outcomes, yet are limited by toxicity and immune escape by target downregulation. Thus, novel less toxic treatment modalities are highly warranted. The tumor mutational burden in ALL is low, which results in a low number of potentially immunogenic neo-antigens that could be used as targets for neo-epitope-specific therapeutic cancer vaccines. However, recent findings in solid cancer demonstrate that it is not the quantity but the quality of neo-antigens in the tumor that determine the tumor-specific immune response. Furthermore, novel sequencing techniques such as long-read sequencing and optical genome mapping can identify unknown genetic aberrations that may be targeted by neo-antigen vaccines. In ALL, both the ETV6-RUNX1 and BCR-ABL1 fusion genes, and the RAS-isoform mutations are frequent, and these genomic alterations generate immunogenic neo-epitopes. Additionally, therapeutic cancer vaccinations are well suited for ALL as the tumor burden is extremely low at time of a potential post-induction vaccination therapy, and patients are relatively young and are therefore less affected by immunosenescence. Thus, we envisage that neo-antigen specific therapeutic cancer vaccines could pose an important modality in future treatment algorithms for ALL.

Epidemiology study of Leukemia Incidences among patients from Baghdad, AL-Karkh District Iraq, Carrying four different types of Leukemia

2025-06-20

Dawood Salim Edan , Shams A.M. Issa , Ali A. A. Al‐Zubaidi +1 more | Journal of Neonatal Surgery

This study carried out in National Center for Research and Treatment of Blood Disease in Baghdad, Iraq. More than 300 patients have been recorded in the above center with more … This study carried out in National Center for Research and Treatment of Blood Disease in Baghdad, Iraq. More than 300 patients have been recorded in the above center with more than 60 different Leukemia types, Because of difficulties in coverage all different types of Leukemia, The current study has focused and selected only four major types of the Leukemia to be studied in details including : Acute Lymphoblastic Leukemia (ALL), Chronic Lymphoblastic Leukemia (CLL), Chronic Myeloid Leukemia (CML) and Acute myeloid leukemia (AML).Only one hundred five of three hundred Iraqi patients have been examined and studied their differences in Ganders, Counts, Ages, percentages and distributions in Iraq among the above four types of Leukemia. ALL was seen as ordinary type of leukemia 48%, whereas the AML 25%, CLL. 19% and CML 8%, decreased respectively. The incidence rate for leukemia in 105 ganders was included 53 males (50.47%) and 52 females (49.52%). The incidence rate of leukemia was generally high in old age groups and in the peak in the age group (70 year). Furthermore, the demography of all four types of leukemia cases were distributed in 12 Iraqi governorates but the highest one in all types of Leukemia was distributed in Baghdad. The aims of current study were to announce the major and minor types of Leukemia particularly in Iraq and identify each type according to this disease.

Bone Marrow Aplasia and Neutropenic Fever Following Azathioprine Dose Escalation in a TPMT-Deficient Patient with Crohn’s Disease and Psoriatic Arthritis—A CARE–Compliant Case

2025-06-19

Konrad Wroński , Michał Holecki , Natalia Boguszewska +2 more | Clinics and Practice

Background: Myelotoxicity, usually manifested by moderate leukopenia (particularly neutropenia), is a well-known adverse drug reaction to azathioprine (AZA) therapy. Thiopurine methyltransferase (TMPT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) … Background: Myelotoxicity, usually manifested by moderate leukopenia (particularly neutropenia), is a well-known adverse drug reaction to azathioprine (AZA) therapy. Thiopurine methyltransferase (TMPT) and nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) genotyping are not routinely performed in patients starting AZA therapy due to their low cost-effectiveness. Additionally, the concomitant use of xanthine oxidase inhibitors and 5-aminosalicylates may slow the metabolism of 6-mercaptopurine. Case Description: We describe a case of a 26-year-old Caucasian man with Crohn's disease and psoriatic arthritis treated with mesalazine and AZA (100 mg daily) who developed prolonged bone marrow aplasia and neutropenic fever after increasing the daily dose of AZA from 100 to 150 mg (from 44 to 66 mg/m2), without frequent total blood count monitoring. Discontinuation of AZA, multiple transfusions of red blood cells and platelet concentrate, filgrastim, empirical antibiotic therapy, and antiviral and antifungal prophylaxis were obtained after 11 days complete recovery of bone marrow aplasia. Methods: Genomic DNA genotyping of coding regions of TPMT (exons 2-9) and NUDT15 (exons 1-3). Results: Heterozygous alleles in the untranslated region (c.460G>A and c.719A>G) associated with TPMT deficiency and a benign variant (c.*7G>A) in the 3'-UTR of NUDT15 with no effect on enzyme activity were found. Conclusions: This case highlights the importance of monitoring the total blood count frequently during the first weeks of treatment with moderate-to-high doses of AZA. Furthermore, the interaction between AZA and mesalazine may play a significant role in the development of prolonged bone marrow aplasia.

Genetic, Cytogenetic and Hematological Features in Newly Diagnosed Acute Lymphoid Leukemia Patients under Eighteen Years Age Rreferred to Ali Asghar Hospital of Tehran, Iran, from 2013 to 2023

2025-06-19

Nafiseh Mortazavi , Aziz Eghbali , Omid Kiani Ghalesardi +5 more | Cardiovascular & Haematological Disorders - Drug Targets

Introduction: Acute lymphoblastic leukemia (ALL), a hematopoietic cancer of T or B lymphoblasts, is the most prevalent cancer in children. Ongoing research aims to better understand the factors contributing to … Introduction: Acute lymphoblastic leukemia (ALL), a hematopoietic cancer of T or B lymphoblasts, is the most prevalent cancer in children. Ongoing research aims to better understand the factors contributing to ALL and create more successful treatment options. Therefore, the current study presented cytogenetic, genetic, and hematologic features from 318 ALL patients under eighteen years of age who were referred to Ali Asghar Hospital of Tehran, Iran, from 2013 to 2023. Methods: This study was designed as a retrospective cross-sectional analysis, focusing on 318 children in Tehran, Iran, who had been newly diagnosed with ALL. All data were extracted from the patient case files that included additional information, such as clinical data, and demographic information. The Flow cytometry technique was employed to perform immunophenotyping for various markers. Moreover, the standardized protocol was carried out for conventional cytogenetic analysis. Results: Out of 318, 179 (56.3%) and 139 (43.7%) were males and females, respectively. The most common subtype of ALL was Common B Cell ALL, accounting for 182 cases (57.23%), followed by Pre B cell ALL with 74 cases (23.27%) and T cell ALL with 27 cases (8.49%). Out of 222 patients, 17 (7.7%) had genetic abnormalities, with the highest incidence of abnormalities being associated with Runx 1 (four cases). Additionally, out of 228 patients, 143 (62.7%) were identified as having cytogenetic abnormalities, with the most prevalent abnormalities being hyperdiploidy (54 cases) and t (12;21) (28 cases). Conclusion: Our findings showed that some cytogenetic abnormalities, such as t (9;22) and hyperdiploidy, were consistent with previous studies. These results offer valuable foundational insights that can help direct future research on ALL patients and inform potential treatment strategies.

The Expression of CD109 in B-Cell Acute Lymphoblastic Leukemia and Its Potential as a Promising Marker for Minimal Residual Disease (MRD) Detection

2025-06-18

Zhifang Xu , Shaotong Dong , Yi Chen +7 more | Research Square (Research Square)

<title>Abstract</title> <bold>Background</bold> CD109 is overexpressed in various tumors, but its role in hematologic malignancies, particularly acute B lymphoblastic leukemia (B-ALL), remains unclear.<bold>Methods</bold> CD109 expression was assessed at both mRNA and … <title>Abstract</title> <bold>Background</bold> CD109 is overexpressed in various tumors, but its role in hematologic malignancies, particularly acute B lymphoblastic leukemia (B-ALL), remains unclear.<bold>Methods</bold> CD109 expression was assessed at both mRNA and protein levels in B-ALL patients using real-time quantitative PCR (RQ-PCR) and multiparameter flow cytometry (MFC). The relationship between CD109 expression and clinical and laboratory parameters was examined. The potential of CD109 as a marker for minimal residual disease (MRD) detection was evaluated. Functional studies were conducted in leukemia cell lines.<bold>Results</bold> CD109 mRNA was significantly upregulated in newly diagnosed and relapsed B-ALL patients compared to healthy controls and remission cases. MFC revealed CD109 positivity in 79.0% of B-ALL blasts, with higher rates in relapsed cases (85.7%) and CD34 + B-ALL patients. CD109 expression was minimal in mature B cells and precursors B cell. CD109 expression remained stable across disease phases including diagnosis, MRD positivity and relapse. Functional assays demonstrated that CD109-positive Nalm6 cells exhibited significantly increased proliferative and invasive abilities.<bold>Conclusion</bold> CD109 is upregulated in B-ALL and promotes leukemia cell proliferation and migration. Its consistent expression across disease stages suggests it may be a reliable marker for MRD detection, highlighting its clinical significance in leukemia management.

Genomic Classification of T-Cell Acute Lymphoblastic Leukemia: Current Paradigms and Future Biomarkers

2025-06-18

Jason Xu , David T. Teachey | Journal of the National Comprehensive Cancer Network

Over the past 20 years, long-term cure rates in T-lymphoblastic leukemia/lymphoma (T-ALL) have improved from 60% to 65% to >80%, largely due to the intensification of chemotherapy regimens. In B-lymphoblastic … Over the past 20 years, long-term cure rates in T-lymphoblastic leukemia/lymphoma (T-ALL) have improved from 60% to 65% to >80%, largely due to the intensification of chemotherapy regimens. In B-lymphoblastic leukemia/lymphoma (B-ALL), outcomes have been improved through risk stratification, integrating clinical and demographic features, response to therapy, and disease biology to identify patients more or less likely to respond to conventional treatment, allowing for the use of regimens adapted to relative risk. Unfortunately, in T-ALL, few features have been identified that can independently predict the risk of poor outcomes beyond response to therapy. Accordingly, most cooperative groups do not use disease biology for T-ALL risk stratification. Recently, several T-ALL genomic initiatives have improved understanding of disease biology, enhanced the ability to classify T-ALL into different biological subtypes, and identified genomic alterations that predict outcome independent of response to treatment. Among these biomarkers is a newly defined high-risk “ETP [early T-cell precursor]-like” transcriptional subtype, which reclassifies immature T-ALL based on transcriptomic rather than immunophenotypic features; a treatment-refractory “bone-marrow-progenitor-like” leukemia fraction enriched in relapsed/refractory T-ALL; and intron-mediated noncanonical NOTCH1 dysregulation. The integration of these new biomarkers into clinical treatment holds promise to inform rapid upfront risk stratification, support new targeted therapeutic approaches, and guide future validation and preclinical studies for high-risk T-ALL.

Efficacy of Blinatumomab in Pediatric Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

2025-06-18

Oboseh J Ogedegbe , Olanipekun Lanny Ntukidem , Gautham Varun Krishna Mohan +5 more | Cureus

Efficacy of NAMPT inhibition in T-cell acute lymphoblastic leukemia

2025-06-17

Chelsea Vrana , M. Zhang , Max Rochette +7 more | PLoS ONE

Novel agents targeting upregulated signaling pathways are needed to improve outcomes in T-cell acute lymphoblastic leukemia (T-ALL), since conventional cytotoxic chemotherapy regimens have reached the limits of tolerability. We identified … Novel agents targeting upregulated signaling pathways are needed to improve outcomes in T-cell acute lymphoblastic leukemia (T-ALL), since conventional cytotoxic chemotherapy regimens have reached the limits of tolerability. We identified upregulated, targetable signaling pathways common to both human T-ALL samples and a Kras LSL-G12D/+ . Mb1 Cre/+ murine model of T-ALL. We found the NAMPT inhibitor FK866 had the greatest cytotoxicity of a panel of small molecule inhibitors tested in human and mouse T-ALL cell lines, and in patient derived xenograft (PDX)-expanded T-ALL patient samples. We subsequently tested FK866 in vivo in PDX mouse models of T-ALL, and found that it significantly reduced the peripheral blood disease burden and prolonged the survival of leukemic mice (median survival of 60.5 vs 21 days, p = 0.0007). This screen for targetable pathways in T-ALL generated in vitro and in vivo preclinical data supporting NAMPT inhibition as a promising strategy for the treatment of T-ALL.

Physicochemical quality assessment of four asparaginases

2025-06-16

Vanessa Radtke , Thorsten König , Christoph Radcke +4 more | PLoS ONE

L-Asparaginases (ASNases) are used for the treatment of acute lymphoblastic leukaemia. There are reports of quality problems for some therapeutic asparaginase products, especially those manufactured in middle-income countries. These products … L-Asparaginases (ASNases) are used for the treatment of acute lymphoblastic leukaemia. There are reports of quality problems for some therapeutic asparaginase products, especially those manufactured in middle-income countries. These products may exhibit decreased potency and/or decreased specific activity, or an elevated level of impurities such as host cell proteins. In this study, four different ASNase preparations that were not modified with polyethylene glycol were compared in detail regarding their quality: Spectrila®, Celginase™, Bionase®, and L-Aspase®. Samples were analyzed for protein content, impurities, and enzyme activity. Various chromatographic methods as well as mass spectrometry were used to assess purity and identity. Sample protein content, host cell protein, and enzyme activity showed some results that were out of target range for Celginase™ and Bionase®. These ASNase preparations also showed detectable levels of endotoxins. In gel electrophoresis, additional bands were found for Bionase®. Size exclusion chromatography showed increased high and low molecular weight species for Bionase® and L-Aspase®, and reversed-phase chromatography showed increased hydrophilic and hydrophobic species for Bionase®. In capillary zone electrophoresis, increased retention time for L-Aspase® and increased levels of charge variants for Bionase®, Celginase™, and L-Aspase® were seen. ASNase quality standards are crucial to ensure patient safety and product efficacy, as decreased potency and specific activity may affect efficacy in acute lymphoblastic leukaemia treatment, and increased impurities may affect immunogenicity. Out of four ASNase preparations tested in this study, only Spectrila® did not raise any quality concerns. The other three products exhibited quality problems, rendering them unsuitable according to established quality requirements defined in European and US guidelines for pharmaceutical development of parenteral drug products.

Inflammation Marker and Leukocyte Parameter Ratio on Erythropoiesis Activity of Pediatric Acute Lymphoblastic Leukemia

2025-06-15

I Nyoman Wande , Ni Made Linawati , Pande Putu Ayu Patria Dewi +1 more | INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY

Acute leukemia is the most common malignancy found in children. A Complete Blood Count (CBC) examination can calculate the lymphocyte-to-leukocyte ratio, neutrophil-to-leukocyte ratio, and neutrophil-to-lymphocyte ratio to monitor the progress … Acute leukemia is the most common malignancy found in children. A Complete Blood Count (CBC) examination can calculate the lymphocyte-to-leukocyte ratio, neutrophil-to-leukocyte ratio, and neutrophil-to-lymphocyte ratio to monitor the progress of Acute Lymphoblastic Leukemia (ALL). C-reactive protein is a marker of inflammation and can determine disease progression during treatment. The study's analytical design was observational, with a cross-sectional design conducted at the laboratory of the Clinical Pathology Faculty of Medicine, University of Udayana, and Ngoerah Hospital from March to August 2020. The study included 48 subjects, divided into three phases: induction, consolidation, and maintenance, in ALL patients. Specimen collection was collected in 2 tubes. Kolmogorov-Smirnov statistical analysis was used to assess normality, and homogeneity was evaluated with Levene’s test. The difference test was performed using the Kruskal-Wallis test. This study aimed to determine the relationship between parameters was performed with Spearman correlation. This study showed a strong correlation between hemoglobin levels and neutrophil/lymphocyte ratio (r= 0.358, p=0.015), hemoglobin and lymphocyte/leukocyte ratio (r= -0.287, p=0.048), hemoglobin and CRP (r= -0.493, p=0.000). Significant correlation between reticulocyte percentage and neutrophil/lymphocyte ratio (r= 0.505, p=0.000), neutrophil/lymphocyte ratio and CRP (r= -0.870, p=0.000), neutrophil/leukocyte ratio and lymphocyte/leukocyte ratio (r= 0.960, p=0.000). Significant correlations have been found between hemoglobin levels and the neutrophil/lymphocyte ratio (NLR), which is a measure of the lymphocyte/leukocyte ratio (LLeu-ratio), along with CRP. This relationship has been connected to inflammation in ALL patients following chemotherapy. CBC is an easy-to-use test to determine whether inflammation is present in ALL patients following chemotherapy.

The Predominance of the Synthesis Phase in Cell Cycles in Childhood Acute Lymphoblastic Leukemia

2025-06-15

Yetti Hernaningsih , Aryati Aryati , I Dewa Gede Ugrasena +1 more | INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY

Uncontrolled proliferation and resistance to apoptosis should be controlled to kill the cancer cells, as the goal of treatment in acute leukemia. It is therefore important to know, which characteristic … Uncontrolled proliferation and resistance to apoptosis should be controlled to kill the cancer cells, as the goal of treatment in acute leukemia. It is therefore important to know, which characteristic dominates the proliferative phase because, to be more effective, new drugs that will be developed should be targeted at that phase. This study aimed to find the dominant phase in the proliferative phase of the cell cycle in childhood Acute Lymphoblastic Leukemia (ALL). This study was conducted on 63 patients, comprising 33 patients with specimens of Bone Marrow Mononuclear Cells (BMMC), 30 patients with specimens of Peripheral Blood Mononuclear Cells (PBMC), and 10 children as controls with specimens of PBMC. Cell cycle examinations were performed with PI/RNase, run on BD FACS Calibur, and analyzed with modfit LT 4.1 software to determine the phases of G0/G1, synthesis (S), and mitosis (G2/M). Regarded the S and G2/M phases as the proliferation phase. Statistical analyses used one-way ANOVA and Kruskal-Wallis to compare S and G2/M phases within groups,and an Independent T-test and Mann-Whitney to compare the same phases between groups. Among the proliferation phases, the synthesis phase had significantly higher domination than the mitotic phase in both the BMMC (10.18±7.81% vs. 5.41±3.77%; p = 0.010) and PBMC (4.33±2.15% vs 2.30±1.56%; p=0.000) groups. A similar result was found in the control group (1.01±0.51% vs 0.36±0.38%; p=0.011). The synthesis phase in BMMC had significantly higher domination than PBMC groups (p=0.024) and control (p 0.002). The synthesis phase predominates among the proliferation phases of the cell cycle in childhood ALL.

The Role of Interleukin-7 in T Cell Acute Lymphoblastic Leukemia: A Systematic Literature Review

2025-06-15

Danny Meganingdyah Primartati , Yetti Hernaningsih , Nastasya Nunki | INDONESIAN JOURNAL OF CLINICAL PATHOLOGY AND MEDICAL LABORATORY

This study aims to provide a comprehensive review of the genetic characteristics of acute lymphoblastic leukemia that has relapsed, discuss the relationship between interleukins and the disease, and explore targeted … This study aims to provide a comprehensive review of the genetic characteristics of acute lymphoblastic leukemia that has relapsed, discuss the relationship between interleukins and the disease, and explore targeted therapy. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines were followed in the development of the current study on acute lymphoblastic leukemia and the role of interleukins in hemato-oncology. The results reveal that relapse rates remain high and the prognosis for individuals who experience a relapse is inferior. Currently, innovative targeted medicines are employed to supplement traditional cancer treatment. The novel strategies are put into practice to lessen the load of toxicity and enhance results. From these findings, it can be concluded that combating refractory T-ALL requires the discovery of innovative medicines that directly target pathways driving Leukemia-Initiating Cell (LIC) activity.

Investigation of the Impact of a Protein Source on the Purification of <scp>l</scp>-Asparaginase Type II from Escherichia coli

2025-06-13

Ariane Pereira Da Costa , Talita Stelling de Araújo , A. Pereira +7 more | ACS Omega

Case report: a critically ill patient with aggressive NK-cell leukemia receiving emergency chemotherapy in the ICU

2025-06-12

Yuqing Zeng , Yuanyuan Yang , Jian Huang +3 more | Virology Journal

Predicting T-ALL response to pre-TCR and IL-7R coinhibition

2025-06-12

Carol Fries | Blood

Pediatric Leukemia: Advances in Diagnosis and Treatment Strategies

2025-06-06

| Journal of Pediatrics and Congenital Disorders

Clinical profile and treatment outcomes of acute lymphoblastic leukemia among children attending at the University of Gondar comprehensive specialized hospital and Tikur Anbessa Specialized Hospital in Ethiopia

2025-06-05

Eyuel Kassa , Mulugeta Ayalew , Mastewal Birhan +7 more | PLoS ONE

Background Acute lymphoblastic leukemia (ALL) is a common childhood cancer characterized by the uncontrolled proliferation of immature white blood cells. While advancements in treatment have significantly improved outcomes in developed … Background Acute lymphoblastic leukemia (ALL) is a common childhood cancer characterized by the uncontrolled proliferation of immature white blood cells. While advancements in treatment have significantly improved outcomes in developed countries, significant challenges remain in resource-limited settings, such as Ethiopia. This study aimed to assess the clinical profiles and treatment outcomes of ALL patients at the University of Gondar Comprehensive Specialized Hospital (UoGCSH) and Tikur Anbessa Specialized Hospital (TASH) in Ethiopia. A prospective longitudinal study was conducted among 179 ALL patients receiving treatment at the outpatient department and pediatric oncology centers of the UoGCSH and TASH between December 25, 2022, and August 30, 2024. Sociodemographic and clinical data were collected using a structured questionnaire. The data were entered and analyzed using SPSS version 25. Descriptive statistics were employed to summarize patient characteristics, while overall survival was evaluated using Kaplan-Meier analysis. Additionally, both univariate and multivariate Cox proportional hazards regression analyses were performed, with statistical significance set at a P -value of < 0.05. Results Among the 179 patients, 81 (45.3%) died during the course of treatment. Of these, 33 (18%) died before initiating induction therapy, while 48 (27.4%) died primarily due to treatment abandonment during various phases of therapy. The event-free survival rate was 75 (41.9%). Mortality rates were significantly higher in patients with certain variables identified through Cox regression analysis, including age, sepsis, and relapse, which nearly doubled the risk of death. Elevated LDH levels, malaria infection, and T-cell ALL were associated with approximately six-fold, three-fold, and seven-fold increases in the risk of death, respectively. Only 22 out of 179 patients (12.29%) achieved remission. Among these patients, hematotoxicities observed during the maintenance phase included anemia in 19/22 (86.4%), grade 3–4 neutropenia in 12/22 (52.2%), and thrombocytopenia in 17/22 (77.3%). Conclusion A high mortality rate was observed among children with ALL, with significant risk factors including relapse, age over 10 years, elevated LDH levels, sepsis, low platelet counts, T-cell ALL, malaria infection, and induction failure. To improve survival rates, it is essential to address these factors by optimizing treatment regimens and minimizing delays in diagnosis and care delivery.

Prediction of methotrexate neurotoxicity using clinical, sociodemographic, and area-based information in children with acute lymphoblastic leukemia.

2025-06-04

Rachel Harris , Olga A. Taylor , M. Monica Gramatges +7 more | PubMed

Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine … Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine learning to develop a neurotoxicity risk prediction model in a diverse cohort of children with ALL. We included children (age 2-20 years) diagnosed with ALL (2005-2019) and treated in Texas without pre-existing neurologic disease. Clinical information was obtained by medical record review. Neurotoxicity occurring post-induction and prior to maintenance therapy was defined as neurologic episodes occurring within 21 days of methotrexate. Suspected cases were independently confirmed by 2 pediatric oncologists. Demographic and clinical factors were compared using logistic regression. The dataset was randomly split (80/20) for training and testing. random forest (RF) with boosting and downsampling using 5-repeat, 10-fold cross-validation was used to construct a predictive model. Neurotoxicity developed in 115 (8.7%) of 1325 eligible patients. Several factors including older age at diagnosis (OR = 1.19, 95% CI: 1.15-1.24) and Latino ethnicity (OR = 2.79, 95% CI: 1.83-4.35) were associated with neurotoxicity. The RF had an area under the curve of 0.77 with a train error rate of 0.29 and a test error rate of 0.24. The overall sensitivity was 0.73, and specificity was 0.69. In one of the largest studies of its kind, we developed a novel risk prediction model of methotrexate-related neurotoxicity. Ultimately, a validated model may help guide the development of personalized treatment strategies to reduce the burden of neurotoxicity in children diagnosed with ALL.

Purification L-asparaginase from Acinetobacter baumannii and study of antitumor activity

2025-06-04

Amenah RAMI Abdullah | Microbes and Infectious Diseases /Microbes and Infectious Diseases

Absorption of Oral Chemotherapy in a Pediatric Patient with T‐Cell Acute Lymphoblastic Leukemia, Short Bowel Syndrome, and Skewed 6‐Mercaptopurine Metabolism

2025-06-02

Khang Nguyen , Bheem S. Shekhawat , Eric S. Schafer +1 more | Pediatric Blood & Cancer

Outcomes of allogeneic stem cell transplant in adult Philadelphia negative acute lymphoblastic leukemia patients treated with the pediatric-inspired GIMEMA 1913 protocol. A Campus ALL study

2025-06-02

Gianluca Cavallaro , Davide Lazzarotto , Chiara Pavoni +7 more | Bone Marrow Transplantation

Survival outcomes in secondary and primary acute lymphoblastic leukemia: a systematic review and meta-analysis

2025-06-02

Fatemeh Abedini , Amirreza Manteghinejad , Zahra Sadat Rezaeian +7 more | Scientific Reports

This systematic review and meta-analysis aimed to compare the survival outcomes and cytogenetic profile of primary acute lymphoblastic leukemia (p-ALL) and secondary ALL (s-ALL), including antecedent-malignancy ALL (am-ALL) and therapy-related … This systematic review and meta-analysis aimed to compare the survival outcomes and cytogenetic profile of primary acute lymphoblastic leukemia (p-ALL) and secondary ALL (s-ALL), including antecedent-malignancy ALL (am-ALL) and therapy-related ALL (tr-ALL). The search was performed in PubMed/MEDLINE, Scopus, Web of Science, Embase, and ProQuest databases from January 1, 1990, to July 31, 2023, using the keywords "acute lymphoblastic leukemia" and "second cancer" to identify cohort studies that compared p-ALL and s-ALL in terms of survival outcomes and cytogenetic profile. The risk of bias in the included studies was assessed using the Joanna Briggs Institute (JBI) for Cohort Studies. A total of 7 studies involving 13,542 participants were analyzed. The results revealed an HR of 2.35 (95%CI:1.38-4.01) for overall survival (OS) and 2.06 (95%CI:1.05-4.06) for relapse-free survival (RFS). Subgroup analysis of tr-ALL patients showed a significantly higher HR of 3.40 (95%CI:2.32-4.99) for OS in this subgroup. Furthermore, the meta-analysis indicated an OR of 3.45 and 5.90 for mixed lineage rearrangement (MLL) and hypodiploidy, respectively. The study highlights the need for a better understanding of the survival rates and cytogenetic profile of secondary ALL, particularly tr-ALL, and the importance of personalized treatment strategies for this subtype.

[Intervention effect analysis of TPMT and NUDT15 genotyping on the tolerability of azathioprine or 6-mercaptopurine therapy in pediatric inflammatory bowel disease].

2025-06-02

Youyou Luo , Qi Cheng , Youhong Fang +4 more

Objective: To investigate the impact of pre-treatment TPMT and NUDT15 genotyping on medication selection, tolerability and discontinuation rates of azathioprine or 6-mercaptopurine therapy in children with inflammatory bowel disease (IBD). … Objective: To investigate the impact of pre-treatment TPMT and NUDT15 genotyping on medication selection, tolerability and discontinuation rates of azathioprine or 6-mercaptopurine therapy in children with inflammatory bowel disease (IBD). Methods: A retrospective cohort study was conducted on 181 children with IBD who were scheduled for azathioprine or 6-mercaptopurine therapy at the Department of Gastroenterology, Children's Hospital, Zhejiang University School of Medicine between January 2010 and January 2023. Among them, 168 children who received treatment were divided into a genotyped group and non-genotyped group based on pre-treatment TPMT and NUDT15 genotyping. The incidence of drug-related adverse reactions was compared between the two groups. The impact of genotyping on medication selection and discontinuation rates was analyzed. Chi-square test or Fisher exact test were used for intergroup comparisons. Logistic regression analysis was used to control the confounding factors. Firth Logistic regression analysis was applied for data with complete separation. The probability of discontinuation was assessed using survival analysis with Cox proportional hazards modeling. Results: Among the 181 children with IBD, 13 did not receive azathioprine or 6-mercaptopurine due to genetic variants, while the remaining 168 underwent the therapy (154 cases of Crohn's disease and 14 cases ulcerative colitis; 108 males and 60 females). Excluding the 13 untreated cases, 77 children underwent TPMT and NUDT15 genotyping were assigned to the genotyped group, and the remaining 91 to the non-genotyped group. Adverse reactions included myelosupression (26 cases,15.5%), hepatotoxicity (18 cases,10.7%), gastrointestinal disturbance (25 cases,14.9%), alopecia (12 cases,7.1%), fever (3 cases,1.8%), rash (2 cases,1.2%), and pancreatitis (1 case,0.6%). The incidence of overall adverse reactions was significantly higher in the non-genotyped group compared to that of the genotyped group (40.7% (37/91) vs. 26.0% (20/77), P<0.05). Specifically, the non-genotyped group had a higher rate of gastrointestinal reactions compared to the genotyped group (24.2% (22/91) vs. 3.3% (3/77), P<0.01). Cox regression analysis revealed that non-genotyped group had a higher risk of treatment discontinuation due to the adverse reactions (HR=1.47, 95%CI 0.65-3.30). Conclusion: Pre-treatment genotyping of TPMT and NUDT15 variants can help guide the selection of clinical drugs, reduce the incidence of drug-related adverse reactions and enhance tolerability of azathioprine or 6-mercaptopurine therapy in IBD children.

Advancing Leukemia Diagnosis and Treatment: WHO-Supported Laboratory Innovations in Africa- A Narrative Review

2025-06-01

Emmanuel Ifeanyi Obeagu | Blood and Lymphatic Cancer Targets and Therapy

AHOD2131: A RANDOMIZED PHASE 3 RESPONSE‐ADAPTED TRIAL COMPARING STANDARD THERAPY TO IMMUNO‐ONCOLOGY FOR CHILDREN & ADULTS WITH NEWLY DIAGNOSED STAGE I/II HODGKIN LYMPHOMA

2025-06-01

Jennifer Seelisch , Boyu Hu , Lindsay A. Renfro +7 more | Hematological Oncology

Meet PRC2: A new player in T-cell acute lymphoblastic leukemia

2025-06-01

Robert Lemos , Marina Chianello Nicolau Fagundes , Ana Luiza Tardem Maciel +1 more | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer