Acute Lymphoblastic Leukemia Subtypes Research Articles

Experiencia del Grupo Español de Trasplante Hematopoyético (GETMON-GETH) en el trasplante alogénico de progenitores hematopoyéticos en leucemia aguda linfoblástica Philadelphia

IntroductionOutcomes in patients diagnosed of acute lymphoblastic leukemia with Philadelphia chromosome (Ph-ALL) remains unfavourable compared to other subtypes of acute lymphoblastic leukemia despite improvements in drug treatments as well as advances in hematopoietic stem cell transplantation (HSCT). Patients and methodsThe role of allogeneic HSCT in Ph-ALL patients has been analysed through a multicentric study where data belonging to 70 patients diagnosed of this entity in different center that received HSCT between years 1998 and 2014, were reported by the Grupo Español de Trasplante Hematopoyético (GETH). ResultsThe performance of HSCT from year 2004, in first complete remission (CR) status with thymoglobulin (ATG) based conditioning had a favorable impact on overall survival (OS). HSTC performance from year 2004, in first CR with ATG-based conditioning in addition to acute graft versus host disease (aGvHD) development, increased event free survival (EFS). Treatment with imatinib as well as undetectable minimal residual disease (MRD) prior to HSCT, combined with aGvHD, reduced risk of relapse (RR). Patient age less than 10 years when HSCT, first CR and ATG-based conditioning were associated to a lower transplant related mortality (TRM). ConclusionsPatients that could achieve first CR that also received ATG-based conditioning had a better OS and EFS, so HSCT should be considered for this group of patients.

Immunophenotypic Pattern and Treatment Outcome after Completion of Induction Remission in Children with Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is presented with different immunophenotypic pattern.
 Objective: The purpose of the study was to evaluate the immunophenotypic pattern of ALL and also, to recognize the frequency of different ALL subtypes and treatment outcome after induction remission therapy.
 Methodology: This prospective study was conducted in the Department of Paediatric Hematology and Oncology at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from June 2017 to July 2018 for a period of one year. Newly diagnosed admitted cases of ALL aged 1 to 17.9 years were included. Immunophenotyping from aspirate marrow samples were done in a special hematology laboratory. Patients were monitored during induction remission period with physical examination and required investigations.
 Result: Among 87 analyzed patients, 81 patients (93.1%) were B-cell ALL and 6 patients (6.9%) were T-cell ALL. After completion of induction remission therapy 61 patients had undergone complete remission and among them B cell ALL were 56(69.1%) and T cell were 5(83.3%) (P=0.464). None of the patient had partial response or induction failure. Complication were developed in 53(60.91%) patients during induction therapy. Most common cause of death was septicemia (22/26). Death was more in patients who had total WBC count >50X109/L (p=0.017) and received regimen B (p=0.031).
 Conclusion: B cell ALL was more common and most of the patients had undergone complete remission after induction remission therapy.
 Journal of Current and Advance Medical Research, January 2021;8(1):59-64

Recognition of acute lymphoblastic leukemia and lymphocytes cell subtypes in microscopic images using random forest classifier.

Acute lymphoblastic leukemia (ALL) is the most frequently leukemia and categorized into three morphological subtypes named L1, L2 and L3. Early diagnosis of ALL plays a key role in treatment procedure especially in the case of children. Several similarities between morphology of three subtypes ALL (L1, L2, L3) and lymphocyte subtypes (normal, reactive and atypical) as noncancerous cells have remained a high challenge. Diagnosis of ALL and lymphocyte subtypes are done by microscopic viewing examination of cells in the peripheral blood samples by hematologists. Since this exam is time-consuming, boring and dependent on the skill of the hematologists, automatic systems are desired to overcome these limitations. In this study, 312 microscopic images including 958 cells are obtained from blood samples of 7 normal subjects and 14 patients. The first step of proposed system is image enhancement to decreases the effects of various luminosity situations with transformation from RGB to HSV color space and then applying histogram equalization on V channel for equalizing the grey level of image lightness. Nuclei segmentation from the blood cell images is the second step and performed using fuzzy c-means (FCM) clustering. After identify cluster of nuclei, we performed opening and closing process in morphological operation binary in order to remove extra noises and fill some minor holes in the nuclei. Moreover, to discrete the link between nuclei, watershed transform was applied. Then, a set of quantitative features (five geometric features about the size and figure of a cell and 36 statistical features about the spatial arrangement of intensities of nuclei image) are extracted to characterize the properties of these nuclei. In the next step, due to high number of features, the best features are selected by exhaustive search of all of the subsets of features and 13 features are selected. The final step is the classification of L1, L2, L3, normal, reactive and atypical cells by applying Random Forest (RF) classifier and result in 98% accuracy. We compared RF classifier with two other commonly classifiers named: MultiLayer Perceptron (MLP), and multi-SVM classifier with more success especially for recognition of L1, normal and reactive cells. So, this system can be used as an assistant diagnostic tool for hematologists to recognize subtypes of ALL and lymphocyte.

Genomic landscape of B-other acute lymphoblastic leukemia in an adult retrospective cohort with a focus on BCR-ABL1-like subtype

Introduction BCR-ABL1-like acute lymphoblastic leukemia (ALL) is a high-risk disease with a complex genomic background. Though extensively studied, data on the frequency and mutual associations of present mutations are still incomplete in adult patients. This retrospective study aims to map the genomic landscape of B-other ALL in a cohort of adult patients with a focus on the BCR-ABL1-like ALL subtype. Methods We analyzed bone marrow and peripheral blood samples of adult B-other ALL patients treated consecutively at three major Czech teaching hospitals. Samples were analyzed by cytogenetic methods, gene expression profiling, multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS). Results Fifty-eight B-other ALL patients (not BCR-ABL1, KMT2A-rearranged, ETV6-RUNX1, TCF3-PBX1, or iAMP21) were included in the study. Median follow-up was 23.8 months. Samples from 33 patients were available for a gene expression analysis, 48.9% identified as BCR-ABL1-like ALL. Of the BCR-ABL1-like ALL cases, 18.8% harbored IGH-CRLF2 and 12.5% P2RY8-CRLF2 fusion gene. We observed a higher MRD failure rate in BCR-ABL1-like than in non-BCR-ABL1-like ALL patients after the induction treatment (50.0 vs. 13.3%, p=.05). There was a trend to worse progression-free and overall survival in the BCR-ABL1-like group, though not statistically significant. Deletions in IKZF1 gene were found in 31.3% of BCR-ABL1-like cases. Patients with concurrent IKZF1 and CDKN2A/B, PAX5 or PAR1 region deletions (IKZF1 plus profile) had significantly worse progression-free survival than those with sole IKZF1 deletion or IKZF1 wild-type (p=.02). NGS analysis was performed in 54 patients and identified 99 short variants in TP53, JAK2, NRAS, PAX5, CREBBP, NF1, FLT3, ATM, KRAS, RUNX1, and other genes. Seventy-five of these gene variants have not yet been described in B-cell precursor ALL to date. Conclusion This study widens existing knowledge of the BCR-ABL1-like and B-other ALL genomic landscape in the adult population, supports previous findings, and identifies a number of novel gene variants.

Profiling chromatin accessibility in pediatric acute lymphoblastic leukemia identifies subtype-specific chromatin landscapes and gene regulatory networks.

Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy comprised of molecular subtypes largely characterized by aneuploidy or recurring chromosomal rearrangements. Despite extensive information on the ALL transcriptome and methylome, there is limited understanding of the ALL chromatin landscape. We therefore mapped accessible chromatin in 24 primary ALL cell biospecimens comprising three common molecular subtypes (DUX4/ERG, ETV6-RUNX1 and hyperdiploid) from patients treated at St. Jude Children's Research Hospital. Our findings highlight extensive chromatin reprogramming in ALL, including the identification ALL subtype-specific chromatin landscapes that are additionally modulated by genetic variation. Chromatin accessibility differences between ALL and normal B-cells implicate the activation of B-cell repressed chromatin domains and detail the disruption of normal B-cell development in ALL. Among ALL subtypes, we uncovered roles for basic helix-loop-helix, homeodomain and activator protein 1 transcription factors in promoting subtype-specific chromatin accessibility and distinct gene regulatory networks. In addition to chromatin subtype-specificity, we further identified over 3500 DNA sequence variants that alter the ALL chromatin landscape and contribute to inter-individual variability in chromatin accessibility. Collectively, our data suggest that subtype-specific chromatin landscapes and gene regulatory networks impact ALL biology and contribute to transcriptomic differences among ALL subtypes.

Genome-wide interference of ZNF423 with B-lineage transcriptional circuitries in acute lymphoblastic leukemia

Aberrant expression of the transcriptional modulator and early B-cell factor 1 (EBF1) antagonist ZNF423 has been implicated in B-cell leukemogenesis, but its impact on transcriptional circuitries in lymphopoiesis has not been elucidated in a comprehensive manner. Herein, in silico analyses of multiple expression data sets on 1354 acute leukemia samples revealed a widespread presence of ZNF423 in various subtypes of acute lymphoblastic leukemia (ALL). Average expression of ZNF423 was highest in ETV6-RUNX1, B-other, and TCF3-PBX1 ALL followed by BCR-ABL, hyperdiploid ALL, and KMT2A-rearranged ALL. In a KMT2A-AFF1 pro-B ALL model, a CRISPR-Cas9–mediated genetic ablation of ZNF423 decreased cell viability and significantly prolonged survival of mice upon xenotransplantation. For the first time, we characterized the genome-wide binding pattern of ZNF423, its impact on the chromatin landscape, and differential gene activities in a B-lineage context. In general, chromatin-bound ZNF423 was associated with a depletion of activating histone marks. At the transcriptional level, EBF1-dependent transactivation was disrupted by ZNF423, whereas repressive and pioneering activities of EBF1 were not discernibly impeded. Unexpectedly, we identified an enrichment of ZNF423 at canonical EBF1-binding sites also in the absence of EBF1, which was indicative of intrinsic EBF1-independent ZNF423 activities. A genome-wide motif search at EBF1 target gene loci revealed that EBF1 and ZNF423 co-regulated genes often contain SMAD1/SMAD4-binding motifs as exemplified by the TGFB1 promoter, which was repressed by ZNF423 outcompeting EBF1 by depending on its ability to bind EBF1 consensus sites and to interact with EBF1 or SMADs. Overall, these findings underscore the wide scope of ZNF423 activities that interfere with B-cell lymphopoiesis and contribute to leukemogenesis.

Early T-cell precursor acute lymphoblastic leukemia and other subtypes: a retrospective case report from a single pediatric center in China.

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is rare in China and case reports are varied. We conducted an in-depth analysis of newly diagnosed children with T-ALL from January 1999 to April 2015 in our center, to show the biological differences between Chinese ETP-ALL children and other immune types of T-ALL. The newly diagnosed children with T-ALL were divided into four groups according to their immunophenotype: ETP-ALL, early non-ETP-ALL, cortical T-ALL and medullary T-ALL. Disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) rates were estimated by the Kaplan-Meier method. The Cox regression model was used for multivariate analysis. A total of 117 newly diagnosed children with T-ALL were enrolled in this study. The 10-year EFS and OS rates for all patients were 59.0 ± 4.7% and 61.0 ± 4.7%, respectively, with a median follow-up of 64 (5-167) months. Univariate analysis showed that ETP-ALL patients had the lowest 10-year DFS rate of 32.1 ± 11.7%, while cortical T-ALL had the highest DFS rate of 81.3 ± 8.5% compared with early non-ETP-ALL (61.6 ± 7.0%) and medullary T-ALL (59.1 ± 10.6%). Multivariate analysis demonstrated that only ETP-ALL and involvement of the central nervous system were independent prognostic factors. Compared with other subtypes, pediatric ETP-ALL had a poor treatment response and high recurrence rate while cortical T-ALL appeared to have much better outcome. Our observations highlight the need for an individualized treatment regime for ETP-ALL.

Successful Treatment of TCF3-HLF–positive Childhood B-ALL with Chimeric Antigen Receptor T-Cell Therapy

BackgroundTCF3-HLF positive leukemia represents a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL), characterized by a high treatment failure rate despite intensive treatment and hematopoietic stem cell transplantation (HSCT). Patients and MethodsFour consecutive children with TCF-HLF3–positive B-ALL who were refractory or relapsed with initial chemotherapy were treated with CD19-specific or combined CD19-and CD22-specific chimeric antigen receptor T-cell therapy (19/22 CAR-T) after conditioning regimen with fludarabine and cyclophosphamide. Clinical features, treatment responses, toxicity, and outcomes were analyzed retrospectively. ResultsFour patients received 18.0, 6.0, 5.0, and 7.4 × 106 CAR-T cells per kilogram and developed grade I, III, II, and III cytokine release syndrome, respectively. They all achieved minimal residual disease-negative complete remission (CR). Two of them (patients 1 and 3) underwent haploid HSCT afterward. Patient 1 relapsed after 7.2 months of transplantation and received donor-derived 19/22 CAR-T cell infusion. He had CR2 after he experienced grade II cytokine release syndrome of the second CAR-T and underwent umbilical cord blood transplantation. Unfortunately, this child died of severe lung graft versus host disease 8.4 months after the second transplantation. Patients 2 and 4 experienced reversible neurotoxicity and had a persistent clinical response to CAR-T cells for 13.8 and 6.8 months, respectively, without HSCT. Patient 3 is in continuous CR for 10.6 months until now. ConclusionCAR-T cells can effectively treat relapsed/refractory TCF3-HLF–positive childhood B-ALL with acceptable toxicity, which could be a new treatment option for this subtype compared with chemotherapy or HSCT.

The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients.

Clinical Features of Disseminated Intravascular Coagulation According to the French-American-British Classification in Patients With Acute Leukemia and Thrombomodulin Alfa Treatment-A Cohort Study Using a Postmarketing Surveillance Database.

The aims of this study were to analyze the clinical features of a large number of cases with disseminated intravascular coagulation (DIC) associated with acute leukemia and to assess the safety and efficacy of thrombomodulin alfa (TM-α) using the French-American-British (FAB) classification of hematological malignancies. We retrospectively examined 644 patients with acute leukemia in postmarketing surveillance for TM-α. M3, M2, M4, M1, and M5 subtypes of acute myeloid leukemia (AML) and L2 and L1 subtypes of acute lymphoblastic leukemia (ALL) have been found more frequently among patients with DIC. Bleeding symptoms at baseline were more frequent in M3 and M7 subtypes. Fibrinogen concentrations were lower, and plasmin-plasmin inhibitor complex values were higher in M3 and Philadelphia-positive (Ph+) ALL. Overall DIC resolution rate was 60.2%, higher in L1 and Ph+ ALL, lower in M1, and generally higher in ALL than in AML. Overall survival rate was generally high, at 79.8%, with higher rates in L3, Ph+ ALL, and M3. Regardless of FAB subgroup, TM-α showed improved bleeding symptoms and DIC scores in clinical practice for DIC patients with acute leukemia.

Disparities in acute lymphoblastic leukemia risk and survival across the lifespan in the United States of America

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer but is less frequent in adolescents and young adults (AYAs) and is rare among older adults. The 5-year survival of ALL is above 90% in children, but drops significantly in AYAs, and over half of ALL-related deaths occur in older adults. In addition to diagnosis age, the race/ethnicity of patients consistently shows association with ALL incidence and outcomes. Here, we review the racial/ethnic disparities in ALL incidence and outcomes, discuss how these vary across the age spectrum, and examine the potential causes of these disparities. In the United States, the incidence of ALL is highest in Hispanics/Latinos and lowest in Black individuals across all age groups. ALL incidence is rising fastest in Hispanics/Latinos, especially in AYAs. In addition, survival is worse in Hispanic/Latino or Black ALL patients compared to those who are non-Hispanic White. Different molecular subtypes of ALL show heterogeneities in incidence rates and survival outcomes across age groups and race/ethnicity. Several ALL risk variants are associated with genetic ancestry, and demonstrate different risk allele frequencies and/or effect sizes across populations. Moreover, non-genetic factors including socioeconomic status, access to care, and environmental exposures all likely influence the disparities in ALL risk and survival. Further studies are needed to investigate the potential joint effects and interactions of genetic and environmental risk factors. Improving survival in Hispanic/Latino and Black patients with ALL requires advances in precision medicine approaches, improved access to care, and inclusion of more diverse populations in future clinical trials.

Kliničke karakteristike i ishod lečenja kod bolesnika sa akutnom limfoblastnom leukemijom

Introduction: Acute lymphoblastic leukemia (ALL) is the malignant transformation and proliferation of lymphoid progenitor cells. The disease outcome is significantly influenced by cytogenetic and molecular characteristics, leukocyte levels, the percentage of blood and bone marrow blasts, infiltration of the CNS, and the modality of the applied therapy. Aim: Determining clinical, immunophenotypic, and cytogenetic characteristics of patients with ALL; ascertaining remission rates, the presence of resistant forms, the rates of relapse and overall survival (OS); determining prognostic factors for patient survival. Materials and methods: This five-year retrospective study included 74 patients. The study covered the period from November 2013 to October 2018. The influence of sex, age, immune subtype of ALL, leukocyte levels, percent of blood and bone marrow blasts, and cytotoxic-molecular characteristics on survival were analyzed. Results: A total of 56 (75.0%) patients had B-cell ALL, while 18 (25.0%) patients had T-cell ALL. The average age was 49.5 years (20 - 77). Complete remission was achieved in 54 (72.9%) patients, 40 (71.4%) B-cell ALL patients and 14 (77.7%) T-cell ALL patients. Refractory leukemia was confirmed in 7 (9.4%) ALL patients, 5 (8.9%) B-cell ALL patients and 2 (11.1%) T-cell ALL patients. Mortality during induction was observed in 13 (17.56%) patients, 8 (14.2%) B-cell ALL patients and 5 (27.7%) T-cell ALL patients. Relapse occurred in 25 (46.3%) patients, 20 (47.5%) B-cell ALL patients and 5 (33.3%) T-cell ALL patients. Univariate analysis showed that an unfavorable outcome was associated with age ≥50 years (p < 0.001), COP chemotherapy (p < 0.001), non-transplant patients (p = 0.011), and infiltration of the CNS (p < 0.001). Conclusion: Survival in ALL patients is significantly affected by patient age, modality of applied therapy, and infiltration of the CNS by disease.

The role of minimal residual disease in specific subtypes of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease whose prognostic factors include minimal residual disease (MRD) and cytogenetic abnormalities. To explore the significance of MRD in ALL subtypes, we analyzed the outcomes of 1126 children treated with risk-stratified therapy based on sequential MRD monitoring. MRD distributions and treatment outcomes differed between distinct leukemia subtypes. Patients with ETV6-RUNX1 or hyperdiploidy had the best prognosis (5-year OS: 97 ± 1.5% and 89.2 ± 2.7%). However, hyperdiploidy patients with MRD ≥ 10% on day 15 had a higher risk of relapse (36.4%) than those with ETV6-RUNX1. TCF3-PBX1 patients had the fastest disease clearance (negative MRD rate on day 33: 92.1%), but the overall prognosis was intermediate (5-year OS: 82.5%). Patients with high-risk characteristics and ALL-T had inferior outcomes: even with undetectable MRD on day 33, cumulative incidence of relapse was 19.9% and 23.4%, respectively. Moreover, those with poor early-treatment response and detectable week-12 MRD had a worse prognosis. After adjusting for other risk factors, re-emergent MRD was the most significant adverse prognostic indicator overall. Sequential MRD measurement is important for MRD-guided therapy, and integration of MRD values at different timepoints based on leukemia subtype could allow for more refined risk stratification.

Genomics and precision medicine in pediatric acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in the pediatric population, accounting for about 25% of childhood cancers. Drastic therapeutic improvements have been made for pediatric ALL since the early 1960s, marking the most successful treatment paradigm in pediatric oncology. The clinical success derived from refined risk-adapted therapy based on presenting features, cytogenetics and minimal residual disease, prevention of central nervous system relapse, and improvement of supportive care measures. With contemporary therapies, survival of children with ALL now exceeds 90%. However, ALL represents one of leading causes of cancer-related death, as 15%-20% of patients continue to relapse and outcomes post-relapse remain poor. Since the early 2000s, large-scale genomic studies of ALL, greatly facilitated by the advent of next generation sequencing (NGS), have enabled the development of a novel taxonomy for ALL in the molecular era. The access to NGS technologies identifies novel ALL subsets characterized by “driver” oncogenic alterations, previously cryptic on conventional karyotyping methods. With genomic characterization, the group of formerly unclassified B-lineage ALL reduces from 25% to a marginal 5% of ALL. The revised molecular classification of ALL confers prognostic significance and describes the predilection of unfavorable ALL subtypes with increasing age, partially elucidating the worst outcome of adolescents and young adults with ALL. Large-scale genomic analysis also reveals inherited alterations predisposing to ALL occurrence or to different drugs’ sensitivities. Most importantly, the genomic portrait of ALL uncovers novel therapeutic vulnerabilities, paving the way towards precision medicine opportunities in ALL.

Pretreatment grade 4 thrombocytopenia is an independent prognostic factor in adult acute lymphoblastic leukemia: an extended analysis of a single-center retrospective study

ABSTRACT Objectives: Low pretreatment platelet count is negatively associated with overall survival (OS) of certain subtypes of acute lymphoblastic leukemia (ALL). However, the prognostic impact of the grade of thrombocytopenia on OS and disease-free survival (DFS) has never been explored. Methods: We conducted an extended analysis of a retrospective study. Newly diagnosed adults with ALL was enrolled in this study. The grade of thrombocytopenia was evaluated in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Prognostic impacts were assessed by the hazard ratios (HRs) and 95% confidence intervals (CIs) obtained from univariate and multivariate Cox proportional hazards regression analyses. Results: A total of 90 participants were included in this study. There were 18 cases with grade 4 thrombocytopenia among the 71 participants presented with thrombocytopenia of any grade. Both univariate and multivariate Cox regression analyses suggested the independent negative prognostic impact of grade 4 thrombocytopenia on both OS (HR = 4.73, 95% CI = 1.95-11.52) and DFS (HR = 9.82, 95% CI = 3.14-30.76) of adult ALL, using the cohort of patients with no thrombocytopenia as a reference. In addition, treatment regimen, cytogenetic profile, time to treatment, and platelet count were independent prognostic factors of the OS. We also found that treatment regimen, cytogenetic profile, and peripheral blood blast percentage were independent prognostic factors of the DFS. Conclusion: Grade 4 thrombocytopenia was a negative prognostic factor for both overall survival and disease-free survival of adults with acute lymphoblastic leukemia.

Early T-Cell Precursor Leukemia Has a Higher Risk of Induction-Related Infection among T-Cell Acute Lymphoblastic Leukemia in Adult.

Background Infections are an important cause of morbidity and mortality for acute lymphoblastic leukemia (ALL). However, the reports regarding risk factors of induction-related infection are roughly unknown/limited in adult T-ALL during induction chemotherapy. Methods We performed a retrospective cohort study for the prevalence and risk predictors of induction-related infection among consecutive T-ALL patients (N = 97) enrolled in a PDT-ALL-LBL clinical trial. Of 97 patients with T-ALL enrolled in the trial, 46 were early T-cell precursor (ETP) ALL and 51 were non-ETP ALL. Results When compared with non-ETP, ETP ALL subtype was characterized with lower neutrophil count (1.35 × 109/L vs. 8.7 × 109/L, P < 0.001) and lower myeloid percentage in the bone marrow (13.35% vs. 35.31%, P = 0.007). Additionally, ETP ALL had longer neutropenia before diagnosis (P < 0.001), as well as during induction chemotherapy (P < 0.001). Notably, the ETP cohort experienced higher cumulative incidence of clinically documented infections (CDI; 33.33%, P = 0.001), microbiologically documented infections (MDI; 45.24%, P = 0.006), resistant infection (11.9%, P = 0.013), and mixed infection (21.43%, P = 0.003), respectively, than those of the non-ETP cohort. Furthermore, multivariable analysis revealed that T-ALL mixed infection was more likely related to chemotherapy response (OR, 0.025; 95% CI 0.127-0.64; P = 0.012) and identified myeloid percentage as a predictor associated with ETP-ALL mixed infection (OR, 0.915; 95% CI 0.843-0.993; P = 0.033), with ROC-defined cut-off value of 2.24% in ETP cohorts. Conclusions Our data for the first time demonstrated that ETP-ALL characterized with impaired myelopoiesis were more susceptible to induction-related infection among T-ALL populations.

Intracellular vincristine levels in lymphoblasts affect treatment outcome in childhood B‐lymphoblastic leukaemia: Ma‐Spore ALL 2010 study

Vincristine (VCR) is a key drug in the successful multidrug chemotherapy for childhood acute lymphoblastic leukaemia (ALL). However, it remains unclear how VCR pharmacokinetics affects its antileukaemic efficacy. The objective of this study is to explore the VCR pharmacokinetic parameters and intracellular VCR levels in an up-front window of Ma-Spore ALL 2010 (MS2010) study. We randomised 429 children with newly diagnosed ALL to 15-minute vs 3-hour infusion for the first dose of VCR to study if prolonging the first dose of VCR infusion improved response. In a subgroup of 115 B-ALL and 20 T-ALL patients, we performed VCR plasma (n = 135 patients) and intracellular (n = 66 patients) pharmacokinetic studies. The correlations between pharmacokinetic parameters and intracellular VCR levels with early treatment response, final outcome and ABCB1 genotypes were analysed. There was no significant difference between 15-minute and 3-hour infusion schedules in median Day 8 peripheral or bone marrow blast response. Plasma VCR pharmacokinetic parameters did not predict outcome. However, in B-ALL, Day 33 minimal residual disease (MRD) negative patients and patients in continuous complete remission had significantly higher median intracellular VCR24h levels (P = .03 and P = .04, respectively). The median VCR24h intracellular levels were similar among the common genetic subtypes of ALL (P = .4). Patients homozygous for wild-type ABCB1 2677GG had significantly higher median intracellular VCR24h (P = .04) than 2677TT. We showed that in childhood B-ALL, the intracellular VCR24h levels in lymphoblasts affected treatment outcomes. The intracellular VCR24h level was independent of leukaemia subtype but dependent on host ABCB1 G2677T genotype.

First person profile: Ching-Hon Pui, MD: An internationally renowned pediatric oncologist, Dr. Pui helped to push the cure rate for pediatric acute lymphoblastic leukemia to more than 90.

First person profile: Ching-Hon Pui, MD: An internationally renowned pediatric oncologist, Dr. Pui helped to push the cure rate for pediatric acute lymphoblastic leukemia to more than 90.

Interactions of Consanguinity and Number of Siblings with Childhood Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a common malignancy in children. Consanguinity has a high prevalence in developing countries and increases the probability of homozygosity for many genes which may affect ALL and its prognosis. We conducted a study to explore the impact of consanguinity and number of siblings on ALL as there are currently no studies to describe this effect. Data were collected from patients' records from the Children's University Hospital of Damascus University, which is the major cancer centre for children in Syria. This study included 193 children with ALL over one year. Number of siblings was not with the French–American–British (FAB) classification, gender, ALL subtype, or risk of ALL children. When comparing consanguinity degrees and complete blood counts at diagnosis, significant contradicting data were found in the third-degree and fourth-degree consanguinity when compared to one another and to not having consanguineous parents as third degree consanguinity was associated with normal platelets but lower WBC counts, and fourth-degree consanguinity was associated with normal haemoglobin levels and WBC counts, but lower platelet counts. Having consanguineous parents was also associated with acquiring ALL at an older age, L2 FAB classification, having a positive family history for malignancies, and not having hepatosplenomegaly (P < 0.05). Although L2 is known to be a poor prognosis indicatory, no association was found with consanguinity and risk. Finally, no association was found with ALL subtype or risk (P > 0.05). Although consanguinity and number of siblings have affected some variables and prognostic features of childhood ALL, the aetiology is not clear and we need further studies to clarify such an association as this will help in optimising therapy and accurately determine the risk.

Molecular Biology of Childhood Leukemia

Childhood hematological malignancies (HM) exhibit profound genetic and biological heterogeneity. Many sporadic and familial HM have a heritable predisposition. Genomic sequencing has revised the taxonomy of lymphoid and myeloid leukemias, indicating the importance of accurate molecular diagnosis in disease management. Notable examples include the identification of gene expression–based subtypes of acute lymphoblastic leukemia (ALL), identification of diverse rearrangements of NUP98 in high-risk acute myeloid leukemia (AML), characterization of the interplay of cell-of-origin and genomic alterations in lineage-ambiguous leukemias, and the prognostic importance of DNA methylation in juvenile myelomonocytic leukemias. These insights provide therapeutic opportunities, including kinase inhibition in Ph-like ALL, menin inhibition in KMT2A-rearranged AML, histone deacetylase inhibition in MEF2D-rearranged ALL, and FLT3 inhibition in T-lineage and myeloid leukemias. We provide an overview of the molecular foundation and classification of childhood leukemias, focusing on recent scientific advances, and discuss potential therapeutic implications.