Incidence Of Acute Lymphoblastic Leukemia Research Articles

IKZF1PLUS alterations contribute to outcome disparities in Hispanic/Latino children with B-lymphoblastic leukemia.

Compared to other ethnicities, Hispanics/Latinos (H/L) have a high incidence of acute lymphoblastic leukemia (ALL), enrichment of unfavorable ALL genetic subtypes, and worse outcomes, even after correcting for socioeconomic factors. We previously demonstrated increased incidence of the high-risk genetic drivers IKZF1 deletion and IGH::CRLF2 rearrangement in H/L compared to non-H/L children with B-ALL. Here in an expanded pediatric cohort, we sought to identify novel genetic drivers and secondary genetic alterations in B-ALL associated with H/L ethnicity. Comprehensive clinicopathologic data from patients with B-ALL treated from 2016 to 2020 were analyzed. Subtype was determined from karyotype, fluorescence in situ hybridization (FISH), chromosome microarray (CMA), and our next-generation sequencing (NGS) panel (OncoKids). Non-driver genetic variants were also examined. p-Values less than.05 (Fisher's exact test) were considered significant. Among patients with B-ALL at diagnosis (n=273), H/L patients (189, 69.2%) were older (p=.018), more likely to present with CNS2 or CNS3 disease (p=.004), and NCI high-risk ALL (p=.014) compared to non-H/L patients. Higher incidence of IGH::CRLF2 rearrangement (B-ALL, BCR::ABL1-like, unfavorable; p=.016) and lower incidence of ETV6::RUNX1 rearrangement (favorable, p=.02) were also associated with H/L ethnicity. Among secondary (non-subtype-defining) genetic variants, B-ALL in H/L was associated with IKFZ1 deletion alone (p=.001) or with IGH::CRLF2 rearrangement (p=.003). The IKZF1PLUS profile (IKZF1 deletion plus CDKN2A/2Bdel, PAX5del, or P2RY8::CRLF2 rearrangement without DUX4 rearrangement) was identified as a novel high-risk feature enriched in H/L patients (p=.001). Our study shows enrichment of high-risk genetic variants in H/L B-ALL and raises consideration for novel therapeutic targets.

Microbiota, Diet and Acute Leukaemia: Tips and Tricks on Their Possible Connections.

Acute leukaemia is probably one of the most recurrent cancers in children and younger adults, with an incidence of acute lymphoblastic leukaemia in 80% of cases and an incidence of acute myeloid leukaemia in 15% of cases. Yet, while incidence is common in children and adolescents, acute leukaemia is a rare disease whose aetiology still requires further analysis. Many studies have investigated the aetiology of acute leukaemia, reporting that the formation of gut microbiota may be modified by the start and development of many diseases. Considering that in patients affected by acute lymphoblastic leukaemia, there is an inherent disequilibrium in the gut microbiota before treatment compared with healthy patients, increasing evidence shows how dysbiosis of the gut microbiota provokes an inflammatory immune response, contributing to the development of cancer. Our analysis suggeststhe key role of gut microbiota in the modulation of the efficacy of leukaemia treatment as well as in the progress of many cancers, such as acute leukaemia. Therefore, in this paper, we present an examination of information found in literature regarding the role of dietary factors and gut microbiota alterations in the development of leukaemia and suggest possible future preventive and therapeutic strategies.

A modified CALGB 10403 in adolescents and young adults with acute lymphoblastic leukemia in Central America.

Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults. Historically, this patient group has been treated using adult-based regimens, which entails a high rate of treatment-related mortality and a poor overall survival (OS). The use of the CALGB 10403, a pediatric-inspired regimen, has been proven effective in this patient subgroup. Nonetheless, low- and middle-income countries (LMICs) may present limited access to standard care treatments implemented elsewhere, warranting the need for further research to improve outcomes among vulnerable populations. In this study, we present the outcomes in terms of safety and effectiveness of using a modified CALGB 10403 regimen to reflect drug and resource availability in LMICs. Modifications included the use of Escherichia coli asparaginase,6-mercaptopurine instead of thioguanine and the use of rituximab among patients with CD20+. A total of 95 patients with a median age of 23 (range, 14-49) years treated with this modified scheme were prospectively assessed at 5 centers in Mexico and 1 in Guatemala. Among these, 87.8% achieved a complete response after induction. During follow-up, 28.3% of patients relapsed. Two-year OS rate was 72.1%. Factors associated with worse OS included hyperleukocytosis (hazard ratio [HR], 4.28; 95% confidence interval [CI], 1.81-10.10) and postinduction minimal residual disease (HR, 4.67; 95%CI, 1.75-12.44). Most patients presented hepatotoxicity (51.6% and 53.7% during induction and consolidation, respectively), and the treatment-related mortality was 9.5%. Overall, results highlight that implementing a modified CALGB 10403 regimen in Central America is feasible, and it is associated with improvements in clinical outcomes and a manageable safety profile.

Acute lymphocytic leukemia incidence and survivability trends in the United States over the last two decades: SEER data set from 2000-2019.

e19050 Background: The primary objective of this study is to evaluate how race, age at which patients were diagnosed, sex, and phenotype affect incidence and survivability for acute lymphocytic leukemia (ALL) patients in the United States. Keeping these factors in consideration this study was developed to see how existing cancer registry data can assist us in early detection of ALL in patients. Our hypothesis was that statistically significant correlations exist between race, age at which patients were diagnosed, sex, and phenotype of the ALL patients. Methods: The rate of incidence and survivability data were evaluated using SEER*Stat statistical software from National Cancer Institute. For incidence calculation we used the SEER 22 registry that covered approximately 47.99% of the U.S. population, while survival statistics were calculated using the SEER 17 registry that covered 26.5% of the U.S. population, both containing records from 2000 through 2019. In calculating the incidence statistics only the first primary tumor and reported diagnosis of the disease was accounted for. Results: There were statistically significant correlations between sex, race/ethnicity, age at which patients were diagnosed, phenotype of the ALL patient, and their rate of incidence. Analysis of All incidence data showed that the disease was more prevalent among Caucasian population. Among ALL patients, 59% patients were between 0 to 19 years of age when diagnosed, and 56% were male. ALL are mostly associated in patients with B-cell phenotype (73%). Evaluation of survivability data showed a slightly higher 5-year survival rate than 10-year survival rate. Conclusions: Survivability rates of African Americans patients were the lowest compared to Caucasian, Asian, Pacific Islanders, Alaskan Native, Native Americans and others. Survivability rates progressively decreased for older patients. Additionally, this study looked into the common treatment approaches that were administered in ALL patients which primarily included chemotherapy supplemented with some form of radiation therapy, as and when needed. The study showed chemotherapy was quite effective in improving patients’ survival probabilities, while the prognosis from the disease was not quite good for those who did not receive any treatment. This updated study on ALL incidence, survival rate, and common treatment options will further assist the health care professionals in effectively screening potential patients, their early detection, and in implementing a successful treatment regimen. This could potentially improve survival rates among those diagnosed at an older age who have a far greater mortality rate from ALL compared to younger patients.

Acute lymphoblastic leukemia after COVID-19 infection: a coincidence or a second hit

Since the advent of COVID-19 in 2019, the virus has affected all age groups and has a very wide clinical spectrum, ranging from asymptomatic infection to serious life-threatening complications including multi-organ dysfunction syndrome in children. The virus tends to affect all organ systems including the hematological system. There are many contradictory views on the effect of the COVID-19 pandemic on the incidence of hematological malignancies. Some studies have shown an increased incidence of acute lymphoblastic leukemia (ALL) after COVID-19 infection supporting the Greaves two-hit hypothesis of leukemogenesis, while others have shown a decline in the incidence of ALL postulated to be due to widespread lockdown and decreased exposure to environmental pathogens. We report the cases of three children who were diagnosed with acute lymphoblastic leukemia shortly after the initial diagnosis of multisystem inflammatory syndrome in children (MIS-C) or COVID related transient erythroblastopenia of childhood.

A retrospective analysis of Acute Lymphoblastic Leukemia incidence among hospitalized patients from Jan-2017 to Sep-2021

A retrospective analysis of Acute Lymphoblastic Leukemia incidence among hospitalized patients from Jan-2017 to Sep-2021

Younger Matched Unrelated Donors Confer a Decreased Relapse Risk As Compared to Older Sibling Donors for Adult B-Cell ALL Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: The incidence of acute lymphoblastic leukemia (ALL) has increased due to aging population and the median age at diagnosis is 56 years among adults. Allogeneic hematopoietic cell transplant (alloHCT) offers cure for ALL patients, however, disease relapse remains a major issue. Human leukocyte antigen (HLA)-matched sibling donors (MSD) are considered the ideal donor type, mainly due to lower incidence and severity of graft-versus-host-disease (GVHD) and improved disease-free survival (DFS) in ALL. However, siblings are also likely to be older, often with higher comorbidities, and adult ALL patients typically undergo reduced-intensity conditioning and need novel strategies to reduce the post-alloHCT relapse risk. While recent data have suggested relapse reduction and survival benefit with younger matched unrelated donors (MUD) in AML and MDS, the impact of donor age on alloHCT outcomes in adult ALL patients remain unknown. Methods: This retrospective cohort study from the Center for International Blood and Marrow Transplant Research database (CIBMTR) data in B-cell ALL patients 50 years or older, undergoing alloHCT from older (>50) MSDs or younger (<35) MUDs between 2011 and 2018, included common allograft types (PB vs BM), conditioning regimens (RIC/NMA vs MAC), and graft-versus-host-disease (GVHD) prophylaxis strategies (FK-based vs CSA-based vs. others). Other exclusion criteria were recipients of ex vivo T-cell depleted grafts, recipients of mismatched unrelated donors, cord blood or identical twin transplants. The primary outcome, compared between the 2 donor age groups, was relapse risk whereas secondary outcomes included non-relapse mortality (NRM), DFS, and overall survival (OS). Cumulative incidence estimates were calculated for competing risks outcomes, including NRM and relapse. The Kaplan-Meier method was used to estimate the probabilities for survival. To evaluate potential risk factors, multivariable cox regression was used, and relevant transplant-related covariates were considered. Interactions between the main effect (donor age group) and significant risk factors were tested. Fine and Gray model was used for NRM and relapse. Given the multicenter nature of the database, center effect was tested for OS by fitting a gamma frailty model. Results: Among 925 eligible patients in the study cohort, 386 underwent alloHCT with an older MSD (median age, 59 [range: 50-75]) whereas 539 received transplant from a younger MUD (median age, 60 [range: 50-77]). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (HR 0.68; 95% CI, 0.53-0.87; p=.002) versus older MSDs (Table 1; Figure 1). The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs compared to older MSDs (26% vs 37%; p=.001) (Table 2). Younger MUDs conferred an increased NRM compared to older MSDs (HR 1.38; 95% CI, 1.05-1.82; p=.02) (Table1; Figure 1). The adjusted cumulative incidence of NRM at 5 years was also significantly higher in B-ALL patients who underwent alloHCT from younger MUDs compared to older MSDs (31% vs 22%; p=.006) (Table2). There were no differences in OS or DFS rates of alloHCT with younger MUDs vs older MSDs (OS: HR 1.09; 95% CI, 0.90-1.32; p=.37; DFS: HR 0.95; 95% CI, 0.79-1.14; p=.57) (Table 1; Figure 1). The adjusted 5-year OS probability was 48% in younger MUDs (95% CI, 43%-52%) and 51% among older MSDs (95% CI, 45%-56%; p=0.37). The adjusted 5-year DFS probability was 44% with younger MUDs (95% CI, 40%-49%) compared to 42% with older MSDs (95% CI, 37%-47%; p=.59) (Table2). Conclusions: This is the largest study to date performed in a mature, prospectively collected registry cohort that aids in donor selection and found significant relapse reduction in adult B-ALL patients who underwent alloHCT with younger MUDs as compared to older MSDs. The results highlight that younger MUD donor type exerts a stronger GVL effect and should be preferred in patients at a higher risk for post-alloHCT relapse. The higher NRM associated with younger MUDs will need enhanced GVHD prophylaxis, infection preemption and preventative strategies, and supportive cares measures to consolidate the leukemia-free survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Relationship Between Family Cultural Orientation in Menu Selection and Incidence of Childhood Acute Lymphoblastic Leukemia (LLA) in Surabaya, Indonesia

Diseases can be caused by consuming foods that do not have a balanced nutritional value, choosing the wrong diet, or choosing the wrong food menu. Diet is also a risk factor for cancer, such as leukemia. In the outpatient pediatric polyclinic of Dr. Soetomo Hospital Surabaya, leukemia is one of the ten most common diseases. This study aims to analyze the relationship between family culture of menu selection and the incidence of leukemia in children at the Surabaya Halfway House. The population in this study were all mothers or families and children suffering from leukemia waiting for treatment in the hospital and living temporarily in a halfway house on Jl Karang Menjangan, a total of 30 people. This type of research is analytic using a simple linear regression approach/desianalyticallye the dominant factors that influence the culture of food from menu selection with the incidence of leukemia in children. The independent variable in this study is the family culture of menu selection, which is a pattern of behavior that has been carried out by parents or families as a way to meet the needs of food which includes beliefs, knowledge about nutrition, social functions of food, and menu selection, preferences or preferences. The dependent variable is the incidence of Acute Lymphocytic Leukemia (Leukemia/ALL), which is the diagnosis of leukemia based on the medical diagnosis of the patient's status. analyzed by simple linear regression test. Results: the culture of food menu selection (beliefs, knowledge about the food menu, social functions, preferences do not contribute to the incidence of leukeand and mia in children. It is recommended that the culture of food menu selection regarding trust, knowledge, social function, preference is a food menu selection culture that must be maintained because the results obtained mostly have good habits and some are still lacking so it is hoped that the menu selection pattern will become an initial assessment for children diagnosed with cancer to prevent subsequent events.

Disparities in pegasparagase-induced toxicity in Hispanic patients with acute lymphoblastic leukemia.

e18590 Background: Hispanic individuals experience the highest incidence of acute lymphoblastic leukemia of any racial or ethnic group in the United States. While Hispanic individuals are known to have disproportionately increased mortality and higher therapy-related toxicity rates in ALL, there is a paucity of data regarding ethnic differences in rates of toxicity related to pegasparagase, a backbone of ALL treatment regimens. In our safety-net hospital system, we sought to evaluate disparities in rates of pegasparagase-induced hepatotoxicity between Hispanic and non-Hispanic patients. Methods: Pegasparagase infusions administered in adult ALL patients from 2011-2020 at Parkland Memorial Hospital in Dallas, Texas, were identified using the electronic medical record. Retrospective review of demographic, clinical, and socioeconomic data was conducted. For each infusion, dosing, timing, transaminase trends, and toxicity data were gathered. Statistical analysis was completed with Excel Analysis ToolPak and R Statistical Software. Accounting for baseline characteristics (age, BMI, sex, metabolic comorbidities, and baseline hepatic function), multiple linear regression models were constructed for peak transaminase and bilirubin levels. ANOVA testing, adjusted R2 values, and AIC were utilized to compare the contribution of race, ethnicity, and socioeconomic variables to modeling. Results: 47 individual patients received pegasparagase during the study period with 196 infusions evaluated. The mean age was 30 years, 29% were female and 73.4% white Hispanic. There were 64 grade 3-4 pegasparagase-related toxicities (54 hepatotoxicity, 4 pancreatitis, 6 thrombosis). 83.3% of grade 3-4 hepatotoxicity events were in Hispanic patients, and 16.7% in non-Hispanics. The median time from infusion to grade 3-4 toxicity was 18 days. Hispanic ethnicity was significantly associated with severe hepatoxicity (P = 0.0004). An interaction was identified with insurance status and primary language which significantly strengthened the impact of ethnicity and race on hepatotoxicity severity (P = 0.005, P = 0.02). Conclusions: In our safety-net population, Hispanic ethnicity was associated with significantly higher grades of hepatotoxicity when compared to non-Hispanic patients. Uninsured status and primary Spanish language use were not only independently associated with increased toxicity but also strengthened the effect of Hispanic ethnicity on the severity of liver dysfunction related to pegasparagase. These findings propose that Hispanic patients may benefit from closer monitoring during treatment with pegasparagase-containing regimens and highlight the need for further studies to improve risk-stratification of Hispanic patients when selecting ALL therapy.

Controversies in the Treatment of Adolescents and Young Adults with Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia.

The incidence of acute lymphoblastic leukemia (ALL) has been increasing steadily in the adolescent and young adult (AYA) population. In this review article focused on the management of AYAs with Philadelphia chromosome-negative (Ph-) B-ALL, we examine topics of clinical interest and identify areas of controversy in need of further investigation. We explore four areas of active investigation: pediatric-inspired front-line treatment regimens, the optimal time of measurable residual disease (MRD) assessment, the role of hematopoietic stem cell transplant and the optimal salvage therapy for relapsed/refractory B-ALL in AYAs. There has been rapid advancement in the management of ALL in the AYA patient population, which has resulted in improved outcomes. We must build on the successes by continuing to promote multi-center innovative clinical research with clinical trial populations reflecting the AYA ALL patient spectrum. The incorporation of novel targeted immunotherapy into front-line treatment will be transformative and redefine treatment paradigms in the coming years.

Weakly Supervised Ternary Stream Data Augmentation Fine-Grained Classification Network for Identifying Acute Lymphoblastic Leukemia.

Due to the high incidence of acute lymphoblastic leukemia (ALL) worldwide as well as its rapid and fatal progression, timely microscopy screening of peripheral blood smears is essential for the rapid diagnosis of ALL. However, screening manually is time-consuming and tedious and may lead to missed or misdiagnosis due to subjective bias; on the other hand, artificially intelligent diagnostic algorithms are constrained by the limited sample size of the data and are prone to overfitting, resulting in limited applications. Conventional data augmentation is commonly adopted to expand the amount of training data, avoid overfitting, and improve the performance of deep models. However, in practical applications, random data augmentation, such as random image cropping or erasing, is difficult to realistically occur in specific tasks and may instead introduce tremendous background noises that modify actual distribution of data, thereby degrading model performance. In this paper, to assist in the early and accurate diagnosis of acute lymphoblastic leukemia, we present a ternary stream-driven weakly supervised data augmentation classification network (WT-DFN) to identify lymphoblasts in a fine-grained scale using microscopic images of peripheral blood smears. Concretely, for each training image, we first generate attention maps to represent the distinguishable part of the target by weakly supervised learning. Then, guided by these attention maps, we produce the other two streams via attention cropping and attention erasing to obtain the fine-grained distinctive features. The proposed WT-DFN improves the classification accuracy of the model from two aspects: (1) in the images can be seen details since cropping attention regions provide the accurate location of the object, which ensures our model looks at the object closer and discovers certain detailed features; (2) images can be seen more since erasing attention mechanism forces the model to extract more discriminative parts’ features. Validation suggests that the proposed method is capable of addressing the high intraclass variances located in lymphocyte classes, as well as the low interclass variances between lymphoblasts and other normal or reactive lymphocytes. The proposed method yields the best performance on the public dataset and the real clinical dataset among competitive methods.

Genetic and genomic analysis of acute lymphoblastic leukemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials.

Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and <1% of patients, respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile was identified in over a third (28/77) of cases of B-cell precursor ALL. The genetic good-risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP arrays and 9% (2/23) of NGS samples, and represent novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with 5-year event-free and overall survival rates of 17% and 24%, respectively, across the cohort, indicating a need for novel therapeutic strategies.

Effectiveness and Security of a Modified CALGB10403 in Adolescents and Young Adults with Acute Lymphoblastic Leukemia in Low-and-Middle-Income Countries: A Multicentric Experience in Central America

▪Background:Mexico and Central America have a high incidence of acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA). Chemotherapy with Hyper-CVAD has been widely used with poor outcomes, with a 3-year overall survival (OS) of 25.7% in this group of age.In low-and middle-income countries (LMIC), limitations in supportive care such as low access to neutrophil stimulant agents, antifungal prophylaxis and limited intensive care access, may increase treatment-related mortality. On the other hand, reports suggest that specific high-risk subgroups may be more frequent in Hispanic patients from Mexico and Central America.We hypothesize that the use of a less-myeloablative regimen, based on L-asparaginase could overcome the bad outcomes previously reported.MethodsWe modified the original CALGB 10403 based on local drug-access. We include patients with newly diagnosed Philadelphia-negative B- or T-cell ALL between 14-49 years from 4 centers in Mexico and one in Guatemala.We modified the regimen as following: replaced pegaspargase by E. Coli asparaginase, thioguanine by 6-mercapatopurine and incorporate rituximab 375mg/m2 for 6 doses in CD20 positive patients. After the first interim analysis (October 2019), we replaced the prednisone by dexamethasone during induction. Minimal residual disease (MRD) was assessed by flow cytometry after induction and after first consolidation. We considered high-risk karyotype if MLL-rearrangements, complex or hypodiploid and high-white blood cell count (WBC) if >30 x10 3/mcL for B-ALL or >100 x10 3/mcL for T-ALL.The main objective was to evaluate OS and as secondary objectives to evaluate complete response (CR) rate, relapse-free survival (RFS) and to assess the safety of this regimen.ResultsFrom January 2017 to December 2020, 95 patients have been enrolled with a median age of 23 years (range 14-49). One third (34.6%) had overweight and 11.7% were obese.The majority (92.6%) had a B-cell ALL and a normal karyotype (81.2%). The median WBC was 18.4 x10 3/mcL (0.2-427.7) and 40.9% had a high-WBC.During induction, adverse events (AE) included grade 3/4 elevated bilirubin (21.1%), transaminases (14.7%), hyperglycemia (14.7%), hypofibrinogenemia (44.2%), thrombosis (10.5%), hypersensitivity (2.2%) and pancreatitis (2.1%). During consolidation, AE included grade 3/4 hepatic toxicity (18.9%), hypertriglyceridemia (14.8%), thrombosis (5.3%) and pancreatitis (2.1%).Neutropenic fever occurred in 55.8% during induction (grade 4: 31.5%), and in 32.9% during consolidation (grade 4/5: 5.3%).A dose adjustment due to AE was required in 22.1% during induction and in 23.2% during consolidation. The induction related-mortality (IRM) rate was 7.4%The CR rate was 87.8%. After-induction, MRD was <0.01% in 39.1%, 0.01-0.1% in 39.1% and > 0.1% in 24.6%. Post-consolidation MRD was only measured in 43 patients and was <0.01% in 37.2%. During follow-up, 26.7% relapsed: 62.5% bone marrow (BM) relapses, 25.0% central nervous system (CNS) relapses and 12.5% CNS + BM relapses. Eight patients (8.4%) received an allogeneic-stem cell transplant (HSCT) as consolidation.The 2-year OS was 72.1%. The post-induction MRD <0.1% was associated with a better OS (figure 1A) (HR: 0.17 (95%CI: 0.06-0.55), p=0.003) and a high-WBC with an inferior OS (figure 1B) (HR: 4.13 (95%CI: 1.68-10.14), p=0.002).The 2-year RFS was 65.2%. The post-induction MRD <0.1% was associate with a better RFS (figure 1C) (HR: 0.19 (95%CI: 0.07-0.50), p=0.001) and a high-WBC and overweight / obesity with an inferior RFS (HR: 4.08 (95%CI: 1.71-9.73), p=0.001 and 2.50 (95%CI: 1.06-5.86), p=0.036 respectively) (figure 1D).Conclusions:The adoption of modified CALGB10403 regimen in Central America based on local resources is feasible. It is associated with a significant improvement in the OS and decrease in IRM when compared with previous reports. Despite a very high-rate of hepatic and metabolic toxicities, these were manageable. As reported by other groups, MRD, high-WBC and overweight/obesity are associated with poor outcomes.Despite being encouraging results, a significant number of patients persist with positive MRD and the main cause of dead is disease progression. Access to cellular therapies, and BiTes is cost restricted in LMIC. Hence, we should generate strategies to intensify treatment in MRD positive patients and expand transplant access to overcome outcomes. [Display omitted] DisclosuresRangel-Patiño: Bristol: Consultancy; Abbvie: Speakers Bureau. Ceniceros: Amgen: Speakers Bureau. Espinosa: Amgen: Speakers Bureau; Janssen: Consultancy; Pfizer: Consultancy. Amador: Abbvie: Consultancy, Speakers Bureau; Bristol: Consultancy. Cabrero Garcia: Takeda: Speakers Bureau; Abbvie: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Astellas: Consultancy; BD: Speakers Bureau. Inclan-Alarcon: Janssen: Speakers Bureau; Boehringer: Speakers Bureau. Neme Yunes: Janssen: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Meillon-García: Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Astellas: Consultancy. Apodaca: Sanofi: Consultancy; Asofarma: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Demichelis: Bristol/Celgene: Consultancy, Speakers Bureau; Astellas: Consultancy; Gilead: Consultancy; ASH: Research Funding; Abbvie: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz: Consultancy.

Tisagenlecleucel Therapy Is Safe and Effective for Children with Down Syndrome with ALL in First Relapse

Introduction: Children with Down Syndrome (DS) have a 20-fold increased incidence of acute lymphoblastic leukemia (ALL) and a 70% higher risk of relapse than children with ALL and no DS. Treatment for DS children with relapsed ALL is challenging due to the high treatment-related mortality associated with both intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) as well as high rates of second relapse. Outcomes for relapsed ALL in DS are dismal, with recent studies citing an event-free survival (EFS) as low as 17%. Alternative treatment approaches are needed for this patient population. Treatment with anti-CD19 chimeric antigen receptor T-cells (CARTs) have shown high remission rates in patients with multiple relapsed/refractory ALL with an acceptable safety profile. CARTs are generally not indicated for first relapse of ALL; DS-specific indications for CARTs do not exist. In Ontario, due to the specific susceptibility of children with DS-ALL, CARTs were made available to this population upon first relapse. We describe the population-based Canadian experience using CARTs for first relapse of DS-ALL.Methods: Efficacy and safety data on all children referred for CARTs at the Hospital for Sick Children, in Toronto, Canada were retrospectively collected in a central database and validated by treating clinicians. Here we report all patients with DS suffering a first relapse of ALL at age <18 years referred for commercially available CARTs (tisagenlecleucel) between 2019 and 2021.Results: Five patients with DS received tisagenlecleucel for first relapse of ALL during the study period. Median age at original diagnosis was 6.3 years (range 3.4-11.5). Four patients presenting with National Cancer Institute (NCI) standard risk and one with NCI high-risk disease were initially treated on Children's Oncology Group based protocols. Four patients presented with relapse >36 months from diagnosis and one patient with early relapse. Mononuclear cells were successfully collected for all patients on the first attempt. Patients were bridged from collection to infusion with low intensity chemotherapy regimens. Tisagenlecleucel was successfully manufactured for all patients and infused at a median of 69 days (range 56-101) from collection of T cells. Four patients developed CRS: two patients grade 1, one patient grade 2, and one patient grade 4 requiring ICU care and treatment with tocilizumab and steroid. All patients achieved minimal residual disease (MRD) negative remission one month after infusion, with B-cell aplasia. Two patients showed early (< 6months post infusion) B-cell recovery consistent with CAR T-cell loss; both received off-label reinfusions of tisagenlecleucel and again achieved B-cell aplasia. One patient had a seizure with the first Fludarabine dose of lymphodepleting (LD) chemotherapy for re-infusion and was found to have elevated intracranial pressure. After treatment with Topiramate and anti-seizure prophylaxis the patient tolerated LD chemotherapy without further neurological events. No patient received further ALL therapy; none went on to HSCT. One patient suffered a CD19-negative relapse 7 months post infusion and was transitioned to palliative-intent treatment. Two patients developed prolonged neutropenia with one patient showing recovery (ANC>1x10E9/l) at 5 months post infusion and the patient who had relapsed disease remained neutropenic until relapse. Infectious complications in the first 6 months post infusion were rare. One patient, who was not neutropenic, required two hospital admissions for line related sepsis. With a median follow-up time of 519 days (range 197-785), the 1-year estimated EFS and overall survival were both 80% (95 th confidence interval 52-100%; Figure 1).Conclusions: Tisagenlecleucel was safe and effective in a small cohort of children with DS and first relapse of CD19+ ALL, with achievement of long-term remissions without further therapy, and an EFS superior to that seen in historical cohorts. Rate of acute complications were not increased compared with reported outcomes in patients without DS. Further evaluation of tisagenlecleucel in this setting is warranted. [Display omitted] DisclosuresKrueger: KITE/Gilead: Consultancy; Novartis: Consultancy; SOBI: Consultancy. Whitlock: Sobi Pharmaceuticals: Consultancy; Novartis: Research Funding; Amgen; Jazz Pharmaceuticals: Honoraria. Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure:tisagenlecleucel for early B-cell recovery

Spatial analysis and geoclimatic factors associated with the incidence of acute lymphoblastic leukemia in Iran during 2006–2014: An environmental epidemiological study

Background and objectivesThe present study aims to determine the cumulative incidence rate of acute lymphoblastic leukemia (ALL), the degree of spatial autocorrelation and clustering of ALL, the hotspot and coldspots of ALL and geoclimatic conditions affecting the incidence of ALL in Iran and to draw a comparison between global and local regression models. Materials and methodsIn this ecological study, an exploratory-etiologic multiple-group method has been adopted to investigate all children under 15 years of age with ALL in Iran during 2006–2014. Data analysis was performed using Mann Whitney U, Pearson correlation coefficients (PCCs), Global Moran's I, Optimized hotspot analysis (OHSA), Global Poisson regression (GPR), Geographically Weighted Poisson Regression (GWPR) at a significant level of α = 0.05. ResultsThe cumulative incidence rate of ALL was estimated at 21,315 per 100,000 Iranian children under 15 years of age. The value of Global Moran's I index was estimated 0.338 and significant (<0.001 P-value). Coldspots were observed in north and northwest of Iran and hotspots were identified in south, southwest and mid-east of Iran. In the present study, Max Temperature of Warmest Month (MTWM) and Direct Normal Irradiation (DNI) were risk factors and Precipitation of the Coldest Quarter (PCQ) and Altitude (AL) were protective factors in the incidence of ALL, even though the non-stationarity of local coefficients and local t-values was clear. GWPR, by capturing and applying spatial heterogeneity and spatial autocorrelation, had a greater performance and goodness of fit than GPR. DiscussionALL has created spatial clusters in Iran. The incidence of ALL is the result of synergistic interaction between environmental, infectious, geographical and genetic risk factors. It is recommended to use of local models in ecological studies.

Clinical and Pathological Features of B-Cell Acute Lymphoblastic Leukemia Following Maintenance Treatment with Lenalidomide for Multiple Myeloma

Introduction: The immunomodulatory agent lenalidomide (Len) has improved overall survival (OS) in patients (pts) with multiple myeloma (MM). Pts receiving Len for MM exhibit increased risk of second primary hematologic malignancies, particularly those with melphalan (Mel) exposure, with a high incidence of acute lymphoblastic leukemia (ALL) observed in some series (Palumbo et al., Lancet Oncol, 2014; Tan et al., Hematol Oncol, 2015). Len degrades or down-regulates known B-cell ALL (B-ALL) tumor suppressors (e.g. IZKF1, IZKF3, IRF4); Len-associated ALL remains relatively uncharacterized.Methods: We identified 9 pts at MSKCC diagnosed with ALL from 2008-2016 during or within 4 months of therapy with Len for MM. Diagnostic molecular studies from bone marrow (BM) to characterize B-ALL included Archer FusionPlex (n=4), FoundationOne Heme (n=3) to assess for Philadelphia chromosome (Ph)-like ALL, other hematologic cancer-targeted mutation analyses (n=2), and NGS based clonality testing (Lymphotrack) for characterization and monitoring of clonal IGH rearrangements (n=3).Results: Of the 9 pts (5M, 4F), median ages at MM and B-ALL diagnoses were 59 years (range, 46-77) and 64 years (range, 50-81), respectively. MM was standard-risk by cytogenetic studies in all pts but 1 who had excess 1q. Pts received Len during first induction (n=5) and/or subsequent salvage (n=2) and/or maintenance (n=9). Median length of Len exposure was 57.3 months (range 23.0-69.2). MM therapy included Mel 200 mg/m2 and autologous stem cell rescue (ASCR, n=6) and radiation therapy to sites of osseous disease (n=4). 3 pts did not receive Mel/ASCR. Median time from MM diagnosis to B-ALL diagnosis was 5.6 years (range 3.0-7.7). Len was discontinued between 109 days before B-ALL diagnosis (largely due to cytopenias) and 42 days after B-ALL recognition in BM (median, day of diagnosis).ALL was B-lineage, Ph-negative, and CD10+ in all 9 pts. Biologic characteristics of B-ALL and treatment are noted in Table 1. In pt #6, LymphoTrack studies confirmed B-ALL and MM clones did not share common IgH rearrangement. In 1 pt with CRLF2 rearrangement, withdrawal of Len alone led to resolution of cytopenias and regression of BM blasts, with only residual MRD detectable. He remains in remission w/o further therapy for 7 months.Of 7 pts receiving B-ALL therapy at MSKCC, 6 achieved CR following first induction (PR in 1 pt, who achieved CR following consolidation). 5 of 6 pts w/ MRD assessment achieved MRD-negative CR after induction ± post-remission chemotherapy. 5 of 7 pts treated at MSKCC then underwent allogeneic hematopoietic cell transplantation (AlloHCT). Conditioning was reduced-intensity (fludarabine + busulfan or Mel) in 4 pts and TBI + cyclophosphamide (Cy) in 1 pt. GVHD prophylaxis was tacrolimus + methotrexate (n=3), post-AlloHCT Cy (n=1), or CD34-selection w/o pharmacologic prophylaxis (n=1). One pt died 41 days post-AlloHCT in CR w/o GVHD. 4 remain in continuous MRD-negative CR post-AlloHCT (median f/u 19.0 months, range 4.6-36.5) w/o IBMTR grade 3-4 acute GVHD; 1 developed mild chronic GVHD based on 2015 Consensus criteria. One pt diagnosed with B-ALL at age 81 did not undergo alloHCT and died 27 months post-diagnosis w/o evidence of B-ALL.None of the 9 pts have experienced relapse of B-ALL or yet required further therapy for MM. Median time from B-ALL diagnosis to last f/u is 10.8 months (range 4.1-41.1).Conclusions: B-ALL following maintenance therapy with Len for MM is uncommon but increasingly recognized, even in the absence of prior Mel/ASCR. Activating CRLF2 fusions were observed in 2 of 4 pts undergoing detailed molecular profiling. Despite advanced age and poor risk features in several pts (MLL rearrangement, Ph-like ALL, complex karyotype, loss of TP53), all pts treated at MSKCC achieved CR, largely MRD-negative. None developed relapse of B-ALL. Withdrawal of Len alone was associated with B-ALL regression in 1 pt and may have facilitated the responses observed in others. AlloHCT may be effective for long-term control of B-ALL and MM in such pts as well.Next-generation sequencing-based assays may be considered as a tool to characterize development of clonal lymphoid populations during Len therapy. Further investigation of Len-associated leukemogenesis warrants further consideration, particularly as extended Len therapy is increasingly used in pts with MM and other malignancies. [Display omitted] DisclosuresLandau:Spectrum Pharmaceuticals: Other: Advisory Board, Research Funding; Karyopharm: Consultancy; Pfizer: Honoraria; Janssen: Honoraria; Takeda: Research Funding; Celgene: Other: Advisory Board; Amgen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Dogan:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy; Roche Pharmaceuticals: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arcila:Archer: Honoraria; Raindance Tecnologies: Honoraria; Invivoscribe: Honoraria. Park:Amgen: Consultancy.

Імунофенотиповий профіль бластних клітин як маркер діагностики рецидивів гострої лімфобластної лейкемії у дітей

Immunophenotyping of leukemia cells was studied in this work; minimal residual disease was monitored among children with acute lymphoblastic leukemia under conditions of relapse and complete remission after the application of ALLIC-BFM 2009 cytostatic therapy. The study showed that after application of ALLIC-BFM 2009 therapy, 88% of children had complete remission, and 12% had relapses. Among patients with relapses, the number of blast cells in the bone marrow was at a high level (more than 6%). Monitoring of patients during therapy established an increase in the minimal residual disease level of more than 1% after treatment in patients with recurrent disease. Immunophenotyping of blast cells among patients with relapse showed the expression of linear independent antigens HLA (93%), Auti-TdT (91%), CD10 (78%), CD38 (91%) and CD34 (57%) and B-linear antigens: CD19, CD22, CD58, CD79a, the highest expression was found for the CD19 antigen. A low level of expression of CD45 (28%) was recorded with relapses of acute lymphoblastic leukemia and high (89%) level was with complete remission of the disease. We did not detect expression of antigens characteristic of T-cell acute lymphoblastic leukemia in bone marrow of patients with acute lymphoblastic leukemia, both with relapses and with remission. At the same time, the expression of myeloid antigens (CD33 and CD13) was noted among acute lymphoblastic leukemia patients. Among patients, the incidence of acute lymphoblastic leukemia was the most pronounced in children aged from 3 to 6 years – 37 patients (35.2%) and aged from 6 to 9 years – 26 (24.8%) patients. The highest accidence was found among patients with chromosomal translocation TEL / AML – 22 (21%) patients with a median age 5 years. In second place, the frequency of mutations is the translocation of E2A / PBX1. BCR / ABL translocation was less common. It was noted in 1.9% of patients, but the expression of this gene indicated a bad course of the disease, as patients after cytostatic therapy under the ALLIC BFM 2009 program had a recurrence. Recurrence was also observed in patients with TEL/AML chromosomal translocation. Determination of minimal residual disease showed its increased level in patients with chromosomal aberrations BCR / ABL and TEL/AML throughout the treatment phase. In addition, patients in these groups were diagnosed with initial leukocytosis followed by leukopenia after a course of chemotherapy. Patients of all groups showed a decrease in hemoglobin. The biggest changes in clinical and laboratory parameters were found between patients with chromosomal translocations BCR/ABL and TEL/AML, as evidenced by the development of relapses in patients of these groups. The low level of association between karyotype disorders, with the formation of AF4/MLL and E2A/PBX1, and clinical and laboratory parameters in patients with acute lymphoblastic leukemia may indicate that the isolated clonal disorders are independent prognostic factors for the course of the disease

Does the Human Development Index relate with acute lymphoblastic leukemia incidence?

The association between childhood cancer and socioeconomic status has been widely studied. However, none of the results are conclusive. This study aimed to analyze the association between the Human Development Index (HDI) and the acute lymphoblastic leukemia (ALL) incidence in children under the Popular Medical Insurance Care. We conducted an observational, descriptive, and population-based study covering 55% of the Mexican population (58 million). The most impoverished states were located in the south east region of Mexico, while the north was more homogeneous, with HDIs varying between 0.73 and 0.79. Our findings emphasize that the metropolitan area of Mexico City and the State of Nuevo Leon have the highest levels of HDI. Regions were graded from I to IV according to their HDIs in ascending order. The HDIs varied from 0.667 to 0.830/100,000 children/year, with a national average of 0.746. The leukemia incidence for regions I, II, III, and IV was 6.12, 6.53, 4.96, and 9.95. An analysis of ALL incidence in Mexico showed significant differences for region IV in comparison with the other regions based on the HDI values (p = 0.0001). Further in-depth studies, including the economic aspects of the different geographic regions and their ethnographic characteristics, would give a more comprehensive panorama.

Genetic ancestry and skeletal toxicities among childhood acute lymphoblastic leukemia patients in the DFCI 05-001 cohort

AbstractHispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) and inferior treatment outcomes relative to non-Hispanic White children. We previously reported that Hispanic children with ALL had lower risk of fracture and osteonecrosis. To unravel the genetic root of such ethnic differences, we genotyped 449 patients from the DFCI 05-001 cohort and analyzed their ancestry. Patients with discordant clinical and genetic ancestral groups were reclassified, and those with unknown ancestry were reassigned on the basis of genetic estimates. Both clinical and genetic ancestries were analyzed in relation to risk of bone toxicities and survival outcomes. Consistent with clinically reported race/ethnicity, genetically defined Hispanic and Black patients had significantly lower risk of fracture (Hispanic: subdistribution hazard ratio [SHR], 0.42; 95% confidence interval [CI], 0.22-0.81; P = .01; Black: SHR, 0.28; 95% CI, 0.10-0.75; P = .01), and osteonecrosis (Hispanic: SHR, 0.12; 95% CI, 0.02-0.93; P = .04; Black: SHR, 0.24; 95% CI, 0.08-0.78; P = .02). The lower risk was driven by African but not Native American or Asian ancestry. In addition, patients with a higher percentage of Native American ancestry had significantly poorer overall survival and event-free survival. Our study revealed that the lower risk of bone toxicities among Black and Hispanic children treated for ALL was attributed, in part, to the percentage of African ancestry in their genetic admixture. The findings provide suggestive evidence for the protective effects of genetic factors associated with African decent against bone damage caused by ALL treatment and clues for future studies to identify underlying biological mechanisms.

Ethnic and border differences on blood cancer presentation and outcomes: A Texas population-based study.

The Texas/Chihuahua (US/Mexico) border is a medically underserved region with many reported barriers for health care access. Although Hispanic ethnicity is associated with health disparities for many different diseases, the population-based estimates of incidence and survival for patients with blood cancer along the border are unknown. The authors hypothesized that Hispanic ethnicity and border proximity is associated with poor blood cancer outcomes. Data from the Texas Cancer Registry (1995-2016) were used to investigate the primary exposures of patient ethnicity (Hispanic vs non-Hispanic) and geographic location (border vs non-border). Other confounders and covariates included sex, age, year of diagnosis, rurality, insurance status, poverty indicators, and comorbidities. The Mantel-Haenszel method and Cox regression analyses were used to determine adjusted effects of ethnicity and border proximity on the relative risk (RR) and survival of patients with different blood cancer types. Hispanic patients were diagnosed at a younger age than non-Hispanic patients and presented with increased comorbidities. Whereas non-Hispanics had a higher incidence of developing blood cancer compared with Hispanics overall, Hispanics demonstrated a higher incidence of acute lymphoblastic leukemia (RR, 1.92; 95% CI, 1.79-2.08; P < .001) with worse outcomes. Hispanics from the Texas/Chihuahua border demonstrated a higher incidence of chronic myeloid leukemia (RR, 1.28; 95% CI, 1.07-1.51; P = .02) and acute myeloid leukemia (RR, 1.17; 95% CI, 1.04-1.33; P = .0009) compared with Hispanics living elsewhere in Texas. Hispanic ethnicity and border proximity were associated with a poor presentation and an adverse prognosis despite the younger age of diagnosis. Future studies should explore differences in disease biology and treatment strategies that could drive these regional disparities.