Time Of Acute Lymphoblastic Leukemia Diagnosis Research Articles

Development and validation of a predictive model for tumor lysis syndrome in childhood acute lymphoblastic leukemia

BackgroundTumor lysis syndrome (TLS) frequently manifests shortly after induction chemotherapy for acute lymphoblastic leukemia (ALL), with the potential for swift progression. This study endeavored to develop a nomogram to predict the risk of TLS, utilizing clinical indicators present at the time of ALL diagnosis. MethodsWe retrospectively gathered data from 2243 patients with ALL, spanning December 2008 to December 2021, utilizing the clinical research big data platform of the National Center for Clinical Research on Children's Health and Diseases. The Least Absolute Shrinkage and Selection Operator (LASSO) method was employed to filter variables and identify predictors, followed by the application of multivariate logistic regression to construct the nomogram. ResultsThe LASSO regression identified six critical variables among ALL patients, upon which a nomogram was subsequently constructed. Multifactorial logistic regression revealed that an elevated white blood cell count (WBC), serum phosphorus <2.1 mmol/L, potassium <3.5 mmol/L, aspartate transaminase (AST) ≥50 U/L, uric acid (UA) ≥476μmol/L, and the presence of acute kidney injury (AKI) at the time of initial diagnosis were significant risk factors for the development of TLS in ALL patients (P<0.05). The predictive model achieved an area under the receiver operating characteristic curve (AUC) of 0.824 [95 % CI (0.783, 0.865)], with an internal validation AUC of 0.859 [95 % CI (0.806, 0.912)]. The Hosmer-Lemeshow goodness-of-fit test confirmed the model’s robustness (P=0.687 for the training cohort; P=0.888 for the validation cohort). Decision curve analysis (DCA) indicated that the predictive model provided substantial clinical benefit across threshold probabilities ranging from 10 % to 70 %. ConclusionsA nomogram incorporating six predictive variables holds significant potential for accurately forecasting TLS in pediatric patients with ALL.

Prediction of tumor lysis syndrome in childhood acute lymphoblastic leukemia based on machine learning models: a retrospective study.

Tumor lysis syndrome (TLS) often occurs early after induction chemotherapy for acute lymphoblastic leukemia (ALL) and can rapidly progress. This study aimed to construct a machine learning model to predict the risk of TLS using clinical indicators at the time of ALL diagnosis. This observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data were collected from pediatric ALL patients diagnosed between December 2008 and December 2021. Four machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. The study included 2,243 pediatric ALL patients, and the occurrence of TLS was 8.87%. A total of 33 indicators with missing values ≤30% were collected, and 12 risk factors were selected through LASSO regression analysis. The CatBoost model with the best performance after feature screening was selected to predict the TLS of ALL patients. The CatBoost model had an AUC of 0.832 and an accuracy of 0.758. The risk factors most associated with TLS were the absence of potassium, phosphorus, aspartate transaminase (AST), white blood cell count (WBC), and urea levels. We developed the first TLS prediction model for pediatric ALL to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200060616). https://www.chictr.org.cn/, identifier ChiCTR2200060616.

Trends of Obesity over Time and Its Prognostic Significance in Children and Adolescents with Newly-Diagnosed Acute Lymphoblastic Leukemia in Canada: A Population-Based Study

Introduction Childhood obesity can result in a variety of adverse health outcomes and it has been associated with inferior survival in children and adolescents with acute lymphoblastic leukemia (ALL). With the rising incidence of childhood obesity in Canada, we seek to assess the prevalence of obesity and its prognostic significance in children and adolescents with newly-diagnosed ALL in Canada. Methods We conducted a retrospective cohort study using the Cancer in Young People in Canada (CYP-C) database, a national population-based pediatric surveillance program collecting in-depth clinical data from all cancer patients &amp;lt;15 years old before 2015 and &amp;lt;19 years old after 2015 in Canada. This study included patients aged 2 to 18 years old with newly-diagnosed ALL and treated at one of the 17 pediatric oncology centers across Canada from January 1, 2001 to December 31, 2020. Obese patients were defined as patients with a body mass index (BMI) at or greater than the 95 th age and sex-adjusted percentile as per the Centers for Disease Control &amp; Prevention (CDC). Patients &amp;lt;2 years old were excluded given no BMI data could be derived from CDC growth charts. The main outcomes were event-free survival (EFS) and overall survival (OS). EFS was defined as time from ALL diagnosis to first event (relapse or death). OS was defined as time from ALL diagnosis to death from any cause. Patients without an event were censored at date of last contact. Predictors of obesity were explored using logistic regression. Univariate and multivariable Cox proportional hazards models were used to compare EFS and OS between patients with and without obesity. Results A total of 3458 ALL patients were included. The median BMI was 16.4 kg/m 2 (interquartile range (IQR): 15.2-18.1 kg/m 2). Eleven percent of children were obese at the time of ALL diagnosis. The prevalence of obesity significantly increased over time compared to that at ALL diagnosis: 18.9% at 1 year (p&amp;lt;0.0001), 25.8% at 2 years (p&amp;lt;0.0001), 23.3% at 3 years (p&amp;lt;0.0001), 21.8 % at 4 years (p&amp;lt;0.0001) and 20% at 5 years (p&amp;lt;0.0001). The prevalence of obesity did not vary according to age at diagnosis, gender, neighborhood income quintile (NIQ), ALL immunophenotype and treatment era ( Table 1). Non-Caucasian race (odds ratio (OR): 1.35 [95% confidence interval (CI) 1.09 -1.67]; p=0.005), presenting white blood cell (WBC) ≥ 50 x 10 9/L (OR: 1.38 [1.07 - 1.77]; p=0.01) and central nervous disease (CNS) disease (OR: 1.44 [1.10 - 1.88]; p=0.009) were significantly associated with increased risk of obesity at diagnosis. The 5-year EFS of obese patients at ALL diagnosis were significantly inferior to those of non-obese patients (85.3% vs. 90.6%; p=0.0008) ( Figure 1). The 5-year OS was 90.4% for obese vs. 94.9% for non-obese patients at diagnosis (p=0.003). The causes of death in the entire cohort were 1) related to disease (73.5%); 2) related to treatment toxicities (15.6%); and 3) due to other causes (10.9%). In univariate analysis, obese patients at ALL diagnosis had a higher risk for worse EFS (Hazard Ratio (HR) 1.76, 95% CI 1.34 - 2.32, p&amp;lt;0.0001)and OS (HR 1.99, 95% CI 1.41- 2.81, p&amp;lt;0.0001) compared to non-obese patients. In addition, age ≥ 10 years old at diagnosis, CNS disease, presenting WBC count ≥ 50x10 9/L, non-favorable cytogenetics and treatment era before 2010 were also significantly associated with worse EFS and OS in univariate analyses. In multivariable models controlling for patients' age at diagnosis, gender, presenting WBC, CNS status, NIQ, ethnicity, treatment era and ALL immunophenotype, obesity at ALL diagnosis retained independent significance with a HR of 1.67, 95% CI 1.26-2.21, p=0.0004 for EFS and a HR of 1.83, 95% CI 1.29-2.61, p=0.0008 for OS. Conclusion In this population-based study of children and adolescents with ALL in Canada, obesity was found in 11% of patients at ALL diagnosis, peaked at 2 years and remained significantly increased at 5 years from initial diagnosis. Patients with higher risk features such as WBC ≥ 50 x 10 9/L and CNS disease were more likely to be obese at diagnosis. Nevertheless, obesity at ALL diagnosis remained independently associated with inferior EFS and OS even after adjustment for these high-risk features. More mechanistic studies are needed to better understand the relationship between obesity and outcome to inform future trial designs.

An Observational Study of Patients with Philadelphia Chromosome-Negative Relapsed or Refractory Acute Lymphoblastic Leukemia in the US

IntroductionTreatment options are limited for adults with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and commonly include multi-agent chemotherapy regimens. Following the approval of blinatumomab (BLINCYTO®) in the US in December 2014 for R/R Philadelphia chromosome-negative (Ph-) B-cell precursor ALL, this observational study was initiated to assess the use of blinatumomab and chemotherapy in a real-world setting with a focus on 1st salvage therapy.MethodsMedical records of patients initiating a treatment for R/R Ph- ALL between June 2014 and December 2016 were comprehensively reviewed to determine treatment patterns, drug and healthcare resource utilization, and clinical outcomes. Particularly, records were reviewed to assess efficacy and safety of salvage treatment. Data were collected from the time of ALL diagnosis through the first occurrence of withdrawal, loss to follow-up, enrollment in a clinical trial, death, or study conclusion. The primary analysis set included patients who received a 1st salvage treatment within the study period. Analyses were descriptive, with continuous variables summarized by medians and categorical variables summarized with proportions and corresponding 95% confidence intervals (CIs). Incidence of adverse events was also reported. Enrollment is ongoing with interim results presented here.ResultsAt the time of data cutoff for this interim analysis on May 5, 2017, 35 patients from 7 academic and community hospitals in the US were included in the primary analysis set. Of these patients, 14 received blinatumomab as 1st salvage treatment (B1ST) and 21 received chemotherapy (C1ST). Patients who received B1ST were older (median age 60.0 years vs 30.0 years for C1ST) and more likely to be male (78.6% vs 57.1%). Patients treated with B1ST also had higher rates of cytogenetic abnormalities than those treated with C1ST (78.6% vs 38.1%) but had comparable percentages of bone marrow blasts at time of salvage therapy (median 73.5% vs 63.1%). Based on this interim snapshot, community oncologists were more likely to administered B1ST than C1ST (n=7 vs n=3) whereas the reverse trend was seen for academic oncologists (n=7 vs n=18, respectively). Baseline demographics and disease characteristics are summarized in Table 1.Approximately 57% of the patients in the primary analysis set received subsequent lines of salvage therapy during the review period (Table 2). Overall, 21/35 (60%) of the patients in the primary analysis set received blinatumomab at some point during the review period (Table 2).Of the treatment-emergent adverse events of grade ≥3 observed in this small group of patients, the most commonly reported in those treated with B1ST were neutropenia/febrile neutropenia (64.3%), infections (42.9%), and elevated liver enzymes (28.6%) (Table 3). One grade 3 cytokine release syndrome and one grade 3 neurological event were reported. Four patients treated with B1ST were hospitalized as a result of adverse events (n=1 each for cholestasis, colitis, eye pain, and thrombocytopenia). Of these, cholestasis, eye pain, and thrombocytopenia were considered related to blinatumomab. One patient treated with C1ST was hospitalized due to a grade 3 serious adverse event of stomatitis. Twelve deaths occurred during the review period (B1ST, n=7; C1ST, n=5); 1 death attributed to infection occurred in the B1ST group.No emergency room visits were recorded for either group and 2 intensive care unit visits were recorded for patients in the C1ST group. All of the patients who received B1ST experienced at least 2 hospitalizations with a median length of stay of 11.3 days. Of the patients in the C1ST group, 13 were hospitalized at least once with a median length of stay of 14.0 days. The median total number of days was comparable between those hospitalized in the B1ST and C1ST groups (81.5 days and 70.0 days, respectively).ConclusionIn this interim analysis of a real-world population of patients with R/R ALL, study data collection is ongoing. The heterogeneous baseline characteristics of the two groups suggest that higher risk patients are receiving blinatumomab as 1st line salvage therapy in a real-world setting. No new safety signals were identified; analysis of effectiveness is ongoing.This study was funded by Amgen. [Display omitted] DisclosuresEmadi:Amgen Inc: Consultancy, Research Funding. Salhotra:Kadmon: Consultancy. Tuglus:Amgen: Employment, Equity Ownership. Chia:Amgen, Inc.: Employment, Equity Ownership. Romanov:Amgen, Inc.: Employment, Equity Ownership.

Age and ABO Blood Group Are Significant Predictors of Thrombosis in Children with Acute Lymphoblastic Leukemia (ALL): Results from Dana-Farber Cancer Institute (DFCI) ALL Consortium Trial 05-001

BackgroundThromboembolism (TE) is a serious complication in pediatric patients with ALL associated with significant morbidity, mortality and therapy alterations. Thromboprophylaxis, though effective in preventing TE in patients at high risk for TE, is associated with increased risk of bleeding. Hence it is important to identify the population at the highest risk for TE for whom preventive strategies may be warranted. However, predictors of TE in pediatric patients with ALL remain uncertain and the role of inherited thrombophilia is ill defined. Adult studies of non-cancer patients and our prior smaller pilot study of pediatric ALL patients showed higher rates of TE with non-O blood types.AimTo identify variables at the time of ALL diagnosis that are associated with increased risk of TE in children and adolescents treated on DFCI ALL 05-001 trial.Design/MethodsEligible and consenting patients (1 to ≤18 yrs. of age) with newly diagnosedALL were enrolled on the DFCI 05-001 trial between 2005-2011 at 11 participating institutions in the USA and Canada. Risk categorization and protocol therapy have previously been described (Lancet Oncol 2015;16:1677-90). Treatment included one dose of pegaspargase (2500 IU/m2) during remission induction and 30 consecutive weeks of L-asparaginase during post-induction therapy (either pegaspargase 2500 IU/m2 every 2-weeks or native E.coli L-asparaginase 25000 IU/m2 weekly). Baseline clinical and laboratory data as well as all TE events requiring intervention (Grade 2 or higher) were prospectively collected. Genomic DNA was isolated from peripheral blood or bone marrow obtained at the time of complete remission in participants who consented for the collection of research samples. Single nucleotide polymorphisms (SNP) were detected using PCR-based allelic discrimination assays for prothrombin (PT)gene G20210A (rs1799963) and Factor V G1691A (rs6025) (Factor V Leiden, FVL) (Applied Biosystems, Carlsbad CA). The cumulative incidence of TE was estimated with induction failure, relapse and death considered as competing events. Effect of clinical [age, gender, body mass index (BMI) ALL immunophenotype, risk-group] and laboratory variables [presenting leukocyte count, blood group, SNPs for PT and FVL] at ALL diagnosis on the cumulative incidence of TE was evaluated in univariate and multivariable competing risk regression models. The impact of TE on ALL outcome (event free and overall survival) was further explored using a time-varying covariate in Cox regression modelling.ResultsOf 794 enrolled patients [median age 4.97 (range 1.04 -17.96) yrs.; males 441], 100 developed TE; the 25-month cumulative incidence was 13.0% (95%CI 10.7,15.5). Twenty-one patients had 21 events during induction (3 with CNS TE) and 79 patients had 88 events post-induction (16 CNS TE). Table 1 provides the cumulative incidence of the time to first event of TE by patient characteristics and is compared using Gray test. Sex, BMI and thrombophilia SNPs had no detectable impact on the incidence of TE. There was no difference in incidence of TE by asparaginase type (data not shown). In the final competing risk multivariable regression model older age group and non-O blood group were each significantly associated with TE (Table 2). Figure 1 depicts the effect of blood group type on the incidence of TE within each age group; the cumulative incidence of TE was significantly higher for non-O blood group only for patients <5 years of age (p=0.01). There was no difference in the event free or overall survival between patients with or without TE.ConclusionOlder age and non-O blood group are significant predictors of TE during ALL therapy. The effect of non-O blood group is more pronounced in younger age patients. Polymorphisms of FVL and PT gene had no impact on the risk of TE. We recommend further evaluation of these risk factors and recommend thromboprophylaxis for pediatric patients with ALL over 10 years of age (and especially those 15 years or older) receiving asparaginase-intensive regimens, and consideration of thromboprophylaxis in younger patients with non-O blood group. [Display omitted] DisclosuresNeuberg:Synta Pharmaceuticals: Other: Stock shares.

A Retrospective Study on Inotuzumab Ozogamicin in Infants and Young Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

A Retrospective Study on Inotuzumab Ozogamicin in Infants and Young Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Acute lymphoblastic leukemia as a clonally unrelated second primary malignancy after multiple myeloma.

Multiple myeloma (MM) patients have an 11-fold increased risk of developing myeloid neoplasms compared to the general population; however, acute lymphoblastic leukemia (ALL) is rarely observed. Given that both MM and the majority of ALL are of B cell origin, this raises the question of whether ALL in patients with MM arises from the same clone. We report 13 cases of B-cell ALL following therapy for MM. The interval from MM diagnosis to ALL onset was 5.4 years (range 3.3-10). The median age at the time of ALL diagnosis was 60 years (range 43-67). MM therapy included immunomodulatory agents in all patients and autologous hematopoietic cell transplantation in 10 (77%) patients preceding ALL diagnosis. ALL genetics showed a normal karyotype, TP53 mutation/deletion, and monosomy 7 or 7q deletion in 5, 3, and 2 cases, respectively. Analysis of paired samples of MM and ALL using whole exome sequencing demonstrated that the malignancies arose from different clones. Thus, ALL as a second primary malignancy following MM is not clonally related but could potentially represent a therapy-related leukemia.

Changes in Oxidant Defense, Apoptosis, and Cognitive Abilities During Treatment for Childhood Leukemia.

Aggressive central nervous system (CNS)-directed treatment for acute lymphoblastic leukemia (ALL), the most prevalent cancer among children and adolescents, prevents metastasis of leukemia cells into the brain. Up to 60% of survivors experience cognitive problems, but knowledge about risk factors for and mechanisms of neurologic injury is lacking. Objectives of the present study were to (1) quantify changes in oxidant defense and apoptosis over the course of ALL therapy and (2) elucidate risk factors for long-term cognitive problems. The sample included 71 children with ALL. Cerebrospinal fluid (CSF) samples were collected at diagnosis and during intrathecal chemotherapy administration. Oxidant defense was measured by reduced glutathione (GSH), oxidized glutathione (GSSG), and the ratio of GSH:GSSG. Apoptosis was measured by activity of several cysteine-dependent aspartate-specific protease (abbreviated as caspase) enzymes that initiate (caspases 8 and 9) or execute (caspases 3/7) apoptosis. Cognitive abilities were assessed by standardized measures of short-term memory, visual-motor integration, and attention 3 years after ALL diagnosis. GSH and GSSG concentration increased significantly during ALL therapy, and a low GSH:GSSG ratio was indicative of an oxidized extracellular environment. Caspase enzyme activity increased significantly, and caspases 3/7 activity was significantly and negatively associated with performance on measures of cognitive abilities. Younger age at time of ALL diagnosis was associated with some measures of attention. Efflux of glutathione into CSF maintains oxidant defense by scavenging free radicals and other reactive oxygen species and is an early event in apoptosis. These mechanisms may be involved in neurologic injury associated with CNS-directed treatment and subsequent cognitive problems.

Fever at Diagnosis of Pediatric Acute Lymphoblastic Leukemia: Are Antibiotics Really Necessary?

With new multidrug-resistant microbes and the paucity of new antibacterial agents, we must identify opportunities to safely minimize antibiotics. Current guidelines encourage empiric antibiotics in febrile patients with chemotherapy-induced neutropenia to reduce infection-related mortalities. No guidelines exist for children with isolated fever at presentation/diagnosis of acute lymphoblastic leukemia (ALL) and before starting chemotherapy. This study evaluates the incidence of bacteremia in this subpopulation. We retrospectively analyzed medical records of 230 consecutive patients under 21 years of age diagnosed with ALL at Children's Hospital & Research Center Oakland (CHRCO) from January 2003 through October 2013. We focused on blood cultures obtained within 24 hours of presentation to CHRCO, which was before general anesthesia for a procedure or systemic chemotherapy. Among 221 patients who met the inclusion criteria, 126 (57%) were febrile and had blood cultures obtained. Two patients (1.6%) had positive blood cultures consistent with bacteremia; 1 had group A β-hemolytic streptococcus and the other had Escherichia coli. Given the rarity of bacteremia in this subpopulation at our institution, we recommend more judicious use of antibiotics in children with isolated fever at time of ALL diagnosis. We encourage other institutions to conduct similar investigations.

Abstract 1633: Calorie and fat restriction during chemotherapy improves survival in obese mice with syngeneic acute lymphoblastic leukemia

Abstract Obesity promotes the pathogenesis of many cancers, including acute lymphoblastic leukemia (ALL), the most common childhood malignancy. Clinical studies have shown that children who are obese at the time of ALL diagnosis have a greater risk of relapse than normal weight children; however, this risk may be attenuated if their weight normalizes over the majority of treatment. One possible explanation is that nutrient-deficiency may induce host, but not ALL, cell senescence, thereby augmenting chemotherapy specificity and efficacy. Here, we hypothesize that a calorie- and fat-restricted diet during chemotherapy differentially alters host and ALL cell metabolism, improving chemotherapy efficacy and overall survival of high-fat diet-induced obese mice with ALL. To test the effect of dietary restriction on survival, C57BL/6J mice were placed on a high-fat diet (60% calories from fat) upon weaning. At 20 weeks of age, obese and control mice were implanted with syngeneic BCR/ABL+ ALL cells. After a 7-day latency, half of the obese mice were switched onto a low-fat (10% calories from fat) diet. Concurrently, vincristine chemotherapy (0.5mg/kg/wk x 4wks) was initiated and mice were tracked for survival. Separate groups of implanted mice were sacrificed 1 day before, 1 day and 1 week after dietary restriction for bone marrow and spleen collection. BrdU incorporation and p-AKT(Ser 473), p-eIF2A(Ser51) and p-S6K(Thr412) levels in marrow and spleen ALL and host cells were analyzed via flow cytometry for changes in cell cycle and metabolism. Finally, we also evaluated the effect of dietary restriction on human ALL outcome, using an obese xenograft ALL model treated with vincristine, dexamethasone and L-asparaginase. Dieted obese C57BL/6J leukemic mice exhibited a greater percentage of weight loss over the first two weeks of chemotherapy compared to non-dieted obese mice (Dieted vs. non-dieted obese: -25.2±10.6% vs. -0.3±4.5%, p&amp;lt;0.001). Dieted obese leukemic mice had significantly higher survival than non-dieted obese and lean mice after 4 months (Dieted: 91.6%, Obese: 16.7%, Lean: 41.7%; n = 12/group; p&amp;lt;0.001). Flow cytometry of the murine bone marrow and spleen showed no diet-induced alterations in BrdU incorporation or AKT pathway activation in either host or ALL cells. Surprisingly, however, we did not observe a similar effect of dietary restriction on survival in the obese xenograft ALL model. Based on these findings, a calorie and fat restricted diet initiated at the onset chemotherapy improves overall survival in obese mice with syngeneic ALL, though this phenomenon was not observed in a human xenograft model. Further work is needed to explore the possibility of a dietary intervention as an effective potential adjuvant during chemotherapy in obese cancer patients. Citation Format: Jonathan Tucci, Waseem Alhushki, Xia Sheng, Steven D. Mittelman. Calorie and fat restriction during chemotherapy improves survival in obese mice with syngeneic acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1633. doi:10.1158/1538-7445.AM2015-1633

Increase in oxidative stress as measured by cerebrospinal fluid lipid peroxidation during treatment for childhood acute lymphoblastic leukemia.

Five-year survival from childhood acute lymphoblastic leukemia (ALL) approaches 90%, but 40% of survivors experience central nervous system (CNS) treatment-related cognitive problems. Despite considerable evidence for cognitive problems, less is known about mechanisms of neurological injury. Our purpose was to investigate oxidative stress, measured by lipid peroxidation, as a mechanism of CNS treatment-related neurological injury. The sample included 55 children (mean age at diagnosis=6.84 y, SD=3.40) who received intrathecal and intravenous chemotherapy for CNS-directed treatment according to Children's Oncology Group protocols. Glycerophospholipids were extracted from cerebrospinal fluid samples obtained at diagnosis and during intrathecal chemotherapy administration. Unoxidized and oxidized phosphatidylcholine (PC) and phosphatidylinositol (PI) were measured by normal phase high-performance liquid chromatography with diode array detection, and analyzed with a general linear model for repeated measures analysis of variance. Compared with the diagnostic cerebrospinal fluid sample, unoxidized and oxidized PC and PI increased significantly across treatment phases. Amount of intravenous methotrexate received was significantly correlated with oxidized PI, and age at time of ALL diagnosis was significantly associated with oxidized PC. These findings support our hypothesis that oxidative stress is a mechanism of neurological injury associated with CNS-directed treatment for ALL.

Cytokines, growth, and environment factors in bone marrow plasma of acute lymphoblastic leukemia pediatric patients.

Acute lymphoblastic leukemia (ALL) cells depend on the microenvironment of the host in vivo and do not survive in in vitro culture. Conversely, the suppression of non-malignant tissues is one of the leading characteristics of the course of ALL. Both the non-malignant suppression and malignant cell survival may be partly affected by soluble factors within the bone marrow (BM) environment. Here, we aimed to identify proteins in BM plasma of children with ALL that may contribute to ALL aggressiveness and/or the microenvironment-mediated survival of ALL cells. LBMp (leukemic bone marrow plasma) at the time of ALL diagnosis was compared to control plasma of bone marrow (CBMp) or peripheral blood (CPBp) using a cytokine antibody array. The cytokine antibody array enabled simultaneous detection of 79 proteins per sample. Candidate proteins exhibiting significantly different profiles were further analyzed and confirmed by ELISA. mRNA expression of one of the candidate proteins (TIMP1) was studied using quantitative reverse transcriptase polymerase chain reaction (qRTPCR). The cytokine antibody array experiments identified 23 proteins that differed significantly (p<0.05); of these, two proteins (TIMP1 and LIF) withstood the Bonferroni correction. In contrast, little difference was observed between CBMp and CPBp. At the diagnosis of ALL, changes in the soluble microenvironment are detectable in BM plasma. These changes probably participate in the pathogenesis and/or result from the changes in the cell composition.

Is the number of blood products transfused associated with lower survival in children with acute lymphoblastic leukemia?

Blood transfusion during acute lymphoblastic leukemia (ALL) of childhood is scarcely documented. Children with ALL are immunosuppressed by both the disease and its therapy. Transfusion may contribute to the course of ALL through its transfusion-related immunomodulation (TRIM) effect. Blood transfusion history and response to therapy for 108 children <16 years of age at the time of ALL diagnosis was documented. Clinical files, electronic records, and blood bank registries were scrutinized. Overall survival (OS) and event-free survival (EFS) in relation to blood product type and number of transfusions was determined. Hazard ratios (HR) for death and relapse were estimated through uni- and multivariate Cox regression analysis. One hundred eight ALL patients were included. Median age was 6 years (range: 0-15 years). Ninety-seven patients (89.8%) were transfused. Median number of transfused products was seven (range: 0-345). After multivariate analysis, transfusion of >5 packed red blood cells (PRBC) remained a significant predictor for death (P = 0.003) and relapse (P = 0.011). For platelets, maximal significance was observed when >30 platelet concentrates (PC) were transfused (P < 0.001). When both, PRBC and PC were considered, maximal significance for predicting death was observed with transfusion of >30 blood products (P < 0.001). The number of blood products transfused to children with ALL appears to be significantly associated with lower survival rates. This may reflect both the severity of the disease and the TRIM effect, which may decrease immune surveillance capacity and the probability of leukemic clone eradication.

Therapy‐related acute myelogenous leukemia and myelodysplastic syndrome in patients with acute lymphoblastic leukemia treated with the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimens

Secondary malignancies including myeloid neoplasms occur infrequently in acute lymphoblastic leukemia (ALL) and to the authors' knowledge have not been as well documented in adults as in children. A total of 641 patients with de novo ALL who were treated with the hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen or its variants were analyzed. Sixteen patients (2.49%) developed secondary acute myelogenous leukemia (AML) (6 patients) or myelodysplastic syndrome (MDS) (10 patients). At the time of ALL diagnosis, the median age was 53 years; cytogenetics were normal in 11 patients, pseudo-diploidy with del(2) in 1 patient, t(9;22) in 1 patient, and unavailable in 3 patients. Frontline therapy included hyper-CVAD in 7 patients, hyper-CVAD with rituximab in 8 patients, and hyper-CVAD with imatinib in 1 patient. Karyotype at time of AML/MDS diagnosis was -5, -7 in 9 patients, normal in 1 patient, complex in 1 patient, inv(11) in 1 patient, t(4;11) in 1 patient, del(20) in 1 patient, and unavailable in 2 patients. Secondary AML/MDS developed at a median of 32 months after ALL diagnosis. Cytarabine plus anthracycline-based treatment was given to 12 patients with AML and high-risk MDS. One patient with MDS received arsenic trioxide, 1 received clofarabine, and 2 received decitabine. Response to treatment was complete remission in 3 patients, partial remission in 6 patients, and no response in 6 patients; 1 patient was untreated. Eight patients (1 with AML and 7 with MDS) underwent allogeneic stem cell transplantation, and all but 2 died at a median of 3 months (range, 0.5-11 months) after transplantation. The median overall survival after a diagnosis of secondary AML and MDS was 9.25 months (range, 1+ to 26+ months). Secondary AML and MDS occur infrequently in adult patients with de novo ALL treated with the hyper-CVAD regimens, and response to therapy is poor.

Therapy Related Acute Myelogenous Leukemia and Myelodysplastic Syndrome in Patients with Acute Lymphoblastic Leukemia Treated with the Hyper-CVAD Regimen.

Secondary malignancies including myeloid neoplasms occur infrequently in patients with acute lymphoblastic leukemia (ALL). This has been well documented in the pediatric population but not for the adult patients. We have reviewed retrospectively 641 patients with de novo ALL, treated with the hyper-CVAD regimen or its variants, at M D Anderson Cancer Center from 1992 to 2007. Fourteen patients (2.18%, 7 female, 7 male) developed secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Six patients had AML and 8 MDS. Median age at the time of ALL diagnosis was 52 years (range, 23 – 66). Cytogenetics at ALL diagnosis was diploid in 10, pseudo-diploid with −2 in 1, t(9;22) in 1, and unavailable in 2 patients. Frontline therapy included hyper-CVAD in 7, hyper-CVAD with rituximab in 6, and hyper-CVAD with imatinib in 1 patient. Karyotype at the time of AML/MDS diagnosis was −5, −7 in 8 patients, diploid in 1, miscellaneous in 1, inv(11) in 1, t(4;11) in 1, and unavailable in 2. Secondary AML/MDS developed at a median of 31 months (range, 11 – 74) after the start of ALL therapy. Treatment for the secondary AML and MDS was varied and included cytarabine plus anthracycline based regimens for AML and high risk MDS. One patient with MDS received arsenic trioxide, 1 clofarabine, and 1 decitabine. The response rate to treatment for AML/MDS was complete remission (CR) in 2, partial remission in 6 and no response in 6 patients. Five patients (all MDS) underwent an allogeneic stem cell transplant and all but one died at a median of 3 months (range, 0.5 – 11) after the transplant. One patient is alive and in CR 14 months after a haplo-identical sibling transplant; 2 other patients are alive 3.5 and 4 months after the diagnosis of MDS. The median overall survival after the diagnosis of secondary AML and MDS is 8.3 months (range 3.5+ to 18.5+). We conclude that secondary AML and MDS occur infrequently (2.18%) in adult patients with de novo ALL treated with the hyper-CVAD regimens and response to their subsequent therapy is poor.

Obesity and hypertension among children after treatment for acute lymphoblastic leukemia

The purpose was to determine the prevalence and treatment-related risk factors for obesity and hypertension among childhood acute lymphoblastic leukemia (ALL) survivors treated with contemporary therapy. In a single-center longitudinal study, serial body mass indices (BMI) and blood pressure (BP) measurements of children ages 2-20 at time of ALL diagnosis and enrolled on pediatric cooperative group trials from 1993-2003 were abstracted from medical records and converted to population-referenced z-scores. Among 165 study participants, BMI z-scores increased significantly between diagnosis (median age 4.8 years) and therapy completion. At the end of therapy, 17.0% of survivors were overweight (BMI of 25-29, or 85-94% for age), 21.2% were obese (BMI >or=30, or >or=95% for age), and 15.3% had BP meeting stage 1+ hypertension thresholds (systolic or diastolic BP >or=140/90 mm Hg, or 95% for age and height plus 5 mm Hg). These proportions were found to be unchanged 2-3 years later. In multivariate analysis, the highest level of corticosteroid exposure was associated with both obesity (odds ratio [OR] 6.0; 95% confidence interval [95% CI], 1.2-28.5) as well as stage 1+ hypertension (OR 2.4; 95% CI, 1.2-5.1) compared with the lowest level. Females also were more likely to have increased BMI and elevated BP compared with males. Treatment intensity and cranial radiotherapy were not found to be associated with BMI or BP changes. Despite reductions in the use of cranial radiotherapy, contemporary childhood survivors of ALL remain at an increased risk of obesity and hypertension at least several years after the completion of treatment, with those exposed to higher doses of corticosteroids at greater risk.

Molecular emergence of acute myeloid leukemia during treatment for acute lymphoblastic leukemia

Therapy-related acute myeloid leukemias (t-AML) with translocations of the MLL gene are associated with the use of topoisomerase II inhibitors. We established the emergence of the malignant clone in a child who developed t-AML with a t(11;19) (q23;p13.3) during treatment for acute lymphoblastic leukemia (ALL). The MLL-ENL and the reciprocal ENL-MLL genomic fusions and their chimeric transcripts were characterized from samples collected at the time of t-AML diagnosis. We used PCR with patient-specific genomic primers to establish the emergence of the MLL-ENL fusion in serially obtained DNA samples. The MLL-ENL fusion was not detectable in bone marrow at the time of ALL diagnosis or after 2 months of chemotherapy (frequency <8.3 x 10(-7) cells(-1)). The genomic fusion was first detected in bone marrow after 6 months of treatment at a frequency of one in 4,000 mononuclear bone marrow cells; the frequency was one in 70 cells after 20 months of therapy. At the first detection of MLL-ENL, the only topoisomerase II inhibitors the patient had received were one dose of daunorubicin and two doses of etoposide. The MLL-ENL fusion was not detectable in blood at the time of ALL diagnosis or after 0.7, 2, 8, 10, and 12 months of therapy but was detectable in blood at 16 months (one in 2.3 x 10(4) cells). Recombinogenic Alu sequences bracketed the breakpoints in both fusions. These data indicate that the malignant clone was not present before therapy, arose early during chemotherapy, and was able to proliferate even during exposure to antileukemic therapy.