Diagnosed Acute Lymphoblastic Leukemia Patients Research Articles

Patterns and prognostic impact of CNS infiltration in adults with newly diagnosed acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is highly associated with central nervous system (CNS) infiltration and can be associated with higher risk of relapse. Conventional cytology (CC) is the traditional method for diagnosing CNS infiltration, although the use of immunophenotyping by flow cytometry (FC) has gained prominence in recent years due to its higher sensitivity. Also, some authors have proposed that CSF contamination by a traumatic lumbar puncture (TLP) could have a clinical impact. This retrospective study accessed the impact of CNS infiltration by CC or FC on overall survival, event-free survival, and relapse rate. In a cohort of 105 newly diagnosed ALL patients, CNS1, CNS2, and CNS3 status were found in 84%, 14%, and 2%, respectively. We found that extramedullary disease at the diagnosis, higher leukocyte counts, and higher blast percentage were associated with a positive CC. Sensitivity and specificity of CC were 53% and 98%, respectively. Three-year overall survival was 42.5%. Conversely, TLP was not associated with a positive CC nor had an impact on relapse rates. In multivariate analysis, a positive CC was associated with an increased relapse rate (HR 2.074, p = 0.037), while its detection by FC did not associate with this endpoint. Survival rates seem to be increasing over the last years by the adoption of a stratified CNS prophylaxis risk strategy. CSF contamination does not represent a major concern according to our report, as it did not increase CNS involvement or relapse rates.

Phase Angle and Body Composition As a Prognostic Factor in Acute Lymphoblastic Leukemia

Acute lymphoblastic leukaemia (ALL) is a malignant proliferation of lymphoid cells blocked at an early stage of differentiation that can invade bone marrow, blood, and extramedullary sites. Age specific incidence is highest in children aged 1-4 years, then drops sharply through childhood (5-14 years), adolescence and young adulthood (AYA) (15-39 years), reaching the lowest point between 25 years and 45 years. Bioelectrical impedance analysis (BIA) is a method used to estimate body composition and cell membrane integrity. BIA is a useful tool as it is non-invasive, relatively inexpensive, can be performed on nearly any patient, does not expose the patient to ionizing radiation, is painless, and has both high intra and inter observer precision (coefficient of variation = 2.7%-4.0%). Phase angle (PhA) is obtained by BIA and is associated with cellular function. It is considered a reliable marker of malnutrition. PhA has been shown to predict survival in solid malignancies and hematopoietic stem cell transplant patients. To date, no studies have evaluated the usage of PhA in ALL patients. Therefore, this retrospective study sought to establish the prognostic significance of baseline PhA and lean mass index on OS and LFS in newly diagnosed ALL patients receiving intensive chemotherapy. Retrospective, cross-section, observational and descriptive study. The records of patients who received intensive chemotherapy from January 2019 to January 2023 were reviewed. Statistical analysis The qualitative variables were studied in frequencies and proportions, the quantitative variables were grouped into medians and ranges. OS and LFS were determined using Kaplan-Meier survival curves with log-Rank with a significant p <0.05 value. Statistical analysis was performed with SPSS version 25 and GraphPad Prism version 9.5.0. Results 85 patients were included, 56.7% (48) men and 43.5% (37) women. 79 patients with ALL-B and 6 patients ALL-T. The mean age was 25 years. 68 were AYA population and 17 not-AYA. The CR was 89%, ND MRD was 57%. The chemotherapy for AYA was CALGB 10403, and not AYA was Hyper-CVAD. Relapse was documented in 38%. The mean body mass index was 26.98±5.27 kg/m 2. The mean PhA was 4.547±0.9983°. The mean lean mass index was 17.8 (12.9-35.5) kg/m 2. The mean fat mass index was 9.195±4.425 kg/m 2. The mean OS was 86% at 1 year and OS at 3 years was 64.5%. The results that were statistically significant in LFS compared by Kaplan Meier curves were: male vs female p=0.0344, PhA >4, p=0.0235, lean mass index ≥16, p=0.0111. Conclusions In conclusion, our findings suggest that in newly diagnosed ALL patients undergoing intensive induction chemotherapy, PhA may provide important prognostic information for LFS and OS. PhA is an objective, repeatable, high-precision measure in ALL patients and, unlike other prognostic factors in this population, is potentially subject to intervention. Future studies of PhA in ALL patients should address the content validity of phase angle while further exploring the promising findings of the effect of strength training and nutritional supplementation on PhA and patient outcomes.

Evaluation of the Effectiveness of Antifungal Prophylaxis in Adult Acute Lymphoblastic Leukemia during Induction Chemotherapy

Background and Objectives: Due to immune suppression, patients with hematological malignancies are at a high risk of invasive fungal disease (IFD) during chemotherapy. For patients with myeloid tumors, antifungal prophylaxis is generally recognized. However, there are evident interactions between agents used in acute lymphoblastic leukemia (ALL) remission-induction and antifungal agents, resulting in most clinical trials excluding ALL patients. The need for primary antifungal prophylaxis in ALL patients during chemotherapy is still under debate. This study analyzed the efficacy of primary antifungal prophylaxis (PAP) and the incidence of IFD during the first remission induction in the PDT-ALL-2016 cohort, as well as evaluated the impact of PAP on the outcomes of ALL patients. Methods: The PDT-ALL-2016 cohort consists of 408 newly diagnosed ALL patients aged ≥ 14 years, treated between January 2016 and December 2021. All patients were treated using the GRAALL-2003 backbone, a pediatric-like regimen. This study included 280 patients, with a total of 128 exclusions. Excluded patients consisted of 103 individuals who received initial induction treatment in other hospitals, 12 individuals who died without IFD during the induction period, 9 individuals who experienced fungal infection before induction treatment, 2 individuals who did not complete induction remission treatment and were discharged, and 2 individuals who had lost their cases. PAP was defined as the administration of any systemic antifungal agent for two or more consecutive days to a patient without any evidence or history of IFD during the neutropenic period. The diagnosis of IFD was based on the European Organization for Research and Treatment of Cancer/Mycosis Study Group criteria. Results: Among the 280 patients, 232 received PAP, with caspofungin (n=104), voriconazole (n=59), micafungin (n=44), and others being used as prophylaxis. The baseline characteristics of patients who did or did not receive PAP were similar, except for the age difference (prophylaxis group median age 28.7 versus without prophylaxis group 23.0, P<0.01). In the cohort, 11 proven/probable and 21 possible IFD cases were identified. The incidence of IFD in patients who did or did not receive PAP was 8.6% and 25.0%, respectively. The cumulative incidence of IFD was significantly lower in patients receiving PAP compared to those who did not (HR 0.3, 95% CI 0.1-0.6; P=0.001). In the cohort, the infections of IFD negatively affected overall survival (HR 1.6, 95% CI 0.9-2.7, P=0.093). Conclusions: Our study demonstrates, in a real-life setting, that IFD is a poor prognostic factor for adult ALL and that PAP significantly reduces the incidence of IFD during induction chemotherapy, thereby improving patient survival. Furthermore, compared to published studies (4.3%-18.3%), the incidence of IFD in the prophylaxis group within our cohort is relatively lower. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

Correlation Analysis between Cerebrospinal Fluid Status and Prognosis in Childhood with Acute Lymphoblastic Leukemia by Flow Cytometry

To study the cerebrospinal fluid (CSF) status and prognosis value in patients with newly diagnosed acute lymphoblastic leukemia (ALL) by flow cytometry (FCM). The clinical features of the 75 newly diagnosed ALL patients from September 2020 to December 2021 in our centre were retrospective analyzed, as well as the bone marrow (BM) and CSF minimal residual disease (MRD) data, and the CSF conventional cytology data. Central nervous system infiltration(CNSI) positive was as CSF MRD positive by FCM or leukemia cells detected by conventional cytology. The status of CSF were compared and analyzed by FCM and conventional cytology, the clinical features and the prognosis value of different CNSI status in these patients were analyzed. Among 75 newly diagnosed ALL, 16 cases (21%) with CNSI positive (CNSI+) were detected by FCM, while only 2 positive cases (3%) were detected by conventional cytology. The CNSI+ rate detected by FCM was significantly higher than conventional cytology(P<0.05). Compared with CNSI- ALL patients, the median age of CNSI+ ALL patients was significantly younger, and the median platelet count was significantly lower, the difference was statistically significant (P<0.05). Up to follow-up time (August 31, 2022), four ALL patients were died, including 3 patients were CNSI- and 1 patient was CNSI+. Furthermore, three cases were primary disease relapse, including 1 case was CNSI+. There was no significant difference in overall survival (OS) rate and relapse-free survival (RFS) rate of the patients with different CNSI status. Compared with conventional cytology, FCM is a more sensitive assay to evaluate the central nervous system status in ALL patients. After active treatment, there was no significant difference in OS and RFS between patients with different CNSI status at diagnosis.

Practice of L-Asparaginase Usage: A Survey among Healthcare Providers Treating Children with Cancer in India

Introduction L-asparaginase is an essential chemotherapeutic agent in the therapy of acute lymphoblastic leukemia (ALL), which has led to improvement in survival. In low- and middle-income countries like India, the outcomes in ALL are inferior compared with the published literature, one of the causes of which is believed to be due to the inferior quality of bioequivalent asparaginase. Objective The following survey attempts to understand the practice of using this agent among oncologists treating children with cancer in our country. Methods The researchers designed a structured online questionnaire comprising 25 aspects of L-asparaginase usage in the study. The questionnaire was directed to the healthcare providers involved in treating children with cancer in India. Results Of the total 80 responses recorded, 51 (64%) respondents had more than 5 years of experience in pediatric oncology and were treating at least 5 to 10 newly diagnosed ALL patients per month. Forty-one (51%) respondents utilized native asparaginase, and 21 (26.3%) oncologists used PEGylated-asparaginase exclusively. The most common route of administration was the intramuscular route (66.3%). Seventy percent of respondents utilized native form at a dose of 10,000 IU/m2 and 20% at 6,000 IU/m2. The amounts used for PEGylated L-asparaginase were 1,000,IU/m2, 2,500,IU/m2, and variable doses in 48, 40, and 10% of responses, respectively. Though serum asparaginase assay (SAA) was not measured routinely in most of the centers, 39 (48.8%) healthcare providers perceived performing SAA helps to make the clinical decision. Conclusion This survey shows a wide variation in L-asparaginase usage among healthcare providers caring for children with cancer in our country. As L-asparaginase is the pivotal component of ALL therapy, uniformity in its usage and dosing with the possibility of monitoring SAA due to the quality of bioequivalent may be one of the critical steps toward improving outcomes in ALL in our country.

A comparison of hypersensitivity reactions between intravenous and intramuscular applications of native E. coli asparaginase in children with acute lymphoblastic leukemia.

Asparaginase is an indispensable drug in treating childhood acute lymphoblastic leukemia (ALL). Hypersensitivity reactions (HSR) are the most common side effects and interfere with the antineoplastic activity of the drug. This study aims to compare the intramuscular (IM) and intravenous (IV) administration routes of Native Escherichia coli Lasparaginase (L-ASNase) in terms of hypersensitive reactions. L-ASNase was randomly administered IV or IM to newly diagnosed ALL patients and HSR was monitored in all patients for 1 h following the end of the IV infusion and for 2 h following the end of the IM administration of L-ASNase. Based on a retrospective review of clinical charts, reactions were identified. In order to determine the severity of each allergic reaction, we used the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 for allergic reactions. A total of 1032 doses of L-ASNase were administered to 85 patients (42 males and 43 females) during the study period. Among 85 patients, 30 reactions were recorded, which means that 35% of the patients reacted. According to the CTCAE, twenty-nine out of 30 reactions (97%) were grade 2, while one (3%) was grade 4. In terms of individual doses, there was a non-significant trend toward increased incidence of reactions with IV administration (3.8% versus 0.9%, p = 0.064). The rate of reactions was higher in patients who received all IV doses (n: 60) as compared to those who received all IM doses (n: 25) (31.7% vs. 3.5%; chi-square= 8.415, p value=0.04). Based on the risk groups and HSR incidence, it was found that high risk group (HRG) patients were significantly more likely to develop HSR compared to the standart risk group (SRG) and intermediate risk group (MRG) patients (chi-square p = 0.003, CI: 95%; odds ratio: 3.12 and 5.91, respectively). In conclusion, IM administration of L-ASNase causes significantly less HSR to L-ASNase than the IV route. Patients with HRGALL have a higher risk of HSR. Since L-ASNase is still used in many developing countries and there are problems in the supply of Erwinia chrysanthemi ASNase (Erwinia), LASNase can be administered IM to reduce the frequency of HSR.

Global DNA Methylation Levels in Epstein-Barr-Virus-Positive Iraqi Patients with Acute Lymphoblastic Leukaemia

Acute lymphoblastic leukemia (ALL) is one of the commonest hematological malignancies affecting children and adults. Recent evidence suggests an involvement of Epstein-Barr virus (EBV) in ALL pathogenicity. Epigenetic aberration, especially altered DNA methylation marks, is a key event of cancer development. The present study aims to investigate how the ALL epimethylome reacts to viral infection through the assessment of the total 5-methylcytosine (5mC) levels in ALL patients, according to EBV infection. The 5mC global DNA methylation levels in 50 diagnosed ALL patients (age mean 26.23 yrs; age range 10-60 yrs) and 25 age-matched healthy controls were assessed using MethylFlash™ Methylated DNA Quantification Kit. Acute primary EBV infection in the studied subjects was detected by measuring Epstein-Barr Virus (EBNA-1) IgG levels using ELISA. The results showed a significant (P˂0.001) decrease in 5mC levels in ALL-EBV positive cases as compared to those who were negative for EBV infection (0.234±0.117 vs. 0.441±0.153, respectively). The reduction in the average 5mC level seemed to be negatively correlated with EBV viral load (r = -0.599, p= 0.001). Additionally, 5mC levels were able to distinguish between ALL main subtypes (B-ALL and T-ALL; derived from B or T lymphocytes), where T-ALL cases showed significantly (P=0.005) higher 5mC levels than those of B-ALL cases (0.587±0.070 vs. 0.180±0.092, respectively). Also significantly (P=0.04) lower 5mC levels were detected in Philadelphia chromosome-positive (Ph+) ALL cases than in those who were negative to this genetic abnormality (Ph- -ALL) (0.13±0.021 vs. 0.179±0.093, respectively). Overall, the findings of the present study suggest an involvement of EBV infection in ALL pathogenicity, with the potential of utilizing the differences in global DNA methylation levels in ALL patients' risk stratification.

Measurement of CD166 in Egyptian adult patients with acute lymphoblastic leukemia and its relation to clinical outcome

Abstract Background ALCAM (CD166) is a transmembrane; it has a role in the adhesion and binding of hematopoietic cells. It increases in different solid malignancies and hematological malignancies as multiple myeloma and acute leukemia. CD166 is considered one of the cancer stem cell markers responsible for most cancer recurrences following chemotherapy. Aim The study aimed to assess the expression of CD166 level in adult Egyptian acute lymphoblastic leukemia (ALL) patients, its correlation with disease-free survival, overall survival and relapse rate, as well as correlation with disease prognosis and response to treatment. Patients and methods This was a prospective cohort study conducted on 40 newly diagnosed ALL patients who will be recruited from the Clinical Hematology Department at Ain Shams University Hospital before initiation of chemotherapy in comparison to 15 patients in the control group. Results In comparison between newly diagnosed ALL patient initiation of chemotherapy and control groups, CD166 is elevated in ALL and has high sensitivity and specificity as a diagnostic and prognostic marker for ALL (P=0.000) and ALL patients with a high CD166 score have a higher overall survival rate. Conclusion ALL patients with a high CD166 score have a higher overall.

Unexpectedly High Prevalence of iAMP21 in Children with Acute Lymphoblastic Leukemia in Mexico: A Report from the "Mexico in Alliance with St. Jude” (MAS) Collaborative Group

Keywords: acute lymphoblastic leukemia, intra-amplification of chromosome 21, genetic characterization. Mexico in Alliance with St. Jude (MAS) has carried out a multi-center collaboration for children with acute lymphoblastic leukemia (ALL) in Mexico since 2019. The "Bridge Project” has granted access to diagnostic tests that allow genetic characterization of children with ALL in participating centers. The Molecular Genetics Laboratory of Hospital Infantil Teleton de Oncologia (HITO) serves as the referral laboratory. 253 newly diagnosed ALL patients from 5 hospitals in Mexico have utilized a comprehensive diagnostic panel that includes cytogenetic and molecular tests to identify relevant abnormalities. iAMP21 is recognized by the 2017 World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues as a characteristic genetic alteration of B-lineage Leukemia/Lymphoma, with a reported incidence of up to 2-5%. It involves amplification of the RUNX1 gene and/or duplication of chromosome 21 dup(21q), and defines a relatively new cytogenetic subgroup in B-lineage ALL with poor prognosis, derived from the genetic instability of chromosome 21.The heterogeneity of iAMP21 contributes to the difficulty in its detection with the sole use of conventional cytogenetic techniques, rendering Fluorescent In Situ Hybridization (FISH) as a better strategy for the distinction between iAMP21 (amplification in tandem) and the sporadic gain of copies of the RUNX1 gene. METHODS: We performed a comprehensive diagnostic panel for 253 patients with ALL; the FISH B-cell lymphoid panel included (KMT2A, ETV6 (TEL)/RUNX1 (AML1), BCR/ ABL, E2A/(TCF3)/(PBX1) and the T-cell lymphoid panel included (MLL, BCR / ABL, E2A / (TCF3) / (PBX1), TLX1, TLX3, CDKN2A and TRA / D). Diagnosis of iAMP21 was made using the interphase FISH technique with the LSI ETV6/RUNX1 (Vysis®) double color double fusion probe (Abbott Molecular®, Ill), and Cytocell probe (OGT Company®, NY). A finding of ≥ 5 RUNX1 gene signals in interphase FISH and/or more than 3 signals within chromosome 21 was considered positive for the identification of iAMP21. Samples were processed according to the specifications to the AGT Cytogenetics Laboratory Manual. FISH analysis was performed by analyzing 200 interphase cells. When ETV6/ RUNX1 probes are used, samples of patients carrying iAMP21 usually show two normal copies of the ETV6 signal and multiple RUNX1 signals (three or more additional signals) and are negative for the ETV6-RUNX1 fusion gene. RESULTS: Among 253 patients with ALL, 233 cases were of lineage B (92%) and 20 (8%) were of lineage T. FISH was reported negative in 57 (23%) and positive in 185 (73%) cases, 11 results were not available (4.3%). We detected iAMP21 in 28 (11%); these cases were classified as high risk. We also report t(12;21) in 41 (16%), MLL gene disruption t(4;11) in 10 (4%), t(1;19) in 14 (6%), and t(9;22) in 7 (3%); 75 (30%) patients had nonspecific genetic gains. The T lineage showed CDKN2A del(9)(p21) in 6 (2.5%) and TRA/D(14)(q11.2) rearrangement in 4 (1.7%) cases. CONCLUSION: Our experience shows that FISH analysis with the ETV6/RUNX1 probe is useful for identifying iAMP21, a chromosomal abnormality with prognostic significance. Genetic risk factors in the Hispanic population that adversely impact survival in Latin America are not yet fully identified. The Molecular genetic analysis and the fluorescence in situ hybridization (FISH) technique are the basic methods used to detect the presence of the most common genetic abnormalities, the presence or absence of which has an impact on the patient's classification into the appropriate risk group. Our findings from this cohort point to an increased prevalence of iAMP21 in ALL patients in Mexico. We will soon incorporate gene sequencing to the diagnostic panel and improve the characterization of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The role of E3 ubiquitin ligase WWP2 and the regulation of PARP1 by ubiquitinated degradation in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) has been a huge threat for people's health and finding effective target therapy is urgent and important. WWP2, as one of E3 ubiquitin ligase, is involved in many biological processes by specifically binding to substrates. PARP1 plays a role in cell apoptosis and is considered as a therapeutic target of certain cancers. In this study, we firstly found that WWP2 expressed higher in newly diagnosed ALL patients comparing with complete remission (CR) ALL patients and normal control people, and WWP2 in relapse ALL patients expressed higher than normal control people. WWP2 expression was related with the FAB subtype of ALL and the proportion of blast cells in bone marrow blood tested by flow cytometry. We demonstrated knockout WWP2 inhibited the ALL growth and enhanced apoptosis induced by Dox in vitro and vivo for the first time. WWP2 negatively regulated and interacted with PARP1 and WWP2 mechanically degraded PARP1 through polyubiquitin-proteasome pathway in ALL. These findings suggested WWP2 played a role in ALL development as well as growth and apoptosis, and also displayed a regulatory pathway of PARP1, which provided a new potential therapeutic target for the treatment of ALL.

Report of Chinese Children's Cancer Group acute lymphoblastic leukemia 2015 multicenter study

Objective: To evaluate the outcomes and identify the prognostic factors of childhood acute lymphoblastic leukemia (ALL) treated with Chinese Children's Cancer Group study ALL-2015 (CCCG-ALL-2015) protocol. Methods: There were two randomization studies in CCCG-ALL-2015 study. A total of 7 640 newly diagnosed ALL patients in 20 hospitals of multi-institutional study group between January 2015 and December 2019 were treated with unified protocol. CCCG-ALL-2015 protocol featured risk-directed therapy based on morphology, immunophenotype, and genetic features, and adjusted according to minimal residual disease (MRD) assay on day 19 and day 46 of induction, which totally omitted prophylactic cranial irradiation. Two randomized controlled trails were designed. Children with Philadelphia chromosome-positive ALL (Ph+ALL) were randomly treated with dasatinib (Ph-D group) or imatinib (Ph-I group). During the latter half of continuation therapy, children were randomly treated with seven pulses of vincristine plus dexamethasone (group A) or not (group B). The survival rates of different groups were compared. Event-free survival (EFS) and overall survival (OS) curves were estimated according to the Kaplan-Meier method and compared by Log-rank test. Cox proportional hazards model was used for multivariate analysis. Results: Of the 7 640 enrolled patients, there were 4 521 males and 3 119 females, 7 508 (98.3%) entered complete remission. The 5-year EFS was 60.1% (95%CI 49.8%-72.5%) in the Ph-D group and 39.4% (95%CI 26.9%-57.7%) in the Ph-I group (χ2=5.00, P=0.020). Between patients with lower risk (LR) and intermediate and higher risk (I/HR) treated with (group A) or without (group B) additional pulse of vincristine plus dexamethasone, there were no difference in 5-year EFS and OS. The one-sided 95% upper confidence bound for the difference in 5-year EFS and OS were 0.02 and 0.01 for LR, 0.05 and 0.01 for I/HR, establishing non-inferiority, lower than 0.05. The follow-up time was 3.5 (2.4,4.8) years. The 5-year OS was 90.9% (95%CI 90.2%-91.7%), and EFS was 80.1% (95%CI 79.0%-81.2%). The 5-year cumulative risk of any relapse was 15.3% (95%CI 14.3%-16.3%).The cumulative risk of isolated central nervous system (CNS) relapse was 1.9% (95%CI 1.6%-2.2%), and any CNS relapse 2.7% (95%CI 2.3%-3.1%). The 5-year cumulative risk of death during remission was 1.3% (95%CI 1.0%-1.6%). In the multivariate analysis, the independent factors associated with inferior EFS of patients with B-ALL were age≥10 years, male sex, white blood cell count ≥50×109/L, CNS2 or CNS3 status, BCR-ABL fusion, KMT2A rearrangements, without ETV6-RUNX1 fusion and the presence of MRD>0.01% at day 19 or 46 (all P<0.05). Among patients with T-ALL, the significant predictors for lower EFS were the BCR-ABL1 fusion and MRD≥0.10% at day 46 (both P<0.05). Conclusions: Patients treated with CCCG-ALL-2015 protocol without the use of prophylactic cranial irradiation have favorable outcomes, and the cumulative risk of isolated CNS relapse and cumulative risk of death during remission are low. Intensive chemotherapy including dasatinib yield superior results compared to imatinib in the treatment of Ph+ALL. Vincristine plus dexamethasone pulses can be omitted for ALL children without decrease in treatment ontcome during the latter half of continuation therapy.

ALL-280 Our Experience Treating Childhood Acute Lymphoblastic Leukemia in Armenia

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer. The 5-year-survival rate for ALL in high-income countries is close to 85%. However, this rate is much lower in low- or middle-income countries. In Armenia, the 5-year survival rate for children with ALL has greatly increased over time, and it is estimated at about 75%. This study aims to evaluate the clinicopathological features and treatment outcomes for childhood ALL in the Pediatric Cancer and Blood Disorders Center of Armenia (PCBDCA) at the Hematology Center (HC) named after Prof. R. Yeolyan. A retrospective analysis of pediatric patients diagnosed with ALL at PCBDCA from 2010 to 2021 was performed. The total number of pediatric leukemia cases was 333. Among them, 13.5% (45) were acute myeloblastic leukemia (AML) and 86.5% (288) were ALL. Only 79.9% (230) of diagnosed ALL patients received treatment at HC; 1.3% (4) of patients refused treatment and 18.8% (54) received treatment abroad. From 2010 to 2018, the number of patients was 147; 48.6% (107) of them received standardized treatment according to the BFM-2000 intermediate-risk group protocol, and 18.3% (40) of patients were treated with the Moscow-Berlin (MB) protocol. From 2019 to 2021, 73 patients received treatment based on the ALLIC-BFM 2009 protocol in accordance with risk groups; 21.9% (16) of the patients were classified as a high-risk group and 78.1% (57) as an intermediate-risk group, and there were no patients treated as a standard-risk group. From 2010 to 2018, the relapse rate was 19.0% (28), 50% (14) of which were early relapses, and 5.4% (8) were refractory to treatment. The mortality rate was 26.5% (39). Treatment-related mortality (TRM) of all patients was 9.5% (14): 7.5% (3) of the MB protocol and 10.2% (11) of the BFM-2000 protocol. The mortality rate related to the ALLIC-BFM 2009 protocol was 6.8% (5). The relapse rate was 5.5% (4); all were early relapses, and 2.73% (2) were TRM. Armenia is a developing county, and over the decades, there have been treatment and survival overall improvements in children with ALL in Armenia. However, several diagnostic and therapeutic challenges remain to be addressed.

Efficacy and Safety of Levofloxacin Prophylaxis During Induction Therapy for Childhood Acute Lymphoblastic Leukemia

Background: Infection related complications represent an important cause of morbidity and mortality in pediatric cancer patients, especially in those receiving chemotherapy. Although antibiotic prophylaxis is used in adult leukemic patients, but it is less practiced in pediatric cancer patients. The aim of this study was to evaluate the efficacy and safety of Levofloxacin prophylaxis to reduce infection which occur during induction phase of chemotherapy among pediatric Acute Lymphoblastic Leukemia (ALL) patients.&#x0D; Materials and methods: This single centered, pilot study in RCT design was conducted in Pediatric HematoOncology Department of Chittagong Medical College Hospital (CMCH). Sixty newly diagnosed ALL patients admitted for chemotherapy were randomly allocated to two groups 30 in each: one group received Levofloxacin prophylaxis (Intervention group) and other group did not receive prophylaxis (Control group). During the whole period of induction, clinical and laboratory features of infection, fever and neutropenia were observed and adverse effects were noted in both groups.&#x0D; Results: In induction phase of chemotherapy of ALL, significantly lower proportion of patients developed fever in the intervention group than in the control group [(18/30, 60.00%) versus (26/30, 86.67%)]. Incidence of infection was significantly less in intervention group compared to control group (60% versus 86.7%, p=0.039). Also, incidence of febrile neutropenia was significantly less in intervention group compared to control group (p=0.039). No major adverse effects were observed in any of the levofloxacin prophylaxis group except only two patients reported mild lower limb pain. &#x0D; Conclusion: It may be concluded from this pilot study that, Levofloxacin prophylaxis in children with ALL during the induction phase of chemotherapy is effective in reducing infection, febrile episodes and febrile neutropenia.&#x0D; JCMCTA 2022 ; 33 (1) : 34-39

Adult acute lymphoblastic leukemia in a resource-constrained setting: outcomes after expansion of genetic evaluation

ABSTRACT Acute lymphoblastic leukemia (ALL) is a challenging disease with a growing genetic landscape, even though there is substantial gap between developed and non-developed countries when it comes to availability of such new technologies. This manuscript reports a 5-year retrospective cohort of newly diagnosed ALL patients and their genetic findings and outcomes. An expanded genetic evaluation by using FISH and RT–PCR was implemented, aiming to identify Ph-like alterations. Patients were treated according to our local protocol, which allocated patients according to age and Philadelphia-chromosome status. A total of 104 patients was included, with median age of 37.5 years. Philadelphia chromosome was detected in 33 cases of B-lineage. Among 45 Ph-negative B-lineage, after excluding KMT2A or TCF3-PBX1 cases, we identified 9 cases with Ph-like fusion. Ph-positive and Ph-like patients had higher initial WBC (p = 0.06). Out of 104 cases, two cases did not start chemotherapy and an early death rate of 10.8% was found. Allogeneic transplantation was performed in 18 cases, being ten performed in first CR. Three-year overall survival (OS) and 3-year event-free survival were 42.8% and 30.8%, respectively. For patients treated with a pediatric regimen, 3-year OS was 52.5%. Extramedullary disease (HR 0.42) and platelet counts (HR 0.9) were independently associated with OS. We still face excessive non-relapse mortality that compromises our results. Alternative strategies implementing FISH and RT–PCR are feasible and able to identify Ph-like fusions. Delays in allogeneic transplantation, as well as the unavailability of new agents, impact long-term survival. Measures to decrease early infection are desirable.

Resistance Mechanisms in Pediatric B-Cell Acute Lymphoblastic Leukemia.

Despite the rapid development of medicine, even nowadays, acute lymphoblastic leukemia (ALL) is still a problem for pediatric clinicians. Modern medicine has reached a limit of curability even though the recovery rate exceeds 90%. Relapse occurs in around 20% of treated patients and, regrettably, 10% of diagnosed ALL patients are still incurable. In this article, we would like to focus on the treatment resistance and disease relapse of patients with B-cell leukemia in the context of prognostic factors of ALL. We demonstrate the mechanisms of the resistance to steroid therapy and Tyrosine Kinase Inhibitors and assess the impact of genetic factors on the treatment resistance, especially TCF3::HLF translocation. We compare therapeutic protocols and decipher how cancer cells become resistant to innovative treatments—including CAR-T-cell therapies and monoclonal antibodies. The comparisons made in our article help to bring closer the main factors of resistance in hematologic malignancies in the context of ALL.

The Effect of Ursodeoxycholic acid and N-acetyl cysteine on Lymphoblast Viability

Aim: To investigate invitro ursodeoxycholic acid (UDCA) and N-acetyl cysteine (NAC) effect on blast cell viability in children newly diagnosed with acute lymphoblastic leukemia (ALL).&#x0D; Patients and Methods: Samples were obtained from 52 newly diagnosed ALL patients aged 1 to 17 years. UDCA and NAC were added at clinically relevant concentrations (0-300 micrograms) onto 5x10^5 cells treated at room temperature in a dark place. Untreated and treated cells were stained with 7-amino-actinomycin D (7AAD PE) and analyzed by flow cytometry&#x0D; Results: Median (interquartile range; IQR) blast percentage and incubation time were 90% (11) and 18 (1.5) hours, respectively. The dead/live blast cells ratio (7AAD+) was lower in lymphoblasts treated with all NAC concentrations than untreated controls (P &lt; 0.001). The use of NAC was noted to, regardless of concentration, contribute to lymphoblasts viability. On the contrary, the dead/live blast cells ratio in samples treated with UDCA at the abovementioned concentrations was relatively high, suggesting the protective role for both hepatotoxicities and against leukemia. However, the difference was not statistically significant (P &gt;0.05). There was also no correlation between different doses of UCDA and NAC regarding blast cell viability (P &gt; 0.232).&#x0D; Conclusion: The present study showed that in vitro NAC use had a protective effect on lymphoblast viability in newly diagnosed ALL patients before starting chemotherapy. Patient-derived ALL cells can be successfully analyzed ex vivo in a short and different period without loss of blasts.

Markers of hypercoagulability in children with newly diagnosed acute lymphoblastic leukemia.

Venous thromboembolism (VTE) is a known complication for children with acute lymphoblastic leukemia (ALL). The aim of this study was to identify laboratory biomarkers that predict which children with ALL are at risk for VTE during induction chemotherapy. Newly diagnosed ALL patients admitted to Children's Hospital Los Angeles with a central venous catheter (CVC) were eligible to participate. Participants' blood samples (complete blood count [CBC], quantitative D-dimer, prothrombin fragment 1.2 [PTF 1.2], and thrombin-antithrombin complexes [TAT]) were collected at day 0 (baseline/prior to induction), day 7 (±2days), day 14 (±2days), day 21 (±2days), and day 28 (±2days) of induction chemotherapy or until participants presented with a symptomatic VTE. Seventy-five participants aged 1-21years were enrolled and included in the final analysis. Twenty-six (35%) of the 75 participants were diagnosed with a CVC-associated VTE (22 asymptomatic and four symptomatic). There was a statistically significant difference between VTE and non-VTE participants for D-dimer (odds ratio [OR] 1.61, 95% confidence interval [CI]: 1.59-1.64), TAT (OR 1.34, 95% CI: 1.32-1.38), and PTF 1.2 (OR 1.31, 95% CI: 1.25-1.37) at all time points. Participants >10years had a significantly higher risk of developing a VTE compared to participants <4years (p=.007). Older children with ALL as well as those with an elevated TAT, PTF 1.2, or D-dimer showed an increased risk of VTE, which may hold potential for predicting VTE in future studies.

Survival benefit of pediatric-based regimen for adults with acute lymphoblastic leukemia: A single-center retrospective cohort

Improving survival of Acute Lymphoblastic Leukemia (ALL) in adult patients has been a challenge. Despite intensive chemotherapy treatment, overall survival is poor. However, several studies demonstrate that young adult patients have better survival when treated with pediatric-based intensive regimens. Considering these results, We decided to treat newly diagnosed ALL patients according to age and risk factors. The goal of this study was to describe the results of this intensive chemotherapy treatment approach for ALL adult patients diagnosed at our institution. Fifty-eight ALL patients, diagnosed from 2004 to 2013, were included in the analysis. Patients were assigned to either the St. Jude Total Therapy XIIIB high-risk arm (St Jude) or the CALGB 8811 (CALGB). The Kaplan-Meier survival curve was used for the survival analyses and the Cox proportional hazard regression, for multivariable analysis. The overall survival was 22.9% at 10 years. The St. Jude improved survival, compared to the CALGB (p=0.007), with 32.6% vs. 7.4% survival rate at 10 years. However, no survival benefit was found for patients younger than 20 years old (p=0.32). The multivariable analysis demonstrated that undetectable minimal residual disease (MRD) and hematopoietic stem cell transplantation (HSCT) had beneficial impact on survival (p=0.0007 and p=0.004, respectively). ALL is a disease of poor prognosis for adults. The joint effort to standardize treatment and seek solutions is the way to start improving this scenario.

Superior Outcomes in Hispanic Patients Compared to Non-Hispanic Patients with Ph-Negative Acute Lymphoblastic Leukemia Using the Modified Pediatric-Based University of Southern California Acute Lymphoblastic Leukemia (USC ALL) Regimen for Newly Diagnosed ALL Patients in the Era of Novel Agents; A Retrospective Study

INTRODUCTIONHispanic patients with acute lymphoblastic leukemia (ALL) are historically known to have poor outcomes compared to non-Hispanic patients. Our institution, LAC-USC (LA County Hospital/University of Southern California) has shown a complete remission rate of 96% with use of pegasparagase at 2000 IU/m2 using the USC ALL regimen (based on CCG-1882) for patients aged 17-55 years with a 7-year OS of 51% reported in 2014. The modified USC ALL regimen now uses a single dose of cytarabine rather than fractionated doses and uses a single dose 3g/m 2 methotrexate compared to 1g/m 2 (2.5g/m 2 if T-cell) D1, 15 in original USC ALL regimen to improve compliance, while consolidation was increased to six cycles allowing for PEG holidays to improve toxicity (Table 1). Since our institution takes care of a large population of Hispanic patients with ALL, we now report outcomes in Hispanic and Non-Hispanic patients using the modified USC ALL regimen in the era of novel agents like blinatumomab and inotuzumab.METHODS:This retrospective, single institution chart review included adults >18 years old with newly diagnosed Ph-negative ALL (2016-2020). Primary objectives were 3-year over-all survival (OS), event-free survival (EFS), disease-free survival (DFS). Secondary objectives were complete remission/complete remission with incomplete recovery (CR/CRi), minimal residual disease (MRD) by flow cytometry, descriptive statistics of patients who were stratified into Hispanic and non-Hispanic cohorts and evaluated using Fisher's exact test. OS, DFS, EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p-value ≤0.05 was significant.RESULTS: 121 Ph-negative patients were reviewed. 87 were Hispanic patients (HP) and 34 non Hispanic patients (NHP). Median ages were 39 and 35 years (p=0.51) and median BMI were 29 and 26.9 kg/m 2 (p=0.42), respectively. There were about equal males and females in HP while NHP had 70.6% males compared to 29.4% females (p=0.076). Both HP and NHP were mainly of the Ph-negative ALL subtype, 50.6% vs 47.1%, followed by Ph-like, 25.4% vs 20.6%, respectively (p=0.884).Majority of the population were unfavorable risk by NCCN karyotypic risk stratification, 55.9% in HP compared to 56.0% in NHP (p=0.99). Over-all, no significant difference between baseline characteristics in both cohorts.After induction 1: CR/CRi was 85.9% in HP and 73.4% in NHP (p=0.09). MRD negativity by flow cytometry in HP was 41.4% compared to 26.4% in NHP (p=0.13).After induction 2: 83% of HP were in CR/CRi compared to 80% in NHP (p=0.99) and MRD negativity by flow was 35.6% in HP compared to 32.4% in NHP (p=0.73).Blinatumomab was given in 33.3% of HP and 32.3% of NHP (p=0.92) while only 5.7% of HP and 2.9% of NHP received inotuzumab (p=0.99). 34.5% of HP underwent allogenic hematopoietic stem cell transplant (allo-HSCT) versus 26.5% in NHP (p=0.40).3-year OS was 92.2% in HP versus 67.4% in NHP (p=0.004). 3-year DFS was 92.8% in HP versus 60.7% in NHP (p=0.003). 3-year EFS was 54.1% in HP versus 32.3% in NHP (p=0.02) (Table 2).Rate of relapse for HP and NHP were 23.4% vs 29.4% (p=0.74) while rate of mortality for HP and NHP were 7.5% vs 28% (p=0.015), respectively.No clear difference in grade 3/4 PEG toxicities were found in HP and NHP except more hypertriglyceridemia in HP (p=0.019). CONCLUSIONSWe present comparison of outcomes in Hispanic and non-Hispanic patients using our modified USC ALL pediatric-based regimen in an era of novel agents. Our data shows significantly better outcomes in Hispanic patients compared to non-Hispanic patients [OS (92.2% vs 67.4%, p=0.004), DFS (92.8% vs 60.7%, p=0.003) and EFS (54.1% vs 32.3%, p=0.02)].This study demonstrates that given equal access to care (eg. receiving blinatumomab, allo-HSCT), outcomes in HP with Ph-negative ALL are not worse, but rather superior to those in NHP. Utilization of novel immunotherapy like blinatumomab in the salvage setting to achieve deeper molecular response and increased utilization of haploidentical allo-HSCT have likely contributed to reducing ethnic disparities in Hispanic ALL patients. Future studies are needed to validate these findings with larger patient populations. [Display omitted] DisclosuresChaudhary: Oncotartis: Consultancy; Pancella: Consultancy; Moderna: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; TCR2: Current equity holder in publicly-traded company; Allogene: Current equity holder in publicly-traded company; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy . Douer: Jazz: Consultancy; Amgen: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Servier: Consultancy, Speakers Bureau. Yaghmour: Takeda: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Jazz: Speakers Bureau.

Study of Expression of Autophagy Related Gene 5 (ATG5) in Egyptian Patients Newly Diagnosed with Acute Lymphoblastic Leukemia (ALL)

Abstract: BACKGROUND Autophagy is the cellular mechanism for homeostasis maintenance and survival under stressful conditions like hypoxia and nutrient deprivation. It has been extensively studied in various types of malignancies. However, the relationship between cancer and autophagy is still controversial. Researchers have been focusing on the exploitation of autophagy in the invention of new cancer therapeutics. Acute lymphoblastic leukemia is one type of malignancies with the highest resistant rates and worst prognosis. Knowing whether autophagy has a role in its initiation or progression would be of a great benefit. It would open the door to adding autophagy modulator drugs to conventional treatments in clinical trials to improve disease outcome. AIM To assess the basal level of autophagy in newly diagnosed ALL cases using ATG5 expression level, a key autophagy gene, and detect the relationship between the level of autophagy and prognosis. PATIENTS AND METHODS 35 newly diagnosed ALL patients and 15 healthy controls were included in the study. ATG5 RNA transcript level was measured by real time RT-PCR in all subjects using peripheral blood samples. Patients were followed up monthly for a year by Bone marrow aspiration and minimal residual disease using multiparameter color flowcytometry to detect resistance and early relapse. RESULTS ATG5 expression level was significantly higher in the ALL patients compared to the control group. Cases had approximately twice the mean expression value of the control (2.15±2.2 vs 1.09 ± 0.47). (P value = 0.01). The median value of the ATG 5 expression of the cases was used as a cut point to divide them into two groups of low and high expression. More B-ALL patients were in the high ATG5 group (83% vs 53%, P value=0.05). In addition, the high ATG5 group displayed a significantly lower haemoglobin level, platelet count, LDH level and CD 8 expression than the low ATG5 group (Mean Hb level of 7.7 g/dl vs 9.6 g/dl respectively, P value=0.04, Mean Platelet count of almost 55 x 109/L vs 105 x 109/L respectively, P value = 0.01, Mean LDH level of 455 vs 1260 U/L respectively, P value=0.02, CD8 + patients 0% vs 23% respectively, P value=0.05). Although ATG5 level was also more associated with a higher white blood cell count, the presence of extramedullary disease, a positive Philadelphia chromosome and post induction refractoriness, no statistical significance was found. ATG5 expression neither showed a significant relation with patients overall survival nor their disease free survival. CONCLUSION Basal autophagy level is high in ALL disease and associated with more aggressive disease characteristics. More researches are needed to detect its clear relationship with disease prognosis.