Outcome In Acute Leukemia Research Articles

IT-ENABLED WGCNA FOR CRITICAL GENE MODULE MAPPING AND THERAPY OPTIMIZATION: ADVANCING LEUKEMIA CARE

Acquiring a profound comprehension of the complex correlation between genes is essential for progressing treatment and diagnostics in acute leukemia research. This work utilizes WGCNA to analyze the gene expression data obtained from 72 patients diagnosed with acute leukemia. This approach has not been widely employed in this particular setting previously. Our first objective was to identify essential gene modules and core genes that could offer a novel insight into the fundamental causes of the disease. To ensure the precision of the gene expression data, a thorough pre-processing is carried out, which includes normalization and quality control techniques. The WGCNA technique produces a gene co-expression network that targets explicitly differentially expressed genes (DEGs). This network is designed primarily to exploit pairwise correlations, as the underlying data is meant to create such a network. The modules identified via hierarchical clustering are assigned distinct colors to aid in recognizing gene expression patterns and associations that may not be readily apparent when examining individual genes in isolation. An essential component of our research involved identifying pivotal genes inside these modules using several centrality metrics, including degree, closeness, and betweenness centralities. These genes are suspected to have a crucial role in starting and progressing acute leukemia. We must mention that genes such as M91438_at and S82362_s_at came out as significant, in line with their centrality in the network analysis. However, it is privileged that these results hold a promise for further validation. The study throws open trails for future research, especially in experimental validation of these genes. These findings indeed have the potential to contribute to the development of targeted therapies and improvement in diagnostic methods, resulting in better patient outcomes in acute leukemia. This study also highlights the applicability of WGCNA towards unraveling leukemia's genomics, underscoring the continued exploration in this critical area of medical research.

Impact of Natural Killer Cell-Associated Factors on Acute Leukemia Outcomes after Haploidentical Hematopoietic Stem Cell Transplantation with αβ T Cell Depletion in a Pediatric Cohort

The technique of αβ T cell depletion (αβTCD) is a well-established method of hematopoietic stem cell transplantation (HSCT) for children with acute leukemia owing to the low rates of graft-versus-host disease and nonrelapse mortality (NRM). The graft-versus-leukemia effect is generally ascribed to natural killer (NK) cells conserved within the graft. It is not known whether NK-related factors affect the outcome of αβTCD HSCT, however. The aim of this retrospective study was to explore the impact of NK alloreactivity (based on donor-recipient killer immunoglobulin-like receptor [KIR] mismatch), graft NK cell dose, and blood NK cell recovery on day +30 post-HSCT on the incidences of leukemia relapse and NRM. The pediatric acute leukemia cohort comprised 295 patients who underwent their first HSCT from a haploidentical donor in complete remission. During post hoc analysis, the total cohort was divided into subcohorts by diagnosis (acute lymphoblastic leukemia [ALL]/acute myeloid leukemia [AML]), NK alloreactivity prediction (KIR match/KIR mismatch), graft NK cell dose (less than versus greater than the median value), and blood NK cell recovery on day +30 post-HSCT (less than versus greater than the median value). We also investigated the influence of serotherapy (antithymocyte globulin [ATG] group) versus abatacept + tocilizumab combination [aba+toci] group) on relapse risk in the context of KIR mismatch. The risks of relapse and NRM were calculated by the cumulative risk method, and groups were compared using the Gray test. Multivariate analysis revealed no apparent impact of predicted NK alloreactivity or any other studied NK cell-related factors for the entire cohort. For patients with AML, a significantly higher relapse risk associated with high NK cell graft content on the background of no predicted KIR mismatch (P = .002) was shown. Multivariate analysis confirmed this finding (P = .018); on the other hand, for the KIR-mismatched patients, there was a trend toward a lower risk of relapse associated with high NK cell dose. The use of ATG was associated with a trend toward reduced relapse risk (P = .074) in the AML patients. There was no significant impact of NK-related factors in the ALL patients. Overall, the evaluated NK-related factors did not show a clear and straightforward correlation with the key outcomes of HSCT in our cohort of children with acute leukemia. In practice, the data support prioritization of KIR-mismatched donors for patients with AML. Importantly, a potential interaction of KIR ligand mismatch and NK cell content in the graft was identified. Indirect evidence suggests that additional cellular constituents of the graft could influence the function of NK cells after HSCT and affect their role as graft-versus-leukemia effectors.

Challenges of detecting measurable/minimal disease in acute leukemia.

Measurable/minimal residual disease (MRD) tracking has emerged as a powerful tool for assessing treatment response and predicting outcomes in acute leukemia. However, the clinical and technological challenges associated with MRD tracking must be addressed to improve its utility in routine patient care. This review article aims to provide a summary of the different MRD methodologies used in acute leukemia. It highlights the strengths, diagnostic pitfalls, and clinical utility associated with MRD tracking in this rapidly evolving field.

Association of ABO mismatch with the outcomes of allogeneic hematopoietic cell transplantation for acute leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT, the independent impact of donor-recipient ABO mismatching remains unclear. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified patients aged ≥18 years with AML or ALL who underwent allo-HCT between 2008 and 2018. Our objectives were to analyze the outcomes of allo-HCT based on the donor-recipient ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Among 4946 eligible patients, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had a minor ABO mismatch, 899 patients (18.1%) had a major ABO mismatch, and 276 patients (5.6%) had a bidirectional ABO mismatch. In multivariable analyses, compared to ABO matched allo-HCT, the presence of a major ABO mismatch was associated with worse overall survival (HR 1.16, 95% CI 1.05-1.29; p=0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p < 0.001), and higher primary graft failure (HR 1.60, 95% CI 1.12-2.30, p=0.01). Relapse, acute graft versus host disease (GVHD) grades III-IV and chronic GVHD were not significantly associated with ABO status. While donor age was not significantly associated with outcomes, older recipient age was associated with worse survival and non-relapse mortality. Our study demonstrates that donor-recipient ABO status is independently associated with survival and other post-transplantation outcomes in acute leukemia. This underscores the importance of considering the ABO status in donor selection algorithms and its impact in acute leukemia.

The incidence and impact of clostridioides difficile infection on transplant outcomes in acute leukemia and MDS after allogeneic hematopoietic cell transplant-a CIBMTR study.

Clostridioides difficile infection (CDI) is common after allogeneic hematopoietic cell transplantation (alloHCT). The determination of incidence, risk factors, and impact of CDI on alloHCT outcomes is an unmet need. The study examines all patients aged 2 years and older who received first alloHCT for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndrome (MDS) between 2013 and 2018 at US centers and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) data registry. In total, 826 patients with CDI and 6723 controls from 127 centers were analyzed. The cumulative incidence of CDI by day 100 was 18.7% (99% CI: 15-22.7%) and 10.2% (99% CI: 9.2-11.1%) in pediatric and adult patients, respectively, with a median time to diagnosis at day +13. CDI was associated with inferior overall survival (OS) (p = 0.0018) and a 2.58-fold [99% CI: 1.43-4.66; p < 0.001] increase in infection-related mortality (IRM). There was a significant overlap in the onset of acute graft versus host disease (aGVHD) and CDI. IRM increased to >4 fold when CDI + aGVHD was considered. Despite advances in the management of CDI, increased IRM and decreased OS still results from CDI.

High Preponderance of High-Risk Phenotypes of Acute Leukemias Among Ugandan Children

In contrast to western countries, outcomes for childhood acute leukemia in Sub Sahara Africa (SSA) remain poor. A preponderance of unfavorable phenotypes of acute leukemia in children in SSA, in addition to disparities in access to cancer care may contribute to these inferior outcomes. We compared clinical phenotypes, immunophenotypes, and outcomes of acute leukemia among two cohorts of children ages 0-14 years at Mulago National Referral Hospital (MNRH) Uganda and Texas Children's Hospital (TCH), USA. The overarching goal is to quantify the disparities in survival of childhood leukemia in SSA and identify targetable causes of the disparities. We conducted a retrospective cohort (February 2019 - December 2021) of children with acute leukemia, n=219 (MNRH) and n=279 (TCH). All new cases of acute leukemia were consecutively included. Children at both hospitals were diagnosed using similar morphology and flow cytometry criteria and treated on Children's Oncology Group-based regimens. We computed odds ratios (OR) and contingent 95% Confidence Intervals (CI) and P values to establish the association of the immunophenotypes of acute leukemia with the children's population of origin (Uganda vs USA). The proportion of children with Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML) was 62% and 38%, vs. 83% vs.18% at MNRH and TCH respectively. Among ALL, the proportion of children with high-risk disease was higher at MNRH vs TCH, 67% and 48%, OR 2.20 (95% CI 1.41-3.44), respectively. There was a higher proportion of T-cell ALL 30% vs.16%, OR 2.24 (95% CI 1.35-3.75), and white blood cell count ³ 50,000/mL, OR 1.81 (1.14-2.90), respectively at MNRH compared to TCH. Overall, 93% vs 96% of children achieved complete remission; 64% vs.77% were negative for minimal residual disease at the end of induction at MNRH and TCH respectively. The 3-year overall survival was 40% and 97% at MNRH and TCH, respectively, HR=2.46 (95% CI 1.73 -3.20). Children in SSA have unfavorable acute leukemia phenotypes. Cytogenetic and genomic analysis is needed to determine and target the biological underpinnings of high risk leukemias in this African population.

Serum Tumor Necrosis Factor-Alpha Levels in Acute Leukemia and Its Prognostic Significance.

IntroductionTumor necrosis factor-alpha (TNF-α) is a pleiotropic cytokine that facilitates malignant cells in immune evasion, survival, and treatment resistance by generating a favorable milieu for them. It is shown to be ectopically produced by malignant/leukemic and immune cells in the tumor microenvironment, providing a tumor-supportive environment and playing an important part in the establishment and progression of malignant cells. It is linked to hyperleukocytosis, high blast count, and poor clinical outcomes in acute leukemia (AL). Considering the varied role and different expression patterns of tumor necrosis factor-alpha in acute leukemia and its clinical relevance, the present study was planned to monitor the level of tumor necrosis factor-alpha in patients with acute leukemia and its correlation with disease outcome. The aim of this study was to monitor the level of tumor necrosis factor-alpha in patients with acute leukemia at the time of diagnosis and after induction chemotherapy.Material and methodsThe study included cases classified as acute leukemia based on morphological examination, bone marrow analysis, and flow cytometry. In all patients with acute leukemia (n = 90) and controls (n = 10), the serum tumor necrosis factor-alpha level was measured using a Diaclone Human ELISA kit (Diaclone, Besancon, France) (solid phase sandwich ELISA) at diagnosis and after induction chemotherapy.ResultsTumor necrosis factor-alpha levels were substantially higher in T-acute lymphoblastic leukemia (T-ALL) cases, followed by acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL), at the time of diagnosis, compared to the control. A significant reduction in serum tumor necrosis factor-alpha level was seen in patients with acute leukemia after induction phase chemotherapy (P < 0.05). Tumor necrosis factor-alpha levels were considerably reduced (P < 0.001) in the majority of acute leukemia cases after the induction phase, while high tumor necrosis factor-alpha levels were positively correlated with incomplete remission status in the remaining cases.ConclusionTumor necrosis factor-alpha is involved in the progression of acute leukemia and its relapse. High levels of tumor necrosis factor-alpha are linked to leukocytosis, high blast counts, and worse survival in patients with acute leukemia. Monitoring of tumor necrosis factor-alpha may be helpful in patients with acute leukemia in view of available antitumor necrosis factor-alpha therapy.

Development of [211At]astatine-based anti-CD123 radioimmunotherapy for acute leukemias and other CD123+ malignancies.

Radioimmunotherapy (RIT) has long been pursued to improve outcomes in acute leukemia and higher-risk myelodysplastic syndrome. Of increasing interest are alpha particle-emitting radionuclides such as astatine-211 (211At) as they deliver large amounts of radiation over just a few cell diameters, enabling efficient and selective target cell kill. Here, we developed 211At-based RIT targeting CD123, an antigen widely displayed on acute leukemia and MDS cells including underlying neoplastic stem cells. We generated and characterized new murine monoclonal antibodies (mAbs) specific for human CD123 and selected four, all of which were internalized by CD123+ target cells, for further characterization. All mAbs could be conjugated to a boron cage, isothiocyanatophenethyl-ureido-closo-decaborate(2-) (B10), and labeled with 211At. CD123+ cell targeting studies in immunodeficient mice demonstrated specific uptake of 211At-labeled anti-CD123 mAbs in human CD123+ MOLM-13 cell tumors in the flank. In mice injected intravenously with MOLM-13 cells or a CD123NULL MOLM-13 subline, a single dose of up to 40 μCi of 211At delivered via anti-CD123 mAb decreased tumor burdens and significantly prolonged survival dose-dependently in mice bearing CD123+ but not CD123− leukemia xenografts, demonstrating potent and target-specific in vivo anti-leukemia efficacy. These data support the further development of 211At-CD123 RIT toward clinical application.

Maternal and Fetal Outcomes of Acute Leukemia in Pregnancy: A Retrospective Study of 52 Patients.

Acute leukemia during pregnancy (P-AL) is a rare disease with limited data regarding the management and outcomes of mothers and fetuses. We retrospectively analyzed the characteristics, pregnancy outcomes and maternal and neonatal prognoses of 52 patients with P-AL collected from January 2013 to December 2020 in our center. Seventeen (32.7%) patients received chemotherapy during pregnancy (exposed cohort), while 35 (67.3%) received chemotherapy after abortion/delivery (nonexposed cohort). Twenty-six (50.0%) pregnancies ended with abortion, and 26 (50.0%) babies were born through spontaneous delivery or cesarean section. Seven infants (26.9%) were born in the exposed cohort, while 19 infants (73.1%) were born in the nonexposed cohort. Fetuses in the exposed cohort had lower gestational ages (P=0.030) and birth weights (P=0.049). Considering the safety of the fetus, seven patients in the exposed cohort received low-dose chemotherapy, one patient received all-trans retinoic acid (ATRA) and one patient only received corticosteroids as induction therapy. Patients received low-dose chemotherapy as induction therapy had a lower complete remission (CR) rate (P=0.041), and more patients in this group received HSCT (P=0.010) than patients received intensive chemotherapy. Patients who delayed chemotherapy in the nonexposed cohort experienced a trend toward a higher mortality rate than patients who received timely chemotherapy (P=0.191). The CR (P = 0.488), OS (P=0.655), and DFS (P=0.453) were similar between the exposed and nonexposed cohorts. Overall, the 4-year overall survival (OS) and disease-free survival (DFS) rates were estimated at 49.1% and 57.8%, respectively. All newborns were living, without deformities, or developmental and intellectual disabilities. Our study indicated that P-AL patients in the first trimester might tend to receive chemotherapy after abortion. Both the status of disease and patients’ willingness should be taken into consideration when clinicians were planning treatment strategies in the second or third trimester. Low-dose or delayed chemotherapy might decrease the efficacy of induction therapy and survival rate of patients, but HSCT could improve the prognosis.

Development of Astatine-211 (211At)-Based Anti-CD123 Radioimmunotherapy for Acute Leukemias and Other CD123+ Hematologic Malignancies

Background: Radioimmunotherapy (RIT) has long been pursued to improve outcomes in acute leukemia. Of current interest are alpha-particle emitting radionuclides as they deliver a very large amount of radiation over just a few cell diameters, enabling efficient and selective target cell kill. So far, alpha-emitters including astatine-211 (211At) have been primarily explored with monoclonal antibodies (mAbs) targeting CD45 or CD33 but their broad display on non-malignant target-expressing cells can lead to marked “on-target, off tumor cell” toxicities. To overcome this limitation, we developed a novel form of 211At-based RIT targeting CD123. CD123 is displayed widely on acute leukemia cells, including underlying leukemic stem cells, but is expressed only on a discrete subset of normal hematopoietic cells and is virtually absent on non-blood cells.Methods: We immunized BALB/c mice with peptides consisting of the extracellular domain of human CD123 to generate anti-CD123 mAbs. Flow cytometry-based assays with human acute leukemia cell lines were used to characterize binding of hybridoma supernatants and mAbs to CD123. mAbs were conjugated with isothiocyantophenethyl-ureido-closo-decaborate(2-) (B10), a boron cage molecule for subsequent astatination, and were then labeled with 211At. In vivo leukemia cell targeting (“biodistribution”) and efficacy studies were conducted in immunodeficient NOD-Rag1 null IL2rɣ null/J (NRG) mice xenografted with MOLM-13 cells, a CD123+ human acute myeloid leukemia cell line.Results: Based on initial hybridoma screening studies, we selected 4 mAbs (10C4, 5G4, 11F11, and 1H8) for further characterization. Phenotyping studies with CD123+ and CD123- human acute leukemia cell lines (including CD123+ cell lines in which CD123 was deleted via CRISPR/Cas9) confirmed specific binding of all mAbs to human CD123 (binding intensity: 10C4>5G4=11F11=1H8), with 10C4 yielding a higher median fluorescence intensity than the widely used commercial anti-CD123 mAb clones, 7G3 and 6H6 (Figure 1). In vitro internalization with a panel of human acute leukemia cell lines studies demonstrated uptake of all mAbs by CD123+ target cells with a kinetic slower than that for anti-CD33 antibodies (typically, 30-50% of the anti-CD123 mAb internalized over 2-4 hours). All 4 anti-CD123 mAbs could be conjugated to B10 and subsequently labeled with 211At. Unlike a non-binding 211At-labeled control mAb, 211At-labeled anti-CD123 mAbs showed uptake at MOLM-13 flank tumors in NRG mice carrying MOLM-13 xenografts. After additional leukemia cell targeting studies to optimize the dosing of 10C4, we conducted proof-of-concept efficacy studies in NRG mice injected intravenously with luciferase-transduced MOLM-13 cells (disseminated leukemia model). Animals were either untreated or treated with 10 µCi, 20 µCi, or 40 µCi of 211At-labeled 10C4-B10 mAb (9-11 animals/group). This was followed by the infusion of bone marrow cells from donor mice as stem cell support 3 days later. As shown in Figure 2 and Figure 3, 211At-10C4-B10 led to a dose dependent decrease in tumor burden. Further, the treatment significantly prolonged survival compared to untreated animals (median survival: 49 days [40 µCi of 211At] vs. 31 days [10 µCi of 211At] vs. 21 days [Ctrl]; P<0.0001 for Ctrl vs. 10 µCi, P<0.004 for 10 µCi vs. 40 µCi), demonstrating potent in vivo anti-leukemia efficacy of a single dose of 211At-CD123 RIT.Conclusion: Our data support the further development of 211At-CD123 RIT for the treatment of patients with acute leukemia and other CD123+ hematologic malignancies. [Display omitted] DisclosuresGreen: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; JANSSEN Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Walter: Kite: Consultancy; Janssen: Consultancy; Genentech: Consultancy; BMS: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amphivena: Consultancy, Other: ownership interests; Selvita: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding.

Valosin-Containing Protein (VCP/p97) Is Prognostically Unfavorable in Subtypes of Acute Leukemia, and Negatively Correlates with UPR-Proteins IRE1 and GRP78

Introduction: The endoplasmic reticulum (ER) is the major site of protein synthesis and folding in the cell. Three pathways are integrated to maintain ER homeostasis: ER-associated degradation (ERAD), unfolded protein response (UPR), and autophagy. One of the chief elements of ERAD is the highly conserved AAA-ATPase superfamily member valosin-containing protein (VCP, or p97). Various studies have reported an upregulation of VCP in cancer and an association between elevated VCP expression and unfavorable cancer outcome. A promising therapeutic approach relies on targeting the cellular stress response, and systemic functional genomic screens have identified VCP as potential target for inhibition in acute myeloid leukemia (AML). As clinical impact of VCP has not been studied, we wondered whether baseline protein expression levels were predictive of outcome in acute leukemia (AL).Methods: Reverse Phase Protein Array (RPPA) was performed with strictly validated antibodies, including antibodies against VCP, IRE1 and GRP78, to determine the protein expression levels of diagnostic leukemic cells from 500 pediatric AML, 818 adult AML, 268 pediatric T-ALL and 93 adult T-ALL patient samples. Pediatric patients participated on either the COG AAML1031 or AALL1231 clinical trial comparing standard therapy (ADE or AFBM) to standard therapy plus bortezomib (ADE+B or AFBM+B). Adults were treated under a variety of protocols. Pearson correlation analyses was used to identify significant protein-protein correlations. Estimates of survival was calculated using the Kaplan-Meier method.Results: VCP protein was expressed in both AML and T-ALL. Although VCP was slightly more highly expressed in AL vs normal CD34+ cells, the majority of patients had VCP expression within the normal range. In pediatric AML, VCP was more highly expressed in younger patients (< 2 y/o), KMT2A (formerly MLL)-rearrangement (p<0.001) and high WBC count (p=0.01) while it was lower in inv(16) (p=0.0003), t(8;21) (p=0.0016), c-Kit (exon 8, p=0.00061; exon 17, p=0.0003), and MYH11 (p=0.0013). FLT3, NPM1, CEBPA, NRAS, KRAS, PTPN11, IDH1/2, and GATA2 mutation status were not associated with VCP expression. Survival analysis identified a significant association between VCP and outcome. In pediatric AML, 5-yr overall survival (OS) was 81% in low-VCP vs 60% and 66% in middle and high-VCP (p<0.001) (Figure 1A). A similar observation was done for event-free survival (5-yr EFS, 59% vs 45-48%, p=0.004) and relapse risk (5-yr RR, 33% vs. 40-47%, p=0.019). This was independent of treatment (with or without bortezomib). High-VCP remained a significant independently unfavorable prognostic variable in multivariate analysis together with high-risk group (per AAML1031 definition) and age < 2 y/o (HR=1.45, HR= 1.75, HR=2.39, respectively). The same observation was seen in adult AML and T-ALL (Figure 1B-C); low-VCP did better than high VCP (AML: 5-yr OS, 32% vs 24%, p=0.029; T-ALL: 4-yr OS, 25% vs 50-60%). In pediatric T-ALL, no association with survival was found (4-yr OS; 89% vs 85%, p=0.45). Protein-protein correlations identified an inverse correlation with VCP and UPR proteins IRE1 and GRP78 in each subtype of AL. Other strong positive correlations were with proteins involved in histone modification, mTor and ribosomal proteins, and strong negative correlations with transcription factors, DNA repair and signal transduction pathways.Conclusion: Using a proteomics approach we identified low-VCP as favorable prognostic indicator. This prognostic association was independent of treatment with a proteasome inhibitor, suggesting that the prognostic effect was potentially separate from the proteasome, and points toward a potential for VCP drug inhibition. Negative correlation with VCP and IRE1 and GRP78 might imply that cells with higher VCP rely on proteasomal degradation, whereas those with low VCP are more dependent on other pathways for protein degradation. Also, adaptation in VCP levels may not be a prominent feature of the stress response to chemotherapy. More information is needed to understand what is driving VCP expression. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Poster: AML-295: Clinical Characteristics and Outcome of Acute Leukemia in Lebanese Patients: A Retrospective Observational Analysis

Poster: AML-295: Clinical Characteristics and Outcome of Acute Leukemia in Lebanese Patients: A Retrospective Observational Analysis

AML-295: Clinical Characteristics and Outcome of Acute Leukemia in Lebanese Patients: A Retrospective Observational Analysis

Context: The molecular characteristics of AML disease remain widely unknown in Lebanon. Cytogenetics and molecular testing in AML are becoming routine practice for disease classification and prognosis. Objective: Our aim was to describe patients’ characteristics and outcome, investigating the association between karyotype on diagnosis, and survival in the Lebanese population. Design: Medical records were retrospectively reviewed for AML patients diagnosed between January 2008 and December 2018. The last update of the data was done in February 2019. Setting: Patients included were treated at Mount Lebanon Hospital University Medical Center or Hotel-Dieu de France University Hospital. Patients: 54 patients were included. Inclusion criteria comprised patients diagnosed with AML and receiving treatment, and availability of data on all sequences of therapy. Patients diagnosed with AML-M3 were not included in the study. Treatment: Fit patients received induction therapy as high dose cytarabine + anthracycline. Then if complete remission: consolidation as cytarabine. Older unfit patients received hypomethylating agent azacytidine. Results: 53.7% were male, median age was 57.06 years at diagnosis. According to FAB classification, the majority (18.5%) were AML-M4, the least (1.9%) M6 and 24.1% were non identifiable. 74.1% were de novo and 16.7% were post-MDS with azacitidine as the major culprit drug. 9.7% were secondary to solid tumors. On diagnosis, 22.6% had hyperleukocytosis and 28.6% were in aplasia. 41.5%, 13.2% and 5.7% were respectively in the intermediate, high, and low risk group. FLT3 was positive in 7.5% of tested cases and NPM1 in 3.8%. No patient was found to have t(16;16) or inversion 16. PML-RARA was positive in 7.5% of patients. 54.7% achieved complete remission, 7.5% were in partial remission and 32.1% were primary refractory. 82.75% relapsed after remission. DFS was 18.4 months with a median OS of 17.8 months ranging from 10.6 months for high-risk group and 20.4 months for the low-risk group. No significant statistical correlation was found between karyotype on diagnosis and survival [P =0.4]. Conclusion: Our study is the first to describe AML characteristics in Lebanon. Multicenter studies are needed to clarify if the Lebanese population has the same molecular and survival pattern as others described in international data.

Using Electronic Medical Record Data and Block Group Level Estimates of Poverty to Investigate the Association between Socioeconomic Status and Bloodstream Infection Among Pediatric Patients with Acute Leukemia

IntroductionAdvances in chemotherapy regimens have greatly improved outcomes in acute leukemia (AL) with 5-year survival being 90% in acute lymphoblastic leukemia (ALL) and 60-70% in acute myeloid leukemia (AML). Despite these advances, AL accounts for the greatest proportion of malignancy-related death among children. We and other investigators have shown that this mortality burden, frequently in the context of infectious complications, is greater in racial minority groups. We sought to expand these prior analyses by using automated data extraction from the electronic medical record (EMR) combined with geocoded block group level estimates of poverty to examine the incidence of bloodstream infection during induction in relation to race and socioeconomic status (SES).MethodsA total of 287 ALL (246 B-ALL, 41 T-ALL) and 61 AML patients who started therapy at The Children's Hospital of Philadelphia between 2006 and 2014 were included. Risk group, chemotherapy protocol, course dates, and initial white blood cell (WBC) count were manually abstracted into a REDCap database. Patient age, sex, race, blood culture results, initial absolute neutrophil count (ANC), and residential address were extracted from the EMR with an automated REDCap/EPIC data query tool. Residential addresses were batch-matched to geo-coordinates that linked each patient to a census-derived block group. Figure 1 shows patient residential address mapped onto the percentage of residents below the federal poverty level in each block group. Percent below poverty was dichotomized at greater than the third quartile (13.31%), as a measure of block group SES. Course level bloodstream infection incidence was computed based on positive blood culture results between course start and end dates. Common commensal organisms were only counted as true pathogens if there were two or more positive blood cultures for the same organism in a three day period. Log-binomial regression was used to compute the unadjusted risk ratios (RR) and corresponding 95% confidence intervals (CI) comparing incidence of bloodstream infection during induction by block group SES, race, sex, age, risk classification and presenting WBC and ANC. Due to the small number of T-ALL patients, T-ALL and B-ALL patients were grouped for modeling.ResultsPatient characteristics are shown in Table 1. The cumulative incidence for any bloodstream infection throughout the course of treatment was 82% for AML patients, and 18% and 24% for B-ALL and T-ALL patients, respectively. 52% of AML patients developed viridans group streptococcal bacteremia during the course of therapy, and 6% had fungemia, from organisms in the Candida, Trichosporon, or Fusarium genera. Incidence of any bloodstream infection during first induction was 5.88% for ALL and 16.13% for AML. In ALL patients, age >10 y (RR: 0.35 , 95% CI: 0.08, 1.51) and black race (RR: 0.75, 95% CI: 0.18, 3.18) were associated with a lower bloodstream infection risk during induction, whereas block group with >13.31% below poverty (RR: 1.27, 95% CI: 0.46, 3.47), females (RR: 1.38, 95% CI: 0.55, 3.47), high risk classification (RR: 1.67, 95% CI: 0.66, 4.18), presenting WBC >50,000 (RR: 3.03, 95% CI: 1.22, 7.53) and presenting ANC ≤500 (RR: 1.58, 0.63, 3.99) suggested a higher bloodstream infection risk during induction, though none of these associations achieved statistical significance. Results of similar magnitude and direction were obtained for AML with the exception of presenting ANC ≤500 (RR: 0.84, 95% CI: 0.24, 2.91).ConclusionsThis study demonstrates the feasibility of linking automatically extracted patient demographic and laboratory data with geocoded estimates of block group level covariates to evaluate the association between socioeconomic status and bloodstream infection risk during induction therapy among children with AL. Work is ongoing to expand the study population to other centers, to extend the bloodstream infection susceptibility analyses to other chemotherapy courses, and to evaluate event free and overall survival. This preliminary analysis suggests that race and poverty may have unexpectedly discrepant relationships with health outcomes. These findings suggest the need for larger studies to better parse the independent effects of race and SES, as well as their potential interaction, on incident bloodstream infection in pediatric AL. [Display omitted] DisclosuresFisher:Merck: Research Funding; Pfizer: Research Funding.

Impact of pre-transplantation minimal residual disease (MRD) on the outcome of Allogeneic hematopoietic stem cell transplantation for acute leukemia

ABSTRACT Objective To investigate the impact of minimal residual disease (MRD) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the outcome of acute leukemia. Methods Data from 114 patients who were diagnosed with acute leukemia (AL) and underwent allo-HSCT between Jan 2013 and Dec 2019 were collected and analyzed. The patients were attributed into MRD positive (MRD+) group and MRD negative (MRD−) group. Results Among the 114 acute leukemia patients, there were 32 MRD+ patients before transplantation, and 82 MRD− patients. No significant difference was found between the MRD+ group and the MRD− group in the incidence of acute graft-versus-host disease (aGvHD) (p = 0.09). Compared with the MRD+ group, the MRD− group had a higher incidence of chronic graft-versus-host disease (cGvHD) (p = 0.008). There is no significance in relapse between the two groups (p = 0.084), while the incidence of relapse was seemingly higher in the MRD+ group: 36.9% Vs 19.7% . We attributed to the lack of sample size and NRM in MRD+ group was remarkably higher. The MRD+ group had significantly worse one-year overall survival (OS) ( , p = 0.003) and one-year progression-free survival (PFS) (, p = 0.009). In the multivariate analysis, MRD+ was an independent prognostic factor for OS (HR = 1.898; 95%CI 1.042–3.457; p = 0.036). Conclusion Pre-transplantation MRD positive status is a risk factor for survival and prognosis after HSCT. Upon this, emphasis should be put on (1) screening more efficient chemo regimen with targeted agents, to help patients reach and keep MRD− status before transplantation; (2) designing better management with different GvHD prophylaxis treatment, timely disease monitoring and preemptive intervention on relapse.

Distance to treatment center is associated with survival in children and young adults with acute lymphoblastic leukemia.

Socioeconomic and demographic categories such as income, race, insurance status, and treatment center type are associated with outcomes in acute leukemia. This study was aimed at determining whether the distance to treatment center affects overall survival for children and young adults with acute leukemia. The National Cancer Database was queried for patients 39 years old or younger who were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). A backward elimination procedure was used to select final multivariate Cox models. In total, 12,301 patients with AML and 22,683 patients with ALL were analyzed. The ALL model included distance to treatment center, Charlson-Deyo score, age, race, insurance status, and community income level. US census definitions of urban and rural were not statistically significant, and no interaction was significant for included variables. Compared with distances > 50 miles, all other distances were associated with improved survival (hazard ratio [HR] for ≤10 miles, 0.91; P=.04; HR for >10 to ≤20 miles, 0.86; P=.004; HR for >20 to ≤50 miles, 0.87; P=.005). The final model for AML included the same variables as the ALL model except for distance to treatment center, which was not statistically significant. For children and young adults with ALL, distances > 50 miles are associated with inferior overall survival; however, no difference is seen for AML. Although it is unknown whether differences in survival for patients with ALL based on distance are driven by relapse or treatment-related mortality, increased attention to adherence, supportive care, and logistics for patients traveling long distances is warranted. For children and young adults with acute lymphoblastic leukemia, living more than 50 miles from the treatment center is associated with worse outcomes.

The value of 18F-FDG PET/CT in the prediction of clinical outcomes of patients with acute leukemia treated with allogeneic hematopoietic stem cell transplantation.

The present study aimed to determine whether 18F-FDG PET/CT performed before and/or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) can predict clinical outcomes in acute leukemia (AL). A total of 79 examinations comprising 72 patients with AL who underwent 18F-FDG PET/CT before and/or after allo-HSCT were retrospectively enrolled between January 2011 and January 2019. Outcomes were assessed using overall survival (OS) and disease-free survival (DFS). A total of 63 examinations were PET-positive, while 16 examinations were PET-negative. Increased BM and splenic 18F-FDG uptake were observed in 24 (19/79) and 14% (11/79) of examinations, respectively. 18F-FDG-avid lymph nodes were observed in 38% (30/79) of examinations. ENEMES involvement was detected in 44% (35/79) of examinations. The presence of ENEMES involvement [OS hazard ratio (HR), 6.399; 95% confidence interval (CI), 1.843–22.224; P=0.003; post-HSCT OS: HR, 7.203; 95% CI, 1.510–34.369; P=0.013; DFS HR, 3.671; 95% CI, 1.145–11.768; P=0.029], post-transplantation minimal residual disease (DFS HR, 4.381; 95% CI, 1.594–12.040; P=0.004; pre-HSCT OS HR, 11.455; 95% CI, 1.336–98.179; P=0.026) and disease status (OS HR, 0.330; 95% CI, 0.128–0.848; P=0.021; post-HSCT OS HR, 0.195; 95% CI, 0.050–0.762; P=0.019; DFS: HR, 0.278; 95% CI, 0.091–0.851; P=0.025) could serve as an adverse prognostic factor in patients with AL treated with allo-HSCT. 18F-FDG PET/CT before and/or after allo-HSCT was a predictor for OS and DFS in patients with AL. ENEMES involvement detected using 18F-FDG PET/CT may help identify patients with AL who are likely to have unfavorable clinical outcomes.

ISSUE HIGHLIGHTS - July 2020.

ISSUE HIGHLIGHTS - July 2020.

A Review on the Impact of Body Mass Index on Outcomes in Pediatric Leukemia.

In the last decades, adults and pediatric obesity have become a major issue in developed countries. Considerable research has been conducted in patients with acute lymphoblastic (ALL) and myeloid leukemia (AML) with the aim of correlating body mass index (BMI) and outcomes in patients undergoing chemotherapy for hematological diseases. In adults, a high BMI has been associated with increased leukemia-related mortality. Whether a similar effect exists in the pediatric setting remains controversial. Some of the studies detailed in this review have reported no differences in outcomes according to BMI, whilst other reports have described higher treatment-related mortality, increased risk of relapse and death. Although the link between BMI and acute leukemia outcomes is controversial, a large number of studies describe poorer survival rates in children with AML or ALL with higher BMI. On the other hand, being underweight has been associated with higher treatment-related toxicity. Understanding more about the impact of BMI in pediatric leukemia is of utmost importance to provide prompt intervention and improve outcomes.

Aberrant Expression of CD Markers in Acute Myeloid Leukaemia

Background: Aberrant expression of cluster differentiation (CD) antigen marker is associated with poor outcome of acute leukaemia. Objective: Aim of this study is to determine the frequency and pattern of aberrant expression of CD markers in acute myeloid leukaemia patients in Bangladesh. Methods: This retrospective data analysis was conducted in the Department of Haematology, Bangabandhu Sheikh Mujib Medical University (BSMMU) to assess the frequency of aberrant CD antigen expression in acute myeloid leukaemia from October 2016 to September 2017. During this period, we did one hundred flow cytometry of acute leukaemia patients and among them we found 48 acute myeloid Leukaemia (AML) who were included in this study. Result: Mean age of patients was 35 years (SD­ +14 years; Rang 3 to 50 years) with male: female ratio of 0.92. Four colour flow cytometry was done on fresh bone marrow aspirates and peripheral blood. Among 48 AML patients, aberrant CD expression was observed in 58% cases. CD5 and cCD79a lymphoid markers were seen to be expressed in 32% cases of AML. Aberrant cCD3 and CD7 were expressed in 29% and 25% cases respectively and aberrant CD10, CD19, cCD22 were expressed in 11%, 3%, 3% cases acute myeloid leukaemia patients respectively. Conclusion: Aberrant CD antigen expression is not uncommon in AML patients of Bangladeshi population that may adversely affect the treatment outcome of the disease.