Acute Leukemia Research Articles

Novel Mutations in Acute Erythroid Leukemia–A Case Report with Review of Literature

Novel Mutations in Acute Erythroid Leukemia–A Case Report with Review of Literature

Sideroblastic anemia Secondary to anti-tubercular Therapy in a Patient with Acute Promyelocytic Leukemia

Sideroblastic anemia Secondary to anti-tubercular Therapy in a Patient with Acute Promyelocytic Leukemia

Venous Thromboembolism Post-allogeneic Hematopoietic Cell Transplant: Risk Factors, Incidence, and Outcomes.

Venous thromboembolism (VTE) is a well-documented complication of both solid and hematologic malignancies, but there are fewer data on allogeneic hematopoietic cell transplant (HCT) recipients. Therefore, we studied the incidence, risk factors, and impact of VTE on post-HCT outcomes in a contemporary cohort. We retrospectively reviewed patients who underwent allogeneic HCT between January 2014 and August 2019 to identify patients with post-HCT VTE. Patient, disease, and transplant-related risk factors for VTE were investigated using competing risk analysis. A total of 431 patients were included in this study. Median (interquartile range [IQR]) age in years was 59 (46-65) at transplant. The most common indication for transplant was acute myelogenous leukemia (49.4%). Within our cohort, 64 patients (14.8%) developed post-HCT VTE with a median (IQR) follow-up time of 24.6 (8.4-47.1) months. The cumulative incidence of VTE was 4.2% at 6 months, 9.0% at 12 months, 12.6% at 24 months, and 13.8% at 36 months. In multivariable analysis, older age (hazard ratio [HR] per 10-year increase: 1.36, 95% confidence interval [CI]: 1.09-1.70), history of VTE (HR: 1.95, 95% CI: 1.09-3.49), and grade 2-4 acute graft versus host disease (GVHD; HR: 1.75, 95% CI: 1.05-2.94) were independently associated with VTE. VTE was significantly associated with an increased risk of nonrelapse mortality (NRM; HR: 4.09, 95% CI: 2.47-6.74) and decreased overall survival (OS; HR: 2.19, 95% CI: 1.48-3.24). VTE is an important complication after allogeneic HCT and is significantly associated with increased NRM and decreased OS. Older patients, those with prior VTE, and patients with acute GVHD are at increased risk for development of VTE after HCT.

CDC27 gene expression patterns as a potential biomarker in Acute Leukemia.

Treating Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) is difficult due to high relapse rates and drug resistance. Tumorigenesis is largely dependent on disruption of the cell cycle progression. While the role of Cell Division Cycle 27 (CDC27) in the anaphase-promoting complex/cyclosome is well-known, its significance in the pathophysiology of acute leukemia and its potential as a biomarker are less well understood. This case-control study used samples from 100 leukemia patients (50 with ALL and 50 with AML) at Shariati Hospital in Tehran, Iran, along with 50 healthy individuals. The expression of CDC27 was analyzed using quantitative real-time PCR (RQ-PCR). Statistical analysis was done using the nonparametric Mann-Whitney U test. The results showed that AML and ALL patients had significantly higher levels of CDC27 expression compared to the control group. Although a weak correlation between CDC27 expression and hematological parameters was found, there was no significant correlation with sample type, demographics, clinical variables or prognosis. This study highlights the potential of CDC27 as an oncogene, as well as a possible prognostic and diagnostic marker in acute leukemias. It suggests that CDC27 could be a valuable biomarker or therapeutic target in the treatment of AML and ALL.

Fluoroquinolone Prophylaxis in Children With Cancer: A Pro/Con Discussion.

There are conflicting recommendations on whether to use or not to use fluoroquinolone prophylaxis in pediatric oncology patients. An international pediatric clinical practice guideline (CPG) recommends administering levofloxacin prophylaxis in patients with acute myeloblastic leukemia and relapsed acute lymphoblastic leukemia receiving intensive chemotherapy as this practice has been found to reduce episodes of fever and bacteremia. A separate European CPG does not recommend levofloxacin prophylaxis because of concerns for adverse effects, including potentiation of fluoroquinolone resistance and possible increased resistance to other classes of antibiotics. The nuance of the decision to give or not give prophylaxis is discussed in the context of published evidence defining the risks and benefits of levofloxacin prophylaxis for pediatric leukemia patients at high risk for bacterial infection. Knowledge gaps are also identified to guide further investigations to optimize the use of fluoroquinolone prophylaxis in pediatric patients receiving chemotherapy for cancer or undergoing a hematopoietic cell transplantation.

In-line RNA-based microreactor direct mass spectrometry for ultrasensitive and rapid assay of terminal deoxynucleotidyl transferase activity

Terminal deoxynucleotidyl transferase (TdT), a unique template-independent DNA polymerase, plays a crucial role in the human adaptive immune system and is considered a promising biomarker for the diagnosis of various forms of acute or chronic leukemia. The accurate and sensitive detection of trace TdT is of pivotal importance to fulfill the significant medical interest in understanding its pathological functions and diagnosing TdT-related diseases. We hereby present an in-line RNA-based microreactor direct mass spectrometry (MS) method and its application for ultrasensitive, accurate, and rapid analysis of trace TdT activity in leukemic cell samples. A specially designed RNA-based microreactor is fabricated by immobilizing short RNA sequence via covalent Au–S bond on the inner surface of a capillary pre-modified with three-dimensional porous layer (PL) and Au nanoparticles (AuNPs). Utilizing this PL@Au@RNA microreactor, the signal of target TdT is conversed into reporter molecules (adenine), which exhibit a strong MS response. This conversion process enables efficient signal amplification and enhances detection sensitivity. The outlet end of the PL@Au@RNA microreactor is deliberately crafted into a porous tip, serving as an electrospray ionization (ESI) interface to directly couple to ESI-MS in-line. This design facilitates the direct transmission of the generated signaling molecules into the MS system, eliminating the need for laborious sample treatment procedures. By implementing this RNA-based microreactor in direct MS analysis, we have achieved remarkable sensitivity in detecting TdT activity with the limit-of-detection of 4 × 10−9 U, surpassing other reported methods in literature by three to four orders of magnitude. Furthermore, each assay requires a minimal sample volume of merely 10 nL. This method has successfully demonstrated its application in accurately and efficiently detecting TdT activity in leukemia cells, and its detection results are consistent with those obtained by ELISA kits.

Immune escape of B-cell lymphoblastic leukemic cells through a lineage switch to acute myeloid leukemia

Acute leukemia (AL) with a lineage switch (LS) is associated with poor prognosis. The predisposing factors of LS are unknown, apart from KMT2A rearrangements that have been reported to be associated with LS. Herein, we present two cases and review all 104 published cases to identify risk factors for LS. Most of the patients (75.5%) experienced a switch from the lymphoid phenotype to the myeloid phenotype. Eighteen patients (17.0%) experienced a transformation from acute myelogenous leukemia (AML) to acute lymphoblastic leukemia (ALL). Forty-nine (46.2%) patients carried a KMT2A rearrangement. Most of the cases involved LS from B-cell ALL (B-ALL) to AML (59.4%), and 49 patients (46.2%) carried KMT2A-rearrangements. Forty patients (37.7%) received lineage-specific immunotherapy. Our findings suggest that the prevalence of KMT2A rearrangements together with the lineage-specific immunotherapy may trigger LS, which supports the thesis of the existence of leukemia stem cells that are capable of lymphoid or myeloid differentiation.

Impact of the Type of Tyrosine Kinase Inhibitor (imatinib or dasatinib) Used Before allo-HCT on Outcome of Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia. A Study on Behalf of the Acute Leukemia Working Party of the EBMT

The use of tyrosine kinase inhibitors (TKIs) during induction and consolidation, followed by allogeneic hematopoietic cell transplantation (allo-HCT), is a standard of care for patients with Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL). The goal of this study was to compare results of allo-HCT according to the type of TKI used pre-transplant, either imatinib, dasatinib or both. This was a retrospective, registry-based analysis including adult patients with Ph-positive ALL treated with allo-HCT between years 2010-2022. The analysis included 606 patients pre-treated with imatinib, 163 with dasatinib and 94 with both imatinib and dasatinib. Allo-HCTs were performed in first complete remission from either unrelated (56%), matched sibling (36%) or haploidentical donors (8%). Relapse incidence at 2 years was 26% in the imatinib group and 21% in the dasatinib group and 19% in the imatinib + dasatinib group (P = .06) while non-relapse mortality was 19%, 15%, and 23%, respectively (P = .37). No significant differences were found for leukemia-free survival (55% vs. 63% vs. 58%, P = .11) and overall survival (72% vs. 76% vs. 65%, P = .32). The incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD was comparable across study groups, while the incidence of grade 3-4 acute GVHD was significantly increased for patients pre-treated with dasatinib alone (20%) than in the imatinib group (10%) or imatinib + dasatinib group (13%) (P = .002). On multivariate analysis a chance of GVHD and relapse-free survival (GRFS) was significantly decreased while the risk of grade 3-4 acute GVHD was increased for the dasatinib compared to imatinib group (hazard ratio, HR = 1.27, P = .048 and HR = 2.26, P = .0009, respectively). This study provides no evidence for the advantage of one TKI over another in terms of LFS and OS. However, the use of dasatinib is associated with increased risk of severe acute GVHD and decreased GRFS.

Effect of magnesium level before allogeneic hematopoietic cell transplantation on outcome in acute leukemia

This study assessed the effect of serum magnesium levels and their role in the outcome of allogeneic hematopoietic cell transplantation (allo-HSCT) in acute leukemia. Fifty-four patients with acute leukemia who underwent allo-HSCT were divided into two groups according to their serum magnesium levels before transplantation. The results showed that serum magnesium level is an independent factor influencing the prognosis of patients undergoing allo-HSCT. Low magnesium levels were associated with inferior overall survival and event-free survival compared with the associations of high magnesium levels (HR = 0.149; (95% CI: 0.029–0.755 for overall survival; HR = 0.369; 95% CI: 0.144–0.949, p = 0.039 for event-free survival). The competing risk model showed that the cumulative incidence of acute graft-versus-host disease was significantly low in the high magnesium group (p = 0.028). In general, there is a correlation between high magnesium levels and superior outcomes, including less and milder acute graft-versus-host disease, which does not affect cyclosporine-A levels. These findings provide valuable information for identifying the risk of poor prognosis in patients preparing for transplantation.

Critical role of tripartite fusion and LBD truncation in certain RARA- and all RARG-related atypical APL

AbstractAtypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene–positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X– or X::RAR::Y–type tripartite fusions in certain RARA-aAPL and all RARG-aAPL cases, with shared features and notable differences between these 2 disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3′ splices was associated with their 5′ fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3′ splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5′ splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3′ fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion–positive aAPL, through a protein allosteric dysfunction mechanism.

MiR-223-3p in Cancer Development and Cancer Drug Resistance: Same Coin, Different Faces.

MicroRNAs (miRNAs) are mighty post-transcriptional regulators in cell physiology and pathophysiology. In this review, we focus on the role of miR-223-3p (henceforth miR-223) in various cancer types. MiR-223 has established roles in hematopoiesis, inflammation, and most cancers, where it can act as either an oncogenic or oncosuppressive miRNA, depending on specific molecular landscapes. MiR-223 has also been linked to either the sensitivity or resistance of cancer cells to treatments in a context-dependent way. Through this detailed review, we highlight that for some cancers (i.e., breast, non-small cell lung carcinoma, and glioblastoma), the oncosuppressive role of miR-223 is consistently reported in the literature, while for others (i.e., colorectal, ovarian, and pancreatic cancers, and acute lymphocytic leukemia), an oncogenic role prevails. In prostate cancer and other hematological malignancies, although an oncosuppressive role is frequently described, there is less of a consensus. Intriguingly, NLRP3 and FBXW7 are consistently identified as miR-223 targets when the miRNA acts as an oncosuppressor or an oncogene, respectively, in different cancers. Our review also describes that miR-223 was increased in biological fluids or their extracellular vesicles in most of the cancers analyzed, as compared to healthy or lower-risk conditions, confirming the potential application of this miRNA as a diagnostic and prognostic biomarker in the clinic.

Exploratory case–control study on childhood cancer near the Mar Menor lagoon Region of Murcia (Spain) 2000 to 2018

The Mar Menor, Europe’s largest saltwater lagoon in the Mediterranean basin (Murcia, southeastern Spain), is an ecosystem facing severe pollution, anoxia events, and marine biodiversity loss. This exploratory study examines the association between residential proximity to the Mar Menor and childhood cancer incidence in Murcia from 2000 to 2018. In our case–control study of 594 cancer cases and 3564 controls, matched by birth year and sex, participants were categorized by proximity to the lagoon (G1 ≥ 20 km, G2 = 10–20 km, G3 = 2–10 km, G4 = ≤ 2 km). Odds ratios (ORs) and 95% confidence intervals (95%CI) were adjusted for sociodemographic and environmental covariates. Analysis of distance as a continuous variable indicated a decrease both in all types of cancer and lymphoid acute leukemia risk with greater distance (OR = 0.99; 95% CI 0.98–0.99), while as a categorical variable, it revealed a non-linear pattern. Specifically, the risk did not increase for those living within 2 km of the lagoon (OR = 0.87; 95% CI 0.52–1.37), whereas increased risks were observed in the 2–20 km range within Campo de Cartagena (G2; OR = 1.32; 95% CI 1.01–1.73 and G3; OR = 1.43; 95% CI 1.00–2.02). This suggests modulating factors near the lagoon may counterbalance risks from broader environmental contamination. These findings highlight the complexity of environmental health dynamics and the importance of detailed research to guide public health strategies and urban planning for environmental and child health protection.

Phase-Based and Lifetime Health System Costs of Care for Patients Diagnosed with Leukemia and Lymphoma: A Population-Based Descriptive Study.

Hematologic cancers, notably leukemias and lymphomas, pose significant challenges to healthcare systems globally, due to rising incidence rates and increasing costs. This study aimed to estimate the phase and lifetime health system total costs (not net costs) of care for patients diagnosed with leukemia and lymphoma in Ontario, Canada. We conducted a population-based study of patients diagnosed between 2005 and 2019, using data from the Ontario Cancer Registry linked with health administrative databases. Costs were estimated using a phase-based approach and stratified by care phase and cancer subtype. Acute lymphocytic leukemia (ALL) patients had the highest mean monthly initial (CAD 19,519) and terminal (CAD 41,901) costs among all cancer subtypes, while acute myeloid leukemia (AML) patients had the highest mean monthly cost (CAD 7185) during the continuing phase. Overall lifetime costs were highest for ALL patients (CAD 778,795), followed by AML patients (CAD 478,516). Comparatively, patients diagnosed with Hodgkin lymphoma (CAD 268,184) and non-Hodgkin lymphoma (CAD 321,834) had lower lifetime costs. Major cost drivers included inpatient care, emergency department visits, same-day surgeries, ambulatory services, and specialized cancer drugs. Since 2005, the cost structure has evolved with rising proportions of interventional drug costs. Additionally, costs were higher among males and younger age groups. Understanding these costs can help guide initiatives to control healthcare spending and improve cancer care quality.

The clinical efficacy of a daratumumab-based regimen in relapsed/refractory acute leukemia: a single-center experience.

Relapsed/refractory acute leukemia (R/R-AL) is associated with a low remission rate, short survival rate, and poor prognosis. Treating R/R-AL remains challenging as there is no standardized effective regimen; hence, there is a need for efficient therapies. CD38 expression has been observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Daratumumab is a humanized anti-CD38 monoclonal antibody used to treat multiple myeloma and has been reported to treat R/R-AL safely and effectively. The clinical data of 10 adult patients with R/R-AL who were treated with a daratumumab-based salvage regimen between July 2018 and May 2023 at our center were analyzed retrospectively. Seven AML and three ALL cases were included in the analysis. Seven (70%) patients showed responses to the treatments (complete response [CR], 60%; partial response [PR], 10%). Of the seven responders, three underwent allogenic stem cell transplantation (ASCT), including one who underwent a second ASCT. Among the five patients with R/R AML who had prior exposure to venetoclax, three achieved a therapeutic response (two CR and one PR) when re-treated with venetoclax in combination with daratumumab. The median follow-up time was 6.15 months (0.9-21 months). Overall survival and event-free survival rates at 12 months were 68.6% and 40.0%, respectively. The main adverse events included grade 3 febrile neutropenia (20%) and grade 3 hematological toxicities (60%). The daratumumab-based salvage regimen offers patients with R/R-AL the opportunity of remission with acceptable tolerability, creating the possibility of bridging ASCT.

Rare Case of Lineage Switch from Acute Myeloid Leukemia to Acute Precursor B Lymphoblastic Leukemia in A 3-Year-Old

Lineage switch defines as an acute leukemia that initially presents with either lymphoid or myeloid phenotype, and then converts to the other one when recurs, while keeping the same genotype. This is associated with poor prognosis and accounts for 0.6% of paediatric leukemia. Hence, we report a rare case of lineage switch from acute myeloid leukemia to precursor B lymphoblastic leukemia in a three-year-old boy.

Exploring the kaleidoscope: Ocular manifestations in leukaemia – A case series revelation

Leukaemia is a systemic cancer of the blood and blood-forming tissues that affects multiple organs. Acute lymphocytic leukemia (ALL) is the dominant leukaemia type in children and more than 50% of these patients can be cured. In adults, acute myelocytic leukemia (AML) is the predominant myeloproliferative disorder, with lower survival rates. Around 35.4% of leukaemia patients present with leukaemic retinopathy. The purpose of the study is to present ocular manifestations in acute leukaemia. This report outlines the clinical presentations of three patients. Among them, one adult presented with AML at diagnosis, exhibiting ocular symptoms. Another adult, 6 months after diagnosis, experienced retrobulbar haemorrhage and leukaemic retinopathy. In addition, a paediatric patient, previously treated for ALL and in remission, developed unilateral vision loss, subsequently indicating disease relapse. During the diagnosis of acute leukaemia patients, it is recommended to conduct a thorough ophthalmic evaluation, which should include a dilated fundus examination, as ocular involvement in these patients is prevalent and may occasionally be asymptomatic.

Arsenic trioxide regulates the glycolytic pathway to treat acute promyelocytic leukemia by inhibiting RPL22L1

ObjectiveTo investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism. MethodsThe GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined. ResultsThe expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells. ConclusionATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects.

Early mortality in acute promyelocytic leukemia - a single center experience.

Early mortality in acute promyelocytic leukemia - a single center experience.

Identification of Gene Regulatory Networks in B-Cell Progenitor Differentiation and Leukemia.

Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of ERG at 21q22, while a deletion of the TGFbeta-receptor gene TGFBR2 at 3p24 resulted in an upregulation of EOMES. Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes.

Comparative Characteristics of Abnormal Karyotypes in Secondary Acute Leukemia

Comparative Characteristics of Abnormal Karyotypes in Secondary Acute Leukemia