Acute Leukemia Patients Research Articles

Inhibition of TGF-β signaling in bone marrow endothelial cells promotes hematopoietic recovery in acute myeloid leukemia patients

Although it is an effective treatment for acute myeloid leukemia (AML), chemotherapy leads to myelosuppression and poor hematopoietic reconstruction. Hematopoiesis is regulated by bone marrow (BM) endothelial cells (ECs), and BM ECs are dysfunctional in acute leukemia patients with poor hematopoietic reconstitution after allogenic hematopoietic stem cell transplantation. Thus, it is crucial to explore the underlying mechanism of EC impairment and establish strategies for targeted therapy. TGF-β signaling was found to be upregulated in ECs from AML patients in complete remission (CR ECs) and led to CR EC damage. Administration of a TGF-β inhibitor rescued the dysfunction of ECs caused by TGF-β1 expression in vitro, especially their hematopoiesis-supporting ability. Moreover, inhibition of TGF-β expression repaired the BM EC damage triggered by chemotherapy in both AML patients in vitro and in an AML-CR murine model, and restored normal hematopoiesis without promoting AML progression. Mechanistically, our data reveal alterations in the transcriptomic pattern of damaged BM ECs, accompanied by the overexpression of downstream molecules TGF-βR1, pSmad2/3, and functional genes related to adhesion, angiogenesis suppression and pro-apoptosis. Collectively, our findings reveal for the first time that the activation of TGF-β signaling leads to BM EC dysfunction and poor hematopoietic reconstitution. Targeting TGF-β represents a potential therapeutic strategy to promote multilineage hematopoiesis, thereby benefiting more cancer patients who suffer from myelosuppression after chemotherapy.

Clinical effect of prophylactic pegfilgrastim in patients with newly diagnosed acute lymphoblastic leukemia who receive intensive chemotherapy.

Using granulocyte colony-stimulating factor (G-CSF) after completing chemotherapy reduces the duration of neutropenia and infections. However, the efficacy and safety of prophylactic pegfilgrastim in acute lymphoblastic leukemia (ALL) patients have not yet been evaluated after intensive cytotoxic chemotherapy compared to the daily G-CSF. This study aimed to evaluate the efficacy of pegfilgrastim for ALL patients who received intensive chemotherapy compared with a short-acting G-CSF. Clinical data of 145 patients treated with hyper-CVAD, modified VPDL/VPD, or KALLA 1406/1407 regimen were retrospectively evaluated. Pegfilgrastim or the short-acting G-CSF was selected according to the clinician's discretion. Patients not receiving pegfilgrastim were treated with the short-acting G-CSF. The median age of enrolled patients was 45years. Sixty newly diagnosed ALL patients were treated with hyper-CVAD regimen, while KALLA and VPDL regimens were administered to 39 and 46 patients, respectively. Among the 60 patients treated with hyper-CVAD, 20 patients received pegfilgrastim. Patients who received pegfilgrastim had a significantly shorter duration of neutropenia and hospitalization and reduced incidence of severe infections compared to patients receiving the short-acting G-CSF. Consistent results were also confirmed in an analysis targeting only patients who achieved remission during hyper-CVAD induction therapy. There was no significant difference in neutrophil recovery ability and hospitalization duration when the daily short-acting G-CSF was used prophylactically after completing hyper-CVAD, KALLA, and VPDL regimens as induction therapy. Using pegfilgrastim after hyper-CVAD therapy was more effective than the short-acting G-CSF in terms of infection, neutropenia recovery, and hospitalization in patients with newly diagnosed ALL.

Invasive fungal infections in patients with acute leukemia: A retrospective cohort study at a tertiary-care hospital.

Invasive fungal infection (IFI) is an important cause of morbidity and mortality in acute leukemia patients. In the past few decades, the incidence of IFI has dramatically increased. Nevertheless, the management of IFI has become more complicated owing to changes in the epidemiology of fungal diseases and therapeutic regimens. Therefore, it is important to establish an appropriate strategy for centers that provide the diagnosis and treatment of acute leukemia patients based on scientific data and with available resources. In this study we investigated the incidence of IFI, pathogens, the use of diagnostic methods, and risk factors for IFI in acute leukemia patients over a 17-year period. A total of 502 acute leukemia patients (male/female: 57%/43%, mean age: 57.7 ± 15.5 years) hospitalized at adult and oncology hospitals between 2003 and 2020 were reviewed retrospectively. The incidence of proven and probable IFI was 13.2% (33.1%, when possible cases were included). The most common IFI was aspergillosis (49 patients, 9.7%), followed by candidemia, mucormycosis, and Pneumocystis jirovecii pneumonia. The galactomannan antigen test was positive in the serum of 39 (23.5%) patients and in bronchoalveolar lavage (BAL) fluid in 6 (3.6%) patients. Thirteen (7.8%) sputum cultures (11 Aspergillus spp. and 2 Candida spp.) and 4 (2.4%) BAL fluid (1 Aspergillus spp., 2 Candida spp., 1 P jirovecii) were positive for a fungal pathogen. Neutropenia, intensive care unit (ICU) follow-up and mechanical ventilation (MV) increased the risk of IFI by 3.5, 2.5, and 1.8 times, respectively. The median survival was 5 (range: 1.9-8) months. ICU follow-up shortened the survival by 12 months and increased the death risk by 2.49-fold. MV shortened survival by 57 months and increased the death risk by 3.82-fold. IFI remains a significant contributor to the morbidity and mortality in acute leukemia patients. Pulmonary involvement is the most common site. Neutropenia, ICU follow-up and MV are associated with an increased risk for IFI and mortality. We recommend in the IFI approach, to be aware of IFI in patients receiving intensive chemotherapy and/or recipients of hematopoietic stem cell transplantation, and to evaluate with microbiological, serological and radiological tests during the clinical follow-up.

Very early remission and increased apoptosis with the use of Pentoxifylline in children with acute lymphoblastic leukemia.

Despite the improvement in survival in acute lymphoblastic leukemia (ALL), there are still cases with evasion of chemotherapy-induced apoptosis. The IKK/NF-κB signaling pathway contributes to antiapoptotic gene expression. Pentoxifylline (PTX) inhibits IkB phosphorylation, blocking NF-κB and antiapoptotic activity. We conducted a randomized, double-blind clinical trial on pediatric ALL patients undergoing induction therapy, assigning them to PTX or placebo group. Bone marrow aspirates were obtained on days 1, 8, 15, and 22. Apoptosis was assessed using Annexin-V/propidium iodide. Results indicated that the PTX group exhibited higher apoptosis on day-8 (41.3% vs. 19.4%, p =0.029) and day-15 (35.0% vs. 14.2%, p <0.01). On day-8, the PTX group displayed an MRD of 0.25% vs. 18.2% (p <0.01) in placebo group; on day-15, the PTX group demonstrated an MRD of 0.09% vs. 1.4% (p =0.02). Patients achieving an MRD <0.01% on day-8 demonstrated a 3-year Overall Survival (OS) of 81.6% vs. 58.3% (p =0.03); on day-15, patients with MRD <0.01% had a 3-year OS of 77.9% vs. 54.5% (p =0.03). The PTX group achieved an MRD of <0.01% earlier on days-8 and 15, along with a higher apoptosis rate, indicating a more favorable therapeutic response. In the entire cohort, patients achieving MRD <0.01% on day-8 or 15 displayed superior OS. Our study demonstrates that PTX enhances apoptosis and reduces MRD in pediatric acute lymphoblastic leukemia patients. https://clinicaltrials.gov/, identifier NCT02451774.

Microfluidic Affinity Selection of B-Lineage Cells from Peripheral Blood for Minimal Residual Disease Monitoring in Pediatric B-Type Acute Lymphoblastic Leukemia Patients.

Assessment of minimal residual disease (MRD) is the most powerful predictor of outcome in B-type acute lymphoblastic leukemia (B-ALL). MRD, defined as the presence of leukemic cells in the blood or bone marrow, is used for the evaluation of therapy efficacy. We report on a microfluidic-based MRD (MF-MRD) assay that allows for frequent evaluation of blood for the presence of circulating leukemia cells (CLCs). The microfluidic chip affinity selects B-lineage cells, including CLCs using anti-CD19 antibodies poised on the wall of the microfluidic chip. Affinity-selected cells are released from the capture surface and can be subjected to immunophenotyping to enumerate the CLCs, perform fluorescence in situ hybridization (FISH), and/or molecular analysis of the CLCs' mRNA/gDNA. During longitudinal testing of 20 patients throughout induction and consolidation therapy, the MF-MRD performed 116 tests, while only 41 were completed with multiparameter flow cytometry (MFC-MRD) using a bone marrow aspirate, as standard-of-care. Overall, 57% MF-MRD tests were MRD(+) as defined by CLC numbers exceeding a threshold of 5 × 10-4%, which was determined to be the limit of quantitation. Above a threshold of 0.01%, MFC-MRD was positive in 34% of patients. The MF offered the advantage of the opportunity for efficiently processing small volumes of blood (2 mL), which is important in the care of pediatric patients, especially infants. The minimally invasive means of blood collection are of high value when treating patients whose MRD is typically tested using an invasive bone marrow biopsy. MF-MRD detection can be useful for stratification of patients into risk groups and monitoring of patient well-being after completion of treatment for early recognition of potential impending disease recurrence.

Влияние маршрутизации на сроки постановки диагноза острого лейкоза у детей: результаты регионального исследования

BACKGROUND. Acute leukemia (AL) is the most common pediatric malignancy with an incidence of 55–62 cases per million population under 18 years. The nonspecificity of primary symptoms creates a challenge for early diagnosis, especially in the regions with a population of up to 100,000, where pediatric AL is diagnosed once every 2–5 years. Furthermore, the outpatient physicians are seldom alert to cancer symptoms. AIM. To assess the impact of routing on a speedy AL diagnosis in children as shown in the Tver Region. MATERIALS &amp; METHODS. The trial enrolled 35 patients with diverse AL variants hospitalized in the hematology department of the Pediatric Regional Clinical Hospital (PRCH) during 2018 to 2023. There were 30 (86 %) children with acute lymphoblastic leukemia (ALL), 3 (9 %) children with acute myeloid leukemia (AML), and 2 (5 %) children with acute leukemia of unspecified cell type (ALUCT). The age of children was 1.1–17 years, the mean age was 5.1 years. There were 18 girls and 17 boys. By the time of initial diagnosis, thrombocytopenia and anemia were identified in 76 % and 78 % patients, respectively. Leukocytosis &gt; 20 × 109/L was detected in 58 % patients, and leukopenia &lt; 3.5 × 109/L was observed in 15 %. Blast cells 2–95 % were found in the peripheral blood in 97 % of cases. On the whole, 16 (46 %) and 19 (54 %) AL patients were identified in the city of Tver (group 1) and in the Tver Region (group 2), respectively. RESULTS. In groups 1 and 2, ALL was diagnosed in 14 (88 %) and 16 (84 %) children, AML was diagnosed in 1 (6 %) and 2 (11 %), and ALUCT in 1 (6 %) and 1 (5 %) children, respectively. The overall diagnosis delay (n = 35) was &lt; 2 weeks in 21 (60 %) children, 2–4 weeks in 7 (20 %), &gt; 4–≤ 8 weeks in 4 (11 %), and &gt; 8 weeks in 3 (9 %) children. In the city of Tver and in the Tver Region, the diagnosis delay was &lt; 2 weeks in 7 (44 %) vs. 13 (68 %) patients, 2–4 weeks in 6 (38 %) vs. 3 (17 %), &gt; 4–≤ 8 weeks in 1 (6 %) vs. 1 (5 %), and &gt; 8 weeks in 2 (12 %) vs. 2 (10 %) patients, respectively. The time of diagnosis could not be reliably associated with the distance from patient’s residence to a third-level[1] pediatric specialized medical care institution (PRCH). With the distance of &lt; 50 km, the diagnosis was delayed &lt; 2, 2–4, &gt; 4–≤ 8, and &gt; 8 weeks in 36 %, 36 %, 21 %, and 7 % of patients, respectively. The same delayed diagnosis in patients with &gt; 100 km residential distance to hospital was observed in 30 %, 30 %, 20 %, and 20 % children, respectively. With the distance of 50–100 km, AL was diagnosed within 2–4 weeks in all 35 children enrolled in this trial. CONCLUSION. The residential distance to the PRCH of Tver had no effect on the time of AL diagnosis in children. For a speedier diagnosis, daily conferences at the medical institutions of the Tver Region as well as timely hospitalization of children with suspected hematologic malignancies at the appropriate department of the PRCH of Tver appeared to be indispensable. [1] Medical institutions are stratified by level of care (staging) in accordance with the Decree No. 358 of the Ministry of Health of the Russian Federation dated June 8, 2016, On the approval of methodological guidelines for the development of the state and municipal healthcare network based on the Federal Act No. 323-ФЗ dated November 21, 2011 (revised 25.12.2023), On fundamental healthcare principles in the Russian Federation, Article 37, Cl. 5.1.

Correlation between phase angle and clinical prognosis in de novo acute lymphoblastic leukemia patients

Correlation between phase angle and clinical prognosis in de novo acute lymphoblastic leukemia patients

Integrative single-cell multi-omics of CD19-CARpos and CARneg T cells suggest drivers of immunotherapy response in B cell neoplasias

The impact of phenotypic, clonal, and functional heterogeneity of chimeric antigen receptor (CAR)-T cells on clinical outcome remains understudied. Here, we integrate clonal kinetics with transcriptomic heterogeneity resolved by single-cell omics to interrogate cellular dynamics of non-transduced (CARneg) and transduced (CARpos) Tcells, in the infusion product (IP) and at the CAR-T cell expansion peak in five B cell acute lymphoblastic leukemia (B-ALL) patients treated with CD19CAR-T cells (varni-cel). We identify significant differences in cellular dynamics in response to therapy. CARpos Tcells at IP of complete response patients exhibit a significantly higher CD4:CD8 ratio, validated in a larger cohort B-ALL patients (n= 47). Conversely, at the expansion peak, there is a clonal expansion of CD8+ effector memory and cytotoxic Tcells. Cytotoxic CARpos γδ-T cells expansion correlates with treatment efficacy validated in a cohort of B-ALL (n= 18) and diffuse large B cell lymphoma (DLBCL) patients (n= 58). Our data provide insights into the complexity of Tcell responses following CAR-T cell therapy and suggest drivers of immunotherapy response.

Comparative analysis of reduced toxicity conditioning regimens between fludarabine plus melphalan and fludarabine plus busulfex in adult patients with acute lymphoblastic leukemia.

Reduced-toxicity conditioning (RTC) regimens aim to mitigate regimen-related toxicity while maintaining anti-leukemic efficacy in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed outcomes of RTC regimens utilizing melphalan versus intravenous busulfan combined with fludarabine in adult acute lymphoblastic leukemia (ALL) patients. A retrospective analysis was conducted with 149 consecutive adult ALL patients (median age 51, range 18-60) in remission undergoing allo-HSCT. Patients received either fludarabine 150 mg/BSA plus 2 days of melphalan 70 mg/BSA (FM140, n = 76) from 2009 to 2015 or fludarabine plus 3 days of busulfan 3.2 mg/kg (FB9.6, n = 73) from 2016 to 2021. At 5 years post-HSCT, FM140 demonstrated superior disease-free survival (53.4% vs. 30.5%, p = 0.007) and lower cumulative relapse (27.4% vs. 46.8%, p = 0.026) than FB9.6. Five-year overall survival and non-relapse mortality did not significantly differ. FM140 exhibited a higher incidence of acute graft-versus-host disease (GVHD) grades II-IV (49.3% vs. 30.3%, p = 0.016), though rates of acute GVHD grades III-IV and chronic GVHD were similar. Multivariate analysis identified Philadelphia chromosome and minimal residual disease positive status, and FB9.6 conditioning as predictors of increased relapse and poorer disease-free survival. FM140 RTC regimen displayed significantly reduced relapse and superior disease-free survival compared to FB9.6 in ALL patients undergoing allo-HSCT, highlighting its current clinical utility.

Interpreting and Reporting Minimal Residual Disease Testing Data for Acute Lymphoblastic Leukemia Patients Using Next-Generation Sequencing

Interpreting and Reporting Minimal Residual Disease Testing Data for Acute Lymphoblastic Leukemia Patients Using Next-Generation Sequencing

Allogeneic CD5-specific CAR-T therapy for relapsed/refractory T-ALL: a phase 1 trial.

Refractory or relapsed T cell acute lymphoblastic leukemia (r/r T-ALL) patients have poor prognoses, due to the lack of effective salvage therapies. Recently, CD7-targeting chimeric antigen receptor (CAR)-T therapies show efficacy in patients with r/r T-ALL, but relapse with CD7 loss is common. This study evaluates a CD5-gene-edited CAR-T cell therapy targeting CD5 in 19 r/r T-ALL patients, most of whom had previously failed CD7 CAR-T interventions. CAR-T products were derived from previous transplant donors (Cohort A) or newly matched donors (Cohort B). Primary endpoints were dose-limiting toxicity at 21 days and adverse events within 30 days. Secondary endpoints were responses, pharmacokinetics and severe adverse events after 30 days. A total of 16 received infusions, 10 at target dose of 1 × 106 kg-1. All encountered grade 3-4 cytopenias and one had a grade 3 infection within 30 days. All patients (100%) achieved complete remission or complete remission with incomplete blood count recovery by day 30. At a median follow-up of 14.3 months, four received transplantation; three were in remission and one died of infection. Of 12 untransplanted patients, 2 were in remission, 3 relapsed, 5 died of infection and 2 of thrombotic microangiopathy. CAR-T cells persisted and cleared CD5+ T cells. CD5- T cells, mostly CD5-gene-edited, increased but remained below normal levels. These results suggest this CD5-specific CAR-T intervention has a high remission rate for T-ALL patients. Evidence also suggests the risk of late-onset severe infection may be mitigated with consolidative transplantation. This study provides insights that could help to optimize this promising intervention. ClinicalTrials.gov registration: NCT05032599 .

Study of Retinal and Peripapillary Vascular Changes in Newly Diagnosed Acute Leukemic Patients Using Optical Coherence Tomography Angiography

Abstract Background Leukemia is a neoplastic blood disorder characterized by an abnormal proliferation of leukocytes. Knowledge of ocular involvement in leukemia is important because the eye is the only site where the leukemic involvement of nerves and blood vessels can be directly observed, because the eye symptoms may be the initial mode of presentation of the systemic illness. Almost all ocular structures have been found to be involved in patients with various types of leukemia. Objective To detect retinal and peripapillary vascular changes in newly diagnosed acute leukemic patients prior to chemotherapy treatment using optical coherence tomography angiography. Patients and Methods This comparative cross sectional study was carried out on 52 eyes of 26 patients and 52 eyes of 26 healthy subjects. Optical coherence tomography angiography was performed for all subjects. Central macular thickness. Retinal nerve fiber layer thickness, ganglion cell complex thickness, superficial and deep vessel density, foveal avascular zone area and radial peripapillary capillaries density were measured and analyzed. Results Significant decrease in the superficial capillary plexus and the radial peripapillary capillary density in the cases group. The FAZ area is larger in the cases group. The central macular thickness is lower in the cases group. But the RNFL thickness, and C/D parameters were higher in the case group. However, there was no significant difference between the two groups regarding the GCC and the DCP density. Conclusion Acute leukemia causes decrease in superficial capillary plexus density and radial peripapillary capillaries density and decreased macular thickness with no affection in deep capillary vessel density.

Glutaredoxin-1 and Others Antioxidants Enzymes in Two Subtypes (B-cell and T-cell) of Acute Lymphoblastic Leukemia Patients

The 5-year event-free viability for acute lymphoblastic leukemia (ALL) have enhanced in many study groups due to modern paediatric clinical trials, however T-cell ALL results are still lagging by 5–10% in most studies. The goal of this study was to measure the Glutaredoxin-1(Grx1) as an antioxidant, and also to measure each of the methionine sulfoxide reductaseA(MsrA),myeloperoxidase(MPO), catalase(CAT), xanthine oxidase(XO), glutathione (GSH), albumin (Alb), and complete blood counts (CBC) in two subtypes (B-cell and T-cell) of ALL patients compared with control group between the ages of two and fifteen years. Revealed with the results of this study, Grx1, CAT, MDA levels increased statistically significantly in two subtypes of acute lymphocytic leukemia Patients compared with control group, but MsrA, GSH, Alb, and CBC levels declined considerably in two subtypes for patients compared with control group. Finally MPO have non-significant difference in compared.The study concluded that there was a high increase in the level of Grx1, which participates in rescuing blood components from the process of breakdown in which a decrease was observed n for two subtypes (B-cell and T-cell), in addition to a decrease in MsrA, GSH, which works to repair the damage occurring in the proteins of cell components, including blood components, malignant B cells are particularly sensitive in contrast to the T cell.

Comparison of the Effectiveness of Risk Models Used in Acute Promyelocytic Leukemia

Newly diagnosed acute promyelocytic leukemia (APL) patients were evaluated, and the effectiveness of the Sanz risk model was compared with other risk models developed for early mortality. To determine a simple, reliable, and highly effective risk model used in clinical practice for earlier recognition of high-risk patients at high risk of mortality. This is a retrospective analysis of 57 patients diagnosed with APL in our clinic between January 2002 and June 2019. Patients were grouped under the risk models of Sanz score, modified Sanz risk score, the International Society on Thrombosis and Haemostasis (ISTH), and other scores by Österroos et al. and Cai et al. We found higher white blood count (WBC) is independently associated with 30-day mortality [Odds ratio (OR): 1.030, 95% confidence interval (CI): 1.005 - 1.055, p= 0.017]. Albumin, another variable included in the multivariable model, was found non-significant (p= 0.055). The modified Sanz risk score had a sensitivity of 77.78% and specificity of 66.67% to predict 30-day mortality for high and ultra-high-risk patients [Area under the curve (AUC): 0.727, 95% CI: 0.514 - 0.939, p= 0.032]. Additionally, the AUC of the modified Sanz risk score was significantly higher than the Sanz risk score (p= 0.028). We found no significant difference between the AUC of the Sanz risk score and Österroos et al.’s, Cai et al.’s, and ISTH risk scores. Timely recognition of high-risk patients, taking appropriate protective measures, and administering more aggressive supportive care can help reduce the early mortality of APL patients. Sanz risk score and other scoring systems have been guiding the identification of high-risk APL patients. However, the most effective scoring system could not be determined at the end of the study. There is still a need for standardized scoring systems to identify high-risk patients more effectively, including comorbidities. Keywords: Acute promyelocytic leukemia, Early mortality, Modified Sanz risk score, Risk scores

Abstract C068: Primary adrenocortical insufficiency as a presenting symptom of acute myeloid leukemia

Abstract Introduction: Primary Adrenal Insufficiency (PAI), also known as Addison's disease, is a rare endocrinopathy resulting from the destruction or dysfunction of the adrenal cortex. It has an estimated increasing prevalence between 100 and 140 cases/million and an incidence of 4 cases per million/year. On the other hand, Acute Myeloid Leukemia (AML) is the most common leukemia among adults and accounts for about 80% of all cases. Even though our case is exceptionally rare, it highlights the coexistence of both conditions in the same patient and that PAI can be the presenting symptom of AML. Case Report: A 52-year-old female with a history of lower extremity cellulitis presented for evaluation after experiencing fever, chills, fatigue, night sweats, nausea, and dysphagia. On arrival, she had pharyngeal erythema with cervical lymphadenopathy. Her white blood cell count was 33,000. A CT chest revealed bilateral neck adenopathy and an enlarged left hilar lymph node. Bone marrow flow cytometry results were consistent with AML, CD33 positive with 68% blasts. Induction chemotherapy with gemtuzumab ozogamicin and dexamethasone IV was initiated. Meanwhile, she developed acute abdominal pain. A CT abdomen/pelvis revealed bilateral adrenal symmetric thickening, indicating adrenal dysfunction, a new finding compared to prior imaging. Endocrinology was consulted. Physical examination revealed hyperpigmented palmar creases, fatigue, and nausea, raising suspicion of adrenal insufficiency. Laboratory work showed sodium 134, basal ACTH 10, and morning cortisol levels less than 1 mcg/dl. An ACTH stimulation test confirmed PAI, with ACTH increasing from 26 to 47, cortisol from 9.2 to 11.7, aldosterone from 2 to 15, and high plasma renin activity 2.64. She continued on steroid therapy with monitoring of blood pressure and sodium levels for two weeks. She was eventually discharged with a medication plan and follow-up appointments with endocrinology and hematology/oncology. Discussion: The coexistence of PAI and AML in the same patient is rare. Obscure clinical presentations complicated the diagnosis. Symptoms like fatigue, weakness, and nausea are common in AML patients, but hyperpigmentation of the palmar creases is not. We recommend evaluating adrenal function in acute leukemia patients to avoid adrenal insufficiency crises. If adrenal insufficiency was considered later, early steroid discontinuation could have provoked an adrenal crisis. Monitoring should continue to determine if the concern is permanent or transient. Conclusion: High suspicion and early evaluation of adrenal function in all acute leukemia patients should be considered to avoid adrenal insufficiency as a later complication. Due to the rarity of the disease and non-specific early symptoms, PAI is frequently not considered, leading to delayed diagnosis and increased risk for adrenal crisis. Successful long-term therapy relies on adequate patient education, frequent assessment of basal and stimulated cortisol levels, testing of HPA axis integrity, and various imaging techniques. Citation Format: Maria Toustsoglou, Aliya M. Khan, Mehmet Hepgur, John McDonald, Rubens Sievert. Primary adrenocortical insufficiency as a presenting symptom of acute myeloid leukemia [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C068.

Comparable Results Between 8 and 12 Gray TBI in Combination With Fludarabine and Post-Transplant Cyclophosphamide in MRD-Negative but Not in MRD-Positive Acute Lymphoblastic Leukemia Patients Transplanted in First Complete Remission.

The optimal TBI dose for ALL patients undergoing allogeneic SCT is still not clearly defined. Single-center retrospective analysis of high-risk ALL patients in CR1 treated with 8 Gy (n = 22) or 12 Gy (n = 50) TBI in combination with fludarabine and PTCy. Median patient age in the 8 Gy TBI cohort was 63 (37-79) and 37 (18-56) in the 12 Gy TBI cohort and median follow-up time was 21 months (range 1-92). OS and LFS at 2 years after 8 Gy were 65% and 55% versus 74% and 74% after 12 Gy (p = 0.3 and p = 0.2, respectively). CIR and NRM at 2 years were 27% and 14% after 8 Gy versus 4% and 20% after 12 Gy (p = 0.004 and p = 0.4, respectively). MRD-positive (+) patients (n = 26) receiving 12 Gy (n = 19) showed better OS (p = 0.01), LFS (p = 0.009), GRFS, lower CIR (p = 0.02), and similar NRM than did MRD+ patients receiving 8 Gy (n = 7). MRD-negative (-) patients (n = 38) receiving 12 Gy (n = 27) had similar OS, LFS, GRFS, lower CIR, and higher NRM (p = 0.04) than did MRD- patients receiving 8 Gy (n = 11). Our study demonstrates that 8 Gy TBI in comparison to 12 Gy TBI results in low NRM but a high relapse rate with similar OS, LFS, and GRFS. In MRD+ high-risk ALL patients, allogeneic SCT with 12 Gy TBI leads to improved OS, LFS, GRFS, and a low relapse rate. Prospective studies comparing the different treatment regimens with larger MRD patient cohorts are needed to confirm this data.

Effect of Combined Exercise and Nutrition Interventions During Inpatient Chemotherapy in Acute Leukemia and Malignant Lymphoma Patients: A Randomized Controlled Trial

The aim of the present study was to determine the effectiveness of combined exercise and nutrition interventions on physical function and quality of life (QOL) in patients with acute leukemia or malignant lymphoma (ML) during inpatient chemotherapy. The study was a randomized controlled trial where patients with acute leukemia or ML who were receiving inpatient chemotherapy and exercise therapy were divided into an intervention group (IG) and a control group (CG). Both groups underwent resistance training and aerobic exercise. The patients in the IG were instructed to take nutritional supplements twice a day. Assessment items were muscle strength (handgrip strength and knee extension strength), 6-min walking test, skeletal muscle mass, QOL, nutritional status, and fatigue. Two-way analysis of variance showed a significant interaction for bilateral handgrip strength and knee extension strength. No significant interactions were found for the other items. The results of the present study showed improved muscle strength in the IG compared to the CG, indicating the effectiveness of combined exercise and nutrition interventions during inpatient chemotherapy in patients with acute leukemia or ML.

Clinical analysis of 7 cases of acute B cell lymphoblastic leukemia with t (17;19) (q21-22;p13)/TCF3-HLF fusion

A retrospective analysis of the clinical data of seven acute B-lymphoblastic leukemia (B-ALL) patients with TCF3-HLF fusion gene-positive admitted to the First Affiliated Hospital of Soochow University from June 2017 to August 2022 was conducted to summarize their clinical features and prognoses. The seven B-ALL patients comprised four males and three females, with a median age of 18 (11-33) years. Five patients tested positive for CD33 expression, and four patients had a normal karyotype. Two patients had hypercalcemia at the initial diagnosis, and one patient developed hypercalcemia at relapse. Six patients presented with coagulation dysfunction at diagnosis. After induction chemotherapy, five out of seven patients achieved complete remission, of which four subsequently relapsed. Two patients did not achieve remission even after two rounds of induction chemotherapy, with one achieving complete remission after treatment with blinatumomab immunotherapy. Three patients underwent chimeric antigen receptor T cell therapy, whereas three patients subsequently underwent hematopoietic stem cell transplantation. Five patients died, while two patients survived with sustained complete remission. TCF3-HLF-positive B-ALL is rare and has a high relapse rate and poor prognosis.

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.

Paired comparisons of venetoclax concentration in cerebrospinal fluid, bone marrow, and plasma in acute leukemia patients.

Venetoclax, a small molecule inhibitor of BCL-2, has demonstrated efficacy in treating acute leukemias and has been recommended as one of the first-line anti-leukemia therapies. Although venetoclax has been suggested to probably possess the ability to penetrate the central nervous system (CNS), current data to elucidate the characteristics of venetoclax in cerebrospinal fluid (CSF), bone marrow (BM), and plasma are still lacking. This study investigated the real-world characteristics of venetoclax concentrations in CSF, BM, and plasma in acute leukemia patients. Thirteen acute leukemia patients treated with venetoclax were included, with paired samples of CSF, BM, and plasma collected and venetoclax concentrations measured using LC-MS/MS. With the results, the median venetoclax concentrations were 2030 ng/mL in plasma, 16.7 ng/mL in CSF, and 1390 ng/mL in BM. The percentages of CSF/plasma and BM/plasma were 0.74% and 70.37%, respectively. While no direct correlation was observed between CSF and plasma venetoclax levels, there was a trend toward an improved CSF/plasma percentage over time following the last administration of venetoclax. In contrast, a strong correlation was found between BM and plasma levels. This study demonstrated that venetoclax could reach its effective concentration in most patients, suggesting its potential clinical utility in the management of CNS involvement in acute leukemia.