Treatment Of Acute Leukemia Research Articles

Hypoxia-initiated Cysteine-rich protein 61 secretion promotes chemoresistance of acute B lymphoblastic leukemia cells.

The drug resistance is a major obstacle in acute B-lymphoblastic leukemia (B-ALL) treatment. Our previous study has indicated that increased levels of Cysteine-rich protein 61 (Cyr61) in the bone marrow can mitigate the chemosensitivity of B-ALL cells, though the specific source of Cyr61 in the bone marrow remains unknown. In this study, we aimed to investigate whether hypoxia can induce Cyr61 production in B-ALL cells, delineates the underlying mechanisms, and evaluates the effect of Cyr61 on the chemosensitivity of B-ALL cells under hypoxia conditions. The results indicate that hypoxia promotes Cyr61 production in B-ALL cells by activating the NF-κB pathway. Increased Cyr61 expression appears to reduce the chemosensitivity of B-ALL cell to vincristine (VCR) and daunorubicin (DNR) through autophagy under hypoxia. Notably, inhibition of Cyr61 restores the chemosensitivity of B-ALL cells to both chemotherapeutic agents. This study is the first time to report that hypoxia decreases the chemosensitivity of B-ALL cells by inducing Cyr61 production, suggesting that targeting Cyr61 or its associated pathways could potentially improve the clinical response of B-ALL patients.

In vitro bioaccessibility and intestinal transport of retinoic acid in ethyl cellulose-based microparticles and impact of meal co-ingestion

The development of carrier-based delivery systems for oral administration of retinoic acid (RA), that provides its release and absorption at intestinal level, is of major relevance in the treatment of acute promyelocytic leukemia. The aim of this work was to evaluate RA bioaccessibility and intestinal transport on ethyl cellulose (EC)- and EC + polyethylene glycol (ECP)-based microparticles and to understand the impact of meal co-ingestion by applying in vitro assays. RA-loaded microparticles were produced by spray-drying with an encapsulation efficiency higher than 90 % for both formulations. The gastric bioaccessibility of RA (after in vitro static digestion of RA-loaded particles) was lower than 3 % for both types of microparticles, with and without meal co-ingestion. Whereas after intestinal digestion, RA bioaccessibility was significantly higher and affected by the type of microparticles and the presence of meal. The digestion of EC- and ECP-based microparticles without diet enabled a significantly higher bioaccessibility of RA when compared to the one recorded for the co-digestion of these microparticles with diet. Herein, RA bioaccessibility decreased from 84 ± 1 to 24 ± 6 % (p < 0.0001) for microparticles EC and 54 ± 4 to 25 ± 5 % (p < 0.001) for microparticles ECP. Moreover, comparing both types of microparticles, RA bioaccessibility was significantly higher for EC-based microparticles digested without diet (p < 0.0001). At last, the bioaccessibility of RA was similar among EC- and ECP-based microparticles when co-digested with diet. Intestinal transport experiments performed in Caco-2 monolayers evidenced that after 2 h of transport the amount of RA retained in the apical compartment was higher than the amount that reached the basolateral compartment evidencing a slow transport at intestinal level that was higher when RA is spiked in the blank of digestion and the meal digestion samples compared to RA dissolved in HBSS (44 ± 6 (p < 0.01) and 38 ± 1 (p < 0.05) vs 26 ± 2 %, respectively).

Arsenic trioxide: applications, mechanisms of action, toxicity and rescue strategies to date.

Arsenical medicine has obtained its status in traditional Chinese medicine for more than 2,000years. In the 1970s, arsenic trioxide was identified to have high efficacy and potency for the treatment of acute promyelocytic leukemia, which promoted many studies on the therapeutic effects of arsenic trioxide. Currently, arsenic trioxide is widely used to treat acute promyelocytic leukemia and various solid tumors through various mechanisms of action in clinical practice; however, it is accompanied by a series of adverse reactions, especially cardiac toxicity. This review presents a comprehensive overview of arsenic trioxide from preclinical and clinical efficacy, potential mechanisms of action, toxicities, and rescue strategies for toxicities to provide guidance or assistance for the clinical application of arsenic trioxide.

Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party

Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n=87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p=0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p=0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p=0.01). Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. There was no external funding source for this study.

Idarubicin versus Doxorubicin in Acute Myeloid Leukemia: A Parallel Randomized Trial with Pharmacoeconomic Analysis

Background: Acute Myeloid Leukemia (AML) is the most common form of acute leukemia among adults. Treatment of acute leukemia has been divided into induction chemotherapy and post-remission therapy. The goal of induction chemotherapy, that consists of anthracycline and cytarabine, is to achieve morphologic complete remission (CR), but the main problem is that it has a high economic burden. Idarubicin is the anthracycline of choice used in AML, while doxorubicin, is mainly used in other types of cancer. The aims of this study were evaluating the use of doxorubicin versus idarubicin in the induction phase for the treatment of AML and analysis the impact of the adoption of this anthracycline in Egypt’s public health system. Methods: A randomized controlled trial was undertaken in 244 patients with AML. A decision tree was developed based on the clinical outcome of the study, safety and efficacy, aiming to get the expected cost of doxorubicin compared with idarubicin in AML management. Results: In the doxorubicin group, 52.5% had a CR, versus 49.2 % in the idarubicin group (P=0.6). The most common toxicities among the 2 groups were febrile neutropenia, diarrhea and vomiting. Oral mucositis (OM) was higher in the doxorubicin group (70.8% vs 37%, P=0.0001), while invasive fungal infections were greater in the idarubicin group (75% vs 88.7%, P=0.004). Doxorubicin arm had a lower cost than idarubicin arm in treatment success group (39,492 LE vs 44,323 LE). Conclusion: Doxorubicin provides a treatment option with comparable efficacy, toxicity profile and survival rates at a lower cost compared to the traditional treatment, idarubicin.

Analysis of acute leukemia complications in children at the disease onset and during induction

Background. Despite the progress achieved in the treatment of acute leukemia (AL) in children, complications, both at the disease onset and those resulting from antitumor therapy, remain the main cause of early mortality, which varies from 3 to 20 %.Aim. To assess the frequency, severity, etiology, risk factors, and outcomes of AL complications in children at the disease onset and during induction chemotherapy (ICT).Results. The study analyzed 92 cases of AL in children aged from 5 months to 17 years. 75 patients had acute lymphoblastic leukemia (ALL), 17 had acute myeloid leukemia (AML). In 1 (1.3 %) patient with ALL and in 5 (29.4 %) with AML, a concomitant diagnosis was Down syndrome. At the AL onset, 34 (36.9 %) patients were diagnosed with infection, of which 27 (36 %) and 7 (41.2 %) patients had ALL and AML, respectively. In both cohorts, febrile neutropenia (55.5 %; n = 15 vs. 14.3 %; n = 1), pneumonia (25.9 %; n = 7 vs. 71.4 %; n = 5), enterocolitis (7.4 %; n = 2 vs. 14.3 %; n = 1) predominated in both cohorts for AML and ALL, respectively. Due to uncontrolled infection in 5 (29.4 %) patients with AML and 13 (17.3 %) with ALL, ICT was delayed until the condition stabilized and the infection was controlled. During ICT, the incidence of infectious complications was 81.3 % (n = 61) and 100 % (n = 17) in patients with ALL and AML, respectively. The most common types were enterocolitis (41.2 %; n = 7 vs. 34.4 %; n = 21), febrile neutropenia (29.4 %; n = 5 vs. 37.7 %; n = 23), pneumonia (47.1 %; n = 8 vs. 29.5 %; n = 18), catheter-associated bloodstream infection (11.8 %; n = 2 vs. 8.2 %; n = 4) in AML and ALL, respectively. By etiology, bacterial infections predominated, accounting for 32 % (n = 8) and 36.8 % (n = 35) in the AML and ALL groups, respectively. More cases of invasive mycoses were reported in AML patients – 23.5 % (n = 4) versus 14.8 % (n = 11). Non-infectious complications were diagnosed in 32.6 % (n = 30) of patients with a predominance in ALL group (34.6 %; n = 26 vs. 23.5 %; n = 4). Hyperleukocytosis at the leukemia onset caused such complications as leukostasis (11.8 %; n = 2) and acute tumor lysis syndrome (11.8 %; n = 2). The most common post-cytostatic complications in ALL were vincristine polyneuropathy (61.5 %; n = 16), hemorrhagic syndrome (15.4 %; n = 4), methotrexate-induced encephalopathy (15.4 %; n = 4), acute tumor lysis syndrome (11.5 %; n = 3). In AML cases, the most common type of non-infectious complications were hemorrhagic (75 %; n = 3). Induction mortality in the ALL group was 2.6 % (n = 2), in the AML group it was higher – 11.8 % (n = 2), however, it should be noted that all deaths were registered in children with Down syndrome. The main cause of mortality in both groups was severe infections secondary to chemotherapy-induced hematopoietic aplasia. There were no deaths associated with non-infectious complications or chemotherapy-induced toxicity.Conclusion. The main type of toxicity in children at the AL onset and during ICT remains infectious complications of various etiologies, while in AML patients a higher frequency of invasive mycoses is registered (23.5 % vs. 14.8 %). Despite the high incidence of chemo-induced toxicity, the mortality rate in ALL remains low, amounting to 2.6 % in our cohort. In the AML group, mortality was higher – 11.8 %, but it should be noted that all cases occurred in patients with Down syndrome. There were no deaths due to non-infectious complications in any of the study cohorts.

Arsenic As a Therapy in Cancer: A Short Review

Acute myeloid leukemia (AML) is a cancer of the blood and bone marrow in which the bone marrow produces immature white blood cells, called myeloblasts. AML (acute myeloid leukemia) prevents these myeloblasts from developing into mature, healthy blood cells, as a result they accumulate and crowd out other healthy cells, such as red blood cells, white blood cells, and platelets. Sometimes acute myeloid leukemia(AML) can also spread to other organs, such as the brain, spinal cord, liver, or spleen. Without prompt treatment, AML can be life-threatening. There has been 2–3 cases per 100,000 people annually. Compared to women, men are more likely to experience it. acute myeloid leukemia(AML) makes up roughly 3% of all malignancies, with a median age of 32 years, according to the population-based Cancer Registry for Delhi. Among the various drugs for treatment of leukemia arsenic has been one of the most effective in treating it. Arsenic has been known as poison over 4000years.Long-term exposure to as has led to various adverse effects on health, but after the discovery of chemo therapeutic properties of As the understanding has been changed from poison to drug. Arsenic trioxide (ATO) is the most active antileukemia agent in treatment of acute promyelocytic leukemia(APL). Arsenic trioxide (ATO) cause degradation of PML RAR alpha promoting differentiation. Not only this but also arsenic induces apoptosis via mitochondrial caspase or formation of reactive oxygen species (ROS) and deleting GSH content of cell. This article focuses on the therapeutic effect of arsenic on acute myeloid leukemia

Ponatinib-induced dilated cardiomyopathy: a case report

Ponatinib is a third-generation tyrosine kinase inhibitor with potent efficacy in the treatment of acute and chronic leukemia. Despite having an effective and sustained activity in all BCR-ABL1 mutations, it may cause cardiovascular adverse effects. Here we report a 56-year-old male patient with Chronic myeloid leukemia and no prior cardiac disorder who developed acute heart failure under ponatinib treatment. Guideline-recommended medical treatment for heart failure was initiated. Coronary angiography to exclude ischemic heart disease revealed no coronary stenosis. Cardiac magnetic resonance imaging showed findings consistent with non-ischemic dilated cardiomyopathy. After interruption of ponatinib treatment, cardiac evaluation showed improvement in left ventricular ejection fraction. Patients on Ponatinib therapy should be closely monitored for signs and symptoms of heart failure.

Changes in White Blood Cell Counts Early during Treatment of Acute Leukemia Using Differentiating Chemotherapies

Background: Differentiation syndrome (DS) is a life-threatening complication that can occur with a number of therapies used for the treatment of acute myeloid leukemia (AML). It is best characterized in patients treated with All-trans retinoic acid (ATRA) and Arsenic for acute promyelocytic leukemia (APL), or for patients receiving an IDH inhibitor for IDH1/2 mutant AML, but can also be seen with other therapies such as with FLT3 inhibitors, and in novel therapies under development such as menin inhibitors. It is critical to identify DS early, as corticosteroids can mitigate complications. The diagnosis of DS is made by recognizing a constellation of symptoms, typically including a rising white blood cell count, peripheral edema, rash, shortness of breath, pulmonary edema, and fevers. We evaluated white blood cell (WBC) count changes during treatment according to whether patients DS or not on chemotherapy. Methods: We identified adult patients who received ATRA+Arsenic for newly diagnosed APL, as well as patients with AML harboring a mutation in IDH1 or IDH2 who were treated with monotherapy IDH inhibitors (enasidenib or ivosidenib) at any point during their treatment for active AML and treated at MGH. Patients were treated at MGH between 2015 and 2023. Patients were 18 or older and had a confirmed pathological diagnosis. We interrogated the medical record to identify patients with clinical documentation of DS during treatment, as well as the treatments used for management and clinical complications. Descriptive statistics were used to identify differences in median WBC counts between patients with DS and those without DS, and comparisons were made using Wilcoxon or chi square testing as appropriate. Results: We identified 33 patients with APL who received ATRA+Arsenic, and 35 patients with AML harboring an IDH1/2 mutation treated with monotherapy IDH inhibition. Our analysis revealed that 26% (18/68) of patients had clinical documentation of differentiation syndrome, including 21% (14/33) of patients treated with ATRA+Arsenic and 11% (4/35) of patients on IDH inhibitors. In APL, the median day of a recorded diagnosis of DS was 4 days after treatment start (range 1-14 days). Patients with APL who developed DS had a higher initial WBC at treatment start compared to those who did not develop DS (6.7 vs 1.05 K/uL, p=0.03). There was no difference in hemoglobin, platelets, ANC, and percentage of peripheral blood blasts (Table 1). The WBC in DS patients started rising during the first week of treatment and peaked on Day 15 (Figure 1). Regarding treatment approaches for DS, the majority of patients were treated with steroids, (78%, 11/14) while 43% (6/14) received cytoreduction, most commonly with gemtuzumab. In IDH-mutant AML, the median day of a recorded diagnosis of DS was 35 days after treatment start (range 16-69 days). Patients with IDH-mutated AML on IDH Inhibitor monotherapy who experienced DS had a similar finding of an early temporal rise in WBC to those with APL on ATRA+Arsenic, although this rise started on day 12 and peaked on day 16 of monotherapy. Of note, these peaks occurred prior to the documentation of a clinical DS diagnosis. In contrast to APL, patients with IDH-mutant AML who developed DS had a lower baseline ANC (p=0.03) and higher percentage of peripheral blasts circulating than those without DS (p=0.03). All patients with IDH inhibitor associated DS received dexamethasone. Discussion: Patients with DS during treatment for APL on ATRA+Arsenic, as well as patients with DS with IDHmut AML on IDH inhibitors, had similar early peaks in the WBC count, occurring around 2 weeks from the start of treatment. In this small group, the IDHmut AML showed a rise in WBC that preceded the actual DS diagnosis. Understanding the timing of and risk factors for DS may help to identify at risk patients early for mitigation strategies.

Acute Abdominal and Pelvic Complications in Patients with Non-Promyelocytic Acute Myeloid Leukaemia Undergoing Intensive Induction Chemotherapy Are Associated with Favorable Prognosis

Acute abdominal abnormalities are relatively uncommon during the treatment of acute leukaemia but, historically, have been associated with high mortality rates (Hawkins JA, Mower WR, Nelson EW. Acute abdominal conditions in patients with leukaemia. Am J Surgery 1985;150:739-742). Given the improvement in diagnostic and supportive measures for patients with acute myeloid leukaemia (AML) over time, we aimed to determine the rate and outcomes of acute abdominal and pelvic complications in a cohort of AML patients at our hospital. We retrospectively reviewed the medical records, radiology reports and laboratory test results of 70 consecutive newly diagnosed, non-promyelocytic AML patients undergoing intensive induction chemotherapy between January 2012 and December 2019. Seventeen patients developed 22 episodes of acute abdominal or pelvic pathology and were investigated by radiology (abdominal X ray, CT scan and/or MRI). Table 1 summarises the underlying causes for these complications, as well as neutrophil count and platelet count at time of presentation. Colitis was the most common complication, occurring 6 times. The neutrophil count was &amp;lt;1x10 9/L in 15 of the 22 episodes. Platelet count &amp;lt;20x10 9/L occurred in 8 of the episodes, including the 2 cases of ureteric obstruction by clot. All complications resolved completely with conservative management, except for 1 patient who required surgical drainage of an intraperitoneal and psoas muscle abscess in addition to intravenous broad spectrum antibiotics. In conclusion, acute abdominal and pelvic complications were relatively rare in our cohort of patients. All but 1 of these episodes resolved with conservative management alone. These results suggest that, with current diagnostic and therapeutic measures, the prognosis for non-promyelocytic AML patients who develop such complications is favorable.

Real-World Validation of the European Leukemia Network 2022 Risk Stratification in Acute Myelogenous Leukemia

Background: The 2017 European LeukemiaNet (ELN 2017) guidelines have become foundational for the risk stratification, prognostication, and treatment of acute myelogenous leukemia (AML). The updated 2022 European LeukemiaNet (ELN 2022) guidelines include additional cytogenetic abnormalities and genetic mutations for risk group assignment. It remains unknown how these updated guidelines compare for risk stratification and prognosis. Methods: We studied (N=287) adults with newly diagnosed AML from MedStar Georgetown University, MedStar Washington Hospital Center, and Baylor University Medical Center from 2012 to June 2023. Patients were stratified as favorable (fav), intermediate (int), or adverse (adv) risk according to ELN 2017 and ELN 2022 criteria. Overall survival (OS) was compared by age, race, and sex. Statistical analysis performed with SAS. Results: Median age was 65+16 years with a predominance of males (N=168, 59%). African-Americans (AA) composed 15% (N=44) of the cohort. Myelodysplastic-related mutations were present in 33 patients (15%), whereas the prevalence of epigenetic mutations was 25% (N=55). By ELN 2017 criteria, 19 (7%) patients were characterized as fav, 64 (23%) as int, and 198 (70%) as adv risk. Using ELN 2022 criteria, 18 (6%) patients were categorized as fav, 52 (19%) as int, and 211 (75%) as adv risk. Kaplan-Meier (KM) curves revealed a median overall survival of 200 days (d), 400 d, and 1532 d in the adv, int, and fav risk groups, respectively (log-rank p&amp;lt;0.001) by ELN 2017 criteria. Median OS was 379 d, 527 d, and 1552 d for the adv, int, and fav groups, respectively (log-rank p&amp;lt;0.001) in the ELN 2022 cohort. Stratifying by age &amp;lt;60 years, median OS was 390 d in the adv group and 832 d in the int group (log-rank p=.021)by ELN 2017 criteria,as compared to 350 d in the adv group and 757 d in the int group (log-rank p=.0012) by ELN 2022 criteria.Among those &amp;gt;60 years of age, median OS was 244 d and 349 d in the adv and int groups, respectively by ELN 2017 criteria (Anova p&amp;lt;0.25). In the ELN 2022 cohort, median OS among those &amp;gt;60 years of age was 284 d for the adv group and 209 days in the int group (Anova p&amp;lt;0.62). Among females, median OS in the adv group was 224 d and 342 d in the int group by ELN 2017 criteria (Anova p=0.4). In the ELN 2022 cohort, median OS among females was 214 d in the adv group and 421 d in the int group (Anova p=.13). Median OS among male patients in the ELN 2017 cohort was 324 d for those of adv risk and 623 d for those of int risk (Anova p&amp;lt;0.004). In the ELN 2022 cohort, median OS in males was 352 d and 563 d in the adv and int groups, respectively (Anova p&amp;lt;0.07) . In the ELN 2017 cohort, median OS was 259 d in AA patients as compared to 719 d in non-AA patients; this was not statistically significant (Anova p=0.16). Comparatively, in the ELN 2022 cohort, median OS for the AA patients was 153 d as compared to 212 d for the non-AA patient population (Anova p=0.86) .Conclusions: In this real-world dataset, the updated ELN 2022 guidelines reproduce differential survival for proposed favorable, intermediate, and adverse risk categories. When considering time to endpoint survival [Kaplan Meier curves] in our study, ELN 2022 seems to lack the ability to clearly discriminate among the adverse and intermediate risk subgroups. It is possible that patients seen in academic institutions not participating in FLT3 directed therapy trials retained inferior survival whereas similar patients fared better through early enrollment in trials using molecular targeted therapy. Finally, neither ELN 2017 nor ELN 2022 discriminate survival in AA populations for either adverse or intermediate subgroups. Efforts should be directed to develop novel risk stratification schemas to better encapsulate this vulnerable population.

Improving Clinical Outcomes in APL: Weight Maintenance Strategies to Reduce Complications during Induction Therapy

Introduction: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the treatment of acute promyelocytic leukemia (APL). However, despite a remission rate exceeding 96% and 5-year disease-free and overall survival rates reaching 96% and 88%, respectively, death during induction in clinical trials occurs in 4% of patients. Differentiation syndrome (DS) is a significant complication during ATRA and/or ATO induction therapy. The signs and symptoms of DS include dyspnea, unexplained fever, weight gain greater than 5 kg, unexplained hypotension, acute renal failure, and the presence of infiltrates and/or pleural/pericardial effusions on chest radiographs. The occurrence of 4 or more of these findings is considered diagnostic. In APL, patients are at risk for fluid overload secondary to multiple blood product transfusions and intravenous hydration. Acute hypoxic respiratory failure (AHRF) and septic shock are common indications for ICU admission in this patient population. At our institution, we monitored patients' daily weights intending to maintain the admission weights with diuresis or intravenous fluids as needed. We assessed the impact of maintaining euvolemia and daily weight monitoring to reduce the incidence of DS and ICU admissions among the APL patients treated at our institution. Methods: A retrospective chart review was conducted on 60 patients with APL who received treatment at our institution between 2016 and 2021. A total of 17 patients who were either not induced at our institution or did not have daily weight monitoring were omitted. Patient demographics, median age at diagnosis, hospitalization complications, ICU admission, and DS were analyzed. Patients were grouped based on if their daily weights were maintained at their admission level, plus or minus 3 kilograms. Only standing weights and weights before ICU transfer were considered. Results: Of the 43 patients who underwent induction therapy at our institution, 25.6% (n=11) had their weight maintained via diuresis and intravenous fluids, and none required ICU admission. Of the remaining 32 patients, 34.4% (n=11) were transferred to the ICU. Of the 11 patients transferred to the ICU, 6 were for AHRF, 2 were for septic shock, 1 was for adrenal insufficiency with vasopressor requirements, 1 was for subdural and epidural hemorrhage, and 1 was for intracranial hemorrhage. Maintaining euvolemia and weight within 3 kilograms of admission level correlated with fewer ICU admissions (OR = 0.085, 95% CI = 0.0046-1.5761) (p=0.0980). Of the 11 patients whose weights were followed and maintained, 9% (n=1) developed DS. Of the 32 patients who did not have their weights followed and maintained, 28% (n=9) met the criteria for DS (OR = 0.256, 95% CI = 0.028-2.296) (p=0.223). Conclusion: Volume overload is a significant concern in APL and its treatment. Our findings suggest that maintaining euvolemia and daily weight monitoring can lead to effective management of patients on the floor and may prevent unnecessary ICU transfers. Although there are limitations to the study due to its retrospective nature and low sample size, the cost-effectiveness and noninvasive methods of maintaining euvolemia support its potential addition to the standard treatment protocols. While maintaining euvolemia and monitoring daily weights is a simple intervention, it represents a promising strategy to improve the management of APL patients during induction therapy by decreasing the incidence of DS and ICU admissions. Further prospective studies are warranted to validate and expand upon these findings.

Fludarabine, Cytarabine (ARA-C) and Pegylated Erwinase (PEGCRISANTASPASE) in Patients with Relapsed or Refractory Leukemia

Background: Asparaginase, which depletes serum asparagine by breaking it down into asparagine, is part of the standard of care along with chemotherapy, in adolescent and young adult patients with acute lymphoblastic leukemia (ALL). Leukemic blasts require asparagine for survival, therefore serving as an important therapeutic target; among the mechanisms of resistance includes the upregulation of expression of asparagine synthetase (AS) (gene located in chromosome 7). Depletion of asparagine and more recently glutamine may also have an important role in the treatment of acute myelogenous leukemia, either alone or in combination with chemotherapy. Pegcristaspase (PegC) is a long-acting pegylated asparaginase derived from Erwinia that also has a glutaminase activity. We hypothesize that the combination of chemotherapy and PegC might overcome resistance and provide therapeutic benefit pts with relapsed and/or refractory leukemias. Methods: This is a phase Ib study of fludarabine, cytarabine (ara-c), and PegC in patients with relapsed or refractory leukemia (NCT 04526795). Pts received induction cycle (C) (defined as 5 weeks) with PegC on day (D) 1 and 15 as single agent. Fludarabine (30mg/m 2/D) and 4 hours later Cytarabine (1.5g/m 2/D) are given D 8 to D 11. A 3+3 dose-escalation approach was implemented to evaluate 3 different dose levels for pegcrisantaspase (level -2: 350 IU/m 2; level -1: 500 IU/m 2; and level 1: 750UI/m 2). Once the MTD is established, an expansion cohort to further evaluate safety and efficacy was opened. Endpoints included safety, overall response rate (complete remission [CR], CR with incomplete count recovery [CRi], partial remission [PR], or morphologic leukemia free state [MLFS] ) of fludarabine, araC, and pegcrisantaspase in patients with relapsed and refractory leukemias. Response was denoted as per the ELN 2017 criteria. Results: From April 2021, 15 pts have been treated on the trial, 12 (80%) pts with AML, 2 pts (13%) with ALL (one patient was Ph+ ALL), and 1 patient with isolated myeloid sarcoma. The median age was 46 years (range, 22-61), median bone marrow blasts were 37% (1-90) . 9/15 (60%) patients had complex karyotype. Patient characteristics are summarized in Table 1. The median lines of prior therapy was 4 (range, 1-9). Six pts were treated at dose level -1 and then at dose level 1. There were no dose limiting toxicities to proceed to the expansion cohort. From the 15 treated pts, 2 patients from the dose level -1 died from sepsis related to disease progression within the first 4 weeks. Overall, 3 pts (20%) responded to treatment (2CRp and 1 CRi). The patient with Ph+ B-ALL achieved CRp, proceeded to SCT, and remains alive in remission. The 2 other patients (both with AML) relapsed after 6 weeks and 4 months, respectively. The median overall survival was 2.6 months. (Figure 1) A total of 29 adverse events (AE) were noted in 13/15 patients. The most common AEs was grade ≥ grade 3 neutropenic fever (10 pts, 67%; including 2 grade 5 events). The only possibly related AE was tumor lysis syndrome in one patient, grade 3, and was successfully managed per institutional guidelines. Conclusion: In this high-risk, heavily treated population, the combination of fludarabine, cytarabine, and PegC is feasible. Responding patients included 2 AML and 1 ALL. Further exploratory analysis about the relation between response and asparagine depletion as well as specific sensitive subsets could clarify which patients might benefit the most from this combination.

Impact of Arsenic Trioxide in the Treatment of Higher Risk Acute Promyelocytic Leukemia

INTRODUCTION: Acute promyelocytic leukemia (APL) accounts for 5-8% of all cases of acute myeloid leukemia (AML). The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) without chemotherapy is currently the reference treatment of standard APL (ie with baseline white blood count (WBC)&amp;lt;10 G/L), curing about 90% of the patients. However, the prognosis of high-risk APL (ie with WBC&amp;gt;10 G/L) remains more challenging, with higher rates of early death and relapse. Here we compared the French practices for the treatment of high-risk APL patients whether patients were treated with ATRA-Chemo or ATRA-ATO according to physician decision, and evaluate the response rates, overall survival (OS) and leukemia-free survival (LFS) in the real-life settings. PATIENTS AND METHODS: ATO (in combination with ATRA) became accessible in France for the first line treatment of standard risk APL in 2012, but some patients with high-risk APL also received the same combination (generally with some form of cytoreductive chemotherapy) from that date. We retrospectively analyzed cases of high-risk APL diagnosed between 2010 and 2021 in 12 French centers, constituting a cohort of 135 patients with diagnostic of APL confirmed by cytogenetic, FISH and molecular biology assays. RESULTS: Among the 135 patients with WBC&amp;gt;10 G/L, 88 (65%) were classified as APL variant according to FAB classification. Median age was 46 years (range 18-89) and 62 % were male. Median diagnostic WBC was 39.1 G/L (range 10-270) and median platelet count was 27 G/L (range 5-344). At diagnosis, 112 patients (83%) had hemorrhagic manifestations and disseminated intravascular coagulation (DIC) was observed in 124 patients (92%). Pulmonary and cerebral leucostasis were reported in 10 (7%) and 14 (10%) patients, respectively. Eighty-five patients received corticosteroid prophylaxis (81 (95%) with Dexamethasone and 5 (5%) with Prednisolone). Induction therapy consisted in ATRA-ATO for 50 patients (38%) while 85 patients (62%) were treated with ATRA combined with chemotherapy (anthracycline and cytarabin) but without ATO. All patients treated with ATO were cytoreduced: 7 with Hydroxyurea (14%), 17 with Idarubicin (34%) and 26 with both (52%). 29 patients treated without ATO during induction were cytoreduced with Hydroxurea (34%). Most patients experienced one or more adverse events during induction, including sepsis (49 in the ATO group versus 71 in the non ATO group, 98% versus 83.5%, p=0.01), differentiation syndrome (20 in the ATO group versus 27 in the non ATO group, 40% versus 31.7%, p=0.33), transaminase increased (14 in ATO group versus 11 in the non ATO group, 28% versus 12.9%, p=0.03), and bleeding (7 in the ATO group versus 13 in the non ATO group, 14% versus 15.3%, p=0.8). Following induction, 110 patients (81%) achieved complete remission (CR): 45 in the ATO group and 65 in the non ATO group (90% versus 76.4%, p=0.052). One patient (receiving ATRA with chemotherapy) was refractory, and 24 patients experienced early death (5 in the ATO group and 19 in the non ATO group, 10% versus 22.3%, p=0.069) mostly due to hemorrhage or sepsis. Median time between diagnosis and early death was 4.5 days (0-42). Relapse was observed in 6 (5.5 %) patients (5 patients treated without ATO and 1 patient with ATO during induction). After a median follow-up of 34.6 months (0-121.1), OS at 3 years was significantly higher for the ATO group (89.9% (81.8-98.7) versus 75.1% (66.3-84.9) for the non ATO group, p= 0.035, Figure). LFS at 3 years was significantly higher for the ATO group (87.6% (78.7-97.4) versus 71.2% (62-81.7) for the non ATO group, p=0.028). CONCLUSIONS: The survival outcomes were significantly poorer in high-risk APL patients treated without ATO during induction, regardless of the cytoreduction strategy. The toxicity profile of ATO was acceptable. Combining ATO and ATRA limits the use of cytotoxic chemotherapy, which could reduce myelosuppression and long-term complications such as cardiotoxicity and secondary myeloid neoplasms. Early disease-related mortality, due to haemorrhagic or infectious complications, remains the major issue for these patients but tend to be reduced in those receiving ATRA-ATO based regiment. This retrospective study shows that ATO-ATRA and limited chemotherapy could be a better approach than ATRA and standard intensive chemotherapy in terms of early deaths, LFS and OS.

No Place like Home: Home-Based Intravenous Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia (APL)

Introduction: APL has transitioned from a highly fatal malignancy to a disease that is curable with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Intravenous (IV) administration of ATO remains the standard of care for consolidation, however, its use is associated with long infusion times, electrolyte disturbances, and QTc prolongation that has historically required frequent outpatient infusion center administration and monitoring. Following induction, patients receive a cumbersome schedule of ATO through daily infusions 5 days each week (typically Monday-Friday) 4 weeks on 4 weeks off for 4 cycles. Oral formulations of ATO are poorly water soluble, have not demonstrated adequate absorption in the gastrointestinal (GI) tract leading to significant GI upset and are not approved for use in the United States. Beginning in 2020, patients treated at our institution were given the option of receiving ATO at home through a partnership via Qualitas Specialty Pharmacy of RWJBarnabas Health. This retrospective review evaluates the feasibility, safety, and efficacy of administration of ATO in the home infusion setting for patients with APL receiving ATO consolidation. Methods: Through retrospective chart review, we evaluated patients who received consolidation therapy of ATO through home infusion from 2020-2023. Eligible patients included those with an ECOG of &amp;lt;2, absence of baseline QTc prolongation (defined as &amp;gt;500ms), and patients without significant kidney dysfunction or hepatotoxicity at baseline. We evaluated each patient for adverse effects such as QTc prolongation, electrolyte disturbances, liver function test (LFT) abnormalities, neutropenic fever, bacteremia, unplanned Emergency Room (ER) or urgent care visits, and unexpected hospitalizations (via Common Terminology Criteria for Adverse Events version 5). Results: Fifteen patients aged 19-79 (median = 43) were reviewed with 60% being male and 40% female. Sixty percent had a baseline ECOG 1 and 40% had an ECOG 0. Twenty percent of patients had a prior malignancy (n=3). Eighty percent of the patients experienced grade (gd) 1-3 electrolyte abnormalities (47% gd 1 hyperphosphatemia, 13% gd 1 hyperkalemia, 7% gd 2 hyperkalemia, 7% gd 3 hyperkalemia, 13% gd 1 hypokalemia, 13% gd 1 hypermagnesemia, 7% gd 3 hypermagnesemia, 7% gd 1 hypomagnesemia, 33% gd 1 hypernatremia, 33% gd 1 hyponatremia, &amp; 7% gd 2 hyponatremia). Of the 15 patients receiving treatment, 27% experienced gd 1 alanine aminotransferase (ALT) increase, 13% of patients experienced gd 1 aspartate aminotransferase (AST) increase, and 7% of patients experienced gd 2 hyperbilirubinemia. For QTc prolongation, 53% of patients experienced gd 1 prolongation, 7% of patients experienced gd 2 prolongation, and 13% of patients experienced gd 3 prolongation. One out of the 15 patients experienced treatment delays due to QTc prolongation. While forty percent of patients visited either the ER and/or urgent care during consolidation therapy, no visits were deemed therapy related. Reasons for urgent evaluation included infections (n=3), vertigo (n=1), low back pain (n=1), facial numbness (n=1), fall (n=1), abdominal pain (n=1), and hemorrhoidal bleeding (n=1). Two patients were hospitalized, due to a renal infarct (n=1) and a subdural hematoma after a fall (n=1). None of the 15 patients experienced febrile neutropenia/bacteremia while receiving consolidation therapy. Of the 11 patients who completed consolidation at the time of this abstraction, all (100%) had complete remission demonstrated on post-consolidation bone marrow. One of the 11 patients relapsed within 6 months of consolidation; however, is now in remission following two additional consolidation courses and a bone marrow transplant. Four patients have not yet completed four cycles of ATO consolidation. One patient was transitioned from home infusion to clinic treatment due to out-of-pocket cost. Conclusions: Our study demonstrates that home infusion of ATO is both safe and highly effective for patients. Therapy was well tolerated with predictable and manageable toxicity. Prospective studies are needed to evaluate the efficacy and safety in comparison to patients receiving ATO in the infusion center as well as to assess patient-reported and cost outcomes. Given the safety profile of home-based ATO, we have implemented at home ATO consolidation as standard therapy for all eligible patients.

Canadian Cancer Trials Group SC.26 - Emotion and Symptom-Focused Engagement (EASE): A Multi-Site Randomized Controlled Trial of an Intervention for Individuals with Acute Leukemia

Background: Despite the rapid onset and life-threatening nature of acute leukemia (AL) and its treatment, there is a lack of research on its psychological and physical consequences and even less on interventions to alleviate them [Bryant 2016]. A longitudinal study of individuals with newly diagnosed or recently relapsed AL showed substantial physical and psychological distress in this population [Rodin 2013; Zimmermann 2013]. Based on these findings, an integrated psychosocial and early palliative care intervention, Emotion And Symptom-focused Engagement (EASE), was developed for patients with AL [Rodin 2015]. A phase II randomized pilot trial of EASE vs. usual care demonstrated feasibility and showed promising positive effects on traumatic stress symptoms (primary outcome) and other secondary outcomes, including depressive symptoms, number and severity of physical symptoms and related distress, pain, quality of life (QOL), satisfaction with care, and attachment security [Rodin 2020]. Study design and methods:The Canadian Cancer Trials Group SC.26 (NCT04224974) randomized phase III trial is underway to test the effectiveness and cost-effectiveness of the EASE intervention in AL. EASE is a novel manualized intervention that combines psychological support with routine symptom screening plus triggered referral to palliative care for symptom control. The goal is to reduce psychological distress and symptom burden, and enhance QOL and satisfaction with care in individuals with newly diagnosed AL undergoing induction therapy. Participants are randomized in a 1:1 unblinded ratio to usual care (UC) or UC and EASE (EASE). EASE consists of two components: the psychotherapy intervention (EASE-psy) and triggered early palliative care (EASE-phys). EASE-psy involves tailored supportive psychotherapy delivered by trained therapists over the initial 8 weeks following hospital admission for treatment of AL. It combines elements of relational support, affect regulation, and trauma-informed cognitive behavioural therapy. All patients randomized to EASE receive weekly symptom screening during the initial inpatient treatment period with triggered referral to early palliative care (EASE-phys). Subjects are stratified by centre, age (≤60 vs. &amp;gt;60) and type of acute leukemia (acute myeloid leukemia vs. acute lymphoblastic leukemia). For patients diagnosed with a mixed phenotype acute leukemia, the dominant sub-type is used for stratification purposes. Patients are ≥18 years, newly diagnosed and recruited within 2 weeks of hospital admission, and receiving or expected to receive induction therapy with curative intent. Current exclusion criteria include major communication difficulties at the time of recruitment; receipt of on-site psychological/psychiatric counselling or palliative care services at the time of recruitment; a diagnosis of acute promyelocytic leukemia or acute leukemia of ambiguous lineage. The two primary outcomes reflect the dual nature of the physical and psychosocial components of the EASE intervention: Mean severity of traumatic stress symptoms at 4 weeks using the 30-item Stanford Acute Stress Reaction Questionnaire (SASRQ) [Cardeña 1996] updated to be DSM-5-concordant [American Psychiatric Association 2013] and mean physical symptom severity at 4 weeks using the Memorial Symptom Assessment Scale (MSAS) [Portenoy 1994]. Hypotheses will be tested using multilevel modeling with maximum likelihood estimation, conducted as intention-to-treat analyses. Economic analysis will be conducted to measure the cost-effectiveness of the EASE intervention. Utilities will be derived from the EQ-5D-5L [Herdman 2011] and FACIT-Sp [Webster 2003] questionnaires. The planned sample size of this study is 266. Since January 2022, 53 patients at 4 Canadian centres have undergone randomization. Conclusion: The information obtained from this study will inform clinicians and decision makers of the value of implementing the EASE intervention in adults with AL.

Deciphering the Impact of Donor Telomere Length on Allogeneic Transplantation Outcomes: Telomere Length Matters More Than Age

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for acute leukemia. The success of transplantation relies significantly on optimal donor selection, with the donor's age being a critical factor affecting recipient survival post allo-HSCT. Telomeres play a vital role in safeguarding genetic information and are considered biomarkers for biological aging. In patients with severe aplastic anemia undergoing allo-HSCT, shorter telomere length is strongly associated with adverse outcomes. However, the relationship between telomere length and transplant outcomes in patients with acute leukemia remains unexplored. Thus, this study aims to investigate the impact of donor telomere length on clinical outcomes following allo-HSCT. Methods This post hoc analysis included 863 patients with acute leukemia who underwent allo-HSCT at the First Affiliated Hospital of Zhejiang University between June 6, 2016, and March 4, 2022. The inclusion criteria were as follows: (1) patient age ≥ 10 years; (2) diagnosis of acute leukemia, including acute myeloid leukemia, acute lymphoblastic leukemia, and mixed phenotype acute leukemia; (3) availability of a pre-transplant blood sample from the donor before mobilization. Peripheral mononuclear cells were sorted and analyzed uniformly for telomere length using qPCR. Based on the quartiles of donor telomere length, patients were categorized into the shortest telomere group (Q1), intermediate length telomere group (Q2, Q3), and longest telomere group (Q4), and the transplant outcomes were compared among the different telomere length groups. Results Out of the 863 eligible patients, 137 underwent allo-HSCT with matched sibling donors, 88 with unrelated donors, and 638 with haploidentical related donors. There were 546 donors aged &amp;lt; 40 years and 317 donors aged ≥ 40 years. An inverse linear correlation was observed between donor age and telomere length (P &amp;lt; 0.001, Figure 1A). However, this age-dependent association was mainly evident in younger donors (age &amp;lt; 40 years, P = 0.021), while in donors aged ≥ 40 years (elderly donors), it did not reach statistical significance as observed in the younger donor group (P = 0.36). In patients receiving grafts from younger donors, there was no significant correlation between telomere length and engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), non-relapse mortality (NRM), relapse, relapse-free survival (RFS), or overall survival (OS). In patients receiving grafts from elderly donors, the shortest telomere length was associated with an elevated incidence of aGVHD, while aGVHD incidence was similar between intermediate and longest telomere groups (49.4%, 38.5%, and 34.2% for shortest, intermediate, and longest, respectively, P = 0.06). Moreover, the intermediate telomere group exhibited improved OS (3-year OS for shortest, intermediate, and longest was 59.2%, 75.6%, and 59.9%, respectively, P = 0.07, Figure 1B) and prolonged RFS (3-year RFS for shortest, intermediate, and longest was 58.8%, 74.1%, and 55.1%, respectively, P = 0.06, Figure 1C). While the donor age has on impact on OS and RFS (P &amp;gt; 0.05). Even after adjusting for prognostic factors such as patient age, pre-transplant disease status, disease risk index stratification, and transplantation type, the multivariate analyses consistently indicated that intermediate telomere length remained an independent protective factor for OS (HR = 0.549, 95% CI, 0.328-0.920, P = 0.023, Figure 1D) and RFS (HR = 0.591, 95% CI, 0.361-0.967, P = 0.036, Figure 1E). Notably, elderly donors with the longest and shortest telomeres showed significantly inferior OS compared to younger donors ( Figure 1F). However, those elderly donors with intermediate telomere lengths demonstrated comparable OS to younger donors ( Figure 1G). Conclusion This study has significantly advanced our comprehension of telomeres, revealing that both excessively long and short telomeres are linked to adverse clinical outcomes in allo-HSCT for acute leukemia. Remarkably, elderly donors with intermediate-length telomeres demonstrate comparable outcomes to younger donors, challenging the conception that “young donors are superior to elderly donors.” These findings underscore the paramount importance of donor telomere length more than donor age, emphasizing its pivotal role in allo-HSCT success.

2722. Risk of Infectious Adverse Events of Venetoclax Therapy in the Treatment of Hematologic Malignancies: A Systematic Review and Bayesian Meta-Analysis of Randomized Controlled Trials

Abstract Background Venetoclax is a small molecule inhibitor of BCL-2 used in the treatment of acute myelogenous leukemia and chronic lymphocytic leukemia. Recent post-marketing studies on venetoclax suggested that it may predispose to opportunistic infections (OIs). We sought to systematically review the randomized controlled trial (RCT) evidence on venetoclax to assess whether it predisposes patients to infectious adverse events (IAEs) and neutropenia. Methods We systematically reviewed the RCTs comparing venetoclax therapy to active (i.e., a regimen with additional anti-cancer agents) or placebo controls in patients with hematologic malignancies, irrespective of treatment line. Data on IAEs and neutropenia were pooled by Bayesian meta-analysis and we computed the probability of any increased risk in infectious or neutropenic complications (Risk Ratio [RR] &amp;gt;1). Subgroup analyses were conducted based on treatment line, use of an inactive comparator, malignancy type, and prophylaxis strategy. Additionally, we pooled the incidence rates of fatal OIs between venetoclax and comparator arms and compared them by univariate meta-regression. Results Seven RCTs were included comprising 2067 patients. In venetoclax versus comparator regimens there was a 81.1% probability of any increase in IAEs (RR=1.14, 95% Confidence Interval [95%CI]=0.76-1.66). The probabilities of venetoclax increasing the risk of grade 3-5 and fatal IAEs were 86.6% (RR=1.16, 95%CI=0.86-1.55) and 81.1% (RR=1.40, 95%CI=0.66-2.94), respectively. There was a 97.2% likelihood that venetoclax increased the risk of grade 3-5 neutropenia (RR=1.44, 95%CI=1.01-2.10). Venetoclax treatment did not increase the incidence of fatal OIs (P=0.55). Conclusion Our results suggest that venetoclax likely increases the risk of high-grade neutropenia and IAEs overall, but not fatal OIs. However, our analyses did not identify any specific IAEs that would benefit from routine anti-infective prophylaxis or pre-emptive testing. Disclosures Michael Sebag, MD, PhD, Amgen: Advisor/Consultant|BMS: Advisor/Consultant|Focus Therapeutics: Advisor/Consultant|Gilead: Advisor/Consultant|Janssen: Advisor/Consultant|Novartis: Advisor/Consultant|Pfizer: Advisor/Consultant|Sanofi: Advisor/Consultant Matthew Cheng, MD, Amplyx Pharmaceuticals: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|Cidara Therapeutics: Grant/Research Support|GEn1E lifesciences: Advisor/Consultant|GEn1E lifesciences: Stocks/Bonds|Kanvas Biosciences, Inc.: Board Member|Kanvas Biosciences, Inc.: Pending patents|Kanvas Biosciences, Inc.: Ownership Interest|Merck: Honoraria|nomic bio: Advisor/Consultant|nomic bio: Stocks/Bonds|Pfizer: Honoraria|Scynexis Inc.: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Honoraria

Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies

Venetoclax is a strongly effective B-cell lymphoma-2 inhibitor (BCL-2) with an ability to selectively restore the apoptotic potential of cancerous cells. It has been proven that in combination with immunotherapy, targeted therapies, and lower-intensity therapies such as hypomethylating agents (HMAs) or low-dose cytarabine (LDAC), the drug can improve overall outcomes for adult patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), amongst other hematological malignancies, but its benefit in pediatric hematology remains unclear. With a number of preclinical and clinical trials emerging, the newest findings suggest that in many cases of younger patients, venetoclax combination treatment can be well-tolerated, with a safety profile similar to that in adults, despite often leading to severe infections. Studies aim to determine the activity of BCL-2 inhibitor in the treatment of both primary and refractory acute leukemias in combination with standard and high-dose chemotherapy. Although more research is required to identify the optimal venetoclax-based regimen for the pediatric population and its long-term effects on patients’ outcomes, it can become a potential therapeutic agent for pediatric oncology.

Prospective Assessment of Treatment-Induced Liver Injury as a Cause of Diffuse Pathologic Hepatic Enhancement in Contrast-Enhanced Ultrasound

A hypo-enhancement of the liver in contrast-enhanced ultrasound (CEUS), pathologic one-minute hepatic enhancement (pOMHE), was recently observed in 70% of allogeneic hematopoietic stem cell transplantation patients with a high-risk profile for veno-occlusive disease (VOD). Whether pOMHE was a pre-clinical sign of VOD or an unspecific feature of liver damage secondary to intensive chemotherapy is unclear. To investigate this, we studied CEUS patterns in patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (auto-HSCT) or intensive induction therapy (IT) for the treatment of acute leukemia. From April 2020 to May 2021, patients undergoing auto-HSCT (n=20) or acute leukemia patients prior to IT (n=20) were included. All patients underwent a B-mode ultrasound and CEUS of the liver and spleen before treatment (d0) and on day 10 (d10) after therapy start. The one-minute hepatic enhancement was quantified. An optical density of liver enhancement less than 90% compared with the spleen was considered pathologic (pOMHE). Clinical and laboratory parameters used to assess a drug-induced liver injury (DILI) were documented. The OMHE was normal (d0 and d10) in 36 (90%) patients. After IT, 2 of 20 patients had a pOMHE. A DILI grade IV was diagnosed in one case and hyperfibrinolysis in the second case. In 2 of 20 (5%) auto-HSCT patients a pOMHE was observed at d10 without clinical symptoms. Chemotherapy-induced effects are not the cause of a pathologic liver enhancement. In contrast, severe DILI or hyperfibrinolysis can be associated with pOMHE.