Prolonged Anemia Research Articles

Time to Resolution of Severe Anemia in Young Children With Iron Deficiency.

Iron deficiency anemia in children remains a pervasive problem. Prolonged iron deficiency anemia (IDA) is linked to adverse neurodevelopmental outcomes, but the duration of severe IDA (hemoglobin <7g/dL) in children is poorly studied, particularly for racial/ethnic minority groups. We reviewed the electronic medical records of 92 children (1 to 5y old) with IDA within a major metropolitan health care system. Duration of anemia, hemoglobin at diagnosis and nadir, age, sex, race/ethnicity, and the use of intravenous interventions were analyzed by Kaplan-Meier curves, Cox regression, and logistic regression. The majority of the included children were Asian (72.8%). Anemia resolution was documented in 68% of cases, and 47% of cases received intravenous intervention. Iron repletion was only confirmed in 37% of cases (n=34), leaving many children with unclear resolution at risk for recurrence. Caucasian children had anemia resolution faster than Black or Asian children, and the latter groups were also less likely to reach hemoglobin normalization. Children with intravenous interventions were more likely to have documented resolution than those with only oral treatment. Those receiving intravenous interventions were more likely to be followed through anemia resolution, although treatment standardization was lacking, and confirmation of iron storage repletion was rarely checked. Future studies should emphasize the importance of ensuring iron storage replacement and potentially utilize time-to-anemia resolution data to determine optimal hemoglobin values for intravenous iron as a first-line intervention.

Using an experience-based co-design approach to develop strategies for implementing an intravenous iron intervention to treat moderate and severe anemia in pregnancy in Malawi

BackgroundIn low- and middle-income countries, women experiencing anemia during pregnancy are recommended to take 30 mg to 60 mg of oral iron daily throughout pregnancy. However, oral iron tablets are often poorly tolerated and slow in correcting anemia, resulting in low adherence, prolonged anemia, and increased risk of adverse maternal and fetal outcomes. An alternative to oral iron is intravenous (IV) iron, commonly used in high-income countries to restore the body’s iron stores rapidly. A randomized controlled trial was conducted to investigate the effectiveness and safety of IV iron compared to standard-of-care oral iron supplementation for pregnant women with moderate and severe anemia in the third trimester in Malawi (REVAMP-TT). Using an experience-based co-design approach, our study aimed to identify barriers and facilitators to IV iron use to treat anemia in pregnancy in the primary healthcare system of Malawi, and develop mitigating strategies for the successful implementation of REVAMP-TT.MethodologyThe co-design process involved two phases: i) We conducted an information-gathering exercise to identify barriers and facilitators to IV iron use to treat anemia in pregnancy in the primary healthcare system of Malawi. We interviewed key informants (n = 53) including the policymakers, government partners, healthcare managers, and healthcare providers. We also gathered previous research findings from a formative qualitative study on the perceptions and experiences of IV iron treatment for pregnant women experiencing anemia in Malawi (n = 29). ii) We conducted two co-design workshops with end-users (n = 20) and healthcare providers (n = 20) to confirm and identify the key barriers and facilitators and developed mitigating strategies to inform the successful implementation of the REVAMP-TT trial. We mapped the emerging barriers to the Consolidated Framework for Implementation Research 2.0 (CFIR 2.0) and matched the mitigating strategies to the corresponding Expert Recommendations for Implementing Change (ERIC) compilation.ResultsThe following were identified as key barriers to IV iron use to treat anemia in pregnancy in the primary healthcare system of Malawi: the cost of IV iron, the lack of available resources and knowledge, local attitudes including myths and misconceptions about IV iron and keeping pregnancy a secret, local conditions, the lack of political will and buy-in from high-level leaders, the lack of capability of healthcare providers to deliver IV iron, and the lack of male involvement to support pregnant women's access to antenatal care. The proposed strategies to mitigate the barriers for the successful implementation of the REVAMP TT trial included providing financial strategy, developing stakeholder relationships, training and educating stakeholders, supporting clinicians, and engaging end-users.ConclusionThe use of the experience-based co-design approach in our study provided a valuable method to expose the potential barriers and facilitators to IV iron use and develop mitigating strategies to successfully implement the REVAMP-TT trial. Engaging both the key informants and end users promoted ownership and consensus among stakeholders and ensured a collaborative environment for sharing deeply rooted real-world experiences and insights. Not only do these findings address the needs of this study, but they also, lay a groundwork for the possible integration of IV iron into routine care in Malawi and provide knowledge for policymakers to make informed decisions on the management of anemia in the primary healthcare systems of Malawi.

Diagnosis of Suspected Precursor-Targeted Immune-Mediated Anemia (PIMA) in a Cat with Prolonged Anemia: A Case Report

Diagnosis of Suspected Precursor-Targeted Immune-Mediated Anemia (PIMA) in a Cat with Prolonged Anemia: A Case Report

Risk Factors for Anemia in Adolescent Pregnancies: Evidence From the Lembah Pantai Urban Health District in Malaysia.

Introduction Adolescent pregnant mothers are at higher risk of acquiring anemia during pregnancy, which has detrimental consequences for the mother and baby. Untreated and prolonged anemia can lead toperinatal morbidity and mortality and antepartum, intrapartum, and postpartum maternal morbidity.Anemia among adolescent pregnant mothers can be attributed to many factors, such as poor nutrition and the physiological demands of pregnancy. Hence, this study aimed to determine the prevalence and characteristics of anemia among adolescent pregnancies in Lembah Pantai Health District in an urban setting. Materials and methods This cross-sectional study utilized secondary data from registry records of adolescentpregnant mothers in the Lembah Pantai District Health Office in Kuala Lumpur,Malaysia from 2019 to 2022. All adolescent pregnancies aged 10 to 19 years were included in this study. Those with a prior diagnosis of thalassemia or other hematological disorders, as indicated in their medical records, were excluded from the study. The chi-square (χ2) test was applied to elicit the association at a univariate level, and those variables with a p-value of <0.25 were included in a multiple logistic regression model. Results A total of 307 records were reviewed, and 272 pregnant adolescent cases were eligible for the analyses. The prevalence of anemia among teenage pregnancies from 2019 to 2022 was 28.7% (95% CI: 23.0-33.6). This prevalence was lower than in many lower-income countries and developing countries.Factors that were significant on using multiple logistic regression analysis included marital status (unmarried) (AOR: 1.87, 95% CI: 1.01-3.45, p=0.046), residing area Seputeh (AOR: 0.29, 95% CI: 0.14-0.61, p=0.001), and third trimester of first antenatal visit/booking (AOR: 5.08, 95% CI: 2.02-12.70, p<0.001).The population in the Seputeh area has a higher overall household income in comparison toLembah Pantai. Conclusions According to the WHO classification, the prevalence of anemia among adolescent pregnant women at the Lembah Pantai District Health Office reflects amoderate public health issue. Consequently, anemia may exacerbate the impact of other health conditions in this population.Hence, local health authorities should ensure that anemia is adequately addressed without ignoring other crucial health issues. A multidisciplinary, comprehensive, holistic strategy involving healthcare providers, school health teams, and community assets offers a potential solution. Strategies that can be employed include providing targeted health and nutrition education in schools through school health teams. Additionally, establishing adolescent-friendly health clinics tailored to the specific needs of pregnant adolescents and enhancing antenatal services to ensure comprehensive screening and management of anemia should also be implemented.Hence, this will ensure achieving safe motherhood goals through an effective healthcare response.

Pure red cell aplasia among ABO mismatched hematopoietic stem cell transplant recipients: a 13-years retrospective study and literature review.

Pure red cell aplasia (PRCA) is a possible complication after allogeneic hematopoietic stem cell transplantation (HSCT) with major ABO incompatibility. Patients experience delayed engraftment of the erythroid series, with prolonged transfusion-dependent anemia and iron overload. We performed a revision of the most recent literature about post-HSCT PRCA treatment procedures. Moreover, we conducted a retrospective study, over the last 13-years, which included all consecutive major ABO mismatched HSCT performed in our unit, with the aim to assess PRCA incidence, risk factors, and response to different treatments. Overall, 194 patients received a major ABO mismatched transplant from 2010 to 2022. For each patient, data about demographic and transplant characteristics, engraftment, blood transfusion, and possible treatment received were collected. The literature review returned 23 eligible papers on PRCA treatment, with high success rate using plasma-exchange (PEX) and immunoadsorption procedures, daratumumab, and eltrombopag. Our study identified a total of 24 cases of PRCA. Among risk factors for PRCA development, we have found older recipient age (p=0.01), high pre-HSCT IgG and IgM IHA titer (p<0.0001), major rather than bidirectional ABO incompatibility (p=0.02), low T CD8 lymphocyte count in the graft (p=0.006), relative donor (p=0.02) and bone marrow as stem cell source (p=0.002). However, multivariate analysis confirmed only pre-HSCT IgG IHA titer as the unique risk factor for PRCA occurrence. The optimal cut-off value of pre-HSCT IgG IHA for PRCA development, resulted to be 1/64, with a 100% sensitivity and 68.8% specificity (p<0.0001). All patients with PRCA had received rhEPO and transfusion support and 20 patients received additional treatments like PEX, rituximab, and more recently daratumumab. Comprehensively, PEX and rituximab obtained a response in half of the cases, at a variable time, while the few cases of patients we treated with daratumumab suggest promising results. The overall response rate in our cohort was 75%, with significantly better survival (94.4% vs. 16.7%) and lower transplant-related mortality (6.3% vs. 80%) for PRCA responders. Standardized guidelines on when and how to treat PRCA are necessary because the current treatment is controversial among centers.

Abstract CT145: The final results of a phase I study using velcade (bortezomib), cladribine, and rituximab (VCR) in treating elderly patient with mantle cell lymphoma

Abstract Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium size B cell lymphoma. In this phase 1 study, we evaluated the safety and efficiency of Valcade, Cladribine, and Rituximab (VCR) combination treatment in MCL. Patients and Methods: This is a single arm, open label, investigator-initiated Phase 1 study. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. The treatment scheme and Cladribine dose escalation levels (1, 2, and 3) are as follows: the therapy consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles, Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 35 mg/m2 (3 mg/m2 for level 1, 4 mg/m2 for level 2, and 5 mg/m2 for level 3) infusion was given on days 1 to 5 for 6 cycles. If the patient was older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, then Day 5 and 19 during Cycles 4 to 6, then once per month as maintenance therapy until toxicity or progression of the disease. The primary endpoint of this study was to investigate the dose limiting toxicity (DLT), safety, and efficiency of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS). This study is registered with clinicaltrials.gov (NCT01439750). Results: No subject experienced dose limited toxicity (DLT) at either level 1 or 2, one possible DLT (infectious colitis) was observed on a subject during 2nd cycle at level 3. Then no additional DLTs were seen in 3 subjects added to level 3. Overall, this study recruited 13 subjects, with a median age of 64 years old (range from 55 to 83), and a total of 11 male and 2 females. Ten subjects were never previously treated, while 3 either relapsed or failed previous treatments. The majority of subjects tolerated this regimen well. Two relapsed patients experienced disease progression after received two cycles of treatments and died in 5 and 7 months after initiating the treatment. Another patient died 15 months after starting treatment. The overall remission (OR) rate was 77% (10/13) and complete remission (CR) rate was 85% (10/13). In newly diagnosed subject cohort, the RR and OS rates were 90% (9/10), PFR was 80% (8/10), and CR rate was 100% (10/10), of which 3 patients have been followed for more than 4 years, 3 other patients for more than 3 years, and 3 others for over 2 years. However, in relapsed/refractory subject cohort, 1 subject achieved CR for 7 months but then relapsed, 2 subjects had no response. There were 2 blastoid subjects, one was newly diagnosed and achieved CR.No severe systemic toxicity was observed in this study. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for for untreated MCL. Cladribine 5 mg/m2 is a tolerable dose with manageable toxicity. Citation Format: Jeffrey J. Pu, Kristin Berger, David Claxton, Joseph Drabick, Thomas Loughran, Elliot Epner. The final results of a phase I study using velcade (bortezomib), cladribine, and rituximab (VCR) in treating elderly patient with mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT145.

Knowledge and practices on anemia in representatives of children under 5 years of age from the "Luz y Libertad" Educational Unit in La Concordia, 2023

Childhood anemia is a public health problem that negatively affects the cognitive and physical development of children, with multifactorial causes including nutritional deficiencies and socioeconomic conditions. Diagnosis is based on a complete blood count, and low hemoglobin levels indicate anemia. In Ecuador, factors such as rural residence and micronutrient deficiencies contribute to the prevalence of anemia, with 25.7% of children under five years of age affected. This study, conducted at the "Luz y Libertad" Educational Unit, evaluated the knowledge and practices of 66 mothers about childhood anemia through questionnaires. The results showed a good level of knowledge, especially about the importance of iron, although areas such as the relationship between prolonged breastfeeding and anemia require more education. The economic situation influences child nutrition, with some prioritizing price over nutritional value. It is recommended that educational programs and economic support be implemented to improve the prevention of childhood anemia and ensure healthy development.

The Final Results of a Phase I Study Using Bortezomib (Velcade), Cladribine, and Rituximab (VCR) in Treating Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium sized B cell lymphoma. No standardized treatment exists for this disease. Cladribine is a hypomethylating agent that indirectly down-regulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Bortezomib (Velcade) is an FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this study, we evaluated the safety and efficacy of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL. Patients and Methods: This is a single arm open label phase I trial. This study employed a standard 3+3 dose escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. Briefly, the treatment scheme was consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m 2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3 to 5 mg/m 2 (3 mg/m 2 for level 1, 4 mg/m 2 for level 2, and 5 mg/m 2 for level 3) infusion was given on days 1 to 5 for 6 cycles. For patient older than 70 years old, Cladribine was only given on days 1 to 3 of each cycle. Velcade 1.6 mg/m 2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1 to 3, Days 5 and 19 for Cycles 4 to 6, then once per month as maintenance therapy. The primary endpoint of this study was the dose limiting toxicity (DLT), safety, and efficacy of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression free survival (PFS) and overall survival (OS) (Figure 1). The analysis was done by intent to treat. Differentially methylated region (DMR) analysis and cytokine assay were performed to explore biomarkers differentiating good-responders from poor-responders. Results: This study recruited 13 patients, with a median age of 64 years old (range from 55 to 83) and including 11 males and 2 females. Ten patients were never previously treated, other 3 either relapsed or failed from previous treatments. Most patients tolerated this regimen well. No patient experienced DLT at either level 1 or 2, one possible DLT (infectious colitis) was observed during 2nd cycle at level 3. Two relapsed patients experienced disease progression after received two cycles of treatment and died in 5 and 7 months. Another patient died in 15 months after receiving treatment. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 77% (10/13). In newly diagnosed patient cohort, CR rate was 100% (10/10), OS rates were 90% (9/10), and PFS was 80% (8/10), of which 3 patients have been followed for more than 4 years, 3 other patients for more than 3 years, and 3 others for over 2 years (Fig.1). In relapsed/refractory patient cohort, 1 achieved CR for 7 months but then relapsed, 2 had no response. There were 2 blastoid patients, 1 of these 2 patients was newly diagnosed and achieved CR. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Cytokine assay showed decreased CXCL12 level in the good responders. Though global methylation pattern showed no difference, DMRs were identified in the good responders and the poor responders. DMRs-related genes involved in CXCL2 pathways were further extracted and enriched biological process analysis revealed the pathway profile difference between good responders and poor responders. Good responders exhibited alternation of apoptotic and Wnt signaling pathways (Fig.2). Conclusions: The VCR combination is a well-tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m 2 is a tolerable dose with manageable toxicity. Individual patient methylation profile may affect response to VCR therapy.

Nutritional Analysis of Aqueous Extract of Snake Fruit Seeds (Salacca Edulis Reinw) for Development of Anemia Treatment

Anemia remains a global nutritional problem, which prevalence continues to increase every year. Children, female adolescents, and pregnant women are more susceptible to anemia than other age groups. Prolonged anemia has negative impacts on their life such as premature birth, low birth weight (LBW) babies and intrauterine fetal death. Snake fruit Pondoh (Salacca edulis Reinw) is an original Indonesian fruit, which is well cultivated at the Sleman regency, Yogyakarta. Snake fruit seeds contribute to 25-30% of the total fruit, which has not been established their health effect. Therefore, this study aims to analyze the nutritional content of aqueous extract of snake fruit seeds (AES). The powder of snake fruit seeds was made using a previous method, which was adopted from our research group. The powder was then extracted using hot aqueous with 65°C. A proximate analysis was used to determine the AES nutritional content. A hundred g AES contained 21.92% water, 41.10% carbohydrates, 12.66% protein, 4.51% fat, 0.62% tannins, 32.8 mg Iron, 10.25 mg zinc, 276.42 mg magnesium, and 495.48 mg vitamin C. In conclusion, the AES has complete macronutrients and contains high levels of Iron, Magnesium, and vitamin C, which becomes a potential nutraceutical for anemia treatment. Further research is required to confirm the beneficial effect of AES administration in female rats with anemia.

Hubungan Partus Lama dan Anemia dalam Kehamilan dengan Kejadian Atonia Uteri pada Ibu Bersalin

Atonia uteri is a state of weak tone or uterine contraction, which causes the uterus to be unable to close open bleeding from the site of placental implantation after the baby and placenta are born. Maternal mortality in Indonesia is still relatively high, one of the causes is postpartum bleeding, especially caused by uterine atonia. This study aims to find out the relationship of prolonged labor and anemia in pregnancy with the incidence of uterine atonia in women giving birth at the NTB Provincial Hospital. This study is observationally analytical using case-control design. The sampling technique is total sampling. The research sampel consisted of 60 samples with each case and control 30 samples that fit the inclusion and exclusion criteria. The data obtained were analyzed with the chi-square correlation test. The result of his study were obtained prolonged labor are 18(71,7%) and who were not prolonged labor 43 (71,7%). While respondents with anemia 34 (56,7%) and who were not anemia 26 (43,3%).There is relationship between prolonged labor with incidence of uterine atony in women giving birth with p-value 0,010 and with OR 4,971 more at risk of uterine atony and there is relationship between anemia in pregnancy with the incidence of uterine atony in women giving birth with p-value 0,037 and with OR 3,051more at risk of uterine atony. There is significant relationship between prolonged labor and anemia in pregnancy with the incidence of uterine atony in women giving birth in the NTB Provincial Hospital.

Imported severe Plasmodium falciparum infection in the first trimester of pregnancy complicated by post-artemisinin delayed hemolysis and intrauterine fetal death, a case report

BackgroundPost-artemisinin delayed hemolysis (PADH) is a serious complication in patients who recover from severe malaria after receiving artemisinin-based combined therapy (ACT), including artemether-lumefantrine. In Japan, among the antimalarial drugs recommended by the World Health Organization (WHO) guideline for severe malaria, intravenous quinine gluconate is available only in 29 designated hospitals, and intravenous artesunate is unavailable. Therefore, oral artemether-lumefantrine is occasionally administered as an alternative, even though it may be a suboptimal treatment. In non-endemic settings like Japan, a lack of knowledge of malaria and the side effects, such as post-artemisinin delayed hemolysis caused by the ACT, can have critical consequences. Like our patient, being a primigravida in the early stages of pregnancy is a serious risk factor for severe malaria and must be carefully monitored.Case presentationThis report describes a severe case of imported Plasmodium falciparum malaria complicated by fetal loss and prolonged anemia, requiring frequent blood transfusions. The patient was a previously healthy pregnant Japanese female in her 30 s. She developed a high fever 2 days after returning from Nigeria. The patient fulfilled the severe malaria criteria by WHO. On arrival, an abdominal ultrasound incidentally revealed a fetus of 5 week gestational age with a heartbeat in the uterus. Given her pregnancy and the severity of the disease, she was administered intravenous quinine 16 mg/kg as a loading dose. However, the second dose of quinine was not administered due to frequent vomiting and QTc prolongation. We initiated treatment with oral artemether-lumefantrine, and clearance of parasitemia was confirmed by microscopic observation on day 4. Miscarriage was noted on day 6 after admission. Moreover, the patient became feverish again up to 39 °C, and from days 14 to 22, the patient required multiple blood transfusions due to PADH. On day 40, follow-up was discontinued as the hemoglobin level exceeded 10 g/dL.ConclusionsIn patients who recover from severe malaria after ACT treatment, monitoring the hemoglobin level for at least a month is strongly recommended for prompt identification of PADH. Travelers to malaria-endemic countries, especially primigravida women, should be provided with adequate information on the risk and prevention of infection.

Abstract A46: Heterozygous mutations in DDX41 cause erythroid progenitor cell defects and cooperate with p53 mutations to cause hematologic malignancy

Abstract Germline mutations in the RNA Helicase gene DDX41 are the most common cause of inherited susceptibility to adult MDS and AML. These mutations are always heterozygous and are typically frameshifts, causing loss of functional protein. We recently reported that at least one functional copy of DDX41 is essential for hematopoiesis, and that DDX41 is required for ribosome biogenesis (Chlon et al., Cell Stem Cell 2021). While biallelic DDX41 mutations cause dramatic defects in hematopoiesis, the role of heterozygous mutations in MDS pathogenesis is not yet understood. DDX41 mutation carriers frequently experience idiopathic cytopenias of unknown significance (ICUS) prior to MDS onset, suggesting that underlying hematopoietic defects contribute to MDS/AML (Choi et al., Haemotologica 2021). The majority of DDX41-mutant MDS patients have refractory anemia, indicating that the erythroid lineage is particularly affected in these patients (Sebert et al., Blood 2019). Since ribosome defects are a common cause of inherited anemias and also contribute to MDS pathogenesis, we characterized the effect of heterozygous DDX41 mutations on erythropoiesis in murine and human models. Mice that were transplanted with Ddx41+/− bone marrow develop anemia at 12-15 months post-transplant. At younger ages, these mice have normal hematopoietic indices, but when stress erythropoiesis is induced by Pheylhydrazine-treatment, the Ddx41+/− mice have prolonged anemia. These observations indicate that heterozygous loss of DDX41 causes defects in erythropoiesis during stress and aging. We further characterized the effect of Ddx41-hetrozyogisty on erythroid progenitor function in vitro. In colony assays, we found that Ddx41+/− HSPC form fewer BFU-E but comparable numbers of myeloid colonies. In liquid culture erythroid differentiation cultures, we found that Ddx41+/− HSPC produce fewer CD71+ Ter119+ progenitors than controls. Mechanistically, we found that in vitro-derived erythroid progenitors from both mice and cell line models had decreased protein translation, suggesting that ribosome defects underlie the observed inefficiency in erythropoiesis. In congenital ribosomopathy diseases, ribosome defects lead to p53 activation which contributes to defects in erythropoiesis. Interestingly, TP53 mutations are common in DDX41-mutant MDS/AML (Sebert et al., Blood 2019), suggesting that the ribosome deficiency selects for these mutations. To assess the role of p53 mutations in the development of DDX41-mutant MDS, we generated Ddx41+/−;p53+/− mice and transplanted the bone marrow into lethally-irradiated recipients and followed the mice for 1 year. These mice developed a lethal MDS-like phenotype at 7-12 months post-transplant while control mice lived until the end of the study period. The sick mice had anemia and other cytopenias accompanied by enlarged spleens and dysplastic myeloid cells. Collectively, these results indicate that p53 mutations cooperate with Ddx41-heterozygosity to promote hematologic malignancy. Citation Format: Timothy M Chlon, Emily Stepanchick, Analise Sulentic, Andrew Wilson, Daniel T Starczynowski. Heterozygous mutations in DDX41 cause erythroid progenitor cell defects and cooperate with p53 mutations to cause hematologic malignancy [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A46.

Abstract CT201: HS-10365, a highly potent and selective RET tyrosine kinase inhibitor, demonstrates robust activity in RET fusion positive NSCLC patients

Abstract Background: Activating RET alterations drive oncogenic signaling in lung, thyroid, and other solid tumors.Until recently, only two RET tyrosine kinase inhibitor (TKI), BLU-667 and LOXO-292, had received approval for advanced NSCLC by FDA and NMPA. And it still had an unmet clinical need in this therapy area.HS-10365 is a highly potent and selective tyrosine kinase inhibitor, and the preclinical studies have indicated its favorable safety and antitumor activity in RET-altered tumor models. Here, we conducted a phase I study to assess the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of HS-10365 in RET-altered solid tumors. Methods: This study (NCT05207787) recruited patients (pts) with RET-altered advanced solid tumors, including RET fusion-positive (+) NSCLC, RET-mutated medullary thyroid carcinoma and so on. Pts were dosed orally in 21-day cycles. A rule-based accelerated titration combined with 3+3 dose-escalation scheme was used to determine the MTD as the primary endpoint. Secondary endpoints contained safety, PK parameters, ORR and DCR assessed by RECIST V1.1. Results: As of Dec.15th 2022, 31 RET fusion+ NSCLC pts with RET TKI-naïve were received HS-10365 at 6 doses (40 mg QD to 200 mg BID), including 25 previously received platinum-based chemotherapy pts and 6 treatment-naïve pts. Among all fusion variants, 15 pts had KIF5B, 14 pts had CCDC6, and 2 pts were others. Dose limiting toxicity occurred only in one pt. at 200 mg BID (grade 3 hypertension). The MTD was not been defined, and the 160mg BID was the potentially recommended phase II dose. The common (≥25%) TRAEs were AST increase, bilirubin increase, ALT increase, WBC decrease, PLT decrease, neutrophil decrease, serum creatinine increase, prolonged QT interval, hypoalbuminemia and anemia. No pts discontinued treatment owing to AEs. Efficacy data was available for 30 RET fusion+ NSCLC pts with 24 pretreated pts and 6 treatment naïve pts. The ORR was 70.0% (21/30, 95% CI 50.6%-85.3%), with 66.7% (16/24) in pretreated pts and 83.3% (5/6) in treatment naïve pts. Furthermore, the DCR was 96.7% (29/30, 95% CI 82.8%-99.9%), with 95.8% (23/24) in pretreated pts and 100% (6/6) in treatment naïve pts. The longest response time was more than 48 weeks. Meanwhile, 25 of 31 pts remained on treatment and responses were ongoing. Plasma exposure of HS-10365 increased proportionally following single dose and multiple doses. The mean plasma half-life of HS-10365 was 5~9 hours. Conclusions: HS-10365 showed a manageable safety profile and favorable PK properties. The promising antitumor activity with expectable response time was observed in RET fusion+ NSCLC pts, no matter with or without previous treatments. Citation Format: Shun Lu, Qiming Wang, Lin Wu, Ligang Xing, Yintao Li, Liang Han, Xiaorong Dong, Hongying Wei, Wen Xu, Chuan Li, Liuqing Yang, Qiong Wu. HS-10365, a highly potent and selective RET tyrosine kinase inhibitor, demonstrates robust activity in RET fusion positive NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT201.

Factors associated with blood product requirements during the transoperative period in pediatric patients.

The efficiency of blood products (BP) requisition in elective non-cardiac surgeries is inherently complex. Moreover, it is aggravated in the pediatric population. This study aimed to identify the factors associated with using less than the requested BP during the transoperative period in pediatric patients undergoing elective non-cardiac surgery. We conducted a cross-sectional comparative study including 320 patients undergoing elective non-cardiac surgery for whom BPs were requested. Low requirements were considered when less than 50% of the requested amount or no BPs were used, and high requirements when more than the requested amount was used. The Mann-Whitney's U test was applied for comparative analysis, and multiple logistic regression was used to adjust for factors associated with lower requirements. The median age of the patients was 3 years. From 320 patients, 68.1% (n = 218) received less than the requested amount of BP, while only 1.25% (n = 4) received more than the requested amount of BP. Factors associated with transfusion of less than the requested BPs were prolonged clotting time (odds ratio (OR) = 2.66) and anemia (OR = 0.43). Factors associated with lower than requested BP transfusion were prolonged clotting time and anemia.

Cytokine profiles are associated with prolonged hematologic toxicities after B-cell maturation antigen targeted chimeric antigen receptor–T-cell therapy

Background aimsThe considerable efficacy of B-cell maturation antigen–targeted chimeric antigen receptor (CAR)–T-cell therapy has been extensively demonstrated in the treatment of relapsed or refractory multiple myeloma. Nevertheless, in clinical practice, prolonged hematologic toxicity (PHT) extends hospital stay and impairs long-term survival. MethodsThis retrospective study reviewed 99 patients with relapsed or refractory multiple myeloma who underwent B-cell maturation antigen CAR–T-cell therapy at our institution between April 2018 and September 2021 (ChiCTR1800017404). ResultsAmong 93 evaluable patients, the incidence of prolonged hematologic toxicities was high after CAR–T-cell infusion, including 38.71% (36/93) of patients with prolonged neutropenia, 22.58% (21/93) with prolonged anemia and 59.14% (55/93) with prolonged thrombocytopenia. In addition, 9.68% (9/93) of patients experienced prolonged pancytopenia. Our multivariate analyses identified that cytokine profiles were independent risk factors for PHTs, whereas a sufficient baseline hematopoietic function and high CD4/CD8 ratio of CAR-T cells were protective factors for PHTs after CAR–T-cell infusion. Subgroup analyses found that the kinetics of post-CAR-T hematologic parameters were primarily determined by the collective effects of cytokine release syndrome and baseline hematopoietic functions, and showed influential weights for the three lineages. ConclusionsOur findings improve the understanding of the impact of cytokines on hematopoietic functions, which could contribute to the mechanism investigation and exploration of potential intervention strategies.

Age of Packed Red Blood Cells Transfused to Patients with Acute Leukemia: A Descriptive Analysis

Background: Patients with acute leukemia frequently present with disease-related severe anemia (hemoglobin <8 g/dL). Packed red blood cell (PRBC) transfusions are standard of care for severe anemia, though cells' ability to transport oxygen decreases with prolonged storage time (maximum 42 days). Evidence exists to support a significant decline in available cells' ability to transport oxygen beyond 21 days, though no guidelines currently exist to inform use of PRBCs based on storage age. Characteristics of transfused PRBC units and hemoglobin (hgb) levels in patients treated for severe anemia during acute leukemia treatment has not been described. Methods: We sought to characterize PRBC units transfused during intensive induction chemotherapy treatment and associated hemoglobin levels following the initial transfusion based on PRBC unit age. We performed a pilot study via retrospective secondary analysis of pre-existing data from the University of Alabama at Birmingham O'Neal Comprehensive Cancer Center patient database and associated blood bank records. We included patients 18 years or older who were newly diagnosed with acute leukemia and required intensive induction chemotherapy treatment between December 2021-March 2022, who had a documented hgb consistent with the World Health Organization definition of severe anemia (<8 g/dL) during hospitalization, and who received at least one unit of PRBCs. Results: Patients (n=11) were primarily Caucasian (90.9%), female (72.7%), with a median age of 56 years (range 34-70) (Table 1). Most patients (72.7%) were diagnosed with acute myeloid leukemia. Median duration of hospital stay for induction chemotherapy treatment was 26 days (range 13-56 days). Median hgb level was 8.9 g/dL (range 3.7-11.5 g/dL) on hospital admission; prior to the initial PRBC transfusion, median hgb was 6.7 g/dL (range 3.7-8.7 g/dL). After initial PRBC transfusion, median hgb increased to 7.7 g/dL (range 5.6-9.6 g/dL), representing a median increase in hgb of 1.1 g/dL (range -0.9-3.2 g/dL). Median age of the initial PRBC unit transfused was 27 days (range 13-32 days). Patients received a median of 9.5 PRBC units (range 0-18) during the intensive induction chemotherapy treatment period; median age of all PRBC units transfused was 23 days (range 3-41 days). Moderate positive correlation was noted between the change in hgb pre- and post-initial transfusion and PRBC age (r=0.55). Across hospitalization, median hgb level was 7.7 g/dL (range 7.3-9.1 g/dL); final hgb level prior to discharge was a median of 7.8 g/dL (range 7.2-9.5 g/dL). Conclusions: In our pilot study, patients undergoing intensive induction chemotherapy treatment for acute leukemia generally received older PRBC units (>21 days) both at their initial transfusion and throughout their hospitalization. PRBC unit age was positively associated with change in hgb. In general, patients did not achieve a normal hgb level prior to hospital discharge despite numerous PRBC transfusions. Our findings are limited by sample size and therefore not generalizable. It is possible that transfusion of older stored PRBCs may result in inadequately treated or prolonged anemia, impacting patients' physiological response to disease and treatment. Further investigation is needed to examine this relationship. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Gastrointestinal symptoms and endoscopy findings after pediatric solid organ transplantation: A case series.

Gastrointestinal symptoms are common among solid organ transplant (SOT) recipients. Information about colonoscopy findings after pediatric SOT is limited. This retrospective study reports endoscopy findings in a nationwide pediatric transplant recipient cohort. All pediatric recipients (kidney, liver, or heart) transplanted between 2010 and 2020 at our institution (n=193) who had undergone ileocolonoscopy and upper gastrointestinal endoscopy after SOT were enrolled. Sixteen patients were identified. A meticulous search on clinical data including transplantation, gastrointestinal symptoms, endoscopy findings, and follow-up data was performed. Endoscopy was performed at a median of 2.6 years (0.4-13.3) after the first transplantation (median age at SOT 1.2 years). Gastrointestinal symptoms leading to endoscopy did not differ between the different transplant groups. The leading endoscopy indications were prolonged diarrhea and anemia. PTLD was found in 8 (50%) patients. Five were histologically early PTLD lesions and three were monomorphic large B-cell PTLDs (two EBV-positive and one EBV-negative), one having previously been diagnosed with autoimmune enteropathy. One patient had EBV enteritis. De novo inflammatory bowel disease was found in one patient, eosinophilic gastroenteritis in another, and in one patient with several episodes of watery diarrhea, the histological finding was mild non-specific colitis. In four patients, the endoscopy finding remained unclear and the symptoms were suspected to be caused by infectious agents or mycophenolate. PTDL with various stages is a common finding after pediatric SOT in patients with gastrointestinal symptoms. Endoscopy should be considered in transplant recipients with prolonged diarrhea, anemia, and/or abdominal pain.

Abnormal Complex Karyotyping in A Patient Suspected of Acute Myeloblastic Leukemia (AML-M5): A Case Study

Hemophagocytic Lymphohistiocytosis (HLH) is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Patients with Acute Myeloblastic Leukemia (AML) may be prone to develop HLH. Hemophagocytic lymphohistiocytosis syndrome in AMLpatients with an abnormal complex karyotyping can worsen the patients' prognosis and outcome. A 47-year-old-female presented with prolonged fever, chills, fatigue, weight loss, productive cough, and anemia (blood transfusion (+)). Laboratory findings: hemoglobin 8.5 g/dL, WBC 151.99x103/μL, and platelet count 28x103/μL, peripheral blood 13% blast like cells, 19% promonocytes, 43% atypical (bizarre) monocytes, 25% neutrophils. Levels of CRP&gt;150 mg/L and procalcitonin 82.67 ng/mL, negative HBsAg, and positive IGRA test. Bone marrow morphology showed hypercellularity, decreased thrombopoiesis and erythropoiesis, increased granulopoiesis, macrophages, and hemophagocytosis. Karyotyping results: abnormal karyotypes: 46: XX (9 cells), 44: X (-18), 45: XX (-4), 45: XX (+7, -2, -16), 46: XX (chtb (3), chtb (4), chtb (5), chtb (9), chtb (12), chtb (22)), 46: XX (chtb (5), chtb (7)), 46: XX (chtb (6), chtb (12)), 46: XX (dic 2), 46: XX (chtb (1) (q12), chtb (3) (p21)), 46: XX (chtb (X) (q25) ), 46: XX (der (9), dic (9)), t (9:22)), 46: XX ((+ 21), (-13) chtb (2), p (23), t ( 9:22)). The conclusion was abnormal complex karyotyping. High concentrations of inflammatory cytokines (interleukin-1, interleukin-6, TNF-alpha, and interferon-gamma) secreted by malignant cells and increased phagocytic function of leukemic cells play an important role in the pathogenesis of HLH. Monocytic components (subtypes AML4 and AML5 of the FAB classification) are predisposing factors in cases of AML-related HLH. Cytogenetic abnormalities involving 8p11 and 16p13 are more common in AML-related HLH. Complex genetic abnormalities exacerbate the prognosis of AML, especially in treatment failure. A concluded that was diagnosed with HLH due to AML-M5 with genetic abnormalities of BCR ABL (+), monosomy, trisomy, and multiple chromatid breakage with high mortality. Karyotyping examination is important to determine the prognosis of the disease.

Adrenergic Modulation of Erythropoiesis After Trauma.

Severe traumatic injury results in a cascade of systemic changes which negatively affect normal erythropoiesis. Immediately after injury, acute blood loss leads to anemia, however, patients can remain anemic for as long as 6 months after injury. Research on the underlying mechanisms of such alterations of erythropoiesis after trauma has focused on the prolonged hypercatecholaminemia seen after trauma. Supraphysiologic elevation of catecholamines leads to an inhibitive effect on erythropoiesis. There is evidence to show that alleviation of the neuroendocrine stress response following trauma reduces these inhibitory effects. Both beta blockade and alpha-2 adrenergic receptor stimulation have demonstrated increased growth of hematopoietic progenitor cells as well as increased pro-erythropoietic cytokines after trauma. This review will describe prior research on the neuroendocrine stress response after trauma and its consequences on erythropoiesis, which offer insight into underlying mechanisms of prolonged anemia postinjury. We will then discuss the beneficial effects of adrenergic modulation to improve erythropoiesis following injury and propose future directions for the field.

Clinical outcomes of uterine artery embolization and experience of postoperative transvaginal fibroid expulsion: a retrospective analysis.

To explore the efficacy of uterine artery embolization (UAE) in the treatment of uterine fibroid and share the experience of transvaginal fibroid expulsion (FE) after UAE. We retrospectively analyzed the changes in uterine and fibroid volume in 152 patients with symptomatic uterine fibroid after UAE at Fujian Provincial Hospital and Fujian Longyan People Hospital from March 2014 to March 2020. After a 12-month follow-up, the improvement in postoperative clinical symptoms and the incidence of complications were evaluated. We also shared the clinical features and imaging findings of four patients with FE after UAE. All 152 patients successfully underwent UAE. After a 12-month follow-up, the postoperative volumes of the uterus and fibroid at 3, 6, and 12months were significantly reduced or disappeared compared to those before surgery (P < 0.05). Clinical symptoms, such as menorrhagia, dysmenorrhea, prolonged menstrual period, anemia, increased leucorrhea, pelvic discomfort, and urinary tract compression, were significantly improved after UAE. Among the 152 patients, the incidences of postoperative fever, nausea, vomiting, lower abdominal pain, and increased vaginal secretion were 7.89%, 7.24%, 3.95%, 19.08%, and 4.61%, respectively. Additionally, there were six cases of FE, with an incidence of 3.95%. Three cases of fibroid specimens and pathological images of fibroid biopsy, which were expelled through the vagina, were also provided. UAE is a satisfactory alternative surgical method for symptomatic uterine fibroid with definitive efficacy and high safety. However, it is necessary to guard against the occurrence of postoperative complications such as FE.