bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining Melphalan or Thiotepa with an Intensive Conditioning Regimen Significantly Reduces Relapse Rates in Minimal Residual Disease-Positive (MRD+) Pediatric Acute Myeloid Leukemia Patients Post Haploidentical Hematopoietic Stem Cell Transplantation
Authors: Zhu Huili , Wei Zhijie , Lu Peihua
Published: December 2024

Introduction

Acute myeloid leukemia (AML) is the second most common hematological malignancy in children, representing 15% to 20% of childhood leukemia cases. Minimal residual disease (MRD) status before transplantation is a key prognostic factor in pediatric AML. MRD positivity (MRD+) is linked to lower survival rates and higher relapse rates.

Methods

We retrospectively analyzed 18 pediatric AML patients with MRD+ who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) at our hospital from January 2020 to November 2023. Among them, 8 had the RUNX1::RUNX1T1 fusion gene, 1 had KMT2A::MLLT3, 1 had KMT2A::MLLT6, and 1 had KMT2A::ENL. MRD was assessed by flow cytometry. The median age was 7.5 years (range: 2 to 17 years) with a male-to-female ratio of 11:7. The median pre-transplant MRD was 2.26% (range: 0.01% to 89.9%). There were 7 cases in first complete remission (CR1), 3 in second complete remission (CR2), 1 in partial remission (PR), and 7 with no remission (NR). All received myeloablative conditioning with melphalan or thiotepa: 14 with Busulfan/Cyclophosphamide (Bu/Cy), 3 with Busulfan/Fludarabine (Bu/Flu), 10 with melphalan, and 8 with thiotepa. Melphalan was given at 110 mg/m² and thiotepa at 5-7.5 mg/kg, both on days -3 and -2. The median follow-up was 37.11 months (range: 4.19 to 53.71 months).

Results

All patients achieved 100% white blood cell engraftment with a median time of 15 days (range: 10 to 19 days) and platelet engraftment with a median of 10 days (range: 7 to 21 days). At one month post-transplant, all had negative bone marrow MRD. No relapse occurred, but 3 patients died (2 from pneumonia and 1 from grade III acute graft-versus-host disease [aGVHD]). All 3 were in NR status pre-transplant. The estimated 4-year overall survival (OS) rate was 83.3%. Grade III-IV aGVHD occurred in 11.11% of patients, and extensive chronic graft-versus-host disease (cGVHD) in 16.67%. Mucositis was noted in 4 patients, with only 1 case being moderate to severe. Cytomegalovirus (CMV) reactivation occurred in 66.67% and Epstein-Barr virus (EBV) in 33.33% of patients, with median onset times of 28 and 32 days, respectively.

Conclusions

In pediatric AML patients with MRD+, haplo-HSCT using a conditioning regimen that includes melphalan or thiotepa resulted in 100% engraftment of white blood cells and platelets without an increased incidence of mucositis. No relapse of the primary disease was observed during the follow-up period, and the estimated 4-year OS rate was 83.3%. The rates of CMV and EBV reactivation, as well as the incidence of GVHD did not increase. These findings suggest that this regimen can effectively reduce the risk of post-transplant relapse and improve survival outcomes.
The Haploid Hematopoietic Stem Cell Transplantation Combined with Umbilical Cord Blood Transfusion in the Treatment of Hematological Malignancies - a Multicenter, Single-Arm Prospective Trial
Authors: Mei Chen , Ren Yanling , Wang Shasha , Xu Yu , Huang Xianbo , Fan Cuihua , Shao Yanping , Qian Jiejing , Tong Hongyan
Published: December 2024

[Background] Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is increasingly utilized as a curative approach for various hematologic malignancies. However, major challenges in haplo-HSCT include a high incidence of graft-versus-host disease (GVHD), frequent occurrences of engraftment failure and transplant rejection. These issues are exacerbated by the increasing age of donors (≥ 40 years). There is an urgent need for more refined treatment strategies that mitigate the negative impact of older donors (≥ 40 years) on patient outcomes. Recent studies have demonstrated that haplo-HSCT combined with umbilical cord blood (UCB) transfusion has achieved rapid engraftment, low incidence of GVHD, and a low rate of disease recurrence in the treatment of hematological malignancies. We therefore conducted a study of haplo-HSCT combined with UCB in the treatment of hematological malignancies.

[Methods] In this multicenter, single-arm trial, patients diagnosed with hematological malignancies, who were planned to undergo haplo-HSCT with donors aged 40 years or older, from 3 different tertiary medical centers in China were included. The patients were received the infusion of UCB within 24 hours following the completion of haplo-HSCT. The UCB was HLA matched (≥ 5/10 alleles) and preference was given to blood group matching. The primary endpoint was the 100-day cumulative incidences of grade II-IV aGVHD. The secondary endpoints were the day of neutrophil and platelet engraftment. Here, we report results of the interim analysis.

[Results] As of June 2024, a total of 36 patients were enrolled, with a median age of 26 years (range, 14-65 years), 23 males and 13 females. The disease diagnoses included myeloid malignancies (20/36, 55.6%) and lymphoid malignancies (16/36 44.4%). The disease status of 3 patients were no remission, 4 patients were MRD positive and 29 patients were complete remission. The median age of donors were 50 years (range, 40-59 years). The 100-day cumulative incidences of grade II-IV aGVHD were 22.2% (8/36). The median day of neutrophil and platelet engraftment was at day 12 (range, 10-24) and day 13 (range, 10-42), respectively.

[Conclusion] This study showed that haplo-HSCT combined with UCB can effectively reduce incidence of grade II-IV aGVHD and achieve rapid engraftment in patients with hematological malignancies.
Trends in Multiple Myeloma Incidence and Mortality (1991-2021) in the United States: A Comprehensive Analysis of Gender and State-Level Disparities
Authors: Bhanushali Charmi , Mukhtiar Vaibhavi , Mehta Mansi , Bhanushali Vidhi , Cabot Clara Elizabeth Rose , Fatoki Raleigh A , Seetharaman Kala
Published: December 2024

Introduction:

Multiple myeloma contributes to cancer-related morbidity and mortality in the United States accounting for about 2% of cancer related deaths every year. However, with the advent of targeted therapeutics, the overall survival of myeloma has increased over the years. Nevertheless, access to novel therapeutics is not uniform across different states of the nation. In this study, we aim to analyze the incidence, mortality, and trends in multiple myeloma from 1991 to 2021, with a focus on trends at both the national and state levels along with sex-based disparities.

Methods:

TheGlobal Burden of Disease database was used to extract age-standardized incidence (ASIR), age standardized mortality rates (ASMR), and disability-adjusted life years (DALYs) of multiple myeloma from 1991 to 2021 for both males and females across all states of the United States. Mortality-to-incidence indices (MIIs) were calculated using the ratio of incidence and mortality rates. Disparities related to gender, geography, and time were analyzed and trends were analyzed using joinpoint regression analysis.

Results:

The ASIR of multiple myeloma in the United States decreased by 10.33% between 1991 and 2021, with a more significant decline in females (15.95%) compared to males (8.18%). Similarly, ASMR for both sexes combined fell by 14.61%, with a more substantial decrease in females (18.52%) than in males (13.5%). Overall, the MIIs decreased by 4.78%. The DALYs for both sexes combined declined by 23.03%, with a larger reduction observed in females (26.26%) compared to males (21.79%).

There were notable variations in these trends across states over the 30-years. Changes in ASIR ranged from a 45.62% increase in Kansas to a 49.23% decrease in New Hampshire. ASMR decreased for both sexes in all states from 1991 to 2021, varying from a 1.14% decrease in Oklahoma to a 32.37% decrease in the District of Columbia. DALYs decreased in all states, ranging from a 37.54% reduction in the District of Columbia to 8.05% reduction in New Mexico.

Conclusion:

This analysis highlights gender-based and region-based disparities in the United States in multiple myeloma morbidity and mortality. While the prognosis for multiple myeloma has significantly improved over the years due to therapeutic advances, there has been a significant difference in health indices such as DALYs and ASMR across genders and regions respectively. These findings enhance our understanding of the gender and state level disparities of multiple myeloma underscoring the importance of targeted studies to explore the reasons behind these epidemiological differences.
Correlation Analysis of DNA Methylation Level and Clinical Characteristics in Pediatric MDS Patients
Authors: Yang Wenyu , Liu Chenmeng , Li Xiaolan , Wan Yang , Ren Yuanyuan , Liu Fang , Guo Ye , Zhu Xiaofan
Published: December 2024

Objective: Pediatric myelodysplastic syndrome (MDS) has a considerably lower prevalence compared to MDS in adults, with an annual incidence rate ranging from 1 to 2 cases per million children.This study aimed to find clinical indicators that were associated with different methylation levels and prognosis.

Methods: The clinical data of 20 pediatric MDS patients with DNA samples admitted to our center from April 2017 to December 2020 were retrospectively analyzed, Quantification of DNA methylation was performed using an Illumina Infinium MethylationEPIC Beadchip platform (Illumina). Unsupervised hierarchical clustering of the most variable CpG sites across all MDS samples classified three clusters, low methylation (LM), intermediate methylation (IM), and high methylation (HM).

Results: 20 cases of pediatric MDS were admitted to our study，according to WHO 2016 myeloid tumor diagnosis criteria RCC 7 RAEB 10 and RAEB-T 3cases. The median age of onset was 7.9 years old (3.5-14.9 years) among the 20 cases, including 13 males and 7 females. At diagnosis, the median WBC count was 13.0×109/L (1.4-130.0×109/L), the median platelet count was 81.1×109/L (18.0-254.0×109/L) the median MCV was 95.5fl (79.2-124.1fl) and the median RDW-SD 56.7fl (13.7-109.6), RDW-CV 19.6 (13.7-57.2). Chromosome karyotype abnormalities were found in 80% (16/20) of patients, 9 cases(56.3%) had chromosome 7 deletion. Genomic DNA methylation levels were classified into three groups: 2 cases in the LM subgroup,9 cases IM subgroup, and 9 cases in the HM subgroup. 16 cases were given hemotopoietic stem cell transplantation(HSCT), There were significant differences in counts of white blood cell(WBC), neutrophil and platelets in different methylation subgroups (P<0.05). All patients were followed up to July 2024, 2 cases lost follow-up. The median overall survival(OS) was 63.6%±11%, the median event free survival(EFS）was 64.6%±18.8%. There were no differnce in OS and EFS among different methylation groups. Compared with the LM and IM subgroup, the HM group had higher WBC (5.17 vs 2.5, 0.01) and neutrophil absolute value (3.03 vs 0.52,0.025), and lower platelet (47 vs 76, 0.067).

Conclusions: Pediatric MDS patients with HM at diagnosis had higher WBC counts and neutrophil, and with lower platelets. In our study There was no significant difference in survival among different methylation groups.
Outcomes and Prevalence of Complications in Patients with Sickle Cell Disease Receiving Blood Transfusions: Insights from the National Inpatient Database 2016-2021
Authors: Mekonen Yemesrach , Barrera Nelson , Chapiolkina Volha , Tole Camila , Guevara Nehemias , Sanchez Jorge , Sangam Sangam , Newman Azana , Bermudez Marco , Fulger Ilmana
Published: December 2024

Introduction

Red blood cell (RBC) transfusion is frequently used in sickle cell disease (SCD) patients to help prevent and treat various acute and long-term medical issues. Since curative therapies are not a viable option for the majority of SCD patients, disease-modifying medications that can slow the progression of the disease and blood transfusion are the main focus of the current management of SCD. Although red blood cell transfusions have the potential to save lives, we are concerned about the severe side effects of transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) in this patient population. In individuals with SCD, TRALI and TACO are frequently misdiagnosed, mainly because the symptoms resemble those of acute chest syndrome. We aim to describe the outcome and prevalence of complications in hospitalized SCD patients receiving blood transfusions.

Methodology

Our study was comprehensive, utilizing the National Inpatient Sample data from 2016 to 2021 to perform a retrospective analysis. We identified and analyzed patients hospitalized with a diagnosis of sickle cell disease and those who received blood product transfusions. The primary outcome was in-hospital mortality, and secondary outcomes included length of stay (LOS), the total cost of hospitalization, and the prevalence of TRALI and TACO.

Results

There were 94,400 admissions for sickle cell disease. Among these, 19,960 patients received blood transfusions during hospitalization. The mean age in the transfusion group was 34 ± 16 years, with 57% female. TRALI was reported in only 0.13% of patients, while TACO occurred in 1.8% of patients. The odds of mortality for sickle cell patients without transfusion [aOR 1.04; 95% CI 1.03-1.05; p=0.001] and the odds of mortality in the transfusion group were similar [aOR 1.04; 95% CI 1.02-1.05; p=0.001]. The mean LOS was 4 ± 3 days for the non-transfusion group and 6 ± 3 days for the transfusion group. The total cost of hospitalization was $52,500 for the non-transfusion group versus $75,213 for the transfusion group.Conclusion

Our study on patients admitted with sickle cell disease who received blood transfusions has significant implications for patient care. We found that mortality did not differ significantly between transfused and non-transfused patients. However, patients who received transfusions had a prolonged length of stay and higher total hospitalization costs. Moreover, the prevalence of TRALI and TACO was low in transfused patients. These findings emphasize the importance of careful consideration when deciding on blood transfusions for sickle cell disease patients, urging healthcare professionals to reassess their practices and strive to provide the best care possible.
Anomalous Peaks Observed in the Mass Spectrometry of Light Chains Correlate with the Diagnosis of AL Amyloidosis
Authors: Dong Mengmeng , Xiao Xiao , Cai Zhen , Wang Jiasheng , Yang Yang , Zheng Gaofeng , Yang Li , Yan Haimeng
Published: December 2024

Background:

Systemic light chain (AL) amyloidosis is a disease characterized by the misfolding of monoclonal immunoglobulin light chains into amyloid proteins. These misfolded proteins deposit in tissues and organs, causing structural damage and organ dysfunction. Pathological biopsy is the gold standard for diagnosing AL. Mass spectrometry, as a recently developed method for detecting light chains, is increasingly being utilized to assist in the diagnosis of plasma cell disorders.

Method:

Matrix-Assisted Laser Desorption Ionization time-of-flight (MALDI-TOF) is used to detect λ and κ light chains in the peripheral blood of patients. This method identifies λ and κ light chains based on the differences in their mass-to-charge ratios.

Result:

In patients suspected of having plasma cell disorders, we utilized MALDI-TOF to detect light chains in their peripheral blood. We observed that the presence of abnormal peaks in the mass spectrum is often associated with a diagnosis of amyloidosis. Among the 56 individuals tested, 9 exhibited abnormal peaks in the light chain profiles: 5 with amyloidosis, 3 with multiple myeloma (MM), and 1 with monoclonal gammopathy of undetermined significance (MGUS). Of these 56 individuals, 6 were diagnosed with AL based on pathological findings, and 5 of them showed abnormal peaks in peripheral blood light chain mass spectrum.

Therefore, based on our estimation with a limited sample size, using pathological diagnosis as the gold standard, the sensitivity of diagnosing amyloidosis through MALDI-TOF detection of light chain abnormal peaks is 83.3%, and the specificity is 92.2%. However, due to our limited sample size, the sensitivity and specificity values require validation through testing with a larger sample size.

The specific significance of the differential peak has not been thoroughly investigated. Based on published literature and the positions of the peaks, it is hypothesized that this may be associated with glycosylation of light chains, which could result in an abnormal protein structure. We intend to further investigate this in our future research.

Conclusion and significance:

The diagnosis of AL amyloidosis primarily depends on pathological assessment via tissue biopsy. Our research indicates that the detection of abnormal peaks in peripheral blood using MALDI-TOF for light chains demonstrates good sensitivity and accuracy for the diagnosis of AL amyloidosis. Although the sample size remains relatively small, our findings offer potential insights and approaches for developing non-invasive diagnostic methods for amyloidosis.
In Vivo Correction of a Genetically Humanized Fanconi Anemia Mouse Bone Marrow Failure Model Using Digital Editing Technologies
Authors: Moriarity Branden S , Webber Beau R , Rogers Colette B , Wagner John E , Peterson Joseph J , Butterbaugh Cassandra , Carlson Paige
Published: December 2024

Fanconi anemia (FA) is a rare genetic disease caused by mutations in certain DNA repair genes (i.e. FA genes), whose gene products make up the FA pathway for interstrand crosslink (ICL) repair. FA patients are predisposed to bone marrow failure (BMF) and cancer development. The current standard-of-care for >90% of FA patients that develop BMF or hematopoietic malignancy is allogeneic hematopoietic stem cell transplant (HSCT). However, conditioning toxicities and development of graft-vs-host disease after transplant are associated with increased risks of cancer after age 20 years, particularly in the aero-esophageal tract. Therefore, there is significant interest in the development of an effective and safe gene therapy approach for FA. While the development of CRISPR/Cas9-mediated gene editing has made it possible to induce site-specific double-strand breaks (DSBs) and correct gene mutations through homology-directed repair (HDR), this approach is impeded in FA cells because of their underlying defect in HDR. Furthermore, the number of FA hematopoietic stem and progenitor cells (HSPC) available for ex vivo manipulation is limiting. To overcome these barriers, we will optimize the efficiency of in vivo HSPC correction using newly developed ‘digital’ base editors (BEs) and prime editors (PEs), which do not require DSB repair. For this work, we developed a humanized murine model that harbors the human FANCA Spanish founder mutation c.295 C>T. We have successfully shown that BEs efficiently correct FANCA Spanish founder mutation in patient-derived cells in vitro (PMID: 35955545). To show that in vivo correction of the FANCA c.295 C>T mutation can be accomplished with BEs or PEs and prevent bone marrow failure typical in FA patients, we are modifying the FA mouse model in the 129S4 background that not only harbors the FANCA Spanish founder mutation at Fanca exon 4, but also a mutated alcohol dehydrogenase 5 (Aldh5) which predisposes cells to genotoxic ICLs and subsequent marrow failure. Using these mice, we will measure correction of the FANCA Spanish founder mutation in vivo by adenosine base editor (ABE) or PE delivered by recombinant adeno-associated viruses or lipid nanoparticles. Furthermore, we will assess FA phenotypes after FANCA correction (i.e. bone marrow HSPC population size, function, sensitivity to ICLs, and repopulation capacity). Completion of our studies will generate preclinical data demonstrating proof-of-concept for the use and superiority of in vivo digital gene editing of bone marrow HSPCs for treatment of FA regardless of FA genotype and potentially other congenital marrow failure syndromes.
Daunorubicin and Cytarabine 3+5 Combined with Venetoclax in De Novo Patients with Acute Myeloid Leukemia: A Single-Center, Open-Label, Controlled Study
Authors: Huang Zhenqi , Dong Xinyi , Wu Wei , Ruan Min , Ge Jian , Long Zhangbiao
Published: December 2024

Background: Daunorubicin and cytarabine 3+5 were the standard first-line induction chemotherapy in newly diagnosed acute myeloid leukemia currently, whereas the complete remission rate is only 70%. In order to detect a more effective and tolerated induction regime, we designed a novelty regime of daunorubicin and cytarabine 3+5 combined with venetoclax as the induction chemotherapy in de novo patients with acute myeloid leukemia, and to evaluate the efficacy and safety of this regime.

Methods: We conducted a single-institutional, non-randomized, open-label, controlled study. We enrolled patients with de novo AML aged between 18 and 60 years and ECOG score was 0-2. The test group received daunorubicin 40mg/m2/d, d1~d3; cytarabine 100mg/m2/d, d1~d5, venetoclax 100mg d1, 200mg d2, 400mg d3 ~d14, whereas the control group received daunorubicin 60mg/m2/d, d1~d3 and cytarabine 100mg/m2/d, d1~d7. The induction chemotherapy length of the two groups was 28 days per cycle, and all patients received one or two cycles of induction chemotherapy. Subsequently, these patients received sustained chemotherapy or hematopoietic stem cell transplantation. The primary endpoint was the complete remission rate after two cycles of induction therapy, the secondary endpoints were adverse events and overall survival.

Results: Between December 2021 and June 2024, forty patients with newly diagnosed acute myeloid leukemia at the first affiliated hospital of Anhui Medical University were enrolled. Twenty-one patients were in the test group and nineteen in the control group. There were 25 males and 15 females, with a median age of 46 (range 18-59) years old in both groups. The baseline characteristics were all balanced differently between the two groups. After two cycles of induction chemotherapy, the complete remission rate was 95% (20 of 21 patients) in the test group, whereas the complete remission rate was 68% (13 of 19 patients) in the control group (P＝0.0395). The most common hematological adverse events were neutropenia, thrombocytopenia, and anemia. The most frequent non-hematological adverse events include infections, vomiting, diarrhea, and hypokalemia. Infection rate was 95% in the test group and 100% in the control group. Fatal adverse events did not occur in both groups. At the median follow-up of 14 months, the median overall survival was not reached in both groups. The estimated 2-year overall survival rate was 72% in the test group and 58% in the control group, respectively.

Conclusions: Daunorubicin and cytarabine 3+5 combined with venetoclax is an effective induction therapy for de novo patients with acute myeloid leukemia, and is well tolerated for these patients in the induction chemotherapy periods.
High-Dimensional Single-Cell Analysis of Clinical-Grade Flow Cytometry Explains the Unpredictable Complex Shifts of Patient-Specific Immunophenotypes during B-ALL Relapse Progression
Authors: Rolf Nina , Liu Lorraine YT , LeClair Pascal , Atre Tanmaya , Vercauteren Suzanne , Lim Chinten James , Reid Gregor S. D.
Published: December 2024

Relapsed precursor B-cell ALL (B-ALL) commonly evolves from minor diagnostic clones, but their early phenotypic characterization remains unachieved despite abundant multi-omics data. Immunophenotyping, an essential diagnostic and therapy-response monitoring tool, identifies the patient-specific expression pattern of bulk leukemia. At time of relapse, most B-ALL immunophenotypes have undergone substantial and seemingly random multi-directional modulations of their diagnostic expression pattern. For decades, these unpredictable immunophenotypic shifts at time of relapse, observed across different methods of antigen expression assessment, have prevented a deeper understanding of phenotypically-defined leukemia progression biology. Addressing this limitation, we applied unsupervised high-dimensional computational analysis of clinical-grade flow cytometry to dissect the intra-leukemic phenotypic heterogeneity at the single-cell level in longitudinally collected B-ALL patients and matched patient-derived xenografts. Our results provide AI-guided and clinically validated evidence that the observed immunophenotypic shifts during disease progression did not result from antigen expression fluctuations, but from enrichment of distinct phenotypically stable subpopulations. As our study identifies patient-specific subpopulation dynamics during disease evolution, it achieves immunophenotypically-defined leukemia progression assessment, which addresses an important unmet clinical and translational need. In each progression series, population dynamics followed a trajectory towards relapse-dominating subpopulations when selective pressures, such as xenotransplantation or in vivo chemotherapy, were applied, often from very minor abundance levels at diagnosis. Each time, the changes in relative proportions of subpopulations explained the observed immunophenotypic shift at the bulk-level. Overcoming decades-old challenges, our findings provide a new conceptual approach to investigate the role of intra-leukemic phenotypic heterogeneity in B-ALL progression to identify treatment-refractory phenotypes, which could significantly impact patient-care, inform precision-medicine options, and enhance relapse-modelling.
Updated Meta-Analysis of Phase III Randomized Controlled Trials (RCTs) to Evaluate the Incidence of Second Primary Malignancies (SPMs) in Patients with Multiple Myeloma (MM) Treated with Isatuximab
Authors: Aboaid Hazem , Nguyen Kevin , Jones Daniel Thomas , Srinivasmurthy Ramaditya , Nanda Rishi Kumar , Thein Kyaw Zin , Htut Thura Win
Published: December 2024

Introduction:

The management of multiple myeloma has experienced significant advancements in recent years.The isatuximab combination regimens are becoming the standard of care nowadays for both newly diagnosed (ND) and relapsed/refractory (RR) MM. However, it is crucial to consider all potential risks, particularly the risk of second primary malignancies (SPMs). The purpose of this meta-analysis is to further investigate the risk of SPMs in patients with MM treated with isatuximab.

Methods:

We conducted a comprehensive systematic literature search using MEDLINE, EMBASE, and cochrane databases from inception through July 22nd, 2024. Phase III RCTs utilizing isatuximab in patients with either RRMM or NDMM that report SPMs were included in the analysis. We reported the total number of SPMs including both solid and non-solid malignancy. We performed a subgroup analysis regarding the incidence of SPMs in the first-line treatment setting (NDMM) and second-line treatment setting (RRMM). Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied.

Results:

A total of 1704 patients from 4 phase III RCTs were eligible (1104 patients with NDMM from GMMG-HD7 and IMROZ trials + 600 patients with RRMM from IKEMA and ICARIA-MM trials). ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. IMROZ and GMMG-HD7 both compared isatuximab (I) + bortezomib (V) + lenalidomide (R) + dexamethasone (d) vs VRd. Randomization ratios were 1:1 in ICARIA-MM and GMMG-HD7 studies, and 3:2 in IKEMA and IMROZ studies. Overall, the incidence of SPMs was 6.50% in the isatuximab group vs 4.22% in the control group (RR, 1.39; 95% CI: 0.83-2.33; P=0.21), (risk difference [RD], 0.02; 95% CI: -0.01-0.05; P=0.24). In the subgroup analysis, the results were also not statistically significant. In the NDMM cohort, incidence of SPMs was 5.38% (isatuximab group) vs 3.92% (control group) (RR, 1.16; 95% CI: 0.48-2.80; P=0.74), (RD, 0.01; 95% CI: -0.04-0.06); P=0.67). In the RRMM cohort, incidence of SPMs was 8.51% (isatuximab group) vs 4.79% (control group) (RR, 1.75; 95% CI: 0.70-4.35; P=0.23), (RD, 0.04; 95% CI: -0.00-0.07; P=0.05).

Conclusion:

This meta-analysis shows no increased risk of SPMs overall in patients with NDMM or RRMM treated with isatuximab. Further investigations and long term follow up with close surveillance of those patients on the studies are needed to monitor for any developing malignancies in the future and define the actual relation and definitive incidence.
Enhanced Mitochondrial Priming By Momelotinib Confers Superior In Vivo Efficacy in Combination with Venetoclax Compared to Gilteritinib or Ruxolitinib
Authors: Kincaid Zachary , Ansari Sekhu , Azhar Mohammad , Kesarwani Meenu , Azam Mohammad
Published: December 2024

Introduction. Acute Myeloid Leukemia (AML) is a complex hematologic malignancy marked by significant genetic heterogeneity, with FLT3 mutations being among the most common and prognostically unfavorable alterations. Despite advancements in targeted therapies, FLT3-mutated AML remains a significant challenge due to frequent relapses and resistance to existing treatments. Targeting mitochondrial apoptosis pathways has emerged as a promising strategy to enhance therapeutic efficacy. Proteomic and signaling studies have revealed that Momelotinib enhances mitochondrial priming in AML cells, irrespective of FLT3 mutational status. Consequently, Momelotinib treatment exhibits superior efficacy when combined with Venetoclax, compared to combinations with Gilteritinib or Ruxolitinib. Preclinical evaluations of Gilteritinib and Ruxolitinib in combination with BCL2 inhibitors have been limited to FLT3 and JAK2 mutant cases, respectively. In contrast, Momelotinib has demonstrated a synergistic response across all AML genotypes.

Result. Mitochondrial priming is a major determinant of therapeutic outcome in FLT3 mutated AML treated with BCL2 inhibitors. BH3 profiling of AML cells with and without FLT3 mutations reveled that momelotinib treatment enhances mitochondrial priming in AML regardless of FLT3 mutational status. In contrast, treatment with Gilteritinib or Ruxolitinib showed minimal change on mitochondrial priming. Our findings indicate that Momelotinib significantly enhances mitochondrial priming, leading to increased apoptosis and reduced leukemic cell viability when used in combination with Venetoclax. In FLT3-mutated AML cell lines and primary patient samples, the Momelotinib+Venetoclax combination exhibited superior response than Gilteritinib+Ventoclax combination. Strikingly, Momelotinib+Venetoclax showed effective suppression of non-FLT3 mutated AML while treatment with Gilteritinib+Ventoclax were ineffective against these cells. In vivo studies utilizing xenograft models of FLT3-mutated AML cells from cell lines and primary patient samples demonstrated that the Momelotinib-Venetoclax combination achieved superior leukemic clearance and prolonged survival.

In conclusion, our study underscores the potent synergistic effect of Momelotinib and Venetoclax in AML regardless of FLT3 mutational status, attributable to enhanced mitochondrial priming. These findings provide a compelling rationale for the clinical evaluation of Momelotinib and Venetoclax combination therapy, highlighting its potential to improve treatment outcomes in patients with high-risk AML.
Epidemiological Analysis of Water Contaminants and Their Correlation with Leukemia and Non-Hodgkin Lymphoma Incidence in Florida
Authors: Nagarajan Samit , Jabbal Iktej , Chaulagain Chakra
Published: December 2024

Introduction

This study investigates the incidence of leukemia and non-Hodgkin lymphoma (NHL) in relation to various water contaminants, including arsenic, across different counties in Florida. Arsenic, a known carcinogen, and other chemicals, such as haloacetic acid, radium, chromium, and trihalomethanes, have been detected in multiple water sources, prompting public health concerns1-4.

Methods

A meticulous and comprehensive epidemiological analysis was conducted using data from National Institute of Health database and the Environmental Working Group's tap water contaminant database. The study population included individuals residing in areas with documented contamination compared to those in regions with low or non-detectable levels. Correlation coefficients were calculated to assess the relationship between contaminant exposure and cancer incidence, ensuring the thoroughness and reliability of the findings.

Results

Statistical analysis revealed a moderately strong correlation between arsenic exposure and the incidence of leukemia (correlation coefficient = 0.47) and NHL (correlation coefficient = 0.21). Similarly, chromium exposure showed a moderately strong correlation with leukemia (correlation coefficient = 0.42) and a weaker correlation with NHL (correlation coefficient = 0.052). In contrast, haloacetic acid and trihalomethanes were negatively correlated with both leukemia and NHL, while radium showed a minimal correlation with leukemia and a weak positive correlation with NHL.

Conclusion

These results underscore the potential impact of continued water quality monitoring and mitigation strategies in reducing exposure to these contaminants. While the study found weak to moderately strong correlations, it highlights the significant role of environmental factors in cancer prevention efforts. Further research is recommended to explore the biological mechanisms underlying contaminant-induced carcinogenesis and to develop effective public health interventions, emphasizing the potential impact of this research on public health.
Hepatocyte Growth Factor Is Overexpressed in AML and Remodels the Mesenchymal Stromal Cell Niche
Authors: Chura Annika , Li Wantong , Oyman Konur , Wang Victoria , Blaser Bradley Wayne
Published: December 2024

Acute Myeloid Leukemia (AML) is a highly heterogenous and aggressive cancer characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow and blood. Despite advances in chemotherapy, targeted therapy, and stem cell transplantation, these treatments are often insufficient, resulting in disease relapse and a 5-year survival rate of under 32% (National Cancer Institute, 2021).

Ficlatuzumab is an anti-HGF (hepatocyte growth factor) antibody that has demonstrated effectiveness in relapsed/refractory AML with an overall response rate of 53% observed in a phase 1b clinical trial (Wang et al, 2021). Aberrant expression of HGF and activation of its receptor, c-MET, is frequently observed in cancers, including AML (Fu, et. al 2021; Kentsis et al., 2012). Complete response to ficlatuzumab was associated with suppression of MET signaling while non-response to ficlatuzumab was associated with augmented expression of HGF by a subpopulation of AML blasts (Wang et al., 2021). Effects of HGF signaling on the hematopoietic microenvironment in this context are unknown.

To address this gap in knowledge, we generated a transgenic zebrafish model in which expression of zebrafish HGF (hgfa) is enforced in hematopoietic stem cells (HSCs) using the Runx1 enhancer element. By fluorescent microscopy, there were no significant changes in HSC numbers in 72 hour-post-fertilization (hpf) embryos with hgfa overexpression compared to clutchmate controls. This suggests that overexpression of hgfa alone may not be sufficient to alter HSC numbers in short term assays.

However, single cell RNA-sequencing (scRNA-seq) performed at this timepoint did show a 1.7-fold expansion of lepr+ mesenchymal stromal cells (MSCs) in Runx1:hgfa transgenic animals compared to controls. Gene expression profiling showed nearly exclusive expression of met in the MSC cluster, consistent with this expansion being a direct consequence of hgf signaling. To identify potential downstream effects of MSC expansion, scRNA-seq data from the ficlatuzumab trial was reanalyzed to identify markers specific for treatment-resistant blasts. One such marker, CD44, was expressed specifically in a population of hematopoietic progenitor cells that was overrepresented by 2.1-fold in Runx1:hgfa transgenic animals. CD44 is a receptor for extracellular matrix proteins including collagen, which is abundantly produced by the MSC population in this study. CD44 transcription is controlled in part by WNT signaling (Wielenga, et. al, 1999; Schmitt, et. al 2014); MSCs were the dominant producer of wnt3, 4, 6 and 9.

Together, these in vivo data point to a novel set of complex interactions between hematopoietic cells and MSCs which may have relevance for therapeutic resistance in AML.
Central Nervous System Complications in Different Types of Sickle Cell Disorders: A Nation-Wide Analysis
Authors: Eltaher Basant , Shah Purva , Mahmoud Amir , Singh Harkarandeep , Sanjeevi Aditya , Mostafa Mariam , Abdelhay Ali
Published: December 2024

Introduction: Sickle cell disorders have long been associated with central nervous system (CNS) complications. Morbidity and outcomes of sickle cell anemia have been extensively studied. However, few studies are available examining CNS complications in adult patients with different types of sickle cell disorders.

Methods: We used the National Inpatient Sample (NIS) ICD-10 codes between 2016 and 2020 in STATA BE software to perform a retrospective study and evaluate CNS complications in adult hospitalized patients with different types of sickle cell disorders. We have applied descriptive statistics to detect baseline characteristics of these patients and logistic regression analysis to assess CNS complications while adjusting for comorbid conditions.

Results: 105,976 patients were hospitalized with sickle cell disorders between 2016 and 2020. The most common sickle cell disorder was sickle cell anemia (SS) (88%), followed by sickle-hemoglobin C disease (SC) (5.8%), sickle-cell thalassemia (ST) (5%), and other unspecified sickle cell disorders (1%). Most patients were women (57%), black (90%), and with a mean age of 34 years. We have analyzed different CNS complications in these patients, including stroke, migraine, and seizures.

All sickle cell disorders were associated with increased association with stroke except for ST, though these findings weren't statistically significant (p =0.92, p=0.71, and P=0.76, respectively). It was observed that African Americans were less likely to have stroke (Odds ratio (OR) 0.7, 95% CI, 0.5-0.97; p =0.03). Hypertension (OR 1.6, 95% CI,1.36-1.8), congestive heart failure (OR 1.4, 95% CI, 1.1-1.7), hyperlipidemia (OR 2.5, 95% CI, 2.1-2.9), and thrombophilia (OR 4.7, 95% CI, 3.5-6.2) had a strong association with stroke in patients with sickle cell disorders. There was no statistically significant difference in the incidence of migraine among sickle cell disorder patients.

Interestingly, the odds of developing seizures were less in SC (OR 0.6, 95% CI, 0.4-0.9; p<0.01) and in ST (OR 0.5, 95% CI, 0.35-0.8; p<0.003). Congestive heart failure (OR 2, 95% CI, 1.7-2.7), chronic kidney disease (OR 1.4, 95% CI, 1.1-1.8), and end-stage renal disease (OR 2.5, 95% CI, 2-3.1) patients with sickle cell disorders had increased likelihood of mortality.

Conclusion: Our analysis didn't show a statistically significant difference in the likelihood of CNS complications in different types of sickle cell disorders, except in less odds of developing seizures in SC and ST. However, multiple comorbidities were associated with worse outcomes. More studies are needed to assess morbidity among different sickle cell disorders in adult patients.
Ketamine for Pain Relief in Sickle Cell Vaso-Occlusive Crises: A Systematic Review
Authors: Martinez Ernesto Calderon , Saji Stephin Zachariah , Carmona Thomas Campos , Abbagoni Vaidarshi , Fernando Druvini , Karnan Nithin , Salman Mohammad , Mylavarapu Suchita , Vargas Mishell Estefania Llerena , Samad Nathalia Schettino , Sheethal Arvapalli Lakshmi , Dost Sara
Published: December 2024

Introduction: Sickle cell disease (SCD) is the most common genetic disorder that is prevalent in the African American population, and vaso occlusive crisis(VOC) is a hallmark of SCD, characterized by intense pain and tissue ischemia due to occlusion of small blood vessels by sickled cells. The standard treatment for relieving pain is intravenous opioid administration. However, it has been hypothesized that frequent exposure to opioids in these patients could lead to tolerance, which is thought to contribute to opioid refractory pain. This analysis aims to determine if the use of ketamine in this type of patient is safe and effective when compared with opioids.

Objectives/Methods: Adhering to PRISMA guidelines, a systematic search was initially conducted on 05/20/2024 in PubMed, MEDLINE, Cochrane, Scopus, Web of Science, EMBASE, and CINAHL using the following keywords: ‘Ketamine’, “Sickle cell disease”, and “Vaso-occlusive Crisis. We meticulously included randomized controlled trials (RCT), cohort, case-crossover and case-control studies.

Results: Five studies (689 participants) met the inclusion criteria. Four out of five studies qualitatively reported pain reduction with ketamine. The meta-analysis of two studies (518 observations) for the Numerical Rating Scale (NRS) pain score showed a standardized mean difference (SMD) of -0.11 (95% CI: -0.42 to 0.21, p=0.50, I²=69.7%). For Morphine Milligram Equivalent (MME), two studies (344 observations) yielded an SMD of 0.0043 (95% CI: -1.31 to 1.32, p=0.99, I²=98.5%). Side effects analysis of four studies (608 observations) showed a relative risk (RR) of 5.74 (95% CI: 2.80 to 11.79, p<0.0001, I²=0%).Though the qualitative analysis showed an effective pain reduction with ketamine, there was no statistically significant difference in the numerical pain score reduction analysis.

Conclusion: Our qualitative analysis highlights ketamine's efficacy in VOC to improve pain management with an incidence of dose-dependent side effects. There still needs to be studies on the safety profile of ketamine and standardization of the pain scale. To establish ketamine as a safe and effective treatment for patients with sickle cell disease experiencing a VOC, additional studies are required to increase the statistical power of the research and lead to a definitive conclusion.
Association of Palliative Care Involvement and Infectious Complications in Hospitalized Multiple Myeloma Patients - National Inpatient Database Study
Authors: Shah Purva , Eltaher Basant , Mahmoud Amir , Herman Adam
Published: December 2024

Background

Pain is the most common symptom in multiple myeloma (MM), and palliative care (PC) involvement often focuses on symptom management. Improvement in MM treatment has increased survival rates, consequently increasing symptom burden and comorbidities. Infection is a major concern in hospitalized MM patients due to their immunocompromised state. Evaluating the association between PC involvement and infectious complications in hospitalized MM patients can provide insights into quality of care and patient outcomes.

Methods

A retrospective cohort study using the ICD10 codes from the National Inpatient Database (2016-2020) was performed with STATA BE software. Chi square test was used for crude analysis and logistic regression was used to adjust for confounders for categorical variables. Z score was calculated to assess the difference between the Log Odds Ratios of two separate analyses. Results were adjusted for age, gender, race, insurance, hospital size and location, nicotine and alcohol use, diabetes, heart failure, chronic kidney disease, obesity, bone marrow transplantation (BMT), chemotherapy, immunotherapy, neutropenia, hypogammaglobulinemia, and myeloma type (multiple myeloma, plasma cell leukemia, solitary and extramedullary plasmacytoma).

Results

This study included 118,369 hospitalized MM patients with a mean age of 69.49土11.46 years and 44.31% females. Palliative care involvement was significantly associated with infection [OR 1.15; 95%CI 1.45-1.58] and in-hospital mortality [OR 15.43; 95%CI 14.55-16.36] likely because of the same ICD 10 code used for PC and hospice care. Delayed involvement of PC in patient care primarily for goals of care conversations might also be contributory. Interestingly, the association between infection and mortality was significantly lower [z-score 6.76; p value<0.001] when PC was involved [OR 2.23; 95%CI 2.04-2.44] as compared to when PC was not involved [OR 3.41; 95%CI 3.14-3.71]. When PC was involved for MM patients with infection, BMT [OR 0.87; 95%CI 0.76-0.99] and chemotherapy [OR 0.61; 95%CI 0.53-0.71] were associated with significantly less mortality. When PC was not involved, BMT [OR 1.16; 95%CI 1.00-1.35] was associated with significantly higher and chemotherapy [OR 0.85; 95%CI 0.73-0.98] with significantly lower mortality.

Conclusion

In addition to symptom management and advance care planning, PC involvement in admitted MM patients with an infection might be associated with lower mortality. Longitudinal studies need to be conducted to establish a causal relationship of this hypothesis. Separate ICD10 codes for PC and hospice would result in a more accurate assessment of PC involvement in patient care.
The Financial Burden of Unnecessary MTHFR Gene Testing
Authors: Singh Anaiya , Ghaffar Yahya , Goyal Shriya , Gaddam Shiva Jashwanth , Ramadas Poornima
Published: December 2024

Introduction:

Polymorphisms of the methylene tetrahydrofolate reductase (MTHFR) gene have controversially been associated with an increased risk of venous thromboembolic event(s) VTEs and cerebrovascular accidents (CVAs). However, as per consensus guidelines and evidence-based recommendations, routine testing of the MTHFR gene has not been recommended for workup of thrombophilia and stroke. Despite these existing guidelines, testing of the MTHFR gene mutation is still frequently performed. We aim to analyze the financial burden of this unnecessary and clinically irrelevant testing.

Methods:

At our institution, we conducted an Institutional Review Board (IRB)-approved retrospective study, collecting data on 196 patients who had undergone testing for MTHFR gene mutations between 12/2019 to 12/2022. We excluded patients with these tests performed for indications other than workup for thrombophilia(s) and cerebrovascular accidents (CVAs). Our data collection included patient demographics, indications for testing, and insurance coverage. We incorporated this data to calculate the financial implication on our institution, associated with unnecessary testing of MTHFR gene mutations in patients with elevated thrombotic risk and stroke(s).

Results:

The median age of testing for the MTHFR gene was 42+/-6 years, with females contributing (58) 64.6% and males (32) constituting 35.5%. Gene testing was done for 24 patients with TIAs and CVAs and in 66 patients with VTEs. Out of all the 90 patients tested for the gene mutations, 16 were covered by Medicare, 27 by Medicaid and 47 benefitted from private-based insurance. MTHFR testing costs approximately $300 to a patient willing to get tested for it at our institution, with prices being higher, around $400, if the testing was done outpatient.

Conclusions:

We found that over three years, an expenditure of $27,000 was spent on testing MTHFR gene mutations. We aim to publish this data within our institution and conduct educational sessions across various departments, and physician education regarding clinical insignificance and excessive costs of this single test. This initiative is focused on minimizing unnecessary testing to decrease patient costs and reduce overall healthcare expenses.