Adult Hematologic Malignancy Research Articles

The prognostic significance of genetics in acute myeloid leukemia under venetoclax-based treatment.

Acute myeloid leukemia (AML) is the most prevalent hematologic malignancy in adults. In 2022, the European LeukemiaNet (ELN) has updated its prognostic system that incorporates cytogenetics and molecular genetics based on data from patients undergoing intensive chemotherapy (IC). Recently, a risk stratification framework has been established for hypomethylating agents (HMA)-based low-intensity treatment (LIT) to fill the gaps in stratification for this treatment modality, but this needs further refinement. Venetoclax (VEN), a BH3 mimetic, targets BCL-2 to modulate apoptosis and metabolism in AML cells. Its combination with HMA or low-dose cytarabine (LDAC) has been shown to enhance the response rates and prolong the survival outcomes of older or unfit patients with AML. In this review, we delved into the prognostic significance of FLT3-ITD and IDH mutations when used in combination with VEN and HMA, as well as in conjunction with their specific inhibitors. We also explored the role of VEN in NPM1-mutated AML and its efficacy in splicing factor mutations AML. Additionally, we examined the response rates and survival outcomes of CBF-AML when treated with a VEN-based regimen. Moving forward, it is imperative that risk stratification for LIT becomes more nuanced to better align with the requirements of personalized diagnosis and treatment strategies.

Effective Prevention and Treatment of Acute Leukemias in Mice by Activation of Thermogenic Adipose Tissues.

Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are common hematological malignancies in adults. Despite considerable research advances, the development of standard therapies, supportive care, and prognosis for the majority of AML and ALL patients remains poor and the development of new effective therapy is urgently needed. Here, it is reported that activation of thermogenic adipose tissues (TATs) by cold exposure or β3-adrenergic receptor agonists markedly alleviated the development and progression of AML and ALL in mouse leukemia models. TAT activation (TATA) monotherapy substantially reduces leukemic cells in bone marrow and peripheral blood, and suppresses leukemic cell invasion, including hepatomegaly and splenomegaly. Notably, TATA therapy prolongs the survivals of AML- and ALL-bearing mice. Surgical removal of thermogenic brown adipose tissue (BAT) or genetic deletion of uncoupling protein 1 (UCP1) largely abolishes the TATA-mediated anti-leukemia effects. Metabolomic pathway analysis demonstrates that glycolytic metabolism, which is essential for anabolic leukemic cell growth, is severely impaired in TATA-treated leukemic cells. Moreover, a combination of TATA therapy with chemotherapy produces enhanced anti-leukemic effects and reduces chemotoxicity. These data provide a new TATA-based therapeutic paradigm for the effective treatment of AML, ALL, and likely other types of hematological malignancies.

Pathogen detection by targeted next-generation sequencing test in adult hematological malignancies patients with suspected infections.

Infections in patients with hematological malignancies (HM) are a significant cause of morbidity and mortality. Timely and effective empirical anti-infective treatment can reduce the infection-related mortality rate. Targeted next-generation sequencing (tNGS) offers a rapid diagnostic approach for identifying diverse pathogens in these patients. However, relevant research is still limited to adult patients with HM. We conducted a retrospective analysis of adult HM patients admitted to our hospital from March 2023 to September 2023, focusing on their clinical characteristics and the results of both tNGS and conventional microbiological tests (CMTs). We evaluated the performance of tNGS and CMTs in pathogenic diagnosis and described the distribution characteristics of pathogens in adult HM patients with infections. The study included 209 samples collected from 137 patients. Results showed that the overall pathogen detection rate differed significantly between tNGS and CMTs (60.3% vs. 24.4%, p < 0.001). The sensitivity (69.7% vs. 35.9%), negative predictive value (NPV) (48.2% vs. 42.4%), and accuracy (66.5% vs. 56.5%) of pathogen detection were notably superior with tNGS compared to CMTs. Among the 142 samples with clinically diagnosed infections, tNGS combined with CMTs identified a definite or probable microbial etiology in 114 samples (80.3%). Of the 36 samples with concordant positive results from both tNGS and CMTs, 72.2% (26/36) exhibited full or partial agreement. Our study further showed the highest detection rate for viral infections (57.0%), predominantly for Epstein-Barr virus (DNA-V, 18.3%). Followed by bacterial infections (46.5%), the detection rate of Gram-negative bacteria (G+, 35.9%) was higher than that of Gram-positive bacteria (G-, 21.8%) in this study. Klebsiella pneumoniae (G-, 12.7%) had the highest detection rate among these emerging bacteria, followed by Pseudomonas aeruginosa (G-, 10.6%) and Enterococcus faecium (G+, 7.7%). Bacterial-viral coinfections were the most common type of mixed infection (35.5%). In conclusion, tNGS outperforms CMTs in both sensitivity and pathogen spectrum. Therefore, it can serve as an adjunct to CMTs to facilitate the precise adjustment of anti-infective regimens for adult HM patients. Our findings establish a basis for formulating empirical anti-infective therapy strategies tailored to the pathogen distribution in this patient population.

Recent Updates in the Diagnosis and Management of Kidney Diseases in Multiple Myeloma

Multiple myeloma (MM) represents a difficult-to-treat plasma cell malignancy and the second most common hematologic malignancy in adults, significantly impacting kidney function. The spectrum of kidney involvement in MM is broad, encompassing electrolyte imbalances, tubular injury, and even rare glomerular diseases. The evolution of MM treatment modalities has led to notable improvements in the long-term survival of patients experiencing kidney-related complications. Over the past decade, groundbreaking therapeutic agents have emerged, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export, and antibody-drug conjugates. These novel therapies have revolutionized the landscape of MM management, offering new hope for patients and challenging the traditional treatment paradigms. This comprehensive review explores recent advances in the diagnosis and management of MM, emphasizing the pivotal role of these innovative therapeutic agents in improving patient outcomes. We delve into the intricacies of diagnosing MM, highlighting the significance of early detection and precise diagnostic tools. We elucidate the evolving treatment strategies, emphasizing the mechanisms of action and clinical efficacy of the latest agents. This manuscript provides valuable insights into the ever-evolving field of MM management, shedding light on the remarkable progress achieved in enhancing the prognosis and quality of life of MM patients.

Miniaturized Sniffing Device based on an Array of Fluorescent Carbon Quantum Dots and Metallic Nanoclusters Efficiently Identifies Hematologic Malignancy in Adults.

The study demonstrates the potential of an optical nose made by depositing an array of fluorescent nanomaterials on a paper substrate for the early detection of leukemia in adults. This is based on the fact that blood volatile organic compounds (VOCs) are useful leukemia biomarkers. The integrated design was miniaturized and comprised both sensing zones and a sample holding zone, which were installed on a small sheet of paper within a miniature cubic reaction chamber fabricated by using 3D printing technology. The sensing device, comprising seven fluorescent sensing elements, namely, metal nanoclusters, quantum dots, and carbon dots was capable of detecting VOCs in the blood headspace and providing a colorimetric signature that could discriminate between blood samples from healthy and cancerous individuals. A total of 70 new leukemia cases and 51 healthy controls aged 20-50 years were studied. The device required a 60 μL portion of the blood sample and reacted to blood VOCs after 3 h when kept at 50 °C. The imaging data from the device was processed by linear discriminant analysis, and the results confirmed efficient identification of patient samples from healthy samples with 100% accuracy. Overall, the array system is noninvasive (or minimally invasive), portable, fast, inexpensive, and requires only a small amount of blood sample.

Pseudohyperkalemia in pediatric patients with newly diagnosed hematological malignancies

Patients with newly diagnosed hematological malignancies often present with a considerable cellular burden, leading to complications including hyperkalemia. However, pseudohyperkalemia, arising from in vitro cell lysis, can pose challenges in clinical practice. Although pseudohyperkalemia is frequently reported in adult hematological malignancies, its occurrence in pediatric patients is underreported, and its incidence in this demographic remains unclear. We retrospectively reviewed the medical records of pediatric patients who received a new diagnosis of hematological malignancies from 2011 to 2022 at Taichung Veterans General Hospital. Hyperkalemia was defined by a serum or plasma potassium level exceeding 5.5 mEq/L. Pseudohyperkalemia was defined by 1) a potassium decrease of over 1 mEq/L in within 4 h without intervention or 2) the absence of electrocardiography changes indicative of hyperkalemia. Cases with apparent red blood cell hemolysis were excluded. A total of 157 pediatric patients with a new diagnosis of hematological malignancies were included, 14 of whom exhibited hyperkalemia. Among these 14 cases, 7 cases (4.5%) were of pseudohyperkalemia. This rate increased to 21.2% in patients with initial hyperleukocytosis. Pseudohyperkalemia was associated with a higher initial white blood cell count and lower serum sodium level. All episodes of pseudohyperkalemia occurred in the pediatric emergency department, where samples were obtained as plasma, whereas all true hyperkalemia cases were observed in the ordinary ward or intensive care unit, where samples were obtained as serum. Timely recognition of pseudohyperkalemia is crucial to avoiding unnecessary potassium-lowering interventions in pediatric patients with newly diagnosed hematological malignancies.

Managing infectious challenges in the age of molecular-targeted therapies for adult hematological malignancies.

Over the last decade, the therapeutic landscape for hematological malignancies (HMs) has witnessed a remarkable surge in the development of novel biological and small-molecule-targeted immunomodulatory agents. These therapies have drastically improved survival, but some come at the cost of increased risk of bacterial, viral, and/or fungal infections and on-target off-tumor immunological side effects. To mitigate such risks, physicians must be well informed about infectious complications and necessary preventive measures, such as screening, vaccinations, and antimicrobial prophylaxis. Furthermore, physicians should be vigilant about the noninfectious side effects of these agents that can mimic infections and understand their potential drug-drug interactions with antimicrobials. Strengthening and harmonizing the current surveillance and reporting system for drug-associated infections in real-world settings is essential to better ascertain the potential infections associated with these agents. In this review, we aimed to summarize the infection risks associated with novel agents used for specific HMs and outline recommended strategies for monitoring and prophylaxis.

SLAM Family Receptors in B Cell Chronic Lymphoproliferative Disorders.

The signaling lymphocytic activation molecule (SLAM) receptor family (SLAMF) consists of nine glycoproteins that belong to the CD2 superfamily of immunoglobulin (Ig) domain-containing molecules. SLAMF receptors modulate the differentiation and activation of a wide range of immune cells. Individual SLAMF receptors are expressed on the surface of hematopoietic stem cells, hematopoietic progenitor cells, B cells, T cells, NK cells, NKT cells, monocytes, macrophages, dendritic cells, neutrophils, and platelets. The expression of SLAMF receptors was studied during normal B cell maturation. Several SLAMF receptors were also detected in cancer cell lines of B-lymphoid origin and in pathological B cells from patients with B cell chronic lymphoproliferative disorders (B-CLPD), the most frequent hematological malignancies in adults. This review summarizes current knowledge on the expression of SLAMF receptors and their adaptor proteins SAP and EAT-2 in B-CLPD. Several SLAMF receptors could be regarded as potential diagnostic and differential diagnostic markers, prognostic factors, and targets for the development of novel drugs for patients with B-CLPD.

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo.

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

COVID-19 Outcomes in Patients with Hematologic Malignancies in the Era of COVID-19 Vaccination and the Omicron Variant.

A greater understanding of clinical trends in COVID-19 outcomes among patients with hematologic malignancies (HM) over the course of the pandemic, particularly the Omicron era, is needed. This ongoing, observational, and registry-based study with prospective data collection evaluated COVID-19 clinical severity and mortality in 1818 adult HM patients diagnosed with COVID-19 between 27 February 2020 and 1 October 2022, at 31 centers in the Madrid region of Spain. Of these, 1281 (70.5%) and 537 (29.5%) were reported in the pre-Omicron and Omicron periods, respectively. Overall, patients aged ≥70 years (odds ratio 2.16, 95% CI 1.64-2.87), with >1 comorbidity (2.44, 1.85-3.21), or with an underlying HM of chronic lymphocytic leukemia (1.64, 1.19-2.27), had greater odds of severe/critical COVID-19; odds were lower during the Omicron BA.1/BA.2 (0.28, 0.2-0.37) or BA.4/BA.5 (0.13, 0.08-0.19) periods and among patients vaccinated with one or two (0.51, 0.34-0.75) or three or four (0.22, 0.16-0.29) doses. The hospitalization rate (75.3% [963/1279], 35.7% [191/535]), rate of intensive care admission (30.0% [289/963], 14.7% [28/191]), and mortality rate overall (31.9% [409/1281], 9.9% [53/536]) and in hospitalized patients (41.3% [398/963], 22.0% [42/191]) decreased from the pre-Omicron to Omicron period. Age ≥70 years was the only factor associated with higher mortality risk in both the pre-Omicron (hazard ratio 2.57, 95% CI 2.03-3.25) and Omicron (3.19, 95% CI 1.59-6.42) periods. Receipt of prior stem cell transplantation, COVID-19 vaccination(s), and treatment with nirmatrelvir/ritonavir or remdesivir were associated with greater survival rates. In conclusion, COVID-19 mortality in HM patients has decreased considerably in the Omicron period; however, mortality in hospitalized HM patients remains high. Specific studies should be undertaken to test new treatments and preventive interventions in HM patients.

Imaging of Multiple Myeloma: Present and Future.

Multiple myeloma (MM) is the second most common adult hematologic malignancy, and early intervention increases survival in asymptomatic high-risk patients. Imaging is crucial for the diagnosis and follow-up of MM, as the detection of bone and bone marrow lesions often dictates the decision to start treatment. Low-dose whole-body computed tomography (CT) is the modality of choice for the initial assessment, and dual-energy CT is a developing technique with the potential for detecting non-lytic marrow infiltration and evaluating the response to treatment. Magnetic resonance imaging (MRI) is more sensitive and specific than 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for the detection of small focal lesions and diffuse marrow infiltration. However, FDG-PET/CT is recommended as the modality of choice for follow-up. Recently, diffusion-weighted MRI has become a new technique for the quantitative assessment of disease burden and therapy response. Although not widespread, we address current proposals for structured reporting to promote standardization and diminish variations. This review provides an up-to-date overview of MM imaging, indications, advantages, limitations, and recommended reporting of each technique. We also cover the main differential diagnosis and pitfalls and discuss the ongoing controversies and future directions, such as PET-MRI and artificial intelligence.

Inhibition of mitochondria induces apoptosis and reduces telomere length and activity in acute myeloid leukemia stem cells.

Acute myeloid leukemia (AML) is a highly lethal hematological malignancy in adults and children. Abnormal proliferation of leukemia stem cells (LSC) with CD34+ and CD38- phenotypes are the main clinical features of AML. Patients with AML face drug resistance and treatment failure due to a default in stem and progenitor cells. Therefore, defining LSC properties is necessary for targeting leukemia-initiating cells. Mitochondrial mass and activity increase in AML initiating cells compared with normal stem cells. This idea has offered the inhibition of the mitochondrial translation machinery to reduce the number of leukemia-initiating cells in patients with AML Tigecycline is an FDA-approved microbial antibiotic that inhibits oxidative phosphorylation in mitochondria, resulting in the suppression of leukemia cell proliferation with little toxicity to normal cells. Thus, the present study was conducted to evaluate whether LSC is influenced by mitochondrial inhibition. We measured the IC50 of tigecycline in KG-1a AML cell lines. KG-1a AML cell lines were separated into CD34+ and CD34- cells by MACS. In the following, these cells were treated with 20 µM (IC50) tigecycline. The expression of Annexin/PI, Caspase 3, apoptotic genes (BCL2, BCLX, BAX, BAD, and P53) and proteins (P53, BAX, BCL2 and Caspase 9) was evaluated in CD34+ , CD34- and KG-1a AML cells. In addition, the telomere length and expression of hTERT were evaluated in this study. The results indicated that BCl2 (gene and protein) and BCLX gene dramatically decreased. In addition, BAD, BAX, and P53 gene and protein expression significantly increased in CD34+ AML cells compared to CD34- AML cells. The results also suggested that tigecycline induced intrinsic (Cleaved-caspase 9/Pro-Caspase 9 ratio) and p53-mediated apoptosis. Furthermore, hTERT gene expression and telomere length decreased in the tigecycline-treated groups. Taken together, our findings indicate that inhibition of mitochondrial activity with tigecycline can induce apoptosis in cancer stem cells and can be used as a novel method for cancer therapy.

Human Pro-T-Cell Manufacturing in Vitro Is a Safe Procedure for Hematopoietic Stem Cell Transplantation with Delayed T-Cell Reconstitution: Interim Results from 2 Different Clinical Trials

Introduction: Alternative donor Hematopoietic stem cell transplantation (HSCT) strategies are followed by a prolonged period of immune deficiency due to delayed T-cell reconstitution. Either Umbilical Cord (CB) blood transplant or CD34+ selected haplo-transplant provided similar T-cell lymphocytes (CD3+ and CD4+) recoveries at any time point, and recipients had significantly fewer CD4+ T-cells during the first six months compared to HLA-matched donors. The GMP generation of Human T lymphoid Progenitors (HTLP) that are competent to rapidly become in vivo differentiated functional and thymic-educated T-cells may overcome the post-transplant delayed immune reconstitution. Method: HTLP safety and efficacy to accelerate immune reconstitution is currently evaluated in 2 multicentric and single-arm clinical trials: after umbilical cord blood in adult hematologic malignancy (Eudract 2019-004883-23) and after partially HLA compatible CD34+ immune-selected allogeneic hematopoietic stem cell transplantation in Severe Combined Immune Deficiency (SCID) patients (Eudract 2018-001029-14). Results: We enrolled and treated six patients, 4 SCID and 2 adults with malignancy, with an average follow-up of 8.00 (range, 1.60 to 37.7) months. HTLP cell product was infused between D7 to D14 post-HSCT for SCID patients after ensuring the decrease of the ATG level while meaning for the adult patient; the expanded pro-T cells were injected at D0. The Pro-T manufacturing process allows to robustly expand CD34+ cells to HTLP with a median of 79.7% (range 54.6; 98.9) of differentiation (CD7+ CD3-) and a median fold of proliferation of 14.7 (range 8.80; 18.5). No chromosome instability was induced during the expansion. Patients received increasing doses ranging from 0.1 to 0.5 10 6 HTLP/kg. The amount of CD3+/kg was less than 11.2 (range 0; 588)/ kg. No early or mid-term toxicity due to the administration of HTLP has been reported for evaluable patients (6/6). One SCID patient died on D53 because of severe VOD. Primary engraftment was confirmed in 4 out of 5 patients. Interestingly, despite the gradual increase of doses, there was no aGVHD over grade &amp;gt;2. Preliminary efficacy results suggest that circulating CD3+ CD4+ TCRαβ+ T cells &amp;gt; 50/μl before M4 depended on the increased infused dose of HTLP and an intrathymic paracrine effect. Notably, there was no viral infection disease or relapse during the outcome. Discussion conclusion: First infusions of HTLP in both clinical trials confirmed the safety and reproducible GMP manufacturing. HLTP offers an exciting perspective for improving immune reconstitution in alternative hematopoietic transplants.

Dual-Targeting CD33/CD123 NANOBODY ® T Cell Engager Targeting Leukemia Blasts and Stem/Progenitor Cells in Relapsed AML

Acute myeloid leukemia (AML) is the most common adult hematologic malignancy. Relapse is common and salvage treatment with cytotoxic chemotherapy is rarely curative. Immunotherapy targeting surface antigens expressed in leukemia cells has emerged as an effective approach for AML treatment for patients who are older/unfit for or relapsed from/refractory to current regimens (Isidori A, et al. Frontiers Oncol. 2021). CD123 and CD33, two clinically validated targets in AML, are jointly expressed on blasts and leukemic stem cells (LSC) in &amp;gt;95% of AML patients. However, their expression is heterogenous between subclones and between patients which may impact the efficacy of single-targeting agents in certain patient populations. We recently reported a novel dual-targeting CD33/CD123 NANOBODY® T-cell engager (CD33/CD123-TCE) and demonstrated the anti-leukemia activity of CD33/CD123-TCE in AML with good safety profile in vivo (Dullaers M, et. al, JITC. 2022). Here we showed that CD33/CD123-TCE effectively targets AML blasts and LSC in relapsed AML. The cell surface expression profiling of samples from 55 patients with relapsed/refractory AML showed that all samples were positive for CD123 and CD33. The frequency of subpopulations in all samples co-expressing CD33 and CD123 is the most prominent, followed by single expression of CD123, and CD33. CD33-CD123- subset represented a minority. To investigate the anti-leukemia effect of CD33/CD123 TCE, we treated 18 primary samples for 7 days and assessed apoptosis by flow cytometry. Treatment of CD33/CD123 TCE at 2.5nM (low dose) and 25nM (high dose) induced more than 50% specific apoptosis in majority of bulk AML, with no significant difference between low and high dose of CD33/123 TCE. Analysis of cytotoxicity towards CD34+ AML-LSC revealed that CD33/CD123 TCE at low and high doses resulted in similar specific apoptosis of CD34+ cells, half of samples reached higher than 50% of apoptosis. Colony-forming assay in 2 primary samples further confirmed that CD33/CD123 TCE effectively inhibited the clonogenicity of primary AML cells expressing CD123 and CD33. While the average activity of CD33/CD123 TCE was comparable to single-targeting CD33-TCE and CD123-TCE reagents, in a subset of patient samples (11% of all samples), the dual-targeting CD33/CD123-TCE induced higher apoptosis in bulk and CD34+ AML cells compared to single-targeting controls, supporting utility of dual targeting. Concomitantly, CD3+ T cell expansion was observed in all dual- and single treatment groups, with a trend toward stronger amplification by CD33/CD123-TCE. Next, we examined AML and T cell phenotypes using mass cytometry (CyTOF) to characterize the impact of the TCE treatments. UMAP plus FlowSOM analysis revealed heterogenous subsets of LSC within samples and across patients. LSC subsets defined by CD34+ are known to co-express various surface markers associated with LSC-drug resistance and disease relapse including CD135 (FLT3), CD117 (c-kit), CLL-1, PD-L1 and TIM-3. These subsets were found highly sensitive to CD33/CD123-TCE, with subset CD34+CD38+CD117+PD-L1+CD123+ and CD34+CD38- showing greater sensitivity to CD33/CD123-TCE. Despite diverse expression of leukemic markers, CD33/CD123-TCE depleted CD34+ AML-LSC in all 3 samples tested by CyTOF, whereas single-targeting CD123-TCE and CD33-TCE were only effective in 2/3 samples. Analysis of T cell subsets revealed that dual- or single- targeting TCE expanded CD4+ helper and CD8+ cytotoxic subsets in all samples compared to control. CD4+ and CD8+ cells co-expressing CD69, TIM-3 or PD-1 were expanded by TCE in all three samples. Expansion of central and effector memory T cells defined by CCR7+CD45RA- and CCR7-CD45RA- in CD4+ and CD8+ subsets were seen in all treatment groups in 2 samples, whereas the highest expansion of CCR7-CD45RA-CD4+ effector memory subsets by CD33/CD123-TCE was seen in 1 sample. Taken together, the CD33/CD123 dual-targeting NANOBODY® TCE exhibits potent anti-AML activity and offers a broad patient coverage. Immunophenotypic profiling confirmed the effectiveness of CD33/CD123-TCE in eliminating various blast- and LSC-subsets, activating CD4+ and CD8+ T cells or expanding central/effector memory CD4+ and CD8+ T cells. These dual-targeting immune engagers may constitute an effective treatment option for patients who are older/unfit for or relapsed from/refractory to current regimens.

New Onset Neurocognitive Impairment in Long-Term Survivors of Early Adolescent and Young Adult Hematologic Malignancies: A Report from the Childhood Cancer Survivor Study

Background: Survivors of hematologic malignancies diagnosed during adolescence and early young adulthood (eAYA survivors) experience neurocognitive impairments as a result of intensive neurotoxic therapies, but the trajectory of these impairments as survivors age are not known. We examined longitudinal changes in neurocognitive outcomes in eAYA survivors compared to younger survivors and sibling controls. Methods: We identified 421 eAYA (diagnosed at 15-21 years) and 1758 pediatric (diagnosed at &amp;lt;15 years) survivors of ALL, AML, and Hodgkin lymphoma (HL), as well as 233 siblings from the Childhood Cancer Survivor Study (&amp;gt;5 year survivors diagnosed 1970-1999) who completed the Neurocognitive Questionnaire (NCQ) at two follow-up surveys (i.e. FU2, FU5) administered 11 years apart. Impairment was defined as a score in the worst 10% of the sibling cohort in task efficiency (TE), organization (Org), memory (Mem), and emotional regulation (ER) domains. Linear regression analysis was performed to estimate the change in neurocognitive T-scores and to identify factors associated with the changes, adjusting for age at initial (FU2) assessment and baseline T-score. The frequency of new onset impairments and associated risk factors were analyzed, specifically to identify survivors who had 1) neurocognitive improvement, ie. impaired at FU2 and became unimpaired vs. remained impaired on FU5, and 2) neurocognitive worsening, ie. unimpaired at FU2 and became impaired vs. remained unimpaired at FU5. Multivariable logistic analysis was performed to identify treatment exposures and chronic health conditions (CHCs) associated with the development or resolution of impairment. Smoking, physical activity, and healthcare utilization were examined as additional risk factors. Results: Compared to siblings, NCQ T-scores worsened over time for both survivors of eAYA (estimated mean score Δ1.9, range 0.5-3.4, p=0.01 in TE; Δ3.0, range 1.5-4.6, p&amp;lt;0.001 in Mem) and pediatric (estimated mean score Δ3.2, range 2.0-4.5, p&amp;lt;0.001 in TE; Δ1.3, range 0.1-2.5, p=0.03 in Org; Δ3.8, range 2.6-5.0, p&amp;lt;0.001 in Mem; Δ2.8, range 1.5-4.1, p&amp;lt;0.001 in ER) malignancies. Risk factors for worsening scores over time in eAYA survivors included having a neurologic CHC (TE: Δ4.9, 95% CI 1.7-8.1; ER: Δ4.2, 95% CI 0.9-7.4), receiving ≥35Gy chest radiation therapy (RT) (TE: Δ4.0, 95% CI 1.7-6.2; Mem: Δ3.3, 95% CI 1.2-5.4), receiving cranial RT (TE: Δ4.0, 95% CI 0.9-7.1; Mem: Δ5.7, 95% CI 2.7-8.7; ER: Δ3.4, 95% CI 0.5-6.4), and being female (Mem: Δ2.8, 95% CI 1.3-4.3). Being a never smoker was associated with improved scores over time in all domains (Δ range -3.2- -6.3). In the new onset impairment analysis, prevalence of TE and Mem impairments increased while Org and ER impairments decreased over time in eAYA and pediatric survivors ( Figure). Factors associated with new onset impairment in eAYA survivors included female sex (Mem: OR 3.2, 95% CI 1.6-6.5), cardiac CHC (ER: OR 3.0, 95% CI 1.03-8.8), respiratory CHC (TE: OR 3.0, 95% CI 1.1-8.0), endocrine CHC (Mem: OR 2.3, 95% CI 1.2-4.6), and neurologic CHC (TE: OR 3.1, 95% CI 1.2-8.2; Org: OR 4.2, 95% CI 1.3-13.7) ( Table). Corresponding CHC-associated impairments were not seen in pediatric survivors, except for neurologic CHC. In a separate model of treatment exposures, eAYA survivors who received salvage HL therapy (Mem: OR 4.8, 95% CI 1.5-15.3), ≥35Gy chest RT (Mem: OR 3.7, 95% CI 1.7-8.2; TE: OR 2.6, 95% CI 1.1-6.1), and cranial RT (Mem: OR 3.4, 95% CI 1.2-9.8; ER: OR 5.3, 95% CI 1.2-22.5) were more likely to experience new onset neurocognitive impairment. While being a never smoker was associated with a decreased odds of new onset impairment (ER: OR 0.1, 95% CI 0.0-0.5), no factors associated with resolution of impairment were found in eAYA survivors. Conclusions: Survivors of eAYA hematologic malignancies experience declining neurocognitive function as well as new onset impairments over time. Memory was the most affected domain. Risk factors for worsening impairment include being female, health comorbidities, and intensive treatment exposures, such as salvage therapy, high-dose chest RT, and cranial RT. Comorbidities may play a larger role in mediating new onset neurocognitive impairments in eAYAs than pediatric survivors. Future studies should focus on characterizing outcomes across the entire AYA age spectrum.

Exploration of rotational thromboelastometry (ROTEM) to characterize the coagulation profiles of newly diagnosed pediatric leukemia patients

BackgroundViscoelastic testing has been used in adult hematologic malignancies in conjunction with conventional coagulation tests (CCTs) to predict coagulopathies and tailor blood product replacement. However, there is a paucity of similar pediatric studies. ObjectivesAnalyze and correlate leukemia-associated coagulopathy in newly diagnosed pediatric leukemia patients using CCT’s and Rotational Thromboelastometry (ROTEM). MethodsPediatric patients with newly diagnosed acute leukemia underwent testing with ROTEM and CCTs on days 0, 15 and 29 of induction chemotherapy. ResultsSixty-two patients were enrolled. At presentation, 54.8 % of patients had platelets <50 K/μL, 73 % had prolonged PT, 1.6 % had fibrinogen <150 mg/dL. Fifteen patients (24.2 %) had WHO grade 1 bleeding and two patients (3 %) had WHO grade 4 bleeding. EXTEM/INTEM values at presentation (day 0) reflected hypocoagulability, however FIBTEM revealed hypercoagulability. Patients showed a progressive hypocoagulability in all ROTEM assays by day 15 (day 0 vs day 15, p < 0.001), with improvement by day 29 (day 15 vs day 29, p < 0.001). Day 0 ROTEM parameters were comparable to day 29. Fibrinogen strongly correlated with ROTEM at all three time points (p < 0.0001), along with platelet count with moderate correlations (p < 0.001). ConclusionFibrinogen and platelets appear to be the drivers of leukemia associated coagulopathy in the pediatric population, suggesting the utility of using CCTs and ROTEM in this population to better evaluate hemostatic function and guide blood product replacement.

A novel prognostic classification integrating lipid metabolism and immune co-related genes in acute myeloid leukemia.

As a severe hematological malignancy in adults, acute myeloid leukemia (AML) is characterized by high heterogeneity and complexity. Emerging evidence highlights the importance of the tumor immune microenvironment and lipid metabolism in cancer progression. In this study, we comprehensively evaluated the expression profiles of genes related to lipid metabolism and immune modifications to develop a prognostic risk signature for AML. First, we extracted the mRNA expression profiles of bone marrow samples from an AML cohort from The Cancer Genome Atlas database and employed Cox regression analysis to select prognostic hub genes associated with lipid metabolism and immunity. We then constructed a prognostic signature with hub genes significantly related to survival and validated the stability and robustness of the prognostic signature using three external datasets. Gene Set Enrichment Analysis was implemented to explore the underlying biological pathways related to the risk signature. Finally, the correlation between signature, immunity, and drug sensitivity was explored. Eight genes were identified from the analysis and verified in the clinical samples, including APOBEC3C, MSMO1, ATP13A2, SMPDL3B, PLA2G4A, TNFSF15, IL2RA, and HGF, to develop a risk-scoring model that effectively stratified patients with AML into low- and high-risk groups, demonstrating significant differences in survival time. The risk signature was negatively related to immune cell infiltration. Samples with AML in the low-risk group, as defined by the risk signature, were more likely to be responsive to immunotherapy, whereas those at high risk responded better to specific targeted drugs. This study reveals the significant role of lipid metabolism- and immune-related genes in prognosis and demonstrated the utility of these signature genes as reliable bioinformatic indicators for predicting survival in patients with AML. The risk-scoring model based on these prognostic signature genes holds promise as a valuable tool for individualized treatment decision-making, providing valuable insights for improving patient prognosis and treatment outcomes in AML.

Improved Neurocognitive Outcomes with Contemporary Treatments in Survivors of Early Adolescent and Young Adult Hematologic Malignancies from the Childhood Cancer Survivor Study

Background: Neurocognitive impairments in survivors of hematologic malignancies diagnosed specifically during adolescence and early young adulthood (eAYA survivors) are not well described, despite use of intensive neurotoxic therapies. We evaluated how recent shifts in therapeutic approaches have impacted neurocognitive outcomes in survivors diagnosed during eAYA compared to younger survivors and sibling controls. Methods: We identified 1213 eAYA (diagnosed at 15-21 years) and 4538 pediatric (diagnosed at &amp;lt;15 years) survivors of acute lymphoblastic lymphoma (ALL; n= 301 v. 3274), acute myeloid leukemia (AML; n= 77 v. 424), and Hodgkin lymphoma (HL; n= 835 v. 840) as well as 1014 siblings from the Childhood Cancer Survivor Study (&amp;gt;5 year survivors diagnosed 1970-1999) who completed the Neurocognitive Questionnaire ( Table 1). Impairment was defined as a score in worst 10% of the sibling cohort in task efficiency (TE), organization (Org), memory (Mem), and emotional regulation (ER) domains. Survivors were stratified into groups reflective of diagnosis, treatment era, and intensity: HL-chest RT ≥35Gy = HL with chest radiation ≥35Gy (High-risk disease, older regimens); HL-chest RT &amp;lt;35Gy = HL with chest radiation &amp;lt;35Gy (Intermediate risk disease, contemporary regimens); HL-salvage = HL with salvage therapy (High-risk disease, higher intensity regimens), ALL-CRT = ALL with use of cranial radiation (CRT) (Older regimens), ALL-no CRT = ALL without use of CRT (Contemporary regimens), ALL-salvage = ALL with salvage therapy (High-risk disease, higher intensity regimens), AML-chemo = AML with chemotherapy only (Lower risk disease), AML-SCT = AML with history of stem cell transplant (Higher risk disease). The prevalence of neurocognitive impairment compared to siblings was estimated using generalized-estimating-equation logistic regression accounting for potential within-family correlation. Health status and health behaviors were examined as risk factors for neurocognitive impairment. Adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) are reported. Results: Prevalence of any neurocognitive impairment in the eAYA, pediatric, and sibling groups was 30.8%, 37.7%, and 25.4%, respectively. Prevalence was similar for eAYAs and pediatric survivors of HL (31.0% v. 29.6%, p=0.54) and AML (36.4% v. 40.6%, p=0.49), while lower in eAYA ALL survivors (28.2% v. 38.7%, p&amp;lt;0.01). Compared to siblings, eAYA HL survivors who received salvage therapy were more likely to have impaired Org (OR 2.5, 95% CI 1.2-5.1) and Mem (OR 2.7, 95% CI 1.3-5.8), while those who received high-dose chest RT experienced more Mem impairment (OR 2.0, 95% CI 1.2-3.4) ( Table 2). Compared to siblings, Mem was the most commonly affected domain in eAYA ALL survivors who received CRT (OR 4.0, 95% CI 2.0-7.9); this was not observed in the non-CRT or salvage groups. In a separate analysis of treatment exposures, anthracycline ≥120mg/m 2 uniquely increased prevalence of ER in eAYA ALL survivors (OR 4.7, 95% CI 1.7-12.9). Compared to siblings, survivors of eAYA AML who underwent SCT had higher odds of Mem impairment (OR 5.3, 95% CI 1.9-14.7). In a direct comparison with pediatric AML survivors, eAYA AML survivors were also more likely to have impaired Mem (OR 2.6, 95% CI 1.1-6.2) (data not shown). Being physically active (OR range 0.3-0.7), a never-smoker (OR range 0.5-0.6), and insured (OR range 0.4-0.5) were protective across all domains in eAYA-cancer survivors. Conclusions: Survivors of hematologic cancers diagnosed during eAYA are susceptible to neurocognitive impairment at rates similar to those diagnosed at younger ages for HL and AML but at reduced rates for survivors of ALL. Memory was the most affected domain in eAYA survivors. Contemporary regimens utilizing intermediate-dose (&amp;lt;35Gy) chest RT for HL or omission of cranial RT for ALL attenuated the extent of risk. Future studies should focus on characterizing outcomes across the entire AYA age spectrum.

Shutting off the fuel supply to target metabolic vulnerabilities in multiple myeloma.

Pathways that govern cellular bioenergetics are deregulated in tumor cells and represent a hallmark of cancer. Tumor cells have the capacity to reprogram pathways that control nutrient acquisition, anabolism and catabolism to enhance their growth and survival. Tumorigenesis requires the autonomous reprogramming of key metabolic pathways that obtain, generate and produce metabolites from a nutrient-deprived tumor microenvironment to meet the increased bioenergetic demands of cancer cells. Intra- and extracellular factors also have a profound effect on gene expression to drive metabolic pathway reprogramming in not only cancer cells but also surrounding cell types that contribute to anti-tumor immunity. Despite a vast amount of genetic and histologic heterogeneity within and between cancer types, a finite set of pathways are commonly deregulated to support anabolism, catabolism and redox balance. Multiple myeloma (MM) is the second most common hematologic malignancy in adults and remains incurable in the vast majority of patients. Genetic events and the hypoxic bone marrow milieu deregulate glycolysis, glutaminolysis and fatty acid synthesis in MM cells to promote their proliferation, survival, metastasis, drug resistance and evasion of immunosurveillance. Here, we discuss mechanisms that disrupt metabolic pathways in MM cells to support the development of therapeutic resistance and thwart the effects of anti-myeloma immunity. A better understanding of the events that reprogram metabolism in myeloma and immune cells may reveal unforeseen vulnerabilities and advance the rational design of drug cocktails that improve patient survival.

Real-world duration of hospitalization for CAR-T treatment: U.S. patient experience in multiple hematologic malignancies.

e18896 Background: Since 2017, 6 CAR-t therapies have been approved to treat pediatric and adult hematologic malignancies (HM). Due to the complexity of administration and severe toxicity including cytokine release syndrome (CRS), CAR-t is usually administered in an inpatient setting. We sought to provide the first pan-cancer, U.S. based analysis of duration of hospitalization during CAR-t overall and for patients who experience CRS. Methods: Patients were identified from a large, US based EMR database including more &gt;40M patients, &gt;500 hospitals and 30 healthcare systems including both community/academic health systems. Patients with ≥1 procedure code for general administration of CAR-t therapy (e.g.: XW033C3, introduction of engineered autologous chimeric antigen receptor t-cell immunotherapy into peripheral vein) or a specific approved CAR-T (XW033K7, introduction of idecabtagene vicleucel immunotherapy into peripheral vein) between 2017 and 2022 and a diagnosis of a HM were selected. CRS was identified as the presence of any ICD-10 diagnosis code of D89.83X post-administration. Time from the date of CAR-t administration to hospital discharge was calculated overall, by cancer type, and for patients with and without a confirmed diagnosis of CRS. Results: A total of 212 patients (multiple myeloma [MM] = 64, b-cell lymphoma = 77, follicular lymphoma = 47, mantle cell lymphoma [MCL] = 13, acute lymphoblastic leukemia = 11) meeting selection criteria were identified. Cohort characteristics are shown in Table 1. Median duration of hospitalization was 12 days (range 1-56); shortest at 10 days for MM and longest at 15 days for MCL. Mean duration of hospitalization decreased slightly from 12.3 days (sd = 11) for patients treated in 2019 or earlier to 11.9 days (sd = 4.2) for patients treated in 2022 Median duration of hospitalization for patients with a CRS diagnosis (n = 100) was 12 (range 1-30) versus 11 days (range 1-56) for those without CRS (n = 112). Conclusions: CAR-t poses a unique set of administrative, logistical and clinical challenges. This study provides the first contemporaneous estimates of the length of hospital stays during CAR-t infusion which was found to be 12 days. Differences in length of hospitalizations did not decline significantly over time or were significantly different between those with and without CRS however further research to examine health system factors and patient factors (i.e., severity of CRS) are needed. [Table: see text]