Adult Malignancies Research Articles

Molecular Classification of Relapsed DLBCL Reveals Novel Biologic Subgroups

Background Diffuse large B cell lymphoma (DLBCL) is the most common aggressive lymphoid malignancy in adults. Though standard immunochemotherapy regimens can result in clinical remission and cure in a majority of patients, approximately 30% of patients are primary treatment resistant or eventually relapse (rrDLBCL), and their prognosis is very poor. Recent molecular classification by large scale genomic and transcriptomic profiling of newly diagnosed DLBCL tumors has resulted in a deeper understanding of disease drivers, however, the molecular heterogeneity of rrDLBCL is yet to be fully explored. Therefore, in this study, we used an unsupervised approach to better define transcriptional and genetic programs in rrDLBCL samples hypothesizing that molecular stratification within this high-risk group may lead to a better understanding of this disease, which remains an unmet need, and a more personalized therapeutic approach. Methods Data used in this study included RNA (n=143) and whole exome (n=126) sequencing data from available FFPE tumor samples at the time of a relapse (any line of treatment, r1-r10 relapse timepoints included in analysis, one per patient), consented to the Molecular Epidemiology Resource (n=61), banked in the Mayo Lymphoma Biobank (n=50), or consented to the CC-122-ST-001 clinical trial (n=32, NCT01421524). Unsupervised clustering was performed on protein coding gene expression values using the non-negative matrix factorization (NMF) approach. NMF was carried out by performing 200 runs on cluster sizes from 2 to 6. Cell of origin (COO) was determined using the method described by Reddy et al. The tumor microenvironment was analyzed using CIBERSORTx and Lymphoma Microenvironment Classification (LME). Genetic classification was done using LymphGen. Results In order to identify unique transcriptional programs in rrDLBCL, we implemented NMF and consensus clustering to define an ideal quantity of stable patient clusters. We identified 4 rrDLBCL patient clusters (rrC1-rrC4) as the most stable solution, based on consensus clustering selection criteria of iterative NMF runs. While relapse timepoint was not associated with individual clusters, we did observe significant differences in tumor characteristics between the clusters. COO classification found that rrC1 and rrC4 were enriched for GCB-DLBCL while rrC3 was enriched for ABC-DLBCL classification (P < .001). To explore the biologic programs in each cluster, we used pathFindR, which leverages protein-protein interaction networks to identify disease related pathways, rrC1 and rrC4 were defined by pathways involved in cell cycle and mismatch repair; oxidative phosphorylation in rrC2; and MAPK and NF-kB in rrC3. Next, LME classification was done to define patterns in the tumor microenvironment and we found a significant difference between groups (P < .001), with rrC2 and rrC4 tumors enriched for a depleted TME, while rrC1 and rrC3 had a more immune rich or inflammatory TME. This was supported by CIBERSORTx analysis identifying significant differences (P > .001) in abundance of CD8 T cells, memory CD4 T cells, and M1 macrophages between clusters, with rrC4 having the lowest abundance. We then explored genetic patterns in each cluster. Gene level mutation enrichment analysis showed BCL7A mutation exclusively in C4 (6/6, P = .03). The clusters were not associated with LymphGen classification. Lastly, our recently published high risk signature classification that is associated with early clinical failure and is characterized by metabolic dysregulation, a depleted TME, T53 alterations, and poor outcome, was significantly different between the groups (P = .03) with enrichment for high-risk cases in rrC4. In summary, we show for the first time that rrDLBCL patients can be classified into four gene expression clusters that are associated with distinct pathway, TME, and genetic programs. These clusters should now be tested to learn if they can help select patients for newer therapies for rrDLBCL such as CAR-T and bispecific antibodies.

Underrepresentation of Older Adults in Clinical Trials of Chimeric Antigen Receptor (CAR) T-Cell Therapy for Hematologic Malignancies: An FDA Analysis

Background: As the population ages, the prevalence of hematologic malignancies in older adults will continue to increase. Older adults, especially older than 75 years, are routinely underrepresented in clinical trials evaluating hematologic malignancies, largely due to access and logistics, comorbidities, toxicity concerns, and eligibility restrictions. Given the recent approvals of multiple CAR T-cell therapies for patients with hematologic malignancies, we evaluated the rates of enrollment of older adults (age ≥ 65 years) in registrational trials of CAR T-cell therapies submitted to the U.S. Food and Drug Administration (FDA). Methods: We conducted a pooled analysis of the registrational trials submitted to the FDA between 2017 and 2021 that supported approvals of autologous CAR T-cell therapies in patients with hematologic malignancies. Datasets submitted with the biologic license applications were pooled and analyzed descriptively for demographics, disease characteristics, and efficacy outcomes. Patients between the ages of 65 and 74 and age 75 and above were analyzed separately. Results: Thirteen registrational trials evaluating six CAR T-cell products in 1,319 patients with hematologic malignancies were submitted to FDA. The median age at enrollment was 60 years (range: 3 to 86). In total, 7% (88) of patients were 75 years and older, 28% (366) were between the ages of 65 and 74 years, and 66% (865) were under the age of 65 years. The hematologic malignancies included large B-cell lymphoma (59%), multiple myeloma (15%), follicular lymphoma (13%), B-cell acute lymphoblastic leukemia (9%), and mantle cell lymphoma (5%). Response rates by age group and histology are shown in Table 1 and Table 2. Conclusions: Older adults, particularly those aged 75 years or older, were underrepresented in the trials supporting FDA approval of CAR T-cell therapies considering the predominant hematologic malignancies included in this pooled analysis and the median age of diagnosis of these diseases in the U.S. population. Although clinically meaningful efficacy was achieved across age groups and diseases, more data are needed to determine the impact of age on efficacy outcomes in specific malignancies. In this analysis, data were limited among patients 75 years and older in all histologies except large B cell lymphoma. Work to evaluate the impact of age on safety and tolerability outcomes is ongoing. To improve accrual, greater efforts to understand and reduce barriers to clinical trial enrollment for older adults are needed, especially given the expanding use of CAR T-cell therapies and their toxicity profiles.

CDK12/13: A Promising New Therapeutic Target in ALL

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy in children and young adults. Upfront resistance to glucocorticoids used as first-line treatment in most regimens confers a poor prognosis for patients with ALL. Of patients who relapse, only half achieve long-term survival. Here we demonstrate that inhibition of cyclin dependant kinases 12 and 13 (CDK12 & CDK13), which are modulators of RNA polymerase II, has a robust synergistic anti-leukemia effect with dexamethasone, in both B-ALL and T-ALL cell lines as well as primary B-ALL patient-derived bone marrow samples. To understand the mechanism underlying the steroid resistance in ALL, we first reanalyzed shRNA screen performed by Poulard et al. This revealed that CDK13 silencing sensitized leukemic cells to dexamethasone. CDK12 is located on chromosome 17q12, containing oncogenic features and genetic alterations in various tumors. CDK12/13 inhibitor exhibits efficacy against an Ewing sarcoma tumor growth in a patient-derived xenograft mouse model. It was shown that the inhibition resensitizes HER2+ breast cancers to HER2-tyrosine kinase inhibitors via suppressing PI3K/AKT in patient-derived organoids in vitro and cell-derived xenograft or patient-derived xenograft in vivo. Forgoing research demonstrates that CDK12/13 inhibition silences transcription of DNA damage response (DDR) genes. In our study, however, we haven't observed a rise in γH2AX, a marker of DNA damage, after CDK12/13 inhibition in ALL cell lines. What we did note was a marked enhancement expression of BIM and SGK1, steroid responsive genes and pro-apoptotic factors, after CDK12/13 inhibition (Figure A). ALL cell lines exhibited high susceptibility to CDK12/13 inhibition with two chemically divergent inhibitors, SR-4835 and THZ-531. We also showcased their synergistic interactions with dexamethasone using flow cytometry and synergyfinder ZIP score analysis (Figure B). Moreover, in the GSEA comparison of ALL cell lines with and without synergy between CDK12/13 inhibitors and dexamethasone, our data underscored significant enrichment in cholesterol biosynthesis-related genesets in cell lines manifesting this synergistic effect. On the other hand, we observed resistance to SR-4835 in cell lines with high enrichment scores in NOTCH, a signaling pathway implicated in about 80% of relapsed T cell ALL/LBL cases. Additionally, new data on mice xenotransplanted with B-ALL CNS-derived patient cells, link upregulated cholesterol biosynthetic pathways to nervous system involvement in childhood ALL. Upon administering CDK12/13 inhibitors, we observed a cell cycle phase shift resulting in G1 arrest and increased apoptosis, whereas human peripheral blood mononuclear cells (PBMCs) from healthy individuals remained unaffected by this treatment. As we continue to decode the pathways through which CDK12/13 inhibitors render ALL cells more susceptible to dexamethasone, our next step includes silencing CDK12/13 using short hairpin RNA models in cell lines and consequently their RNA sequencing. This approach may mitigate the influence of secondary pathways, paving the way for enhanced treatment strategies for relapsed ALL by unmasking the underlying molecular events.

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 >2. Preliminary efficacy results suggest that circulating CD3+ CD4+ TCRαβ+ T cells > 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 >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 <15 years) survivors of ALL, AML, and Hodgkin lymphoma (HL), as well as 233 siblings from the Childhood Cancer Survivor Study (>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<0.001 in Mem) and pediatric (estimated mean score Δ3.2, range 2.0-4.5, p<0.001 in TE; Δ1.3, range 0.1-2.5, p=0.03 in Org; Δ3.8, range 2.6-5.0, p<0.001 in Mem; Δ2.8, range 1.5-4.1, p<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.

Identifying a core protein signature of small extracellular vesicles derived from B-cell precursor acute lymphoblastic leukaemia.

Acute paediatric leukaemia is diagnosed and monitored via bone marrow aspirate assessment of blasts as a measure of minimal residual disease. Liquid biopsies in the form of blood samples could greatly reduce the need for invasive bone marrow aspirations, but there are currently no blood markers that match the sensitivity of bone marrow diagnostics. Circulating extracellular vesicles (EVs) represent candidate biomarkers that may reflect the blast burden in bone marrow, and several studies have reported on the utility of EVs as biomarkers for adult haematological malignancies. Increased levels of EVs have been reported for several haematological malignancies, and we similarly report here elevated EV concentrations in plasma from paediatric BCP-ALL patients. Plasma EVs are very heterogeneous in terms of their cellular origin, thus identifying a cancer selective EV-marker is challenging. Here, we undertook a reductionistic approach to identify protein markers selectively associated to plasma EVs derived from BCP-ALL patients. The EV proteome of primary BCP-ALL cell-derived EVs were compared against EVs from healthy donor B cells and the BCP-ALL cell line REH, and further against EVs isolated from plasma of healthy paediatric donors and paediatric BCP-ALL patients. With this approach, we identified a signature of 6 proteins (CD317, CD38, IGF2BP1, PCNA, CSDE1, and GPR116) that were specifically identified in BCP-ALL derived EVs only and not in healthy control EVs, and that could be exploited as diagnostic biomarkers.

Pediatric Pleomorphic Xanthoastrocytoma with Neoplastic Meningitis: A Case Report with Cytopathological Evidence with Literature Review

AbstractPleomorphic xanthoastrocytoma (PXA) was regarded as grade II tumor and considered to be associated with favorable outcome. The World Health Organization Central Nervous System 5 (WHO CNS5) has classified PXA under circumscribed astrocytic gliomas and graded 2 or 3 depending on histology. Cerebrospinal fluid (CSF) and leptomeningeal spread are observed rarely in these tumors. The present case report describes a PXA, grade 3 tumor in a young male with neoplastic meningitis. This 17-year-old male child presented with history of seizure, signs of raised intracranial pressure, and meningeal irritation. Well-defined, T2 heterogeneously hyperintense lesion (5.5*4.8 cm) was seen in right frontal lobe with mild heterogenous contrast enhancement and adjacent pachy-meningeal enhancement. Right frontal craniotomy and near total excision were done. Postoperative hydrocephalus was treated with CSF diversion. Histopathology showed epithelioid and rhabdoid morphology with significant cellular pleomorphism and atypical mitosis consistent with the PXA, grade 3. The CSF cytology showed numerous tumor cells with marked nuclear and cytoplasmic pleomorphism. PXA is a rare malignancy of children and young adults, commonly seen in the temporal lobes. BRAF point mutations of V600E type are most common in PXA, grade 2. Meningeal dissemination is uncommon in PXA and its presence marks poor outcome. PXA, grade 2 tumors could be followed with serial imaging following gross total resection. PXA, grade 3 tumors are managed with maximal-safe resection, radiotherapy, and/ or chemotherapy. PXA, grade 3 with CSF spread tends to have rapid decline in the clinical course and it is advisable to get routine baseline and follow-up craniospinal screening and needs aggressive management.

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.

IMMU-23. FRUCTOSE METABOLISM IN MICROGLIA PROMOTES GLIOBLASTOMA GROWTH

Abstract Glioblastoma (GBM) is the most common brain malignancy in adults and has a dismal prognosis. Advances in standard-of-care treatments for GBM have not kept pace with those for other malignancies, in part due to the inefficacy of immunotherapies in treating GBM. The tumor microenvironment (TME) of GBM is heavily populated with pro-tumorigenic tumor-associated macrophages (TAMs) and lacks robust infiltration of T cells. Given that the number of TAMs in the TME correlates with poor prognosis, understanding the mechanisms by which they thrive is essential for discovering new therapies. Bulk RNASeq data from mouse tumors indicates that the fructose transporter, SLC2A5, is highly expressed on TAMs relative to peripheral myeloid cells. Furthermore, human glioblastoma single cell RNASeq (scRNASeq) data indicates that SLC2A5 is expressed specifically on microglia, the tissue resident macrophage of the brain. To assess the necessity of SLC2A5 in microglia, we orthotopically implanted CT2A or QPP4 glioblastoma cells into wild-type mice and mice lacking SLC2A5 (SLC2A5 KO mice). We observed a significant increase in median survival in SLC2A5 KO mice compared to wild-type mice. This indicates a necessity of fructose metabolism in microglia to promote tumorigenesis. Upon ex vivo analysis of the immune compartment of the TME, we observed that microglial cells from tumors in SLC2A5 KO mice have higher expression of MHC-II and PDL1 molecules on the cell surface compared to those from wild-type mice. Additionally, the CD4:CD8 T cell ratio in tumors from SLC2A5 KO mice was lower than that in tumors from wild-type mice. These data suggest that fructose metabolism in microglia facilitates an immunosuppressive phenotype that promotes GBM progression.

TMIC-69. TARGETING TUMOR-ASSOCIATED MACROPHAGES IN THE IMMUNE-MICROENVIRONMENT OF MENINGIOMAS

Abstract Meningiomas represent the most common primary brain malignancies in adults with a subset of tumors exhibiting aggressive clinical behavior. Immunotherapy might present a new treatment strategy but is highly dependent on the immunological composition of the tumor microenvironment. Our previous data have shown that tumor-associated macrophages (TAMs) make up the main immune cell population in meningiomas with a significant negative impact on patient outcome. In this study, we investigated whether TAMs from meningioma tissue could be reprogrammed to an immunologically active and tumoricidal phenotype. For this purpose, CD11b+ sorted macrophages derived from &amp;gt; 40 patients were treated with small molecule inhibitors targeting the colony-stimulating factor-1 receptor (CSF-1R). In a first analysis, the direct treatment response of CD11b+ patient-derived macrophages was investigated by various techniques including flow cytometry and bulk RNA-sequencing of treated TAMs and further analysis of the macrophage-conditioned media after treatment. In addition, we studied the influence of CSF-1R-targeted macrophage treatment on the phenotype and functional activity of T cells to assess a potential indirect treatment response in the tumor microenvironment. Our data revealed that CSF-1R-targeted treatment of CD11b+ TAMs induced significant changes in the protein and gene expression of macrophage polarization markers towards a more immunologically active state and a significantly higher metabolic nitric oxide production as another sign of immunological activation. Subsequent analysis of indirect effects on T cells showed not only a significantly increased expression of the T cell activation marker CD69+, but also a significantly increased tumor cell killing by autologous T cells after macrophage-targeted treatment. Together these data suggest both a direct and indirect CSF-1R-targeted macrophage treatment response in the local tumor microenvironment and give first promising results on the efficacy of macrophage-targeted immunotherapy in human meningiomas.

RTID-08. A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY WITH ANTISENSE OLIGO IMV-001 TARGETING IGF-1R, VS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS

Abstract Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusion criteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.

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.

Renal cell carcinoma

SummaryKidney cancer accounts for 5% and 3% of all adult malignancies in men and women. Renal cell carcinoma (RCC) accounts for approximately 80% of all kidney cancer. This year’s American Society of Clinical Oncology (ASCO) Annual Meeting was held from 2–6 June 2023, in Chicago, USA. Combination therapies for advanced RCC continue to be of interest at ASCO 2023, with the presentation of updated results from some ongoing studies. There were several studies presented at ASCO looking at treatments for non clear renal cell carcinoma. Immunotherapy- based therapy regimes are now the gold standard for rare histological subtypes of RCC.

Natriuretic Peptides in Gastrointestinal Cancer: Biomarkers and Potential Therapeutic Targets.

Gastrointestinal (GI) cancers are an important health problem globally. Natriuretic peptides are hormones that have a crucial role in human physiology. There are a variety of treatments for GI cancer, but conventional therapies have side effects and low efficacy. Studies have demonstrated that natriuretic peptides are therapeutic in different cancer types. Natriuretic peptides are best known for their involvement in regulating blood pressure and blood volume. The anti-tumor effect exerted by natriuretic peptides is via their inhibitory effects on DNA synthesis and by their effects on apoptosis. The anti-proliferative role of natriuretic peptides has been shown in human breast cancer, prostate, colon, pancreatic, lung, ovarian, and other tumors. The roles of natriuretic peptides in these cancers are diverse and not well understood. Therefore, we have reviewed the recent literature on natriuretic peptides in GI cancers as a common malignancy in adults to assess the pathways that NPs are involved in the progression of GI cancers and its effect on the prevention or treatment of GI cancers.

Real-World Retrospective Study of Non-Transfusion Dependent Patients with Myelodysplastic Syndromes Treated with Luspatercept: A Healthcare Claims Database Study

Background: Myelodysplastic syndromes (MDS) are common hematologic malignancies in older adults that are characterized by abnormal bone marrow function leading to reduced blood cell production, persistent cytopenias, with a risk that patients may progress to acute myeloid leukemia (AML). Due to the high rate of anemia, many patients with MDS require red blood cell transfusions (RBCT), which, in turn, are associated with a high clinical and economic burden. In the phase 3 randomized COMMANDS and MEDALIST clinical trials, luspatercept reduced the severity of anemia among transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)-refractory and ESA-naive patients with lower-risk (LR)-MDS (Platzbecker U, et al. Lancet 2023. doi:10.1016/S0140-6736(23)00874-7, Fenaux P, et al. N Engl J Med 2020;382:140-151). However, there are limited real-world data on the use of luspatercept in patients who are non-transfusion dependent (NTD) or have a low transfusion burden. This study aims to describe the real-world clinical outcomes and treatment patterns before and after the initiation of luspatercept in patients with LR-MDS who were NTD before luspatercept initiation, in the USA. Methods:In this retrospective claims-based cohort study, data from the Symphony Health database (Jan 1, 2010 to June 30, 2022) were used to identify adults with a diagnosis of MDS (initial diagnosis on or after Jan 1, 2015) before the first claim for luspatercept (index date). Patients were considered NTD if they had no unique dates with a claim for RBCT during the 8-week period before or on the index date. Patients were excluded if they received chemotherapy or had a diagnosis of refractory anemia with excess blasts or AML during the study period, as they were presumed to have higher-risk MDS. Patients were also excluded if they had a diagnosis of β-thalassemia, myelofibrosis, aplastic anemia, or breast cancer in the 6 months pre-index (baseline period) or prior use of hypomethylating agents (HMAs). Patient demographics and clinical characteristics were assessed during the baseline period, and patients' RBCT status (NTD or TD) was measured for 6 months after the index date. A patient was considered 8-week NTD if they had no RBCT in ≥ 1 rolling 8-week period; 12-week, 16-week, and 24-week NTD patients were defined similarly, using increasing durations of NTD. Administration of other MDS therapies (ie, chemotherapy, ESA, granulocyte colony stimulating factor [G-CSF], HMA, and immunomodulatory imide drug [IMiD ®] agent) was measured pre-index and post-index until the end of clinical activity or data availability (follow-up). Results: Of the 871 eligible patients who received luspatercept 589 (67.6%) were NTD before luspatercept initiation. Among this NTD population, the mean (standard deviation [SD]) age was 74.7 (6.3) years and 57.2% were male. Before luspatercept initiation, 15.3% of patients received 2 treatment classes and 0.8% received ≥ 3 treatment classes. Almost all patients (98.5%) maintained 8-week NTD status in the 6 months after luspatercept initiation. Similarly, 96.8%, 94.1%, and 88.6% of patients maintained NTD status for at least 12, 16, and 24 weeks in the 6 months after luspatercept initiation, respectively (Figure 1). Most patients (64.7%) did not require any additional MDS-related treatments during the study follow-up period, (median [SD] 15.7 [7.4] months). Overall, 77.1% of patients were treated with luspatercept for &amp;gt; 6 months and 68.4% for &amp;gt; 12 months. After luspatercept initiation, patients most commonly received treatment with ESAs or HMAs (14.9%; Figure 2). Conclusion:This is the first real-world evidence study to address luspatercept treatment in patients who were NTD prior to luspatercept treatment, which resulted in positive clinical outcomes and few RBCTs.Almost all patients with LR-MDS who were NTD at luspatercept initiation maintained 8-week NTD status during the 6 months after luspatercept initiation. The majority of patients did not receive a RBCT for a 24-week period after luspatercept initiation. Finally, over three-quarters of the patients remained on luspatercept and two-thirds of patients did not receive additional MDS-related treatments after a median follow-up of 15.7 months.

DHODH Inhibitor Therapy for the Treatment of T-ALL Spares the Developing Thymus

Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy in children and young adults. When compared to B-ALL, T-ALL has a higher rate of induction failure as well as relapse, with very poor overall survival in both scenarios. Furthermore, T-ALL has not benefitted from immune-mediated therapies and continues to pose an ongoing treatment challenge with an unmet therapeutic need. DHODH has been highlighted as a potential therapeutic target in many hematologic and solid tumor malignancies including AML, neuroblastoma, glioblastoma, pancreatic cancer, and breast cancer. DHODH inhibition has a robust anti-leukemia effect in both in vitro and in vivo models of T-ALL. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T-ALL, including an aggressive NOTCH driven model in syngeneic recipients and two human patient derived xenografts. Given the goal of making DHODHi therapy available to young children with relapsed/refractory T-ALL, we wished to understand the ramifications of nucleotide starvation on normal T-cells and other hematopoietic progenitors. To specifically address this, we turned our attention to the effects of DHODH inhibition on the developing thymus. This compartment would be of particular interest in pediatric patients, whose thymi have not yet finished developing. We studied juvenile mice (3 weeks) whose thymi are just reaching their peak size and growth rate. These mice were treated with the small molecule DHODHi brequinar (BRQ) 50 mg/kg every 72 hours, and were paired with age and gender-matched controls at each time point of analysis. A subset of mice were analyzed following two doses of BRQ, and thymus, bone marrow, spleen, and peripheral blood were analyzed for T-cell populations, both relative and absolute numbers. Another cohort was allowed to “recover” for 2 weeks following treatment before analysis, and a third cohort was allowed a four week recovery period. We discovered that initial treatment with brequinar significantly impacts T-cells across all stages of development ( Figure 1). This is expected, as developing T-cells are rapidly proliferative (often dividing as quickly as every 6 hours) and therefore highly dependent on their supply of nucleotides for DNA replication as well as transcription. However, after the two-week and the four-week recovery periods, these differences are no longer detectable, demonstrating the resilience of the developing thymus, and demonstrating that the effects of nucleotide starvation are temporary and reversible. These data are encouraging, as this may also suggest that the developing human thymus which is similarly rapidly proliferative in nature would also recover once nucleotide starvation was removed. Based on these data, we were interested in understanding the differential sensitivity of normal thymocytes as compared to malignant T-lymphoblasts to DHODHi. The resilience shown by normal thymocytes following treatment with BRQ may be due to their ability to tolerate periods of inhibition of de novo pyrimidine synthesis by preferentially relying on extracellular nucleotide salvage, whereas the sensitivity of malignant T-cells to DHODH may be due to their lack of ability to utilize the salvage pathway. We performed experiments to understand how cells balance de novo synthesis vs extracellular salvage. First, we performed metabolite flux tracing in Jurkat cells to directly measure nucleotide salvage. Here, we followed incorporation of isotopically labeled glutamine ( 15N) and uridine ( 13C) to determine the relative contributions of synthesis vs salvage, as de novo pyrimidine synthesis initiates from glutamine and aspartate while a cell can also use membrane nucleoside transporters (SLC28A and SLC29A family of proteins) to salvage extracellular uridine. These experiments were performed in the presence and absence of BRQ. Once BRQ is added and the cell's ability to synthesize pyrimidines is shut down, the cell must rely more on extracellular salvage as shown in Figure 2. A defective or less efficient process of extracellular salvage could help to explain this cell line's unusual dependence on de novo nucleotide synthesis. Overall, we hope that these findings will pave the way for additional preclinical studies and eventually clinical trials for pediatric patients with T-cell disease.

A Potential Paradigm for the Robust and Systematic Prioritisation of Assets in Academic-Led, Multi-Industry Collaborative Trials in Rare Populations (Glo-BNHL)

Overview Given the rarity of children and adolescents with relapsed and refractory (r/r) B-cell Non-Hodgkin Lymphoma (B-NHL) and the large number of potential agents in development for adult mature B-cell malignancies, there is urgent need for prioritisation of agents as proposed by the ACCELERATE Paediatric Strategy Forum for medicinal development in paediatric B-NHL (Pearson 2019). The process developed for the global platform study Glo-BNHL (published separately) is described here. Prioritisation process Assets submitted for review by industry collaborators are prioritised under Confidentiality Disclosure Agreements by the Glo-BNHL Trial Steering Committee (TSC) comprising expert clinicians, statisticians and patient representatives. The assessment includes a quantitative element addressing each of the following areas, with greater weighting given to more relevant criteria such as paediatric-specific and clinical data. Target and scientific rationaleAsset position within current prioritisation strategy*Pre-clinical data evaluating in vitro sensitivity, including the number, heterogeneity and relevance of cell lines tested and quality of the submitted elements of evidencePre-clinical data evaluating in vivo activity of the asset including the number, type and relevance of models and quality of the elements of evidence submittedClinical data regarding monotherapy efficacy in single arm and randomised trials, including the disease-type and therapeutic regimen studiedClinical data regarding combination efficacy (if studied)Clinical data regarding safety of the agent with regard to frequency, severity and modifiability of adverse events, including applicability to the paediatric populationFeasibility of delivery in paediatrics, including formulation and dose-confirmation processes *Classes of novel agents prioritised for inclusion at the initiation of the trial were: (1) Bispecific antibodies (2) antibody-drug conjugates (3) chimeric antigen receptor T-cell products. The TSC has committed to updating this list as the field evolves. The assessment also includes a qualitative element incorporating expert opinion regarding relevance of the target, mechanism of action, and overall impression of the asset. These elements are combined to inform the final discussion before a decision is made. A formal written response from the Sponsor and TSC Chair outlining the TSC decision on whether the asset has been prioritised for evaluation within Glo-BNHL, and associated rationale, is issued to the relevant industry partner (now also copied to the European Medicines Agency (EMA)) within 28 days of receipt of the asset information pack. A follow-up clarification meeting is offered. For prioritised assets, following agreement from the relevant industry partner, the process of formal inclusion in Glo-BNHL then begins. Scope of assets reviewed Between September 2020 and June 2023, information packs for 7 assets were submitted for review from 6 pharmaceutical companies. The assets spanned 5 classes of drugs: 3 bispecific antibodies, 1 antibody-drug conjugate, 1 chimeric antigen receptor T-cell product, 1 small molecule inhibitor and 1 immunomodulator. Formal responses were issued within a median of 20 days (mean 21.3 days) followed by a clarification meeting on 5 occasions. Prioritised assets Four of the 7 reviewed assets were prioritised for inclusion within Glo-BNHL. At time of planned opening only 2 of these assets are included. The other 2 assets are being investigated in industry-led competitive trials. A further asset was deemed to be of potential interest but insufficient data were available due to the early stage of development to reach a final conclusion (further review pending). Non-prioritised assets The rationale for non-prioritisation of assets included irrelevant target in paediatric B-NHL, insufficiently convincing mechanism of action, and lack of superiority over other agents within a non-prioritised class. The EMA has subsequently waived the obligation to submit the results of paediatric B-NHL studies for both non-prioritised assets reasoning they do not represent potential for significant therapeutic benefit. Summary The Glo-BNHL international platform trial prioritisation process represents a model for handling the challenge of development of multiple potential agents in very rare populations in the global arena.

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.

Papillary Renal Cell Carcinoma Type 1 Accompanied by Hemorrhagic Anemia: A Case Report

Background: Kidney cancer or renal cell carcinoma (RCC) accounts for 5% and 3% of all adult malignancies in men and women, respectively, thus representing the 7th most common cancer in men, and the 10th most common cancer in women. The incidence of kidney cancer in the last two decades has shown an increase, but in recent years the death rate due to kidney cancer has decreased because it is increasing.&#x0D; Case Presentation: A 27 year old male patient came with complaints of bloody urination. Patients also complain of body weakness. Every time they are active, the weakness decreases if the patient rests. The patient was stated to be suffering from anemia and a left kidney tumor. There was bilateral antebrachial pitting edema. There was bilateral pretibial edema. Cytological examination revealed papillary renal cell carcinoma type 1.&#x0D; Conclusion: Papillary cell carcinoma type 1 is a kidney tumor that has a good prognosis, especially if found at an early stage. The classic symptoms of type 1 pRCC are anemia, hematuria and kidney swelling.