Hematologic Malignancies Research Articles

Improving the Utility of a Cancer Gene Mutation Panel for Multiple Myeloma Patients

Abstract Multiple myeloma is a plasma cell malignancy that accounts for 1-2% of all cancer diagnoses and 10-15% of hematopoietic neoplasms. Clonal rearrangement of the IG locus suggests a monoclonal model for pathogenesis. The presence of cytogenetic abnormalities in >90% of cases suggests transformation by chromosomal instability and rearrangement. Classification and consensus guidelines by The International Myeloma Working Group (IMWG) and others reflect this by categorizing myeloma based on ploidy, translocations, and chromosomal abnormalities. Interestingly, a portion of Emory’s test volume for cancer gene mutation profiling by second generation short-read sequencing is for multiple myeloma cases. This suggests our 75-gene myeloid neoplasm panel (MMP75) is being utilized for medical purposes that are not met by cytogenetic and microarray characterizations performed during the diagnostic workup of multiple myeloma. Inspired by this observation, this study investigates providers motivations for ordering MMP75 and assesses the adequacy of our current implementation for their stated purposes. Anecdotes from ordering physicians indicate interest in MMP75 results when informing prognosis, selecting treatments, and evaluating for treatment associated secondary neoplasms. A more formal survey is underway that will statistically capture how the results of MMP75 testing were ultimately used: to inform diagnosis, determine prognosis, guide treatment, explain progression, identify/rule-out secondary neoplasia, or no effect on management. We also explore the variants called by MMP75 when performed using bone marrow from patients who received a cytogenetic workup for multiple myeloma at some point. A retrospective analysis of the 5-year interval between Jan 2019 and Jan 2024 identified 156 cases meeting this criterion. The number of pathogenic variants per case ranged between 1 and 8, with mutations detected across 42 genes. The genes most frequently identified with pathogenic mutations were TP53 (22.4%), DNMT3A (19.2%), TET2 (14.7%), and ASXL1 (12.2%). All four have been associated with adverse outcomes in patients with multiple myeloma. Activating events in therapeutic targets included mutations in the RAS/RAF pathway (16.7%), JAK/STAT signaling (2.6%), and the kinase KIT (0.6%). While these findings support the use of MMP75 for detection of relevant mutations, the genetic variants identified are not unique to multiple myeloma. Mutations detected in DNMT3A, TET2, and ASXL1 are common in clonal hematopoiesis of indeterminant potential (CHIP) and myeloid neoplasms. Hotspot mutations in TP53 and activating events in the RAS/RAF pathway also occur in various hematologic malignancies. This test therefore detects events that occur in both the plasma cell compartment and other cells of origin. This encumbers distinguishing variants that inform on a patient’s multiple myeloma from events that suggest a secondary neoplasm. Future directions include determining whether the effect of plasma cell enrichment on a mutations variant allele frequency (VAF) in repeat testing can help distinguish true multiple myeloma variants from events in other cells.

A success story in a low-resource setting: Advancing cancer diagnostics in underserved region

Abstract Introduction/Objective Shefaa Al Orman Hospital (SOH) is the first oncology hospital in Luxor. Since its inception in 2016, the hospital has served approximately 45,000 patients from Luxor and other governorates. The hospital’s lab provides excellent routine laboratory services. However, there is a pressing demand for molecular genetics and cytogenetics, that is necessary for diagnosis of hematological malignancies. This strategic expansion faced several challenges: lack of expertise and the need for special expensive equipment and reagents. Methods/Case Report The project started with collaboration with oncologists to convene on a simplified panel with the aim of prioritizing clinically relevant tests. At first, these investigations were referred to a specialized oncology hospital in Cairo. This entailed 2 problems: transport of samples led to deterioration of the quality of some samples and delay in results reporting. In the second phase, experienced consultants from Cairo were enlisted to provide training and mentorship to local staff. Infrastructure setup included the allocation of dedicated laboratory space and the procurement of specialized equipment. Test method selection was used to achieve successful transition. In cytogenetics, we started with FISH technique which, while more expensive, gave rapid and reliable results. After gaining experience, the technique of conventional karyotyping was established. On the other hand, in molecular genetics, we resorted to custom made reagent mix preparation, instead of commercial kits. This approach, while more laborious, is less expensive. Results (if a Case Study enter NA) With the gradual successful in-house setup of these tests, there has been a notable reduction of out-sourced samples to 5%. This has led to shorter result turnaround times. Cytogenetics and FISH improved from 4 to 1 week, while molecular genetics decreased from 4 to 2 weeks. Moreover, the local processing of samples has minimized the risk of sample damage during transportation, ensuring the integrity of test results. Conclusion The establishment of the Molecular Genetics and Cytogenetics Laboratory at SOH represents a significant milestone. The hospital has successfully overcome logistical challenges and enhanced diagnostic capabilities for hematological malignancies, contributing to better patient outcomes and satisfaction. Moving forward, the continued investment in infrastructure, personnel training, and quality assurance measures will further strengthen the hospital’s capacity to provide high-quality cancer care to the community.

Rare Adult acute leukemia with Coexisting myeloblastic (basophilic differentiation) & B-lymphoblastic subpopulations Case Study

Abstract Introduction/Objective Acute basophilic leukemia is a very rare subgroup of acute myeloid leukemia that is defined in the 2022 WHO classification by presence of at least 20% blast cells in peripheral blood or bone marrow with immature and maturing cells of basophil lineage. The simultaneous occurrence of two hematological malignancies in a middle- aged adult patient is quite a rare event as evidenced by the rare cases reported in the literature. To our knowledge, this is the first case to be reported with concomitant acute basophilic and B-lymphoblastic leukemia in adult patients. these findings necessitates the comprehensive systematic approach to attain accurate diagnosis and plan the appropriate treatment protocol. Methods/Case Report Bone marrow aspiration & biopsy procedure was performed under local anesthesia and marrow samples were subjected to: lieshman staining of marrow films and direct examination. Immunophenotypic analysis of marrow aspirate by FACS Canto II flow cytometer. Cytogenetics studies were done as karyotyping and gene mutation detection by FISH. Results (if a Case Study enter NA) NA Conclusion Morphology of marrow films: 50% Blast cells, group of them are medium to larg-cells with high nucleocytoplasmic ratio and immature chromatin and the other group shows blast cells with sparse basophilic granulations, plus 20% immatue and maturing basophils. IPT shows two populations: the Myeloblast population (basophilic differentiation) is Positive for CD45dim, CD34het, CD13, CD33, CD117prt, CD25het, CD123het, cyt MPO part, HLA-DR partial. the B lineage lymphoblast population is Positive for CD45dim, CD34het, CD19, CD79a, TdT, CD20het, CD38. Cytogenetics studies: hyperploidy 56, (X, Y, 9, 10, 12, 13, 15, 18, 22, mar+ extra-chromosomes) FISH: +ve for FLT3-ITD mutation. the picture is by morphology & IPT consistent with biclonal leukemia, myeloid clone (acute basophilic leukemia) & ProB-ALL. The systematic laboratory approach from careful morphological examination of peripheral blood and bone marrow smears to confirmatory immunophenotypic analysis of marrow specimens by flow cytometry, and the comprehensive cytogenetics analysis, has a vital role in diagnosing such rare and aggressive phenomenon and provide a good chance for planning the appropriate treatment protocol with critical timesaving and cost effectiveness.

Utility of Targeted Next Generation Sequencing (NGS) to Predict Hematologic Neoplasms with Germline Predisposition

Abstract Introduction/Objective Hematologic neoplasms with germline predisposition are increasingly gaining clinical relevance as associated gene variants are emerging. These variants confer an increased risk for developing hematologic neoplasms as additional somatic aberrations accumulate. Recognition of germline predisposition is crucial to patient management as it would prompt genetic counseling and regular surveillance in affected patients and biological family members, as well as guide therapy, as many patients undergo allogeneic stem cell transplantation for which relatives are typically the preferred donors. Furthermore, these patients may respond differently to conventional therapies. Clinical recognition of germline predisposition is challenging due to phenotypic heterogeneity and a lack of germline testing standards and resources. Next generation sequencing is routinely utilized to detect somatic variants associated with hematopoietic neoplasms. Molecular profiling may also potentially serve as a screening tool to suggest pathogenic germline variants. Methods/Case Report Comprehensive genomic profiling data was reviewed for 301 patients with known hematologic neoplasms. A somatic-germline-zygosity (SGZ) computational method classified variants by origin. Variants of unknown clinical significance were excluded. The final study showed 94 patients predicted to have germline variants. The variables analyzed include germline variants, concurrent mutations, diagnosis, sex, age, and ancestry. Results (if a Case Study enter NA) Acute myeloid leukemia was the most frequent diagnosis, followed by B-cell acute lymphoblastic leukemia, myeloproliferative neoplasms, myelodysplastic syndrome, and chronic myelomonocytic leukemia. The median patient age was 60 years, ranging from 6 months to 91 years. Male gender and European ancestry were proportionally greater. In this study, we identified 70 distinct genes with 145 germline pathogenic variants. The most common pathogenic germline variants were TET2, SRSF2, RUNX1, DNMT3A, and CHEK2. Conclusion In conclusion, SGZ computational methods can be used as a screening tool to predict possible germline mutations in hematologic malignancies, which will help guide treatment and improve patient and family outcomes

Incidence of immune effector cell-associated neurotoxicity among patients treated with CAR T-cell therapy for hematologic malignancies: systematic review and meta-analysis.

We aim to assess the pooled incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) in clinical trials and real-world studies of chimeric antigen receptor (CAR) T-cell therapy for hematologic malignancy and compare the incidences among different agents. The PubMed, Embase, and Web of Science databases were searched for clinical trials and real-world studies. An inverse-variance weighting model was used to calculate pooled incidences and subgroup analyses. Multivariable analysis was conducted using binomial-normal modeling. Seventy-five trials comprising 3,184 patients were included. The overall pooled incidence was 26.9% (95% CI, 21.7-32.7%) for all-grade and 10.5% (95% CI, 8.1-13.6%) for high-grade ICANS. In subgroup analysis, cohorts with anti-CD19 drugs had significantly higher ICANS incidences than cohorts with other agents. The multivariable analysis demonstrated higher odds of ICANS in anti-CD19 drug studies for high-grade (OR, 4.6) compared to anti-BCMA drug studies. In 12 real-world studies, studies used axicabtagene ciloleucel with CD28 (54.0% all-grade, 26.4% high-grade) exhibited significantly higher rates of all-grade and high-grade ICANS than studies using tisagenlecleucel with 4-1BB (17.2% all-grade, 6.1% high-grade). The overall incidences of ICANS with CAR T-cell therapy were 26.9% for all-grade and 10.5% for high-grade. Compared with other agents, patients with anti-CD19 drugs had a significantly increased risk of developing high-grade ICANS. Therefore, careful monitoring of ICANS should be considered for patients undergoing CAR T-cell therapy.

Ordering and Utilization of Peripheral Blood Flow Cytometry in an Academic Medical Center

Abstract Introduction/Objective The American Society for Clinical Pathology and the American Board of Internal Medicine’s Choosing Wisely campaign have developed best practice utilization guidelines for laboratory testing. Wisconsin Diagnostic Laboratories and Medical College of Wisconsin leadership noticed an increase in inappropriate peripheral blood flow cytometry testing in the last two years. An intervention was developed to help reduce inappropriate testing requests. Methods/Case Report The laboratory implemented a clinical decision support tool in the electronic medical record system that looked at patient diagnosis, history of stem cell transplant, and recommendations from pathology to help improve utilization of peripheral blood flow cytometry testing. Based on patient history, flow cytometry testing would move forward, or an alternative order of a peripheral blood pathology smear review with reflex to flow cytometry was offered. Pathologists would reflex flow cytometry if abnormalities were present by light microscopy or predetermined reflexing criteria were met. Results (if a Case Study enter NA) 314 cases were included for analysis. The intervention reduced volumes of peripheral blood flow cytometry in patients without a history of hematologic malignancy by 49.1% (p=<0.001). Appropriate utilization increased from 47.0% in the pre-intervention period to 80.4% in the post intervention period (p=<0.001). Significant diagnosis rate increased from 42.5% to 50.0% (p=.261). This resulted in a cost savings of $12,232 for the health system during the intervention period. Conclusion Clinical decision support based utilization efforts provide strong and consistent interventions to reduce the unnecessary and inappropriate ordering of peripheral blood flow cytometry.

Deep Learning-Based Integration of Morphology and Immunophenotype Predicts Molecular Genetic Subtypes of Multiple Myeloma

Abstract Multiple myeloma, the second most common hematologic malignancy, is characterized by recurrent molecular genetic variants which portend important prognostic and therapeutic implications. These variants, which include chromosomal aneuploidies, translocations, and other structural changes, are currently identified by performing karyotyping and fluorescence in situ hybridization analysis on bone marrow biopsy samples. Comprehensive variant testing for full characterization of multiple myeloma cases can take days to weeks, is costly, and is not available to all patients. Past studies have explored to what extent cellular morphologic information from bone marrow aspirates or immunophenotypic information from flow cytometry can predict these genetic variants via the use of machine learning algorithms. However, the integration of multiple hematopathology data modalities using machine learning towards improving the diagnosis and characterization of hematologic neoplasms has yet to be explored. To this end, we developed a deep learning-based algorithm which, for individual patients, integrates tens-of-thousands of cell images from Wright-stained bone marrow aspirate smears with hundreds-of-thousands of events from myeloma flow cytometry panels to predict the presence or absence of particular molecular genetic variants among 85 cases of multiple myeloma. Attention-based multi-instance learning models were developed utilizing convolutional neural networks to analyze cell image data and multi-layer perceptrons to analyze flow cytometry data. Models trained solely on cell image data showed variable performance in predicting genetic subtypes of multiple myeloma cases: t(11;14), AUROC = 0.795; 1q+, AUROC = 0.743; del(17p), AUROC = 0.520. Similar models trained solely on flow cytometry data showed fair performance for all subtypes: t(11;14), AUROC = 0.761; 1q+, AUROC = 0.761; del(17p), AUROC = 0.787. However, models which combine features among high-attention events from both cell image and flow cytometry data yield significantly improved performance: t(11;14), AUROC = 0.892; 1q+, AUROC = 0.789; del(17p), AUROC = 0.876. Similarly, models trained to predict established prognostic classifications of multiple myeloma cases performed best when cell image and flow cytometry data is integrated: cell images alone, AUROC = 0.721; flow cytometry alone, AUROC = 0.827; both data combined, AUROC = 0.839. Additional improvements in prognostic classification were obtained when utilizing a Kronecker product to more completely utilize pairwise interactions between cell image and flow cytometry features: AUROC = 0.864. This study is, to our knowledge, the first to utilize deep learning to integrate multiple hematopathology data modalities towards automated diagnosis or subclassification of hematologic neoplasms in individual patients. The results of this study demonstrate the feasibility of accurately predicting molecular genetic subtypes of multiple myeloma cases solely from cell morphology and flow cytometric information. With further refinement, these promising models could be applied in low resource settings as well as research settings to better understand the biological relationship between plasma cell genetics with morphology and immunophenotype.

Assessment of Molecular Response to Treatment of Chronic Myeloid Leukemia at Kigali University Teaching Hospital of Kigali

Abstract Introduction/Objective Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative neoplasm that gives proliferation advantage to the granulocytes, it is one of the commonest chronic hematological malignancies and it is a burden to the world especially Rwanda. Since the introduction of Tyrosine Kinase Inhibitors (TKIs) especially the first line Imatinib in 2001, the outcomes of CML have been much improved and currently, in developed world, the life expectancy of patients with CML is almost the same as general population. However, it is not the case in developing world especially Rwanda due to limitation on access of all TKIs. The aim of this study is to assess molecular response on Imatinib of patients with CML. Methods/Case Report This was a one arm open label prospective cohort study that recruited 31 patients with CML and on Imatinib for at least three months and followed for 11 months. The clinical features at diagnosis and recruitment were captured from the hospitals filing systems and investigator’s own assessment at the time of recruitment respectively. Information was filled to a well-structured questionnaire. Lab results at the time of diagnosis was obtained from laboratories reporting systems. Samples for full blood count and BCR-ABL1/ABL1 were withdrawn from the patients at the time of diagnosis and they were run at University Teaching Hospital of Kigali (CHUK). Data analysis was performed using Statistical Package for the Social Sciences (SPSS 28) and South Texas Art Therapy Association (STATA 15.0). Results (if a Case Study enter NA) Better response according to European LeukemiaNet (ELN) defined as optimal response was found among only 38.7% and resistance to imatinib defined by ELN as Failure and warning was found in 45.2% and 16.1% respectively. The eleven months survival rate was 93.5% in which it is 85.7% among those in treatment failure group. Late presentation showed by presence of very high White Blood Cells above 100x109/L and massive splenomegaly at diagnosis, and poor adherence to Imatinib according to Morsiky Medication Adherence Scale (MMAS-8) are associated with poor molecular response to Imatinib. Conclusion CML is a serious disease especially to those who suffer from it; on time diagnosis, access to all available lines of TKIs and better follow up are crucial for patients with CML to access the same life expectancy as general population as it is in developed world.

Elucidating the role of MLL1 nsSNPs: Structural and functional alterations and their contribution to leukemia development.

The Mixed lineage leukemia 1 (MLL1) gene, located on chromosome 11q23, plays a pivotal role in histone lysine-specific methylation and is consistently associated with various types of leukemia. Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) have been tied to numerous diseases, including cancers, and have become valuable cancer biomarkers. There's a notable gap in studies probing the influence of SNPs on MLL1 protein structure, function, and subsequent modifications. We utilized an array of bioinformatics tools, including PredictSNP, InterPro, ConSurf, I-Mutant2.0, MUpro, Musitedeep, Project HOPE, RegulomeDB, Mutpred2, and both CScape and CScape Somatic, to meticulously analyze the consequences of nsSNPs in the MLL1 gene. Out of 2,097 nsSNPs analyzed, 62 were determined to be significantly pathogenic by the PredictSNP tool, with ten crucial MLL1 functional domains identified using InterPro. Additionally, 50 of these nsSNPs had high conservation scores, hinting at potential effects on protein structure and function, while 32 were found to undermine MLL1 protein stability. Notably, four nsSNPs were deemed oncogenic, with two identified as cancer drivers. The nsSNP, D2724G, between the MLL1 protein's FY-rich domains, could disrupt proteolytic cleavage, altering gene expression patterns and potentially promoting cancer. Our research provides a comprehensive assessment of nsSNPs' impact in the MLL1 protein structure and function and consequently on leukemia development, suggesting potential avenues for personalized treatment, early detection, improved prognosis, and a deeper understanding of hematological malignancy genesis.

Alopecia Areata and malignancies: uncertainties clarified by a large-scale population-based study

The association of AA with malignancies has been a scope of controversy as the current literature is highly inconsistent in this regard. To evaluate the association between AA and hematological malignancies (HMs) and solid malignancies (SMs) using a large-scale, real-life computerized database. A cross-sectional study was conducted to compare the prevalence of HMs and SMs among patients with AA relative to age-, sex-, and ethnicity-matched control subjects. Chi-square and t-tests were used for univariate analysis, and a logistic regression model was used for multivariate analysis. The study included 51,561 patients with AA and 51,410 controls. AA was significantly associated with HMs (adjusted OR, 1.27; 95% CI, 1.07–1.51; P = 0.006). This association was more robust among patients with late-onset AA (≥ 50 years; OR, 1.33; 95% CI, 1.04–1.71; P = 0.025). On the other hand, AA was not found to be significantly associated with SM (adjusted OR, 0.97; 95% CI, 0.88–1.06; P = 0.487), excluding among patients with alopecia totalis and universalis (OR, 2.10; 95% CI, 1.03–4.27; P = 0.036). In a granular analysis including 5 HMs and 18 SMs, non-Hodgkin lymphoma was the only malignancy that proved positively associated with AA (adjusted OR, 1.32; 95% CI, 1.03–1.69; P = 0.028). AA is associated with HMs but not SMs. Further research is warranted to validate our observations in other study cohorts.

Haploidentical hematopoietic stem cell transplantation for hematologic malignancies: a novel conditioning regimen with anti-T lymphocyte immunoglobulin instead of anti-thymocyte globulin for in vivo T cell depletion.

We evaluated the safety and efficacy of a novel protocol for haploidentical stem cell transplantation (haplo-SCT) in 312 patients with hematologic malignancies. The protocol evolved from the Beijing platform replacing ATG with ATLG; adding Fludarabine and removing cytarabine and Simustine. GVHD prophylaxis combined Basiliximab and low-dose cyclophosphamide post-transplant; overall, the conditioning duration was shortened. Median times to neutrophil and platelet recovery were both 11 days. Graft rejection occurred in 0.96% of patients. Cumulative incidences of grades II-IV and III-IV acute GVHD by day 200 were 35.3% and 8.9%, respectively. Probabilities of total and extensive chronic GVHD at 2 years were 40.7% and 14.7%. CMV viremia was observed in 35.6% of patients, with a 1.9% 100-day CMV pneumonia incidence and no CMV-related mortality. Cumulative incidences of non-relapse mortality at 100 days, 1 year, and 2 years were 2.9, 4.4, and 6.6%. The 4-year OS, RFS, and GRFS rates were 78.9, 70.7, and 47.3%. Older recipient age was associated with higher NRM, while positive pre-transplant MRD predicted worse OS, RFS, and higher relapse incidence. Our novel protocol for haplo-SCT is associated with low infection rates and acceptable risks of graft failure, severe GVHD, and mortality, representing a safe and effective haploidentical transplantation strategy.

Red Blood Cell Transfusions in Patients with Advanced Cancer Receiving Home Palliative Care.

Background: Red blood cell (RBC) transfusion is the standard treatment for anemia in advanced cancer. Nevertheless, guidelines for managing this condition are still not exhaustive. Objective: To investigate frequency, timing, and clinical characteristics associated with RBC transfusions in patients with advanced cancer assisted by at-home oncological care service and to evaluate the association between parameters at the entry and the possibility of receiving RBC transfusions during homecare. Design: Retrospective observational study without medication. Setting/Subjects: Patients with advanced cancer entered in homecare during 2021 living in Bologna (Italy). Measurements: Gender, tumor primary site, oncological therapy, and symptoms at the entry were considered as possible factors in a binary logistic regression for the possibility of receiving at least one RBC transfusion during assistance. Data about transfusions were analyzed, and the transfusion history for each patient from the entry to death was traced. Results: Among the 1108 patients admitted, 179 (16.2%) were given at least one RBC transfusion during homecare. Genitourinary, hematological malignancies, and being still in therapy for advanced cancer are associated with a higher probability of receiving RBC transfusion during assistance (p = 0.017, p < 0.001, and p = 0.032, respectively). Half of the patients (52%) underwent RBC transfusions less than a month before death. Duration of the assistance was correlated with the period from last transfusion to death (p < 0.001). Conclusion: Hematological and genitourinary cancer and being in simultaneous care at the entry were associated with transfusion. Although the appropriateness of this treatment remains to be defined in this population, transfused patients frequently received "late in life" transfusions.

The heterogeneous syndrome of non-infectious causes of persistent fever in neutropenic patients with hematologic malignancy: another opportunity for stewardship?

Although occult fungal, viral and multidrug-resistant bacterial infections can cause persistent fever in neutropenic patients with hematologic cancer, a variety of non-infectious entities should be considered in case-by-case basis in the context of negative diagnostic workup for infection.

The role of nutrition and gut microbiome in the progression of multiple myeloma and its precursor disease.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by unregulated monoclonal proliferation in the bone marrow. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are premalignant conditions that can progress to MM. Identifying etiological risk factors for MM and its precursor diseases is crucial for prevention. Obesity, diet, vitamin D levels, and gut microbiota alterations have been identified as lifestyle factors affecting MM and MGUS risk. Upon disease onset, treatment strategies aim to reduce disease burden, enhance prognosis, and optimize patients' quality of life. Nutrition and body weight have been shown to affect disease progression and treatment outcomes. MM patients often present with vitamin D, vitamin B12, and folate deficiencies, which worsen disease prognosis. High body mass index is linked to increased death rates among MM patients and an increased risk of MGUS transformation to MM. Gut microbiota has also been associated with disease progression and response to treatment. This literature review aims to summarize the available evidence regarding the impact of nutrition and nutritional status on MM patients beyond prevention, highlighting the significance of gut microbiome and dysbiosis in MM progression.

Outcome of Pneumocystis Jirovecii pneumonia (PcP) in post-CAR-T patients with hematological malignancies

BackgroundPneumocystis jirovecii pneumonia (PcP) is an opportunistic infection associated with immunocompromised patients. The development of novel immunotherapies has promoted the incidence of PcP. This study describes the clinical course and outcome of PcP in chimeric antigen receptor (CAR) T cell recipients with hematological malignancies.MethodsThis is a retrospective case series of CAR-T recipients diagnosed with PcP in our center. The cases were all confirmed by metagenomic next-generation sequencing of clinical samples. The demographic, clinical, and outcome data were retrieved from the patients’ medical charts and electronic medical record system.ResultsIn total, 8 cases of PcP were identified. The underlying malignancies included T-acute lymphoblastic leukemia (ALL) (n = 1), diffuse large B cell lymphoma (DLBCL) (n = 4), and B-ALL (n = 3). One patient received short-term sulfamethoxazole-trimethoprim (SMZ-TMP) while the others had no prophylaxis. Four patients had neutropenia/lymphopenia at the diagnosis of PcP, and two patients had immunosuppressants within one month before PcP manifestation. The median time from CAR-T infusion to PcP diagnosis was 98.5 days (range 52–251). Seven patients recovered from PcP after proper management while one died of septic shock.ConclusionPcP can occur after different CAR-T product, and the long-term depletion of immune cells seems to be related to PcP. SMZ-TMP is effective in this setting. More real-world experience of CAR-T therapy is required to assess the incidence and outcome of PcP in this population.

Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma

BackgroundChimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.MethodsGlypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry.ResultsIn this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells.ConclusionsOur results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.

Eosinophilic dermatosis of haematologic malignancy treated with ibrutinib: A case report

AbstractEosinophilic dermatosis of haematologic malignancy is an infrequent skin disorder characterised by severe pruritus and skin lesions resembling arthropod bites. It primarily affects individuals with underlying haematological conditions, most commonly chronic lymphocytic leukaemia (CLL). While it does not correlate with a worse prognosis for the haematological disease itself, it significantly impacts patients' quality of life due to the distressing pruritus and recurring nature. Clinical presentation typically shows erythematous papules resembling arthropod bites, with less frequent occurrences of urticarial plaques or bullous lesions. Histologically, an intense and polymorphous inflammatory infiltrate is found both in the superficial and deep dermis, marked by an abundance of eosinophils and the absence of atypical cells. Treatment of this disease remains uncertain, with corticosteroids often being the only effective therapy. Here, we present the case of an 80‐year‐old patient with a history of CLL, who experienced a widespread, itchy eruption of papules and plaques over 2 months. Despite various therapeutic attempts, the lesions only responded to high‐dose corticosteroids. Following the initiation of ibrutinib at a daily dose of 420 mg, both the skin lesions and pruritus resolved within 3 months. Ibrutinib, a tyrosine kinase inhibitor, is approved as a first‐line treatment for CLL. However, its potential as a remedy for refractory eosinophilic dermatosis has not been reported thus far.

From Deworming to Cancer Therapy: Benzimidazoles in Hematological Malignancies.

Drug repurposing is a strategy to discover new therapeutic uses for existing drugs, which have well-established toxicity profiles and are often more affordable. This approach has gained significant attention in recent years due to the high costs and low success rates associated with traditional drug development. Drug repositioning offers a more time- and cost-effective path for identifying new treatments. Several FDA-approved non-chemotherapy drugs have been investigated for their anticancer potential. Among these, anthelmintic benzimidazoles (such as albendazole, mebendazole, and flubendazole) have garnered interest due to their effects on microtubules and oncogenic signaling pathways. Blood cancers, which frequently develop resistance and have high mortality rates, present a critical need for effective therapies. This review highlights the recent advances in repurposing benzimidazoles for blood malignancies. These compounds induce cell cycle arrest, differentiation, tubulin depolymerization, loss of heterozygosity, proteasomal degradation, and inhibit oncogenic signaling to exert their anticancer effects. We also discuss current limitations and strategies to overcome them, emphasizing the potential of combining benzimidazoles with standard therapies for improved treatment of hematological cancers.

SARS-CoV-2 Vaccination in Patients with Cancer and COVID-19 in Mexico

Objectives: Vaccination is the best preventive measure for SARS-CoV-2 infection; however, efficacy is lower in cancer patients. During the pandemic period, Mexico was characterized by the use of seven different COVID-19 vaccine platforms, and oncologic patients were not prioritized for vaccination. We report the outcomes of COVID-19 in cancer patients after the beginning of the national vaccine campaign in Mexico. Methods: All patients with cancer and COVID-19 diagnosed at Instituto Nacional de Cancerología from 14 February 2021 to 28 February 2022 were included. Primary outcomes were the proportion of individuals who required hospital admission and/or invasive mechanical ventilation, according to the vaccination status; 30-day mortality; the period of infection; and other cancer-related variables. Results: A total of 691 patients were included; 524 (76%) had solid tumors (STs), and 167 (24%) had hematologic malignancies (HMs). Patients infected in the first two periods, had lower rates of vaccination and higher rates of mortality and hospitalization compared to those infected in the Omicron period. In the multivariate analysis, vaccination status was independently associated with hospitalization in patients with STs (aOR 0.38, 95%CI 0.19–0.75, p = 0.005), but it was not associated with invasive mechanical ventilation and 30-day mortality. In those with HMs, vaccination status was not associated with any outcome; in this group, only recent chemotherapy and time of infection were associated with invasive ventilation. Conclusions: Vaccination significantly reduced hospital admissions in patients with STs. Infections occurring during the Omicron period were associated with improved outcomes in both ST and HM patients. Despite having a lesser impact in immunosuppressed patients, vaccination is an essential strategy, and access to vaccination campaigns in patients with cancer needs to be prioritized.

The Potential of Nuclear Pore Complexes in Cancer Therapy

Nuclear pore complexes (NPCs) play a critical role in regulating transport-dependent gene expression, influencing various stages of cancer development and progression. Dysregulation of nucleocytoplasmic transport has profound implications, particularly in the context of cancer-associated protein mislocalization. This review provides specific information about the relationship between nuclear pore complexes, key regulatory proteins, and their impact on cancer biology. Highlighting the influence of tumor-suppressor proteins as well as the potential of gold nanoparticles and intelligent nanosystems in cancer treatment, their role in inhibiting cell invasion is examined. This article concludes with the clinical implications of nuclear export inhibitors, particularly XPO1, as a therapeutic target in various cancers, with selective inhibitors of nuclear export compounds demonstrating efficacy in both hematological and solid malignancies. The review aims to explore the role of NPCs in cancer biology, focusing on their influence on gene expression, cancer progression, protein mislocalization, and the potential of targeted therapies such as nuclear export inhibitors and intelligent nanosystems in cancer treatment. Despite their significance and the number of research studies, the direct role of NPCs in carcinogenesis remains incompletely understood.