Rare Case of Cryptococcal Meningitis in Non-HIV Patient with Mantle Cell Lymphoma Associated with Acalabrutinib (Tyrosine Kinase Inhibitor)

Cryptococcus neoformans infections are more common among immunosuppressed individuals, causing the most widespread opportunistic CNS infection among HIV-positive patients [1]. Specifically, those with cellular immunosuppression, such as patients with HIV positive CD4 counts less than 100. When a patient presents with atypical symptoms, it can be difficult to diagnose due to its infrequent presentation in HIV negative patients. Due to the rarity of encounters in HIV-negative patients, when atypical symptoms are present, it poses a diagnostic challenge. Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin B-cell lymphoma that is known to be associated with cellular immunosuppression [2]. This demonstrates the need for early diagnosis and recognition of cryptococcal infections and as a physician should be vigilant to diagnose cryptococcal who is on Acalabrutinib with MCL [3]. CLL patients receiving ibrutinib should be evaluated for cryptococcal infection, which is potentially life threatening if overlooked [4]. Meningitis caused by Cryptococcus mainly presents with fever and altered mental status but in this case, our patient 78-year-old male with mantle cell lymphoma, undergoing a regimen of Rituximab-Bendamustine (BR) in combination with acalabrutinib (TKI), presented with hypotension to ED in June 2021. Cryptococcal infection in patient receiving ibrutinib were mostly reported in patients with Chronic lymphocytic leukemia, who have poor immune reconstitution. Here we are reporting case of cryptococcal meningoencephalitis in patient with MCL on acalabrutinib which is never reported before.

Combinatorial inhibition of BTK, PI3K-AKT and BRD4-MYC as a strategy for treatment of mantle cell lymphoma

Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin’s lymphoma characterized by poor prognosis. The complexity of MCL pathogenesis arises from aberrant activities of diverse signaling pathways, including BTK, PI3K–AKT–mTOR and MYC-BRD4. Here, we report that MCL-related signaling pathways can be altered by a single small molecule inhibitor, SRX3305. Binding and kinase activities along with resonance changes in NMR experiments reveal that SRX3305 targets both bromodomains of BRD4 and is highly potent in inhibition of the PI3K isoforms α, γ and δ, as well as BTK and the drug-resistant BTK mutant. Preclinical investigations herein reveal that SRX3305 perturbs the cell cycle, promotes apoptosis in MCL cell lines and shows dose dependent anti-proliferative activity in both MCL and drug-resistant MCL cells. Our findings underscore the effectiveness of novel multi-action small molecule inhibitors for potential treatment of MCL.

Artificial Intelligence Analysis of Gene Expression Predicted the Overall Survival of Mantle Cell Lymphoma and a Large Pan-Cancer Series

Mantle cell lymphoma (MCL) is a subtype of mature B-cell non-Hodgkin lymphoma characterized by a poor prognosis. First, we analyzed a series of 123 cases (GSE93291). An algorithm using multilayer perceptron artificial neural network, radial basis function, gene set enrichment analysis (GSEA), and conventional statistics, correlated 20,862 genes with 28 MCL prognostic genes for dimensionality reduction, to predict the patients’ overall survival and highlight new markers. As a result, 58 genes predicted survival with high accuracy (area under the curve = 0.9). Further reduction identified 10 genes: KIF18A, YBX3, PEMT, GCNA, and POGLUT3 that associated with a poor survival; and SELENOP, AMOTL2, IGFBP7, KCTD12, and ADGRG2 with a favorable survival. Correlation with the proliferation index (Ki67) was also made. Interestingly, these genes, which were related to cell cycle, apoptosis, and metabolism, also predicted the survival of diffuse large B-cell lymphoma (GSE10846, n = 414), and a pan-cancer series of The Cancer Genome Atlas (TCGA, n = 7289), which included the most relevant cancers (lung, breast, colorectal, prostate, stomach, liver, etcetera). Secondly, survival was predicted using 10 oncology panels (transcriptome, cancer progression and pathways, metabolic pathways, immuno-oncology, and host response), and TYMS was highlighted. Finally, using machine learning, C5 tree and Bayesian network had the highest accuracy for prediction and correlation with the LLMPP MCL35 proliferation assay and RGS1 was made. In conclusion, artificial intelligence analysis predicted the overall survival of MCL with high accuracy, and highlighted genes that predicted the survival of a large pan-cancer series.

Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial

PURPOSE The need for an individualized management of indolent clinical forms in mantle cell lymphoma (MCL) is increasingly recognized. We hypothesized that a tailored treatment with ibrutinib in combination with rituximab (IR) could obtain significant responses in these patients. METHODS This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 12 Spanish GELTAMO sites (ClinicalTrials.gov identifier: NCT02682641 ). Previously untreated MCL patients with indolent clinical forms defined by the following criteria were eligible: no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. Both leukemic non-nodal and nodal subtypes were recruited. Patients received ibrutinib 560 mg once daily and a total of eight doses of rituximab 375 mg/m2. Ibrutinib could be discontinued after 2 years in the case of sustained undetectable minimal residual disease (MRD). The primary end point was the complete response (CR) rate achieved after 12 cycles according to Lugano criteria. RESULTS Fifty patients with MCL (male 66%; median age 65 years) were enrolled. After 12 cycles of treatment, 42 (84%; 95% CI, 74 to 94) patients had an overall response, including 40 (80%; 95% CI, 69 to 91) with CR. Moreover, undetectable MRD in peripheral blood was achieved in 87% (95% CI, 77 to 97) of cases. At 2 years, 24 of 35 evaluable patients (69%) could discontinue ibrutinib because of undetectable MRD. Four patients had disease progression; three were non-nodal MCL and carried high genomic complexity and TP53 mutations at enrollment. No unexpected toxicity was seen except one patient with severe aplastic anemia. CONCLUSION Frontline IR combination achieves a high rate of CRs and undetectable MRD in indolent clinical forms of MCL. Discontinuation seems appropriate in cases with undetectable MRD, except for TP53-mutated cases.

Longitudinal CT Imaging to Explore the Predictive Power of 3D Radiomic Tumour Heterogeneity in Precise Imaging of Mantle Cell Lymphoma (MCL)

The study’s primary aim is to evaluate the predictive performance of CT-derived 3D radiomics for MCL risk stratification. The secondary objective is to search for radiomic features associated with sustained remission. Included were 70 patients: 31 MCL patients and 39 control subjects with normal axillary lymph nodes followed over five years. Radiomic analysis of all targets (n = 745) was performed and features selected using the Mann Whitney U test; the discriminative power of identifying “high-risk MCL” was evaluated by receiver operating characteristics (ROC). The four radiomic features, “Uniformity”, “Entropy”, “Skewness” and “Difference Entropy” showed predictive significance for relapse (p < 0.05)—in contrast to the routine size measurements, which showed no relevant difference. The best prognostication for relapse achieved the feature “Uniformity” (AUC-ROC-curve 0.87; optimal cut-off ≤0.0159 to predict relapse with 87% sensitivity, 65% specificity, 69% accuracy). Several radiomic features, including the parameter “Short Axis,” were associated with sustained remission. CT-derived 3D radiomics improves the predictive estimation of MCL patients; in combination with the ability to identify potential radiomic features that are characteristic for sustained remission, it may assist physicians in the clinical management of MCL.

Chronic aseptic meningitis caused by enterovirus in a humorally immunosuppressed adult patient presenting with sensorineural hearing loss: a case report

Background Enterovirus has been described as a cause of aseptic meningitis in humorally immunosuppressed patients. Case presentation A 67-year-old female with a history of mantle cell lymphoma on rituximab therapy presented with subacute hepatitis, myalgias, and sensorineural hearing loss several months after an initial febrile illness. She was diagnosed with enterovirus infection by CSF PCR as a unifying etiology of her presentation, representing an unusual presentation of disease. Discussion and conclusions This patient’s unique presentation and clinical course presents important implications in the care of similarly immunosuppressed patients with cryptic complaints.

Initial Treatment Patterns and Survival Outcomes of Mantle Cell Lymphoma Patients Managed at Chinese Academic Centers in the Rituximab Era: A Real-World Study

PurposeThe aim of the study was to delineate the disease characteristics, the initial treatment patterns, and survival in patients with mantle cell lymphoma (MCL) managed in the real world.MethodsData of 518 MCL patients from 5 major Chinese Hematology Centers in the period from 2007 to 2017 were retrospectively analyzed.ResultsThe median age was 58 years. Of the patients, 88.6% had Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1 and 80.7% had advanced-stage disease. Ki67 expression was &lt;30% in 39.6% of the patients, and 43.2% of patients were categorized into a low-risk group based on the Mantle Cell Lymphoma International Prognostic Index (MIPI) scoring system. Overall, 73.4% of the patients received rituximab as their first-line therapy. The most commonly used chemotherapy was the CHOP-like (cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone) regimen (45.2%), followed by high-dose cytarabine-containing chemotherapy (31.3%) and bendamustine (3.3%). Of the patients, 13.7% (n = 71) underwent consolidative autologous stem cell transplantation (ASCT), and 19.3% (n = 100) received novel agents containing first-line regimens. With a median follow-up time of 52 months, the 3- and 5-year overall survival (OS) rates were 73.7% and 61.4%, respectively. Age ≤60 years, ECOG PS 0–1, stages I–II, normal lactate dehydrogenase (LDH), absence of bone marrow involvement, Ki67 &lt;30%, and lower-risk IPI/MIPI scores were significantly associated with improved OS (p &lt; 0.05). The inclusion of rituximab improved the 5-year OS, with borderline significance (62.5% vs. 55.2%, p = 0.076). High-dose cytarabine-containing chemotherapy showed significant clinical benefit in 5-year OS (72.1% vs. 55.9%, p = 0.010). Patients with ASCT had better 5-year OS in the younger (≤60 years) age group (87.2% vs. 64.8%, p = 0.002).ConclusionThis large retrospective dataset unequivocally confirmed the survival advantage afforded by cytarabine-containing regimen and ASCT in a first-line setting under real-world management in the rituximab era.