Integrative Prognostic Machine Learning Models in Mantle Cell Lymphoma.

Patients with mantle cell lymphoma (MCL), an incurable B-cell malignancy, benefit from accurate pretreatment disease stratification. We curated an extensive database of 862 patients diagnosed between 2014 and 2022. A machine learning (ML) gradient-boosted model incorporated baseline features from clinicopathologic, cytogenetic, and genomic data with high predictive power discriminating between patients with indolent or responsive MCL and those with aggressive disease (AUC ROC = 0.83). In addition, we utilized the gradient-boosted framework as a robust feature selection method for multivariate logistic and survival modeling. The best ML models incorporated features from clinical and genomic data types highlighting the need for correlative molecular studies in precision oncology. As proof of concept, we launched our most accurate and practical models using an application interface, which has potential for clinical implementation. We designated the 20-feature ML model-based index the "integrative MIPI" or iMIPI and a similar 10-feature ML index the "integrative simplified MIPI" or iMIPI-s. The top 10 baseline prognostic features represented in the iMIPI-s are: lactase dehydrogenase (LDH), Ki-67%, platelet count, bone marrow involvement percentage, hemoglobin levels, the total number of observed somatic mutations, TP53 mutational status, Eastern Cooperative Oncology Group performance level, beta-2 microglobulin, and morphology. Our findings emphasize that prognostic applications and indices should include molecular features, especially TP53 mutational status. This work demonstrates the clinical utility of complex ML models and provides further evidence for existing prognostic markers in MCL. Significance: Our model is the first to integrate a dynamic algorithm with multiple clinical and molecular features, allowing for accurate predictions of MCL disease outcomes in a large patient cohort.

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations.

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.

Ibrutinib-rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial.

BACKGROUND: Induction with ibrutinib and rituximab provides an opportunity to minimise chemotherapy exposure, because upfront use of these targeted therapies could result in remission without chemotherapy and allow for consolidation with only four cycles of chemotherapy instead of the conventional eight. We aimed to determine the activity and safety of ibrutinib-rituximab induction followed by shortened chemoimmunotherapy (four cycles) with rituximab plus hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-HCVAD) alternating with methotrexate-cytarabine in previously untreated patients with mantle cell lymphoma. METHODS: We did a single-centre, single-arm, phase 2 trial in previously untreated patients with mantle cell lymphoma. Eligible patients were aged 65 years or younger and had serum bilirubin of less than 1·5 mg/dL, creatinine clearance of 30 mL/min or more, Eastern Cooperative Oncology Group performance status of 2 or less, and cardiac ejection fraction 50% or more by echocardiogram. Patients received 12 cycles of ibrutinib-rituximab induction (part A; oral ibrutinib 560 mg daily and intravenous rituximab 375 mg/m2 weekly for the first 4 weeks and then on day 1 of cycles 3-12). As soon as patients had a complete response, four cycles of R-HCVAD alternating with methotrexate-cytarabine (part B) were administered. If they did not have a complete response or had a partial response, patients received two cycles of R-HCVAD alternating with methotrexate-cytarabine followed by reassessment, up to a total of eight cycles. Patients were taken off study if they had stable disease or progression during R-HCVAD. The primary outcome was the overall response rate after part A. The analyses were conducted on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT02427620. FINDINGS: 131 patients were enrolled between June 12, 2015, and Dec 6, 2018. The median age was 56 years (IQR 49-60). 58 (50%) of 117 patients had high Ki-67 (≥30%). 129 (98%, 95% CI 95-100) of 131 patients had an overall response in part A. The most common grade 3-4 adverse events were lymphocytopenia (19 [14%] of 131), skin rash (16 [12%]), thrombocytopenia (12 [9%]), infections (11 [8%]), and fatigue (ten [8%]) in part A and lymphocytopenia (96 [73%]), leukocytopenia (42 [32%]), thrombocytopenia (40 [30%]), and neutropenia (26 [20%]) in part B. There was one on-study death, which was not deemed to be treatment-related. INTERPRETATION: Induction with ibrutinib-rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. FUNDING: Pharmacyclics, Janssen.

Ibrutinib With Rituximab in First-Line Treatment of Older Patients With Mantle Cell Lymphoma.

PURPOSE: Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years). METHODS: We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed. RESULTS: The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response. CONCLUSION: IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

Longitudinal single-cell profiling reveals molecular heterogeneity and tumor-immune evolution in refractory mantle cell lymphoma.

The mechanisms driving therapeutic resistance and poor outcomes of mantle cell lymphoma (MCL) are incompletely understood. We characterize the cellular and molecular heterogeneity within and across patients and delineate the dynamic evolution of tumor and immune cell compartments at single cell resolution in longitudinal specimens from ibrutinib-sensitive patients and non-responders. Temporal activation of multiple cancer hallmark pathways and acquisition of 17q are observed in a refractory MCL. Multi-platform validation is performed at genomic and cellular levels in PDX models and larger patient cohorts. We demonstrate that due to 17q gain, BIRC5/survivin expression is upregulated in resistant MCL tumor cells and targeting BIRC5 results in marked tumor inhibition in preclinical models. In addition, we discover notable differences in the tumor microenvironment including progressive dampening of CD8+ T cells and aberrant cell-to-cell communication networks in refractory MCLs. This study reveals diverse and dynamic tumor and immune programs underlying therapy resistance in MCL.

Genetic mutations and features of mantle cell lymphoma: a systematic review and meta-analysis.

Mantle cell lymphoma (MCL) is an incurable rare subtype of non-Hodgkin lymphoma and is subject to relapse and therapeutic resistance. Molecular aberrations in MCL affect pathogenesis, prognosis, and therapeutic response. In this systematic review, we searched 3 databases and selected 32 articles that described mutations in MCL patients. We then conducted a meta-analysis using a Bayesian multiregression model to analyze patient-level data in 2127 MCL patients, including prevalence of mutations. In tumor or bone marrow samples taken at diagnosis or baseline, ATM was the most frequently mutated gene (43.5%) followed by TP53 (26.8%), CDKN2A (23.9%), and CCND1 (20.2%). Aberrations were also detected in IGH (38.4%) and MYC (20.8%), primarily through cytogenetic methods. Other common baseline mutations were NSD2 (15.0%), KMT2A (8.9%), S1PR1 (8.6%), and CARD11 (8.5%). Our data also show a change in mutational status from baseline samples to samples at disease progression and present mutations of interest in MCL that should be considered for future analysis. The genes with the highest mutational frequency difference (>5%) are TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A, and S1PR1. These findings provide a summary of the mutational landscape of MCL. The genes with the highest change in mutation frequency should be included in targeted next-generation sequencing panels for future studies. These findings also highlight the need for analysis of serial samples in MCL. Patient-level data of prevalent mutations in MCL provide additional evidence emphasizing molecular variability in advancing precision medicine initiatives in MCL.

Efficacy of venetoclax in high risk relapsed mantle cell lymphoma (MCL) - outcomes and mutation profile from venetoclax resistant MCL patients.

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.

Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL.

Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (<50%). AH-t patients have poor outcomes and distinct genomic profile. This is the first study to report that AH-MCL patients with high Ki-67 (≥50%) exhibit a distinct mutation profile and very poor survival.

Vaccination coverage among foreign-born and U.S.-born adolescents in the United States: Successes and gaps - National Immunization Survey-Teen, 2012-2014.

BACKGROUND: An overall increase has been reported in vaccination rates among adolescents during the past decade. Studies of vaccination coverage have shown disparities when comparing foreign-born and U.S.-born populations among children and adults; however, limited information is available concerning potential disparities in adolescents. METHODS: The National Immunization Survey-Teen is a random-digit-dialed telephone survey of caregivers of adolescents aged 13-17 years, followed by a mail survey to vaccination providers that is used to estimate vaccination coverage among the U.S. population of adolescents. Using the National Immunization Survey-Teen data, we assessed vaccination coverage during 2012-2014 among adolescents for routinely recommended vaccines for this age group (≥1 dose tetanus and diphtheria toxoids and acellular pertussis [Tdap] vaccine, ≥1 dose quadrivalent meningococcal conjugate [MenACWY] vaccine, ≥3 doses human papillomavirus [HPV] vaccine) and for routine childhood vaccination catch-up doses (≥2 doses measles, mumps, and rubella [MMR] vaccine, ≥2 doses varicella vaccine, and ≥3 doses hepatitis B [HepB] vaccine). Vaccination coverage prevalence and vaccination prevalence ratios were estimated. RESULTS: Of the 58,090 respondents included, 3.3% were foreign-born adolescents. Significant differences were observed between foreign-born and U.S.-born adolescents for insurance status, income-to-poverty ratio, education, interview language, and household size. Foreign-born adolescents had significantly lower unadjusted vaccination coverage for HepB (89% vs. 93%), and higher coverage for the recommended ≥3 doses of HPV vaccine among males, compared with U.S.-born adolescents (22% vs. 14%). Adjustment for demographic and socioeconomic factors accounted for the disparity in HPV but not HepB vaccination coverage. CONCLUSIONS: We report comparable unadjusted vaccination coverage among foreign-born and U.S.-born adolescents for Tdap, MenACWY, MMR, ≥2 varicella. Although coverage was high for HepB vaccine, it was significantly lower among foreign-born adolescents, compared with U.S.-born adolescents. HPV and ≥2-dose varicella vaccination coverage were low among both groups.

Thrombosis associated with ventriculoatrial shunts.

OBJECT: In this single-center study, the authors examined the clinical characteristics, risk factors, treatment strategies, and outcomes in patients with thrombosis associated with ventriculoatrial (VA) shunts. METHODS: Inpatient and outpatient charts of patients who underwent treatment and follow-up in the Hematology-Oncology Division at the authors' institution and in whom thrombosis developed secondary to a VA shunt placement were reviewed. A complete thrombophilia work-up was performed in each patient, and these records were also reviewed. Treatment including medical and surgical management was noted and outcome data were recorded. RESULTS: Resolution of thrombosis was seen after anticoagulation therapy in all patients; this may be an alternative to surgical therapy. CONCLUSIONS: Patients with VA shunts represent a unique group at risk for thrombosis. The duration of anticoagulation therapy must be individualized. However, larger studies are needed to evaluate the efficacy of screening for asymptomatic thrombosis and to investigate the role of prophylactic anticoagulation.

The neurosurgical workforce in North America: a critical review of gender issues.

OBJECTIVE: The role of women in Western society has changed dramatically in the past several decades. Despite this, many gender disparities still exist for professionals in the health care sector. In neurosurgery, a disproportionately small percentage of the workforce in the United States and Canada is female. These figures are lower than most reported in other medical specialties. This review critically examines factors that may be influencing women's ability to advance in demanding subspecialties such as neurosurgery. METHODS: The literature on women in medicine, and surgery in particular, were reviewed to identify different issues facing women currently in practice in neurosurgery. In addition, the concerns of prospective trainees were examined. RESULTS: There remain many challenges for women entering neurosurgery, including unique lifestyle concerns, limited mentorship, out-dated career programs, and deep-seeded societal beliefs. Discrimination and harassment are also contributing factors. CONCLUSION: If neurosurgery is to continue to progress as a subspecialty, the issue of gender inequality needs to be scrutinized more closely. Innovative programs must be developed to meet the needs of current female faculty members and to ensure attracting the brightest individuals of both genders into a career in neurosurgery.

Response of GAP-43 and p75 in human neuromas over time after traumatic injury.

OBJECTIVE: GAP-43 and p75 are proteins that promote growth cone and neurite formation, elongation, and arborization in regenerating nerve axons. The objectives of this study were to determine whether GAP-43 and the low-affinity nerve growth factor receptor p75 are elevated in traumatic neuromas and whether there is a correlation between the relative amount of GAP-43 or p75 and demographic characteristics such as time elapsed between injury and repair. METHODS: Traumatic neuromas from 21 randomly selected patients were studied, and the charts were reviewed. Specimens were collected at the time of nerve resection and grafting. Immunohistochemical analysis was performed on each sample and normal human nerve with antibodies to GAP-43 and p75. Western blot and computerized gel analyses were performed. RESULTS: All neuroma specimens harvested within 13 months of injury exhibited markedly elevated GAP-43 levels compared with normal nerve. Specimens harvested at 14 months or more after injury showed precipitously lower GAP-43 levels, similar to or less than those of normal nerve. The correlation between the amount of intra-axonal GAP-43 and postinjury time interval was statistically significant, P = 0.0038. High GAP-43 levels were also correlated with transection injury, high postoperative sensory grade, and pain. p75 levels were elevated, without consistent variation in our population. CONCLUSION: These preliminary data suggest that the expression of intra-axonal GAP-43 may vary over time after injury, remaining elevated for approximately the first year, then decreasing abruptly to normal or subnormal levels. These results correlate with clinical experience, indicating that peripheral nerves should be repaired relatively early if repair is indicated.