Virtual multi-institutional tumor board: a strategy for personalized diagnoses and management of rare CNS tumors.

PURPOSE: Multidisciplinary tumor boards (MTBs) integrate clinical, molecular, and radiological information and facilitate coordination of neuro-oncology care. During the COVID-19 pandemic, our MTB transitioned to a virtual and multi-institutional format. We hypothesized that this expansion would allow expert review of challenging neuro-oncology cases and contribute to the care of patients with limited access to specialized centers. METHODS: We retrospectively reviewed records from virtual MTBs held between 04/2020-03/2021. Data collected included measures of potential clinical impact, including referrals to observational or therapeutic studies, referrals for specialized neuropathology analysis, and whether molecular findings led to a change in diagnosis and/or guided management suggestions. RESULTS: During 25 meetings, 32 presenters discussed 44 cases. Approximately half (n = 20; 48%) involved a rare central nervous system (CNS) tumor. In 21% (n = 9) the diagnosis was changed or refined based on molecular profiling obtained at the NIH and in 36% (n = 15) molecular findings guided management. Clinical trial suggestions were offered to 31% (n = 13), enrollment in the observational NCI Natural History Study to 21% (n = 9), neuropathology review and molecular testing at the NIH to 17% (n = 7), and all received management suggestions. CONCLUSION: Virtual multi-institutional MTBs enable remote expert review of CNS tumors. We propose them as a strategy to facilitate expert opinions from specialized centers, especially for rare CNS tumors, helping mitigate geographic barriers to patient care and serving as a pre-screening tool for studies. Advanced molecular testing is key to obtaining a precise diagnosis, discovering potentially actionable targets, and guiding management.

Critical Appraisal of Proton Therapy for Patients with Central Nervous System (CNS) Malignancies.

OPINION STATEMENT: As more hospital-based proton treatment centres become operational, the indications for proton beam therapy (PBT) are being evaluated. Recent advances in PBT technology are expanding the indications for the use of protons in the treatment of central nervous system (CNS) tumours. Prospective trials that assess the late toxicity of different radiation therapy (RT) techniques are needed to confirm any expected reduction in long-term side effects with PBT. The ASTRO Model Policy on proton beam therapy currently supports the reasonable use of protons in the treatment of specific CNS tumour types. Specifically, PBT plays a key role in the management of CNS tumours where anatomy, extent of disease or previous treatment cannot be satisfactorily addressed with conventional RT. As the availability of PBT rises around the world, the number of patients with CNS disease treated with PBT will continue to grow.

A Bayesian dose-finding design for outcomes evaluated with uncertainty.

INTRODUCTION: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. METHODS: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. RESULTS: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. CONCLUSION: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma.

BACKGROUND AND PURPOSE: We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era. MATERIALS AND METHODS: Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66-81 Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression. RESULTS: Median follow-up was 23 months (95% CI 4-124 months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4 months (95% CI 7.3-11.0) and OS was 18.7 months (95% CI 13.1-25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93-0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16-0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16-0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09-0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival. CONCLUSION: Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression.

NRG brain tumor specialists consensus guidelines for glioblastoma contouring.

INTRODUCTION: NRG protocols for glioblastoma allow for clinical target volume (CTV) reductions at natural barriers; however, literature examining CTV contouring and the relevant white matter pathways is lacking. This study proposes consensus CTV guidelines, with a focus on areas of controversy while highlighting common errors in glioblastoma target delineation. METHODS: Ten academic radiation oncologists specializing in brain tumor treatment contoured CTVs on four glioblastoma cases. CTV expansions were based on NRG trial guidelines. Contour consensus was assessed and summarized by kappa statistics. A meeting was held to discuss the mathematically averaged contours and form consensus contours and recommendations. RESULTS: Contours of the cavity plus enhancement (mean kappa 0.69) and T2-FLAIR signal (mean kappa 0.74) showed moderate to substantial agreement. Experts were asked to trim off anatomic barriers while respecting pathways of spread to develop their CTVs. Submitted CTV_4600 (mean kappa 0.80) and CTV_6000 (mean kappa 0.81) contours showed substantial to near perfect agreement. Simultaneous truth and performance level estimation (STAPLE) contours were then reviewed and modified by group consensus. Anatomic trimming reduced the amount of total brain tissue planned for radiation targeting by a 13.6% (range 8.7-17.9%) mean proportional reduction. Areas for close scrutiny of target delineation were described, with accompanying recommendations. CONCLUSIONS: Consensus contouring guidelines were established based on expert contours. Careful delineation of anatomic pathways and barriers to spread can spare radiation to uninvolved tissue without compromising target coverage. Further study is necessary to accurately define optimal target volumes beyond isometric expansion techniques for individual patients.

Characterization and validation of an intra-fraction motion management system for masked-based radiosurgery.

PURPOSE: Characterize the intra-fraction motion management (IFMM) system found on the Gamma Knife Icon (GKI), including spatial accuracy, latency, temporal performance, and overall effect on delivered dose. METHODS: A phantom was constructed, consisting of a three-axis translation mount, a remote motorized flipper, and a thermoplastic sphere surrounding a radiation detector. An infrared marker was placed on the translation mount secured to the flipper. The spatial accuracy of the IFMM was measured via the translation mount in all Cartesian planes. The detector was centered at the radiation focal point. A remote signal was used to move the marker out of the IFMM tolerance and pause the beam. A two-channel electrometer was used to record the signals from the detector and the flipper when motion was signaled. These signals determined the latency and temporal performance of the GKI. RESULTS: The spatial accuracy of the IFMM was found to be <0.1 mm. The measured latency was <200 ms. The dose difference with five interruptions was <0.5%. CONCLUSION: This work provides a quantitative characterization of the GKI IFMM system as required by the Nuclear Regulatory Commission. This provides a methodology for GKI users to satisfy these requirements using common laboratory equipment in lieu of a commercial solution.

Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma.

Disulfiram has shown promising activity including proteasome inhibitory properties and synergy with temozolomide in preclinical glioblastoma (GBM) models. In a phase I study for newly diagnosed GBM after chemoradiotherapy, we have previously reported our initial dose-escalation results combining disulfiram with adjuvant temozolomide and established the maximum tolerated dose (MTD) as 500 mg per day. Here we report the final results of the phase I study including an additional dose-expansion cohort of disulfiram with concurrent copper. The phase I study consisted of an initial dose-escalation phase of disulfiram 500-1000 mg daily during adjuvant temozolomide, followed by a dose-expansion phase of disulfiram 500 mg daily with copper 2 mg three times daily. Proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cell. A total of 18 patients were enrolled: 7 patients received 500 mg disulfiram, 5 patients received 1000 mg disulfiram, and 6 patients received 500 mg disulfiram with copper. Two dose-limiting toxicities occurred with 1000 mg disulfiram. At disulfiram 500 mg with or without copper, only 1 patient (7%) required dose-reduction during the first month of therapy. Addition of copper to disulfiram did not increase toxicity nor proteasome inhibition. The median progression-free survival was 4.5 months (95% CI 0.8-8.2). The median overall survival (OS) was 14.0 months (95% CI 8.3-19.6), and the 2-year OS was 24%. The MTD of disulfiram at 500 mg daily in combination with adjuvant temozolomide was well tolerated by GBM patients, but 1000 mg daily was not. Toxicity and pharmacodynamic effect of disulfiram were similar with or without concurrent copper. The clinical efficacy appeared to be comparable to historical data. Additional clinical trials to combine disulfiram and copper with chemoradiotherapy or to resensitize recurrent GBM to temozolomide are ongoing.

Standard dose and dose-escalated radiation therapy are associated with favorable survival in select elderly patients with newly diagnosed glioblastoma.

We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan-Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60-100) and median age was 67 years (range 60-81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9-11.0) and OS was 12.7 months (95% CI 9.7-14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8-0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1-0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3-0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment.

Analysis of point mutations and copy number variation in Grade II and III meningioma.

Meningiomas are among the most common tumors of the adult central nervous system (CNS). They are classified by the World Health Organization into three pathologic grades with increasing severity: grade I are benign with favorable treatment outcomes and low recurrence rates while grade III display malignant behavior and poor progression-free survival. Previous studies have shown that inactivation of NF-2 is the most common genetic event in high-grade meningioma; however, there is dearth of molecular data to distinguish grade II (AM-II) from the even more aggressive grade III (AM-III). As part of a routine diagnostic workup, 19 AM-II and 5 AM-III were submitted for targeted sequencing on a panel of twenty-four genes relevant to CNS tumors. The data generated during the course of clinical care was collected and re-analyzed with the aim of identifying molecular features to distinguish AM-II and AM-III. Our cases contained several well-characterized, potentially actionable mutations, but we did not find any novel, recurrent sequence variants. Copy number variations were common in both AM-II and AM-III; chr22q loss was the most prevalent followed in decreasing frequency by losses of chr1p, chr14q, and chr10. In particular, chr10 loss was noted in 4 of 5 AM-III cases but none of the AM-II cases. This suggests that chr10 loss may serve as a diagnostic and perhaps a prognostic marker to differentiate AM-II from AM-III. If confirmed in larger studies, our finding could further aid the classification of meningioma.

Completion of Gamma Knife radiosurgery for AVM treatment after unplanned interruption-technical note.

BACKGROUND AND IMPORTANCE: Gamma Knife radiosurgery is an established technique for non-urgent treatment of various intracranial pathologies. Intra-procedural dislodgement of the stereotactic frame is an uncommon occurrence that could lead to abortion of ongoing treatment and necessitate more invasive treatment strategies. CLINICAL PRESENTATION: In this case report, we describe a novel method for resumption of Gamma Knife treatment after an unplanned intra-procedural interruption. The case example involves a radiosurgical treatment of a Spetzler-Martin grade I arteriovenous malformation. CONCLUSION: Our technique involves integration of scans and coordinate systems from two imaging sessions using the composite isodose line to resolve translational differences, thereby limiting delivery of remaining shots to the untreated region of the lesion. MRI follow-up at 13 months showed a reduction in the nidus size with no evidence of any radiation injury to the surrounding brain parenchyma. We believe this technique will allow care teams to effectively salvage interrupted Gamma Knife procedures and reduce progression to more invasive treatment options.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

The evolving role for re-irradiation in the management of recurrent grade 4 glioma.

Although significant gains have been realized in the management of grade 4 glioma, the majority of these patients will ultimately suffer local recurrence within the prior field of treatment. Clearly, novel local treatment strategies are required to improve patient outcomes. Concerns of toxicity have limited enthusiasm for the utilization of re-irradiation as a treatment option. However, using modern imaging technology and precision radiotherapy delivery techniques re-irradiation has proven a feasible option achieving both a palliative benefit and prolongation of survival with low toxicity rates. The evolution of re-irradiation as a treatment modality for recurrent grade 4 glioma is reviewed. In addition, potential targeted radiosensitizers to be used in conjunction with re-irradiation are also discussed.

Impact of concurrent chemotherapy with radiation therapy for elderly patients with newly diagnosed glioblastoma: a review of the National Cancer Data Base.

To investigate the utilization and overall survival (OS) impact of concurrent chemotherapy in combination with radiation therapy (RT) for elderly glioblastoma (GBM) patients. Elderly patients (age >70) with supratentorial and nonmetastatic GBM who received RT of 20-75 Gy with concurrent single-agent chemotherapy (ChemoRT) or without (RT alone) during 2004-2012 were identified from the National Cancer Data Base (NCDB). The Cochran-Armitage test was used for trend analysis. Hazard ratios (HR) and 95% confidence intervals (CIs) were determined using Cox proportional hazards. Propensity score analysis was performed to reduce selection bias in treatment allocation. A total of 5252 patients were identified (RT alone: n = 1389; ChemoRT: n = 3863). There was increasing utilization of chemotherapy during this period (45-80%, P < .001). A similar trend was also observed for the subset of age >80 (25-68%, P < .001). ChemoRT was associated with significantly better OS than RT alone (HR 0.79, 95% CI 0.70-0.89, P < .001) on multivariate analysis, and similar OS benefit was demonstrated with 1202 pairs of propensity-matched patients (HR 0.79, 95% CI 0.73-0.86, P < .001). For the matched pair, the median OS was 5.8 months with ChemoRT and 5.0 months with RT alone; the 2-year OS rate was 9% with ChemoRT and 4% with RT alone (P < .001). Concurrent chemotherapy has been administered with RT for the majority of elderly GBM patients. Addition of chemotherapy to RT for elderly GBM patients is associated with significantly improve OS in routine clinical practice.

Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation.

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4-12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased (P < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment (P < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.

A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy.

Disulfiram, a generic alcohol aversion drug, has promising preclinical activity against glioblastoma (GBM). This phase I study aims to evaluate its safety, maximum tolerated dose (MTD), pharmacodynamic effect, and preliminary efficacy when combined with adjuvant temozolomide in GBM patients after standard chemoradiotherapy. Patients received disulfiram 500-1000 mg once daily, in combination with 150-200 mg/m(2) temozolomide. A modified 3 + 3 dose-escalation design was used to determine the MTD. The pharmacodynamic effect of proteasome inhibition was assessed using fluorometric 20S proteasome assay on peripheral blood cells. The MTD was determined based on the dose-limiting toxicities (DLTs) within the first month of therapy. Twelve patients were enrolled to two dose levels: 500 and 1000 mg. Two DLTs of grade 3 delirium occurred after 15 days of administration at 1000 mg per day. Other possible grade 2-3 DSF-related toxicities included fatigue, ataxia, dizziness, and peripheral neuropathy. The toxicities were self-limiting or resolved after discontinuing DSF. The MTD was determined to be 500 mg per day. Limited proteasome inhibition was observed at week 4 and showed an increased trend with escalated disulfiram. Median progression-free survival with 500 mg of DSF was 5.4 months from the start of disulfiram and 8.1 months from the start of chemoradiotherapy. Disulfiram can be safely combined with temozolomide but can cause reversible neurological toxicities. The MTD of disulfiram with adjuvant temozolomide appears to produce limited proteasome inhibition on peripheral blood cells.

Molecular and histologic characteristics of pseudoprogression in diffuse gliomas.

During the 6 month period following chemoradiotherapy, gliomas frequently develop new areas of contrast enhancement, which are due to treatment effect rather than tumor progression. We sought to characterize this phenomenon in oligodendrogliomas (OG) and mixed oligoastrocytomas (MOA). We reviewed the imaging findings from 143 patients with a WHO grade II or III OG or MOA for evidence of pseudoprogression (PsP) or early tumor progression. We characterized these cases for 1p/19q codeletions by FISH, IDH1 R132H mutation by immunohistochemistry, and TP53, ATRX, and EGFR mutations by next generation sequencing. We then reviewed the pathologic specimens of the patient cases in which a re-resection was performed. We found that OG and MOA that are 1p/19q intact developed PsP at a higher rate than tumors that are 1p/19q codeleted (27 vs. 8 %). Moreover, IDH1 wild-type (WT) tumors developed PsP at a higher rate than IDH1 R132H cases (27 vs. 11 %). Patients with ATRX or TP53 mutations developed PsP at an intermediate rate of 21 %. Ten patients in our cohort underwent a re-resection for early contrast enhancement; these tumors were predominantly 1p/19q intact (90 %) and had a low rate of IDH1 R132H mutation (50 %). 8 of 10 tumors demonstrated primarily treatment effects, while the remaining 2 of 10 demonstrated recurrent/residual tumor of the same grade. Early contrast enhancement that develops during the first 6 months after chemoradiotherapy is typically due to PsP and occurs primarily in OG and MOA that are 1p/19q intact and IDH WT.

Hodgkin lymphoma, version 2.2015.

Hodgkin lymphoma (HL) is an uncommon malignancy involving lymph nodes and the lymphatic system. Classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant Hodgkin lymphoma are the 2 main types of HL. CHL accounts for most HL diagnosed in the Western countries. Chemotherapy or combined modality therapy, followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale), is the standard initial treatment for patients with newly diagnosed CHL. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, has produced encouraging results in the treatment of relapsed or refractory disease. The potential long-term effects of treatment remain an important consideration, and long-term follow-up is essential after completion of treatment.

Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

Imaging Advances in Stereotactic Radiosurgery.

Novel functional and metabolic MRI imaging provides the ability to analyze tumor tissue properties including tumor vasculature, vascular permeability, tumor cellularity, hypoxia, and tumor proliferation. Stereotactic radiosurgery involves the delivery of a very precise, focal dose of radiation to a target. Recent advances in MR imaging have the potential to improve accuracy for target volume delineation and to potentially improve outcome. Novel MR imaging techniques may also be used in subsequent post-treatment follow-up to distinguish between tumor recurrences versus non-neoplastic treatment-related changes. In this paper, we address multiparametric MR imaging and cerebral angiography as tools to reduce toxicity.

Non-Hodgkin's lymphomas, version 4.2014.

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.