Mantle Cell Lymphoma Cohort Research Articles

Clinical and biological impact of SAMHD1 expression in mantle cell lymphoma

SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase (dNTPase) that restricts viral replication in infected cells and limits the sensitivity to cytarabine by hydrolysing its active metabolite, as recently shown in acute myeloid leukemia. Cytarabine is an essential component in the Nordic mantle cell lymphoma protocols (MCL2 and MCL3) for induction and high-dose chemotherapy treatment before autologous stem cell transplantation for younger patients with mantle cell lymphoma (MCL). We here investigated the expression of SAMHD1 in a population-based cohort of MCL (N = 150). SAMHD1 was highly variably expressed in MCL (range, 0.4% to 100% of positive tumor cells). Cases with blastoid/pleomorphic morphology had higher SAMHD1 expression (P = 0.028) and SAMHD1 was also correlated to tumor cell proliferation (P = 0.016). SAMHD1 expression showed moderate correlation to the expression of the transcriptional regulator SOX11 (P = 0.036) but genetic silencing of SOX11 and SAMHD1 by siRNA in MCL cell lines did not suggest mutual regulation. We hypothesized that expression of SAMHD1 could predict short time to progression in patients treated with Cytarabine as part of high-dose chemotherapy. Despite the correlation with known biological adverse prognostic factors, neither low or high SAMHD1 expression correlated to PFS or OS in patients treated according to the Nordic MCL2 or MCL3 protocols (N = 158).

The Role of Upfront Autologous Hematopoietic Cell Transplantation in the Treatment of Mantle Cell Lymphoma, a Population Based Study Using the National Cancer Data Base (NCDB)

Introduction: There are no prospective randomized data supporting the use of upfront consolidative autologous stem cell transplant (ASCT) in newly diagnosed mantle cell lymphoma (MCL) patients (pts). The aim of this population-based study in MCL pts is to better define the impact of frontline ASCT on overall survival (OS), and to identify factors influencing treatment selection.Methods: Using the National Cancer Data Base (NCDB), we identified pts with newly diagnosed MCL treated from 2004-2012 with multi-agent chemo alone or in combination with consolidative ASCT as part of first line treatment. Univariable and multivariable Cox proportional hazards regression analyses were used to identify predictors for treatment selection and OS, including age, gender, race, stage, Charlson-Deyo comorbidity index (CDCI), income, education, insurance, treatment facility type, distance to treatment facility and year of diagnosis. Income was recorded as quartiles of median annual household income and education as percentage of persons with less than high school education in pts' residence census. Including these same factors, a propensity score matched analysis (PSMA) was performed to further account for confounding variables.Results: We identified 16,035 MCL pts with known survival times. The following groups were excluded: no chemo (n=3,193), chemo status/type unknown (n=1,056), chemo contraindicated (n=199), single-agent chemo (n=983), received allogeneic SCT (n=79) or ASCT data missing (n=235). The final analysis included 10,290 pts. Median age was 65 years (range 20-90); 66% were > 60 years, 73% male, 93% Caucasian, and 78% had stage III-IV. CDCI was 0 in 79%, 1 in 16% and ≥2 in 5%. Forty percent of pts were treated at academic institutions and 49% travelled >11.5 miles to receive treatment. Medicare was the most common insurance type (48%), followed by private (43%) and Medicaid (4%). Median follow up was 34 months (interquartile range (IQR) 16-60). Median OS for the entire cohort was 64 months; 5- and 10-year OS rates were 52% and 33%, respectively. Seventeen percent of the pts (n=1774) underwent upfront ASCT, and there was a trend of increased use from 2004-2012 (11.9% in 2004 and 21.2% in 2012) that resulted in an annual increase of 1.2% (p<0.001). 31% of pts ≤60 and 25% of pts ≤70 years received ASCT. For the ASCT group, median age was 58 years (IQR 52-64; range 23-77); 89 pts (5%) were ≥70 years of age. Predictors for ASCT use included (p<0.001 for each): stage III-IV (odds ratio (OR) 2.4), having private insurance (OR 2.71), higher education (OR 2.1), no transition of care (diagnosis and treatment done at the same facility) (OR 3.15), longer distance (> 11.5 miles) to treatment facility (OR 1.73) and year of diagnosis ≥2009 (OR 1.62) (Figure 1). Median follow up was 44 months (IQR 28-69) for ASCT group and 31 months (IQR 14-58) for chemo only group. Five and 10-year OS rates for ASCT and chemo group were 77%, 57%, 47% and 28%, respectively. After adjusting for other covariates, the use of ASCT was associated with superior OS (HR: 0.46; 95% CI 0.41-0.52; p<0.001). Other factors associated with superior OS were: female gender (HR 0.92, p=0.01), income (HR 0.92, p<0.001), private insurance (HR 0.71, p<0.001), no transition of care (HR 0.82, p<0.001) and diagnosis year ≥2009 (HR 0.91, p=0.005). Predictors for inferior OS were: age >60 (HR 1.62, p<0.001), African American race (HR 1.23, p=0.009), stage III-IV (HR 1.58, p<0.001) and CDCI ≥2 (HR 2.0, p<0.001). Using a subset of 1582 pts treated with ASCT and 1582 matched controls treated with chemo only, PSMA confirmed the OS benefit associated with ASCT (HR 0.5; CI 0.44-0.57, p<0.001). This OS benefit was observed in both younger (≤60 years: HR 0.44, CI 0.37-0.53, p<0.001) and older pts (>60 years: HR 0.59, CI 0.46-0.68; p<0.001) (Figure 2).Conclusion: In this large MCL cohort, the use of upfront consolidative ASCT was associated with superior OS when compared to chemo alone. Less than one third of young MCL pts treated with multi-agent chemo received consolidative ASCT, and this was influenced by sociodemographic factors with patterns favoring pts with higher education and private insurance. While one caveat in interpreting this retrospective study is that ASCT may have been preferentially applied to pts who responded to induction therapy, these data suggest clinical efficacy of ASCT in MCL. Prospective randomized trials are needed for further validation. [Display omitted] DisclosuresMajhail:Sanofi: Honoraria; Anthem, Inc.: Consultancy.

Targeted genomic investigations in a population-based cohort of mantle cell lymphoma reveal novel clinically relevant targets

Mantle cell lymphoma (MCL) is an aggressive B-cell neoplasm that follows a heterogeneous clinical course. Recurrent mutations have been described, but their applicability in the clinical setting is currently limited. The main reasons are challenges in the sequencing of DNA retrieved from formalin-fixed tissue commonly used for tissue collection in clinical biobanks. In this study, we sequenced 77 samples from a population-based de novo MCL cohort to investigate the utility of targeted sequencing in guiding personalized treatment approaches. Tumors were genetically variable, and a similar genetic landscape as previous studies using non-formalin fixed samples was identified, with recurrent mutations including ATM, KMT2D, and TP53. Novel alterations that can be considered actionable and/or indicative of treatment response were also identified. Our approach shows the potential benefits of using target sequencing of formalin fixed samples to facilitate treatment selection and individualized clinical decisions in MCL.

Safety and Preliminary Efficacy in Patients with Relapsed/Refractory Mantle Cell Lymphoma Receiving Lisocabtagene Maraleucel in Transcend NHL 001

Safety and Preliminary Efficacy in Patients with Relapsed/Refractory Mantle Cell Lymphoma Receiving Lisocabtagene Maraleucel in Transcend NHL 001

Primary Analysis of the Tegar Study: A Phase II Study Exploring the Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab or Rituximab in Patients with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), or Waldenstrom Macroglobulinemia (WM)

Primary Analysis of the Tegar Study: A Phase II Study Exploring the Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab or Rituximab in Patients with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), or Waldenstrom Macroglobulinemia (WM)

Unraveling Actionable Target Mutations in Formalin Fixed Tissue in Mantle Cell Lymphoma

Introduction: Mantle Cell Lymphoma (MCL) is a B-cell neoplasm with poor prognosis and high relapse frequency. It follows an heterogenous clinical course and, despite clear improvements in survival among young and fit patients, most patients eventually relapse. Recurrent mutations have been previously described, pinpointing alterations in DNA damage pathways, cell survival and cell-cycle regulation. Nevertheless, the current genomic knowledge of the disease cannot fully explain its high clinical variability. The present study aimed at revealing the mutation profile for the development of personalized treatment approaches in a population-based cohort of patients diagnosed with MCL. Material &amp; Methods: We performed sequencing across ~230 lymphomagenesis-related genes on 75 formalin-fixed paraffin-embedded (FFPE) samples from symptomatic patients diagnosed with MCL in Southern Sweden. The panel covered the exonic parts of the chosen genes with capture probes provided by TWIST Bioscience. Sequence alignment was done against the human genome version 37 and variant calling was performed resorting to Sention TNscope. IGV was used for manual validation of each identified mutation. Samples were pre-selected according to DNA quality. Data on patient characteristics, prognostic factors and treatment was extracted from the Swedish Lymphoma Register. Results: MCL tumors were highly heterogenous with respect to the mutational status of the analyzed genes, ranging between 0 and 45 mutated genes in this cohort. ATM was the most commonly mutated gene (49%), followed by KMT2D, NOTCH2, TP53, FAT4, BIRC3, CCND1, UBR5, MEF2B, NOTCH1,SMARCA4, DNAH5,SAMHD1 and SP140 (Figure 1). Our results are in accordance with the previously published analyses, although the frequency of samples with mutated NOTCH2 was higher (18.7%, compared to 3-12.5% of affected tumors in previous studies), and with less samples with mutated NOTCH3 (6.7% of the studied tumors were mutated, vs 12.5% reported by Yang et al., (2018)). We found mutations in DNAH5, PCLO, FAT3 and BRCA1 genes, which have not been previously reported in MCL. Additionally, FAT4 (14.7%) showed recurrent mutations in our cohort, but has only been referred as commonly mutated in MCL before by Zhang et al. (2014). Main affected pathways were NOTCH-related and TP53-related pathways, followed by chromatin remodeling and cell cycle pathways. Due to low numbers of patients with non-classic morphology, no mutations were significantly different comparing classical and non-classical histology, although there was an enrichment of TP53 and NOTCH1 mutations in non-classic cases. It seems that cases with non-classic morphology have stronger driver mutations, which may reflect their aggressiveness. Cases with high proliferation (Ki67 &amp;gt;30%) showed a higher frequency of SMARCA4 (30%, vs 7.7% for low proliferation tumors) and TP53 mutations (36% in highly proliferative tumors vs. 17% in low proliferative tumors). No differences in mutation patterns were found in cases with low vs. high SOX11 expression. Unsurprisingly, TP53 mutations were the strongest independent factor for prognosis among the studied genes. Conclusions: Using the results from a population-based cohort of MCL, we report the feasibility of applying a targeted panel and sequencing technologies on DNA from formalin fixed tissue, as a method applicable in clinical routine in tailoring treatment approaches for MCL. Figure 1. Top 15 genes mutated in the cohort studied. Frequency of mutations on each gene is presented on the right panel and in the upper panel the proportion of affected genes by sample can be seen. Darker blue identifies a missense mutation, light blue corresponds to a frameshift deletion, pink color matches frameshift insertions, orange represent in frame deletions, whereas red in frame insertions. Light green identifies nonsense mutations and dark green stands for different types of mutation affecting that gene in that sample. Figure Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Janssen: Research Funding.

Complex Karyotype Is a Significant Predictor for Worst Outcomes in Patients with Mantle Cell Lymphoma (MCL) Treated with BTK Inhibitors - Comprehensive Analysis of 396 Patients

Complex Karyotype Is a Significant Predictor for Worst Outcomes in Patients with Mantle Cell Lymphoma (MCL) Treated with BTK Inhibitors - Comprehensive Analysis of 396 Patients

Clinical Outcomes of Non-Hodgkin Lymphoma Patients on Acalabrutinib Including Off-Label Utilization

Clinical Outcomes of Non-Hodgkin Lymphoma Patients on Acalabrutinib Including Off-Label Utilization

Gastrointestinal (GI) Involvement with Non-Hodgkin's Lymphoma (NHL) Impacts Outcome; A Retrospective Single Tertiary Care Center Analysis of Clinico-Pathologic Characteristics Provides an Alternate Insight to Presentation and Outcome

Introduction Historically, the GI tract is involved in 10-15% of patients with newly diagnosed NHL. Despite being the predominant extranodal site for lymphoma involvement little is known about its pathophysiologic presentation given its overall rarity. Nonetheless its evaluation, diagnosis, prognosis and management is distinct from lymphomas at other sites hence their recognition irrespective of whether being the primary site is prudent. Methods We performed a single center retrospective study of patients to describe clinical characteristics and outcome of newly diagnosed NHL presenting with GI involvement defined by tissue biopsy between January 2003 and April 2019. Descriptive statistics were calculated by Fisher's exact test and Chi2 test for categorical variables and rank-sum analyses for continuous variables. Results We identified 91 patients with one patient presenting with 2 different GI NHL involvement. The median age at presentation was 70 years (range 33-92) and 61 were male. 41 (45%) patients had diffuse large B cell lymphoma (DLBCL) and 5 had concomitant low grade component, 28 (30.8%) mucosal associated lymphoid tissue (MALT) lymphoma, 10 (11%) mantle cell lymphoma (MCL), 4 (4.4%) enteropathy associated T cell lymphoma (EATL), 3 (3.3%) follicular lymphoma, 2 (2.2%) Burkitt's lymphoma and 2 (2.2%) EBV driven lymphoproliferative disorder (LPD). There were 1 case each of plasmablastic lymphoma and extranodal NK/T-cell lymphoma, nasal type. 37 with DLBCL and 2 with MCL had primary GI involvement. Gastric involvement was the commonest site, 43 (55.8%) cases followed by the large intestine, 22 (28.6%). PET-CT scan was done in 42 cases with high grade NHL; GI involvement by FDG avidity was noted in 23 cases and negative in 19 (45.2%). Serum albumin at presentation was available in all patient. Patients with presenting serum albumin &lt; 25 g/L were more likely to die in the first 30-days post diagnosis; p&lt;0.0001. A total of 20 patients died as a result of lymphoma; presenting serum albumin was significantly lower in that group (mean 29 g/L versus 37 g/L; p=0.0077). H pylori status was assessed by either antigen testing in stool and/or histology. This was known in 50 patients and was available by the 2 assessment methods in 31 cases but discordant in 17. A positive result was more likely noted with the antigen test. None of the T-cell LPD were H pylori positive. 12 of the 26 DLBCL and 9 (53%) of the 17 MALT lymphoma patients were H pylori status was known were positive. Nonetheless all H pylori negative MALT lymphoma cases were localized to the stomach and responded to triple eradication therapy and Rituximab monotherapy +/- surgical resection. In the DLBCL cohort, the cell of origin was known in 22 of 39 cases; 17 were non-germinal center phenotype. In the MCL cohort, all patients whom underwent surveillance endoscopies irrespective of symptoms and/or radiologic finding had histologic evidence of GI involvement with lymphoma with only 3 (18%) patients being symptomatic +/- had radiologic finding in keeping with GI involvement. Conclusions Despite the relatively small sample size this real-world data of GI lymphomas outlines some of its recognized features; advanced age at diagnosis, male prevalence and gastric involvement as the commonest site of involvement. Presenting serum albumin &lt;25 g/L was associated with higher 30-day mortality highlighting its relevance and need for its inclusion as a biomarker in risk stratification of NHL where GI tract is involved. There is however several other significant findings not previously recognized; the incidence of GI involvement in MCL is much higher than reported; 100% in all patients whom have undergone endoscopy in our cohort suggesting that GI involvement is a feature of MCL. With only 53% of MALT lymphoma being H pylori positive which is much lower than previously described this renders the prototypical association of H pylori infection in MALT lymphoma pathogenesis void and suggests an alternate etiology. Nonetheless their response to antibiotic therapy with only minimal additional systemic therapy in some indicates that H pylori status does not necessary predict its efficacy and should be considered when treating MALT lymphomas irrespective of H pylori status. CT scans but also PET-CT scans are insensitive in detecting GI involvement even in high grade NHL. Endoscopy with random mapping biopsies even with normal macroscopic GI findings remains the gold standard. Disclosures No relevant conflicts of interest to declare.

Characteristics of Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) Patients Treated with Acalabrutinib in a Real World Setting in the United States

Introduction Acalabrutinib was approved by the US Food and Drug Administration on October 31, 2017 for patients with MCL who have progressed on at least one prior therapy and is currently being evaluated in phase III trials for first-line MCL, first-line CLL, and relapsed/refractory (r/r) CLL. Additionally, acalabrutinib received guideline and compendia listing for use in MCL and CLL patients. There is a lack of information on the current treatment patterns with acalabrutinib in real world clinical practice. To that end, we conducted a descriptive analysis of the use of acalabrutinib in the real-world setting for MCL and CLL patients. Methods A retrospective cohort study was conducted using IQVIA's longitudinal prescription (LRx) database linked to the medical claims (Dx) database. Patients ≥18 years old with ≥1 claim for acalabrutinib in LRx between November 1, 2017 and April 30, 2019 were identified; the first claim was index date. Patients were also required to have ≥ 1 Dx claim between November 1, 2016 and April 30, 2019, and ≥ 12 months baseline (defined as ≥ 1 LRx claim and ≥ 1 Dx claim within 12 months pre-index and &amp;gt; 12 months pre-index). Patients were required to have ≥2 diagnoses of either MCL or CLL before index (without diagnosis of the other cancer) to create two mutually exclusive cohorts. Patients were excluded if they had data quality issues or evidence of clinical trial enrollment during the study period. Descriptive statistics were used to summarize baseline demographic and clinical characteristics overall and stratified by prior ibrutinib use. Results were described for MCL and CLL cohorts separately. Results A total of 264 MCL and 204 CLL patients treated with acalabrutinib were identified in the study. For both cohorts, the majority (57.2% MCL / 59.3% CLL) were 70 years or older, with a median (interquartile range [IQR]) age of 71.0 (15.0), mean (standard deviation [SD]) of 70.5 (9.7) for MCL and median age of 71.5 (15.0), mean 69.9 (11.1) for CLL patients (Table 1). 76.9% of MCL and 59.8% of CLL patients were male, and over half were commercially insured (50.4% MCL / 52.5% CLL). In the 12-month pre-index period, MCL and CLL patients had a mean (SD) Charlson Comorbidity Index (CCI, excluding hematologic malignancies) of 1.6 (2.2) and 1.4 (1.8), respectively; hypertension (67.8% MCL / 67.7% CLL), other hematologic malignancies (48.9% MCL / 52.0% CLL), and infection (28.0% MCL / 31.4% CLL) were the most common comorbidities. Other common (i.e., ≥ 20%) conditions included anemia and neutropenia for the MCL cohort, and arrhythmia, fatigue/asthenia, atrial fibrillation (A-fib), anemia and thrombocytopenia for the CLL cohort. Over 60% of MCL and CLL acalabrutinib-treated patients were defined as high risk of A-Fib (Chyou, Hunter et al. 2015). In terms of prior Bruton's Tyrosine Kinase-inhibitor (BTKi) treatment, 37.9% of MCL and 64.7% of CLL patients had prior ibrutinib use. More prior ibrutinib users were defined as high risk A-Fib status at time of acalabrutinib start than patients without prior ibrutinib use, and prior ibrutinib users had a higher frequency of several comorbidities (e.g., hypertension, fatigue/asthenia; Table 1). Conclusions With the relatively recent approval, this is the first analysis of acalabrutinib use in clinical practice and description of characteristics of MCL and CLL patients being treated with this medication in the real world. Before initiating acalabrutinib, approximately one-third of MCL patients and two-thirds of CLL patients received ibrutinib (reasons for discontinuing ibrutinib were not explored). Although the overall comorbidity score was similar between patients with and without prior BTKi exposure, BTKi-naïve patients had a slightly lower frequency of high-risk A-Fib status at acalabrutinib initiation. Future studies are warranted to evaluate the treatment patterns of acalabrutinib and outcomes in the real-world setting. Disclosures Ryan: AstraZeneca: Employment, Equity Ownership. Burudpakdee:IQVIA: Consultancy. Zhao:IQVIA: Consultancy. Le:AstraZeneca: Employment, Other: Stocks. Near:IQVIA: Consultancy. OffLabel Disclosure: Acalabrutinib is an oral inhibitor of Bruton's Tyrosine Kinase. It was approved by the US Food and Drug Administration on October 31, 2017 for patients with mantle cell lymphoma (MCL) who have progressed on at least one prior therapy and is currently being evaluated in phase III trials for first-line MCL, first-line chronic lymphocytic leukemia (CLL), and relapsed/refractory CLL.

Tumor Microenvironment Molecular Signatures That Define Therapeutic Resistance in Mantle Cell Lymphoma

Introduction The tumor microenvironment of mantle cell lymphoma (MCL), an aggressive and incurable subtype of B-cell lymphoma, is dynamic and complex. The MCL microenvironment provides a niche for the tumor by promoting survival, therapeutic resistance, and immune evasion. Although the intrinsic mechanisms underlying MCL pathogenesis have been well-studied, as demonstrated by our understanding of the important roles that B-cell receptor signaling, the PI3K/AKT/mTOR axis, and OXPHOS play in MCL survival and the development of therapeutic resistance, the extrinsic mechanisms regulated by the lymphoma microenvironment are less well-known. Methods Whole exome sequencing (WES; n = 42) and RNA-seq (n = 76) were performed on fresh peripheral blood or apheresis patient primary samples with an extremely high MCL tumor percentage as determined by flow cytometry versus biopsies with a more diverse cellular mixture, including MCL tumor microenvironment components such as macrophages, T-cells, NK cells, and monocytes. Our previously published MCL cohort was also analyzed in this study (Zhang et al., Science Translational Medicine, 2019). Joint WES and RNAseq mutation calling, expression analysis, and cell type deconvolution from the transcriptome were performed using the BostonGene automated pipeline. Results To characterize the cellular composition and functional state of the MCL tumor microenvironment as well as tumor properties, we created 26 separate molecular signatures related to various functional processes such as anti-tumor immune infiltration, immune checkpoint inhibition, immunosuppression, and stromal compartment represented by angiogenesis and mesenchymal stromal cells. We also utilized these 26 immune and stromal signatures in conjunction with PROGENy (Pathway RespOnsive GENes) analysis to create a signature-based model associated with sensitivity or resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib. In this model, increased T-cell, NK cell, and B-cell processes, in addition to p53 pathway activity, were associated with sensitivity to ibrutinib, demonstrating that the tumor microenvironment plays a critical role in the MCL response to this widely used FDA-approved agent. Moreover, initial analysis only identified one BTKC481S mutation in an ibrutinib-resistant MCL sample, again demonstrating that mutations in BTK are rare in ibrutinib-resistant MCL and that diverse mechanisms underlie the development of this resistance. For more in-depth analysis, we performed concurrent analysis of only the biopsy samples in conjunction with an additional previously published cohort (n = 123; Scott et al., JCO, 2017). Unsupervised clustering based on the activities of the proposed signatures produced 4 MCL types as follows: immune infiltration combined with increased stromal signatures (type MCL-A), high immune and checkpoint molecules expression with low stromal expression (type MCL-B), non-immune with increased stromal signature and tumor-promoting cytokines (type MCL-C), and lacking immune infiltration and stromal expression with highest content of malignant B cells (type MCL-D). Interestingly, the ibrutinib-resistant MCL samples primarily belonged to the MCL-C subtype (80%), whereas most of the ibrutinib-sensitive samples (70%) were assigned to subtype MCL-B (Chi-square test p-value = 0.01), which is prominent in anti-tumor immune infiltration without tumor-promoting stromal context, suggesting that ibrutinib may promote immune microenvironment effective action against MCL or work more effectively in an active immune environment. Conclusion The identified enriched immune cell signatures suggest that MCL cells may be sensitive to specific and novel immune checkpoint inhibitors and other immune activators. Ibrutinib sensitivity and resistance are clearly separated based on their tumor microenvironment portraits, suggesting that the tumor microenvironment has a prominent role in regulating ibrutinib activity and response. Furthermore, ibrutinib may alter the tumor microenvironment to promote anti-tumor activity, which requires further investigation. Disclosures Wang: MoreHealth: Consultancy, Equity Ownership; Celgene: Consultancy, Research Funding; Juno Therapeutics: Research Funding; Kite Pharma: Consultancy, Research Funding; Dava Oncology: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Aviara: Research Funding; BeiGene: Research Funding; BioInvent: Consultancy, Research Funding; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Outcomes Following Early Relapse in Patients with Mantle Cell Lymphoma

Outcomes Following Early Relapse in Patients with Mantle Cell Lymphoma

Proapoptotic protein BIM as a novel prognostic marker in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Numerous studies have demonstrated many genetic aberrations in MCL in addition to the characteristic t(11:14), including frequent biallelic deletions of Bim, a proapoptotic member of the BCL-2 family. In mice, Bim deletion coupled with cyclin D1 overexpression generates pathologic and molecular features of human MCL. Since the regulation of apoptosis is crucial in MCL pathogenesis, we hypothesize that BIM expression may be associated with tumor cell survival. Clinical data and tissue from 100 nodal MCL cases between 1988 and 2009 were collected from three large academic medical centers. The average patient age of our MCL cohort was 65.5 years old (range, 42-97) with a 2:1 male to female ratio. Immunohistochemistry was performed with a validated anti-BIM antibody. Patients were separated into low and high BIM-expressing categories with a cutoff of 80%. As expected for a proapoptotic tumor suppressor, patients with high BIM expression were less likely to have progressive disease and more likely to have a complete response (P = .022). In addition, high BIM-expressing MCL tumors revealed a trend toward increased overall survival with this trend persisting in sub-analysis of Ann Arbor stages III and IV. No correlation between BIM expression, Ki-67 index, and MIPI score was observed, suggesting a role for BIM as a novel independent prognostic factor. While BIM is only one member of a complex family of apoptosis-regulating proteins, these findings may yield clinically relevant information for the prognosis and therapeutic susceptibility of MCL.

Phase 2 Study of Daratumumab in Relapsed/Refractory Mantle-Cell Lymphoma, Diffuse Large B-Cell Lymphoma, and Follicular Lymphoma

BackgroundDaratumumab is a CD38 monoclonal antibody approved for treating relapsed/refractory and newly diagnosed multiple myeloma. Preclinical daratumumab studies demonstrated cytotoxic activity and reduced tumor growth in B-cell non-Hodgkin lymphoma (NHL) subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle-cell lymphoma (MCL). Patients and MethodsThis was a phase 2, open-label, multicenter, 2-stage trial. Patients with relapsed/refractory DLBCL, FL, or MCL with ≥ 50% CD38 expression were eligible for stage 1. Daratumumab (16 mg/kg; 28-day cycles) was administered intravenously weekly for 2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Overall response rate was the primary end point. Pharmacokinetic and safety were also evaluated. Stage 2 was planned to further assess daratumumab in larger populations of NHL subtypes if futility criteria were not met. The study was registered with ClinicalTrials.gov (NCT02413489). ResultsThe trial screened 138 patients resulting in accrual of 15 patients with DLBCL, 16 with FL, and 5 with MCL. Median CD38 expression across treated patients was 70%. Overall response rate was 6.7%, 12.5%, and not evaluable in DLBCL, FL, and MCL cohorts, respectively. The most common grade 3/4 treatment-emergent adverse event was thrombocytopenia (11.1%), and 4 (11.1%) patients discontinued treatment because of treatment-emergent adverse events. Infusion-related reactions occurred in 72.2% of patients (3 patients with grade 3; no grade 4). ConclusionIn NHL, the safety and pharmacokinetics of daratumumab were consistent with myeloma studies. Screen-fail rates were high, prespecified futility thresholds were met in 2 cohorts, and the study was terminated. Studies in other hematologic malignancies and amyloidosis are ongoing.

A Systemic Review of CD5-Negative Mantle Cell Lymphoma Identifies Potential Clinical and Biological Implications

Introduction: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) with a median survival of 3 to 5 years. MCL is characterized by the translocation t(11;14)(q13;32) which results in the overexpression of cyclin-D1 and ultimately an uninhibited G1/S cell cycle transition. MCL has a distinctive immunophenotype among B-cell NHL, characterized by a strong expression of the pan B-cell markers CD19 and CD20, absence of CD10 and CD23, overexpression of the anti-apoptotic protein BCL2, and aberrant expression of the T-cell marker CD5. However, up to 10% of MCL lack CD5 expression and remain ill-characterized. Whether this absence of CD5 expression impacts MCL biology and clinical course remains unknown. We performed a systematic review of all reported cases of CD5-negative MCL and analyzed their biological and clinical characteristics.Patients and methods: A systematic literature search was performed and included studies published from 1st June 1994 to 1st June 2016 in PubMed, Embase, and Web of Science. We used the key words CD5 negative, CD5-, mantle cell lymphoma, and MCL. Data was tabulated regarding the following 16 variables: t(11;14)(q13;q32), cyclin-D1, CD5, CD10, CD19, CD20, CD23, BCL2, BCL6, Ki-67 (higher or lower than 30%), IGHV mutation status (mutated IGHV >3% discordance with germline), male to female ratio, light chain expression (kappa or lambda), presence of a leukemic phase, stage, and overall survival (OS). Data was reported as percent and total number of cases with available data of each variable.Results and discussion: 68 out of 470 screened articles included CD5-negative MCL cases. After exclusion of duplicates, 50 sources (46 full articles and 4 abstracts) were included. Data of 222 cases of CD5-negative MCL were collected.To a degree, reviewed cases of CD-5 negative MCL shared similarities to classic MCL. Both sub-types had a median age at diagnosis of approximately 65 and presented as stage IV disease 70% of the time. Both subtypes overexpressed cyclin-D1 (100%, 222/222), possessed the t(11;14)(q13;q32) (93%, 49/53: 49 of 53 cases with available data on the translocation), were CD-19 positive (100%,18/18), CD20-positive (100%, 58/58), BCL2-positive (97%, 34/35), CD10-negative (93%, 42/45), and CD23-negative (95%,56/59). Presence or absence of leukemic phase was reported in 16 cases, 8 of those were positive for circulating MCL cells (50%). The proliferation marker Ki-67 was reported in 22 cases, 7 (32%) of which were >30%.CD5-negative MCL deviated from the classic MCL presentation in a number of clinical and biological variables. Most importantly, the median OS of 47 cases with available follow-up was greater than 16 years (Figure 1), which compared very favorably to the historic survival of 3 to 5 years in classic MCL. Interestingly, the number of affected males was less than expected in the CD5-negative group. Male-to-female ratio was 2:1 (74 males and 36 females of 110 cases with available gender data), which is lower than the expected 3:1 ratio.From a biological standpoint, the CD5-negative MCL cohort had more kappa than lambda-restricted cases (62%, 13 of 21 available light chain data), and more mutated than unmutated IGHV (61% mutated, 11 of 18 cases with available IGHV data). Classically, lambda-restricted MCL and unmutated IGHV are more commonly seen and were associated with worse clinical outcomes. In addition, we observed BCL6 expression in 23% of CD5-negative MCL cases, which is higher than expected (6 of 26 cases with BCL6 available data).Conclusions: To our knowledge this is the most comprehensive review of CD5-negative MCL. Lack of CD5 expression was associated with important clinical and biological differences compared to classic MCL. The higher survival observed in our analysis suggest that CD5 can potentially be incorporated in identifying a subset of a more indolent MCL that might benefit from a watch and wait approach. Currently, treatment in MCL can be differed in a subset of patients with an indolent presentation characterized by leukemic-only disease with absence of lymphadenopathy, mutated IGHV, and lack of SOX11 expression. SOX11 data was not available in our cohort, and only 18 patients had available IGHV mutation data. While the exact role of CD5 in MCL remains unknown, our findings highlight the need for a deeper investigation of CD5-negative MCL at the genetic, phenotypic, and clinical levels. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Results of a Phase 2 Trial Evaluating Efficacy and Safety of Entospletinib (GS-9973) in Patients with Mantle Cell Lymphoma

Introduction: Entospletinib (GS-9973) is an orally bioavailable, selective inhibitor of spleen tyrosine kinase (Syk). Syk is a mediator of B-cell receptor signaling in normal and transformed B-cells. Targeting the B-cell receptor (BCR)-signaling pathway has been the focus in many types of B-cell related hematological malignancies including mantle cell lymphoma (MCL).Methods: This reports the MCL cohort in a phase 2 trial that more broadly evaluated the efficacy and safety of entospletinib (800 mg BID) in patients with relapsed and refractory hematological malignancies (NCT01799889). Tumor response was assessed per Cheson 2007 criteria with imaging planned at weeks 8, 16, 24, and then every 12 weeks. The primary endpoint was PFS at week 16. All efficacy data were assessed by an Independent Review Committee.Results: A cohort of 39 patients with MCL was enrolled. The median age was 72 years (range: 49-92), 64% were male, and a median number of prior regimens were 2 (range: 1-6). Prior therapy included anti-CD20 antibodies (95%), alkylating agents (95%; bendamustine 44%), and anthracyclines (77%). Three patients (8%) have received ibrutinib either as investigational drug (n = 1) or as an approved drug (n = 2), and 1 patient (3%) received idelalisib. Median duration of treatment was 21 weeks (range: 1-87), with 1 patient continuing on treatment. Thirty-five (90%) patients were evaluable for tumor response. Four patients (10%) discontinued prior to initial tumor assessment: death (n = 1), disease progression (n = 2) and investigator’s discretion (n = 1). The most common TEAEs (any grade/≥gr 3, independent of causality) and common lab abnormalities are summarized in Table 1. There were 4 TEAEs that led to study drug discontinuation (all n = 1): cardiac arrest, pruritus, pyrexia, and maculopapular rash. Six deaths were reported, none of which were related to study drug. The ORR was 15% (90% CI: 6.9%, 28.1%), with 6 (15%) patients achieving a PR and 23 (59%) patients maintaining a stable disease. The PFS rate at week 16 was 66% (95% CI: 46%, 79%). Median PFS was 5.6 months (95% CI: 3.6 months, 8.9 months). These results are based on data analysis of June 28, 2016.Conclusion: Entospletinib was well tolerated and demonstrated modest activity in patients with relapsed or refractory MCL. Further development of entospletinib in MCL will focus on the development of combination therapy. [Display omitted] [Display omitted] [Display omitted] DisclosuresSharman:Gilead Sciences, Inc.: Honoraria, Research Funding. Kolibaba:Amgen: Research Funding; Celgene: Research Funding; Cell Therapeutics: Research Funding; Genentech: Research Funding; GSK: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Novartis: Research Funding; Pharmcyclics: Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Shustov:Seattle Genetics: Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; SPECTRUM: Consultancy, Research Funding; Novartis: Research Funding. Nay:Gilead Sciences, Inc.: Honoraria; Janssen: Honoraria, Other: Advisory board; Celgene: Honoraria, Other: Advisory board; Amgen: Other: Advisory board; Lyndbeck: Honoraria; BMS: Honoraria. Zhang:Gilead Sciences: Employment, Equity Ownership. Shi:Gilead Sciences, Inc.: Employment, Equity Ownership. Forero:University of Alabama at Birmingham: Research Funding. Assouline:BMS: Speakers Bureau; Lundbeck: Consultancy; Janssen: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau.

The G-Protein Coupled Receptors and G-Proteins Alpha Expression in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a B cell Non-Hodgkin lymphoma comprising approximately 8% of malignant lymphomas. MCL is considered to be an incurable disease even though survival has improved with novel biological therapies that interrupt survival signaling from the lymphoma microenvironment. The signaling pathways that are deregulated and the factors leading to systemic dissemination of the disease are still poorly understood. There is also a clear need to identify additional druggable targets for therapy (Saba and Wiestner, Curr Opin Hematol, 2014). Druggable targets may be G-protein coupled receptors (GPCRs) and G-proteins. GPCRs belong to the family of seven transmembrane receptors, which upon activation by extracellular ligands transfer the signals inside the cell for activation of the specific pathway. The signaling involves G-proteins. G-proteins consist of the subunits: alpha, beta and gamma and their subtypes. During GPCR activation the G alpha subunit is released and the subtype of G-protein subunit determines which downstream signaling pathways (including Akt, PI3K, ERK, JNK, MAPK, NFkappaB and others) is then activated. In the immune cells different subtypes of G-proteins alpha are instrumental for leukocyte migration, architecture of B cells compartments in spleen, thymus, lymph nodes, and gastrointestinal tract (Hwang et al., PlosOne, 2013) and BCR-mediated cell death (Misra et al., J Exp Med, 2010). G alpha13 signaling is involved in development of germinal centre-derived lymphomas (Muppidi et al., Nature, 2014).In order to map the aberrant expression of GPCR and G-proteins in MCL, the expression of genes encoding for GPCRs and G-protein alpha subunits was analyzed by Affymetrix U133A Array of seventeen MCL biopsies and eight non-malignant lymph nodes. Among investigated GPCR and G-protein alpha subunit genes 25/298 were differently expressed in MCL compared to reactive lymph nodes (moderated t-test, adj. p=or< than 0.05). The four most significantly different genes expressed were: LPAR6, GPRC5C, OPN3 and GNAZ (all adj.p<0.003). The latter, GNAZ, encodes for G-protein alpha z. The analysis of GNAZ by qPCR in 77 additional MCL biopsies from a population-based Stockholm MCL cohort showed varied expression of GNAZ. Interestingly, the MCL cases, which expressed the highest levels of GNAZ, had significantly worse survival (Kaplan-Meier, log rank, p<0.003) suggesting that GNAZ has, a yet unknown, role in MCL biology. Further analysis showed that GNAZ expression was correlated to lymphocytosis (Mann-Whitney test, p=0.023) and leukocytosis (Mann-Whitney test, p=0.011) in MCL patients but not to: high tumor cell proliferation, blastoid morphology nor to p53 immunoreactivity. Our results suggest that GNAZ-signaling is of importance for cell-cell interaction in the tumor microenvironment and/or for egress of lymphoma cells to the blood. DisclosuresNo relevant conflicts of interest to declare.

Ki-67 Labeling Indices in 'Classic' versus 'Blastoid' Mantle Cell Lymphomas--Proposed Cutoff Values for Routine Diagnostic Workup.

Mantle-cell lymphoma (MCL) is a unique entity of peripheral B-cell lymphoma that has a discrete morphologic, immunologic, and genetic phenotype, with more common 'classic' and less frequent 'blastoid' and 'pleomorphic' variants, associated with an aggressive clinical course. The aim of this study was to analyze proliferation (Ki-67) indices of 'classic' (c-MCL) and 'blastoid' (b-MCL) variants of a cohort of MCL and to suggest cut off values for the Ki-67 proliferation index in these two subsets. MCL cases diagnosed over 4 1/2 years at Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi were retrieved and reviewed. Ki-67 labelling was scored and analysed. A total of 90 of cases of MCL were scrutinized. Mean age±SD was 60.2±12.5 years and the male to female ratio was 4:1, with 67 (75%) cases of c-MCL and 23 (25%) cases of b-MCL. Most samples were lymph node biopsies (n=68), whereas the remainder were from various extranodal sites The mean Ki-67 proliferation index was 29.5%±14.4% in classic variants and 64.4±15.2% for the blastoid variant, the difference being statistically significant (p=0.029). It was concluded that differential cut-off values of Ki-67 labeling may be used in more objective way to reliably classify MCL into classic or blastoid variants by diagnostic pathologists. We propose a <40 proliferative index to be suggestive of c-MCL and one of >50 for the blastoid variant.

MiR-18b overexpression identifies mantle cell lymphoma patients with poor outcome and improves the MIPI-B prognosticator

AbstractRecent studies show that mantle cell lymphoma (MCL) express aberrant microRNA (miRNA) profiles; however, the clinical effect of miRNA expression has not previously been examined and validated in large prospective homogenously treated cohorts. We performed genome-wide miRNA microarray profiling of 74 diagnostic MCL samples from the Nordic MCL2 trial (screening cohort). Prognostic miRNAs were validated in diagnostic MCL samples from 94 patients of the independent Nordic MCL3 trial (validation cohort). Three miRNAs (miR-18b, miR-92a, and miR-378d) were significantly differentially expressed in patients who died of MCL in both cohorts. MiR-18b was superior to miR-92a and miR-378d in predicting high risk. Thus, we generated a new biological MCL International Prognostic Index (MIPI-B)-miR prognosticator, combining expression levels of miR-18b with MIPI-B data. Compared to the MIPI-B, this prognosticator improved identification of high-risk patients with regard to cause-specific, overall, and progression-free survival. Transfection of 2 MCL cell lines with miR-18b decreased their proliferation rate without inducing apoptosis, suggesting that miR-18b may render MCL cells resistant to chemotherapy by decelerating cell proliferation. We conclude that overexpression of miR-18b identifies patients with poor prognosis in 2 large prospective MCL cohorts and adds prognostic information to the MIPI-B. MiR-18b may reduce the proliferation rate of MCL cells as a mechanism of chemoresistance.

Novel Chromatin Modifying Gene Alterations and Significant Survival Association of ATM and P53 in Mantle Cell Lymphoma

Background: The survival of mantle cell lymphoma (MCL) has improved (median OS now >5 years) due to the use of dose-intensive strategies in younger patients (pts) achieving a deeper and earlier response (including molecular CR) and the application of novel therapies in the relapsed/refractory setting, where patients are typically chemoresistant. However, given the median age at onset in the mid to late 60’s, and the remaining variability in outcomes, additional strategies are needed. A number of prognostic factors have been reported in MCL including MIPI, Ki67 and blastoid variants among others, the latter being frequently associated with del 17p or p53 mutations and a particularly poor outcome. Recent studies have begun to describe the genomic landscape of MCL by whole-genome, whole-exome and targeted sequencing. However, comprehensive evaluation of genomic alterations relevant for MCL pathogenesis and that could be potentially informative for patient’s prognosis and patient’s stratification remains to be elucidated.Methods: We studied 33 FFPE or cryopreserved blood MCL specimens by performing integrated DNA and RNA sequencing (N=18) or DNA sequencing alone (N=15). All samples were obtained at diagnosis before patients received Rituximab-HyperCVAD as frontline therapy. In this MCL cohort, treated at our institution, the median age was 59 y (range 35-75), all were stage IV, median Ki-67 was 30 % (range 5-80%), MIPI was low risk (27%), intermediate risk (30%), high risk (42%), and there were 4 blastoid variants (2 with del 17p by FISH or cytogenetics). Genomic DNA and total RNA were extracted and captured using custom bait-sets targeting all exons of 405 cancer-related genes by DNA-Seq, and 265 frequently rearranged genes by RNA-Seq (FoundationOne Heme). Captured libraries were sequenced to high depth in a CLIA-certified, CAP-accredited, NYS-approved clinical laboratory, with an average depth of 400X for DNA and >8M unique pairs for RNA.Results: In total, we identified 125 genomic alterations with an average of 3.8 per sample, including 45 base substitutions/indels, 33 truncations, 1 gene amplification, 6 gene deletions, and 40 rearrangements (Figure 1). IGH/CCND1 t(11,14) translocation was detected in 32/33 samples, and CCND1 over-expression was found in all translocation positive cases by RNA-seq, when available. Consistent with published reports, ATM and TP53 were among the most frequently altered genes, found in 45% and 18% of the samples, respectively. Mutations of TP53 and ATM were correlated with the short overall survival (OS) in our cohort. The median OS was not reached in TP53wt pts compared with 5.3 months in TP53mut pts, and not reached in pts with wild-type TP53 and ATM versus 10.4 months in either TP53mut or ATMmut pts (Fisher’s exact test p-value=0.01, Figure 2).Gene alterations of chromatin remodeling pathway were identified in 18 out of 33 samples, including SMARCB1 (4), SMARCA4 (2), ARID1A (3), ARID2 (1), PBRM1 (1), CHD2 (1), WHSC1 (5), MLL2 (2), SETD2 (1), EZH2 (1), and ASXL1 (1). Alterations in SMARCB1 (also known as SNF5 and INI1) and ARID1A, members of the SWI/SNF chromatin-remodeling complex, have not been reported in MCL previously. Other frequently altered genes included NOTCH1/2 (12%), and the cell cycle genes CDKN2A/B (9%). GAs associated with approved agents or clinical trials of targeted therapies were identified in 67% of the samples. The most common genes with potential therapeutic implications were ATM (PARP inhibitors), CDKN2A and CCND1 (CDK4/6 inhibitors) and NOTCH1 (Notch1 inhibitors).Summary:1. We identified relevant genomic alterations in MCL patients from baseline peripheral blood and/or tissue (with no significant difference in source of materials) in all samples tested.2. We discovered novel recurrent mutations in chromatin remodeling genes SMARCB1 and ARID1A in MCL, and demonstrated that 55% of tumors carried alterations in epigenetic regulation overall.3. In our frontline cohort of MCL patients treated with R-HyperCVAD, we identified the prognostic value of DNA damage response genes ATM and TP53 on outcome. These findings highlight the possibilities for improved prognosis and novel therapeutic strategies based on comprehensive genomic analysis of these pathways [Display omitted] [Display omitted] DisclosuresWang:Foundation Medicine, Inc.: Employment, Equity Ownership. Nahas:Foundation Medicine, Inc.: Employment, Equity Ownership. Yelensky:Foundation Medicine, Inc.: Employment, Equity Ownership. Otto:Foundation Medicine, Inc.: Employment, Equity Ownership. Lipson:Foundation Medicine, Inc.: Employment, Equity Ownership. He:Foundation Medicine, Inc.: Employment, Equity Ownership. Ross:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Research Funding. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership.