Cell lines represent an essential tool used in preclinical research. Most hematologic malignancies have a wide array of cell lines representing their respective molecular and pathologic spectra. In ...mantle cell lymphoma (MCL), cell lines become specifically valuable in view of the heterogeneity of this disease. Unfortunately, the number of MCL cell lines that are available for the research community remains small, with only nine cell lines available for purchase through the American Type Culture Collection (ATCC). We have established a novel blastoid MCL cell line, isolated from the malignant pleural effusion of a 69‐year‐old male with refractory MCL. Arbo was fully characterized with cytogenetics, immunophenotyping, whole exome sequencing and drug sensitivity assays. One of the most notable mutations identified in Arbo (but not in normal tissue) was the missense mutation NOTCH2 R2400*, which has been proposed as a clinically significant mutation in MCL seen in 5% of cases. NOTCH2 R2400* results in a truncated Notch2 protein, leading to a more stable and active protein. Using pharmacologic inhibition of Notch2, we showed a dependence of Arbo on NOTCH2 signaling, as well as a link between CD23 expression on Arbo and NOTCH2 activity. Arbo represents a NOTCH2 mutated model that is useful in MCL as well as other lymphomas with such mutation. We plan to deposit Arbo at the ATCC to be available for the research community.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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Mantle cell lymphoma rarely presents with testicular involvement.
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Testicular MCL may be associated with more aggressive features of MCL.
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Testicular involvement of MCL may be associated with ...decreased overall survival.
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Patients with testicular MCL are at higher risk of CNS involvement.
Mantle cell lymphoma (MCL) with testicular involvement is a rare presentation and only a few cases have been described in the literature. We present a case of MCL with testicular involvement and the first analysis of all previously reported cases assessing trends in immunohistochemical features, prognostic indicators, and survival. Our data suggest that among all MCL, testicular MCL is more likely to present with aggressive features: blastoid/pleomorphic morphology, high Ki-67 proliferative index, and CNS involvement. Testicular MCL is also associated with shorter overall survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests ...that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors.
Objective
The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL.
Methods
This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria.
Results
Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component.
Conclusions
The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL.
ClinicalTrials.gov Identifier
NCT02951156.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Lymphoma of the central nervous system (CNS) forms a rare type of lymphoma with a poor prognosis. Chemo-immunotherapy containing a methotrexate backbone remains the treatment of choice in the first ...line setting. When responses are achieved, this treatment needs to be followed, whenever possible, by treatment intensification followed by autologous stem cell transplantation (ASCT). There is no consensus on the optimal conditioning regimen for ASCT. Most studied regimens contain thiotepa, an agent that can cross the blood brain barrier, which confer excellent survival outcomes. However, this drug is not widely accessible in the United States for multiple reasons. An alternative to thiotepa-based regimens is the combination of busulfan, cyclophosphamide, and etoposide (BuCyE), which has resulted in conflicting outcomes. Here we report our experience with 3 cases of CNS lymphoma, treated with BuCyE, with a protocol using dosages different from what was previously reported, specifically with busulfan 3.2 mg/kg at days -8 to -5 (with pharmacokinetics adapted dosing at days -6 and -5), etoposide 30 mg/kg on day -4, and cyclophosphamide 60 mg/kg on day -3. Treatment resulted in excellent long-term outcomes with all 3 patients being alive at least 4 years following ASCT with no evidence of relapse. The side effect profile was acceptable, with the exception of a case of pulmonary toxicity. This cohort is limited by its small size, and further work comparing it to other treatments is being done at our institution.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Highlights • Enzastaurin induces apoptosis and cell cycle arrest in B-ALL cell lines. • Targeting PKCβ with enzastaurin inhibits AKT, GSK3β, and β-catenin phosphorylation. • PKCβ inhibition results ...in significant accumulation of β-catenin. • p73 isoforms are protected following PKCβ inhibition through upregulation of c-Jun.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Primary adrenal lymphoma (PAL) and primary renal lymphoma (PRL) are rare extranodal lymphomas, predominantly of diffuse large B-cell lymphoma subtype. Primary adrenal and renal lymphomas (PARL) ...exhibit a high predilection for the central nervous system (CNS). Therefore, current guidelines support the use of CNS prophylaxis in PARL, particularly in cases of high-risk Central Nervous System International Prognostic Index (CNS-IPI). However, the route of administration (i.e. systemic vs. intrathecal chemotherapy) has not been clearly elucidated. With this in mind, we initiated an international collaboration and literature review to analyze 50 patient cases, 20 of whome received CNS prophylaxis. Based on our analysis, we conclude that PARL may indicate a need for CNS chemo-prophylaxis in the form of systemic high-dose methotrexate (HD-MTX) over intrathecal methotrexate (IT-MTX), although IT-MTX may still have utility in certain cases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
While the incidence of non-Hodgkin's lymphoma (NHL) has declined ~1% per year (Y) since 2015, it is not known if this trend holds true for mantle cell lymphoma (MCL). The Surveillance, Epidemiology ...and End Results (SEER) 17 database includes MCL data collected from 12 US states between 2000 and 2013. However, since the launch of the new SEER 22 database, there has not yet been a study analyzing MCL trends. SEER 22 added seven more years of follow up (up to 2020) compared to SEER 17 (up to 2013), as well as the states of Illinois, Texas, Idaho, Massachusetts, and New York to the 12 states of SEER 17. Here we provide updated trends in MCL incidence and survival using the SEER 22 database, with subset analysis of age, race, and gender. Age-adjusted incidence (per 100,000 Persons/Y) of reported MCL cases were extracted from SEER 22 and tabulated at 5Y intervals (2000-2019). We found an initial increase in MCL incidence from 0.675 (2000-2004) to 0.789 (2005-2009) to 0.833 (2010-2014), followed by a slight decrease to 0.826 (2015-2019) (Fig. 1A). Using the SEER*Stat platform, we calculated the Annual Percent Change (APC) of MCL incidence from 2000 to 2019. The APC is a standard way to statistically characterize trends in MCL rates over time assuming the rates are to change at a constant percentage of the rate of the previous year. While the MCL APC from 2000 to 2014 was +2.02% signaling an annual increase, that for the years 2015 to 2019 was -0.49% indicating an average 0.49% annual decline in MCL incidence since 2015. This decline was found to be statistically significant when compared the 2000-2014 APC. Unsurprisingly, the incidence of MCL in 2020, the first year of the COVID-19 pandemic, declined to 0.767 compared to 0.814 in 2019, translating into a -5.77% percent change (PC). The PC was calculated as follows: PC=100 x rate (2020)/rate (2019)-1. This decrease in MCL rate is less pronounced than the -7.76% PC in NHL incidence in 2020. While these remarkable PCs reflect a drop in reporting and delayed/postponed diagnosis during the first year of the pandemic, the MCL incidence is expected to be less affected considering the aggressive nature of this disease prompting immediate diagnosis and medical care. Notably, the PC in diffuse large B-cell lymphoma (DLBCL) incidence in 2020 compared to 2019 was -3.77%, which contrasts with a larger PC of -8.69% in follicular lymphoma (FL). While DLBCL is aggressive and warrants immediate attention, FL is indolent, and diagnosis tended to be postponed during the early months of the pandemic. Collectively, the observed decrease in MCL incidence in 2020 could potentially reflect a real trend in the continuous MCL decline over time. When we included the 2020 data in the APC analysis, the 2014-2020 APC further decreased to -0.89% compared to -0.49% (2014-2019). The initial increase in MCL incidence (2000-2014) can be explained by improved reporting (access to electronic medical records, MCL being reported as MCL rather than NHL) and improved diagnostic identification of MCL (SOX11, CD5-negative MCL, indolent MCL, adoption of colonoscopy leading to early MCL detection). Following the observed peak in 2014, MCL incidence seems to follow the overall NHL downward trend. Subset analysis of age, gender, and race will be included in the presentation. Overall, we observed no major trends, except for an uptrend in the MCL incidence in the Black population potentially reflecting improved access to healthcare. To compare trends in MCL survival, we analyzed the 5Y observed overall survival (OS). Additionally, we calculated the relative survival rate (RSR) as the ratio of the observed OS divided by the expected OS of an age-matched comparable group from the general population. The 5Y observed OS improved over time: 45.2% (2000-2004), 49.1% (2005-2009), 53.8% (2010-2014), and 57.1% (2015-2019). This translated in a marked improvement in the 5Y RSR reaching 65.5% in 2015-2019. Unfortunately, while the 5Y RSR of the Hispanic population improved over time, it continues to be significantly lower than the non-Hispanic populations, reflecting either a disparity in access to healthcare or an overall worse prognosis. This dramatically contrasts with the 5Y RSR of the Black population, which once was among the lowest (47.3%, 2000-2004), became the highest 72.5%, (2015-2019) reflecting not only a better access to healthcare, but also a shift to a previously unrecognized better overall prognosis of MCL in Black patients (Fig. 1B).
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IJS, IMTLJ, KILJ, NLZOH, NUK, SAZU, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Objectives
Since a study published in 2002 showed a survival advantage of melphalan‐only conditioning for stem cell transplantation (HSCT) over melphalan‐total body irradiation ...(mel‐TBI) in patients with multiple myeloma (MM), most centers abandoned mel‐TBI. Mel‐TBI causes more early toxicity and is more complicated to administer, but we speculated it may result in longer term survival with radiation as an independent treatment modality. Therefore, we analyzed the long‐term outcome of patients with MM who received mel‐TBI as part of conditioning at our center.
Patients and Methods
From 1995 to 2013, 50 patients with MM underwent autologous HSCT at Tulane University Medical Center using mel‐TBI conditioning. We used Kaplan‐Meier survival analysis and compared our patients with data available from the Louisiana Tumor Registry.
Results
The mean survival of our patients was 70.98 months from time of transplant and 84.2 months from time of initial diagnosis. No differences were observed according to gender, ethnicity, or age at transplant. The expected median survival in a population‐based registry (matched for age and year of treatment) was 27 months (P<.001).
Conclusions
Total body irradiation in conjunction with melphalan as conditioning is feasible and can lead to long‐term survival. More research is necessary to determine which patients benefit most. Mel‐TBI should also be explored in conjunction with immunotherapy.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
“Accelerated” chronic lymphocytic leukemia/small lymphocytic lymphoma (A-CLL) is a rare histological variant of CLL/SLL, which tends to exhibit an aggressive clinical behavior compared to CLL. Due to ...the rarity of A-CLL (<1% of all cases), the optimal management remains ill-defined. We report two cases of A-CLL from our institution, in which both relapsed following initial chemoimmunotherapy regimens. Both patients were treated with single agent ibrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), and achieved rapid, deep and durable responses. With the absence of clear guidance on A-CLL treatment, BTKi agents should be considered in the frontline treatment of A-CLL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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