Impact of Rituximab and Methotrexate on the Survival of the Patients with Sinonasal Tract Diffuse Large B-Cell Lymphoma

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) of the sinonasal track (SNT) is a rare presentation of the aggressive lymphoid malignancy with the incidence of 0.06-0.17 per 100 000 in the Western population. SNT involvement is associated with increased risk of central nervous system (CNS) progression, and thus eligible patients are often treated with chemoimmunotherapy in combination with CNS prophylaxis with intrathecally (it) or intravenously (iv) administered methotrexate (MTX). However, the data demonstrating that the addition of CD20 antibody rituximab and/or CNS penetrating MTX improves the outcome of the patients with SNT-DLBCL are lacking. Materials and Methods: The aim of the study was to characterize the clinical findings of the patients with SNT-DLBCL treated at two University Hospital districts in Finland (Helsinki and Tampere University Hospitals). The hospital records of 59 patients were retrospectively reviewed on parameters for patient demographics, tumor characteristics, treatment and outcome. Results: Forty-five patients were treated with curative intent with CHOP-like chemotherapy, 24 (53%) of them with chemoimmunotherapy containing rituximab (R+) and 21 (47%) before the rituximab era (R-). Among the patients treated with curative intent, iv MTX was given to 24 patients (53%; M+ group), whereas the remaining 21 patients (47%) did not receive MTX (M- group). The median age was 65 years for the whole cohort, and 64 years for the patients treated with curative intent. The patients treated with curative intent had better performance status in comparison to all patients. Otherwise, the patient characteristics were similar. Follow-up data was collected to 60 months. Median follow-up time for the entire cohort was 47 months. No differences were observed in the patient characteristics between the R+ and R- groups. The patients in the M+ group were younger than the patients in the M- group (67% vs 24% were <60 years, p=0.007). Otherwise, no significant differences in the patient characteristics were found between the two groups. MTX was used equally often during the pre-R and R eras. The patients in the R+ group had lower risk of progression (RR 0.384, 95% CI 0.145-1.018, p=0.054) and death (RR 0.235, 95% CI 0.066-0.836, p=0.025) in comparison to the patients in the R- group. According to Kaplan-Meier analyses, the patients in the R+ group had better survival rates than the patients in the R- group (5-y progression free survival (PFS) 66% vs 38%, p=0.046; 5-y overall survival (OS) 80% vs 43%, p=0.015). Addition of MTX to chemotherapy also reduced the risk of progression (RR 0.384, 95% CI 0.151-0.977, p=0.044) and death (RR 0.253, 95% CI 0.080-0.795, p=0.019). According to Kaplan-Meier analyses, the patients in the M+ group had better survival rates than the patients in the M- group (5-y PFS, 67% vs 31%, p=0.036; 5-y OS 82% vs 35%, p=0.011). Only one patient in the cohort experienced CNS progression. Conclusions: SNT-DLBCL patients treated with curative intent with R containing regimen have superior survival in comparison to the patients treated in the pre-R era. Likewise, intravenously administered CNS penetrating MTX improves survival. In this cohort, only one patient experienced CNS progression, and thus the impact of different treatments on the risk of CNS progression could not be evaluated. Disclosures Mannisto: SOBI: Honoraria; Pfizer: Honoraria; Gilead: Other: Travel expenses; Celgene: Other: Travel expenses; Novartis: Other: Travel expenses; Amgen: Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Roche: Honoraria, Other: Travel expenses. Leppä:Amgen: Research Funding; Takeda: Honoraria, Other: Travel expenses; Bayer: Honoraria, Research Funding; Mundipharma: Research Funding; Roche: Honoraria, Other: Travel Expenses, Research Funding; Janssen: Research Funding; CTI Life Sciences: Honoraria.

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Immunohistochemical Expression of CD10, BCL6, and MUM1 in Primary Nodal Diffuse Large B-Cell Lymphoma: MUM1 Expression Alone (but Not Germinal Center B-Cell Immunophenotype) Is an Independent Prognostic Factor.

Blood ◽

10.1182/blood.v106.11.4706.4706 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4706-4706

Author(s):

Nicholas Wongchaowart ◽

Ena Segota ◽

Tao Jin ◽

Brad Pohlman ◽

Eric D. Hsi

Keyword(s):

B Cell ◽

Disease Progression ◽

Lower Risk ◽

B Cell Lymphoma ◽

Primary Therapy ◽

Large B Cell Lymphoma ◽

Germinal Center B Cell ◽

Risk Of Progression ◽

Bcl6 Expression

Abstract Introduction: Diffuse large B-cell lymphoma (DLBL) is a biologically and clinically heterogeneous lymphoma. Gene expression profiling studies using cDNA microarray have led to the development of a new paradigm for the subclassification of DLBL into germinal center B-cell (GCB) and activated B-cell types with a favorable and an unfavorable prognosis, respectively. The expression pattern of CD10, BCL6 and MUM1 by immunohistochemistry (IHC) has been proposed as a surrogate to distinguish GCB from non-GCB types. This immunohistochemical model must be validated in other data sets. Methods: We identified 57 cases of primary nodal DLBL for which the initial diagnostic biopsy, International Prognostic Index (IPI), and clinical follow-up were available. These patients (pts) received CHOP (n=51) or CHOP-like (n=6) chemotherapy, rituximab (n=12), radiation therapy (n=20), and high dose therapy with stem cell transplantation (SCT)(n=6) as planned primary therapy with curative intent. A tissue microarray (TMA) was constructed and cases were assessed for expression of CD10, BCL6, and MUM1. GCB and non-GCB immunophenotypes (IP) were defined as previously described (Hans et al. Blood 2004, 103:272–85). Clinical endpoints were disease progression and death. Analyses were performed using Cox proportional hazards testing. Results: The pts consisted of 32 men and 25 women with median age of 60 (range 29–82) years. 26 pts progressed and 25 pts died. Median follow-up of surviving pts was 69.9 (range 8.3–148.1) months. 64%, 82%, and 58% of cases expressed CD10, BCL6, and MUM 1, respectively, and 69% had a GCB IP using the Hans criteria. Univariate analysis showed that high IPI and MUM1 expression predicted a higher risk of progression (P<.001 and P=.027) while IPI, MUM1, and GCB IP predicted a higher risk of death (P<.001, P=.031, and P=.023). BCL6 expression was associated with a trend toward a lower risk of progression (P=.10) but not death (P=.38). By multivariate analysis, high IPI and MUM1 expression remained independent predictors of both progression (HR 7.07, 95% CI 2.68–18.63, P<.001 and HR=3.88, 95% CI 1.51–9.95, P=.005, respectively) and death (HR 6.48, 95% CI 2.57–16.34, P<.001 and HR 3.21, 95% CI 1.25–825, P.015, respectively) while BCL6 expression predicted a lower risk of progression only (HR 0.29, 95% CI 0.11–0.74, P=0.01). Two re-analyses excluding pts that received rituximab or SCT as a planned part of primary therapy gave similar results. Conclusions: We were unable to confirm the significance of GCB vs non-GCB types using CD10, BCL6, and MUM1 immuhistochemical expression patterns as independent predictors of either progression or death in this cohort of nodal DLBL. However, MUM1 expression (in addition to high IPI) was an independent predictor of a higher risk of both disease progression and death. BCL6 was an independent predictor of a lower risk of disease progression. BCL6 and MUM1 assessment using IHC in nodal DLBL provides useful prognostic information and simplifies pathological risk stratification of nodal DLBL from 3 to 2 markers. These data require confirmation in a larger, independent cohort of nodal DLBL pts treated with a rituximab-containing chemotherapy regimen.

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Prognostic Impact of Gastrointestinal Involvement in Newly Diagnosed Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-117125 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5400-5400

Author(s):

David Kasouha ◽

Nicola Lehners ◽

Katharina Kriegsmann ◽

Gerlinde Egerer ◽

Anthony D Ho ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

Univariate Analysis ◽

Elevated Serum ◽

B Cell Lymphoma ◽

Treatment Modalities ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Curative Intent ◽

Large B Cell Lymphoma

Abstract Introduction: Involvement of >1 extranodal site is regarded as a poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL). It is necessary to clarify the prognostic impact of specific extranodal sites. Gastrointestinal (GI) involvement is one of the most frequently involved extranodal sites. Methods: Patients with newly diagnosed DLBCL treated at the University of Heidelberg between 06/2001 and 07/2015 were identified and included in this retrospective analysis. Data on clinical characteristics and treatment modalities were obtained by review of medical charts. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact of variables on PFS and OS was evaluated by univariate log-rank tests and by multivariate analysis using the Cox proportional hazards model. Results: A total of 1001 patients were identified of whom 119 (11.9%) presented with GI involvement. Median age of patients with GI involvement was 63.3 years [range 19.1-86.7], 71 (59.7%) were male. 92 patients had an available international prognostic index (IPI) score, 36 (39.1%) IPI 0-1, 33 (35.9%) IPI 2-3, and 23 (25%) IPI 4-5. The most frequently involved organs of GI were stomach (51.3%), small intestine (39.5%), colon (20.2%), and esophagus (2.5%). 107 (89.9%) patients were treated in curative intent and were further analyzed regarding the prognostic impact of several factors on outcome. 80.4% of them received CHOP-like therapies, 17.8% received chemotherapy more aggressive than CHOP, typically addition of etoposide or treatment with high-dose methotrexate in case of CNS involvement, 87.9% received additional rituximab, and 22.4% additional radiotherapy In DLBCL patients with GI involvement, we identified factors associated with worse OS (P<.05) by univariate analysis: B symptoms, elevated serum LDH, and involvement of more than two extranodal sites. On the contrary, age (>60 years), sex, Ann Arbor Stage (AAS) III/IV, and Performance Status of Eastern Cooperative Oncology Group (ECOG) more than one, and elevated serum sCD25 did not have any significant impact on OS. B symptoms were as well associated with decreased PFS (P<.05) by univariate analysis. Multivariate Cox Regression analysis revealed that patients with elevated serum LDH at diagnosis had significantly worse OS (P<.05), and patients with B symptoms had significantly worse PFS (P<.05). Regarding first-line treatment modalities, escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS in univariate analysis, not in multivariate analysis. Radiotherapy did not have any significant impact on OS or PFS. Regarding all DLBCL patients treated with curative intent, GI involvement did not have any significant prognostic impact on OS or PFS. Conclusions: In this retrospective registry analysis of patients with newly diagnosed DLBCL with GI involvement, B symptoms, elevated serum LDH, and involvement of more than two extranodal sites were identified as risk factors for inferior OS. Escalation of chemotherapy to more aggressive regimes than CHOP was associated with a prolonged OS and PFS. Further analyses are required as toward which treatment modalities might be best suited to improve prognosis of GI involvement. Disclosures Kriegsmann: Celgene: Research Funding; BMS: Research Funding.

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Clinical Features, Treatments and Outcomes of HIV-Associated Diffuse Large B-Cell Lymphoma: A Single-Center Experience

Blood ◽

10.1182/blood-2020-143253 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-20

Author(s):

Tylan Magnusson ◽

Greer Burkholder ◽

Nathan Erdmann ◽

Amitkumar Mehta ◽

Mayur Narkhede ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Cd4 Count ◽

Advisory Committees ◽

Entire Cohort ◽

Large B Cell Lymphoma ◽

Extranodal Disease ◽

Hiv Negative

INTRODUCTION Recent studies have suggested that the prognosis of HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) may be improving with advances in anti-retroviral therapies (ART). A pooled analysis of clinical trial data showed that EPOCH may be associated with superior outcomes as compared to CHOP (Barta et al. Blood. 2013), but about two-third of patients in the combined analysis were treated without rituximab. A recent French study, however, showed similar overall survival (OS) between R-CHOP and R-EPOCH treated patients (Besson et al. AIDS 2017) and a phase III trial showed similar efficacy of R-CHOP vs. R-EPOCH in HIV-uninfected DLBCL (Bartlett et al. JCO 2019). The optimum frontline therapy in HIV-DLBCL is unknown as most clinical trials exclude HIV-infected patients or restrict accrual to those with undetectable HIV viral load and minimum CD4 count cut-off. Moreover, most existing studies include a majority (>60%) Caucasian population, and there is a paucity of studies on outcomes in African-American population. In this retrospective study, we describe the clinical features and outcomes of HIV-DLBCL patients seen at our institution and compare them with HIV negative DLBCL patients. METHODS We conducted a retrospective review of HIV+ DLBCL cases diagnosed and treated at our institution from 2008-2020. We used the Kaplan-Meier method to assess overall survival (OS). Univariate and multivariate analyses were performed to assess prognostic factors. HIV-DLBCL patients were matched 1:2 with HIV negative DLBCL by age and stage of lymphoma at diagnosis. Comparison of OS analysis was conducted using log-rank method and predictors of progression or death using Cox proportional hazards regression. RESULTS We included a total of 33 patients with HIV-DLBCL in our study. Median age was 46.6 years (IQR 40-53.3), 25 (76%) were males, and 20 (61%) were African-Americans (Table). 28 (85%) patients had stage III/IV and 24 (73%) had extranodal disease at diagnosis. The median CD4 count at diagnosis was 252 (IQR 89.5-409). 6 (18%) had CNS involvement at diagnosis, for which the median OS was 8.3 months. First-line treatment included rituximab-chemotherapy combinations in 25 (76%) patients. All patients continued ART during first line treatment. Median follow up duration of the entire cohort was 2.06 years (IQR 0.53-5.02 years) and 5 (15.2%) were lost to follow up. The 2-year OS for R-CHOP treated patients was 63% vs. 38% for R-EPOCH treated patients, although this failed to reach statistical significance (p=0.125). On multivariate analysis, the only factor significantly associated with difference in event free survival (EFS; progression or death) was female sex (HR 19.86; [2.652-148.7]; p=0.004). Trends were seen towards shorter EFS among patients who were tobacco smokers at time of DLBCL diagnosis (HR 2.69; 0.463-15.6]; p=0.271), CD4+ count <200 at time of DLBCL diagnosis (HR 2.39; [0.519-11.0]; p=0.264), IPI score >3 (HR 2.98; [0.480-18.5]; p=0.241), and presence of MYC gene rearrangement (HR 3.93; [0.569-27.2]; p=0.165). Treatment type (R-CHOP, R-EPOCH), ART use prior to lymphoma diagnosis, race, and insurance status were not correlated with EFS. 11 (33.3%) patients died within 1 year of diagnosis. The 2-year OS for the entire cohort was 64% vs. 68% in matched HIV-negative DLBCL patients (p=0.651). Median OS for HIV+ patients was 2.14 years (IQR 0.23-5.77) vs 2.97 years (IQR 0.76-6.48) in matched HIV-negative DLBCL patients (p=0.3996). One patient died from acute hypoxemic respiratory failure prior to starting treatment. Four patients died of complications during their first inpatient chemotherapy administration. CONCLUSION In our cohort, most HIV-DLBCL patients were African-Americans, presented with advanced stage and extranodal disease. The survival of HIV-associated DLBCL was similar to HIV-negative counterparts. All HIV-DLBCL continued ART during chemotherapy, suggesting the feasibility of this approach. There was no difference in OS between patients treated with R-CHOP vs. R-EPOCH, however there was a trend towards increased OS in patients treated with R-CHOP. CNS involvement at diagnosis was frequently seen. Despite limited sample size, we observed a significant association with gender, and a trend toward significant factors including tobacco use and low CD4 count at time of diagnosis. Disclosures Mehta: TG Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Merck:Research Funding;Roche-Genentech:Research Funding;Kite/Gilead:Research Funding;Innate Pharmaceuticals:Research Funding;Seattle Genetics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Oncotartis:Research Funding;Gelgene/BMS:Research Funding;Juno Parmaceuticals/BMS:Research Funding;fortyseven Inc/Gilead:Research Funding;Takeda:Research Funding;Incyte:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Affimed:Research Funding.

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Rituximab-CHOP and Central Nervous System Prophylaxis Using Intrathecal Methotrexate in Primary Breast Diffuse Large B-Cell Lymphoma: A Prospective, Multicenter, Single-Arm Phase II Study

Blood ◽

10.1182/blood-2019-122631 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4076-4076

Author(s):

Ho-Young Yhim ◽

Cheolwon Suh ◽

Seok Jin Kim ◽

Deok-Hwan Yang ◽

Hyeon-Seok Eom ◽

...

Keyword(s):

Phase Ii ◽

Cumulative Incidence ◽

Research Funding ◽

Phase Ii Study ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Intrathecal Methotrexate ◽

Cns Prophylaxis ◽

Large B Cell Lymphoma

Background: Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). To prevent CNS recurrence, we designed this phase II trial that addressed feasibility and activity of conventional immunochemotherapy and CNS prophylaxis. Methods: This prospective, multicenter, single-arm phase II study was conducted to evaluate efficacy and safety of 6 cycles of conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP) with the addition of 4 doses of intrathecal methotrexate (IT MTX; 12mg) during the first 4 cycles of R-CHOP in patients with primary breast DLBCL. Primary breast lymphoma was defined as lymphoma involving one or both breasts as a sole extranodal site regardless of specific nodal involvement status. The primary end-point was 2-year progression-free survival (PFS). Secondary end-points included cumulative incidence of CNS recurrence, overall survival (OS), and safety. All patients provided written informed consents and the study was registered at www.clinicaltrials.gov as #NCT01448096. Results: Thirty-three patients with primary breast DLBCL were enrolled between Jan 2012 and Jul 2017 in the Consortium for Improving Survival of Lymphoma (CISL) member institutions. The median age was 50 years at diagnosis (range, 29-75) and all were female. Right breast involvement was more common than left (18 [55%] vs 14 [42%]) and bilateral breast involvement was found in one patient (3%). Nodal involvement was present in 16 patients (49%), primarily in regional nodes (14 patients). Thus, the Ann Arbor stage was IE in 17 (52%), IIE in 13 (39%), IIIE in 2 (6.1%), and IV in 1 (3.0%). ECOG performance status was ≥2 in 1 patient (3%) and serum LDH level was elevated in 9 (27%). Therefore, the IPI and the CNS-IPI risk were mainly low (28 patients, 85%; respectively). No patients had CNS involvement at diagnosis. 32 (97%) of the 33 patients completed R-CHOP as planned, and the remaining patient withdraw a consent after four cycles of R-CHOP because of poor tolerance. CNS prophylaxis using IT MTX was completed as planned in 31 patients (94%), but it was discontinued in 2 patients because of patient's refusal. These 2 patients received two and three IT MTX doses, respectively. 32 patients (97%) were evaluable for treatment response and all these patients achieved a complete response. At the cutoff date of this analysis (10 Jul 2019), all patients who entered a follow-up phase had at least 24.0 months of follow-up. With a median follow-up duration of 46.1 months (IQR 31.1-66.8), 6 patients had experienced treatment failure and 3 of these died. The 2-year PFS and OS were 81.3% (95% CI, 67.7-94.8) and 93.5% (95% CI, 84.9-100.0), respectively (fig 1A and B). Of the 6 patients with treatment failure, diseases involved CNS with or without lymph nodes in 4 patients and breasts in 2 patients (1 ipsilateral and 1 contralateral breast recurrence). 3 of the four patients with CNS recurrence had isolated CNS recurrences (2 brain parenchymal and 1 meningeal disease) and one had a concurrent meningeal and lymph nodal recurrence. All 4 patients with CNS recurrence had received prophylactic IT MTX as planned by protocol. The 2-year cumulative incidence of CNS recurrence, taking into account the competing risk of death, was 12.5% (95% CI, 0.3-23.2, fig 1C). Although the number of patients with intermediate CNS-IPI risk was small (5 patients, 15%), the cumulative incidence of CNS recurrence did not differ significantly according to the CNS-IPI risk group. All CNS recurrences occurred within the first 2 years after enrolment. Toxicities were generally manageable during the R-CHOP and IT MTX treatment. No deaths as a result of toxicity occurred during treatment. Conclusion: Our study shows that conventional R-CHOP with prophylactic IT MTX is feasible in patients with primary breast DLBCL. However, given a substantially high rate of CNS recurrence, further studies to properly define the best strategy for CNS prophylaxis should be needed in patients with primary breast DLBCL. Figure 1 Disclosures Yoon: F. Hoffmann-La Roche Ltd: Research Funding. Kim:Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

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Comparison of adjuvant chemoradiation to perioperative chemotherapy for the treatment of resected gastric and gastroesophageal junction adenocarincoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.139 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 139-139

Author(s):

Howard John Lim ◽

Hae Rin Kim ◽

Devin Schellenberg ◽

Christian K. Kollmannsberger ◽

Winson Y. Cheung

Keyword(s):

Gastroesophageal Junction ◽

Survival Rates ◽

Patient Characteristics ◽

Operative Management ◽

Descriptive Statistics ◽

Treatment Modalities ◽

Pharmacy Records ◽

Adjuvant Chemoradiation ◽

Kaplan Meier

139 Background: There are several accepted peri-operative treatment modalities for resected gastric (GC) and gastroesophageal junction (GEJ) adenocarcinoma. In 2008, peri-operative chemotherapy (CT) using the MAGIC protocol was adopted as the preferred approach over adjuvant chemoradiation with the MacDonald protocol (cXRT) in British Columbia. An era to era comparison was performed to determine if there were differences in outcomes. Methods: Data from pharmacy records of patients (pts) referred to 1 of 5 cancer treatment centres in BC were analyzed from Jan 2001-July 2010. Pts that underwent curative resection for GC or GEJ were included. The cXRT cohort was defined as those treated from Jan 2001-Dec 2007, prior to the introduction of CT. The CT cohort included those treated from Jan 2008-July 2010. Descriptive statistics were used to compare the groups. Survival analysis was performed using Kaplan Meier methods. Results: Table 1 summarizes the patient characteristics. In the CT arm, there were more males, fewer pts with a LN ratio >0.2, and shorter median follow-up. 92.1% completed pre-operative chemotherapy and 44.7% completed post-operative chemotherapy whereas 73.3% of pts completed cXRT (p<0.05). Median survival was 37.5 and 36.9 months in the CT and cXRT arms, respectively. Conclusions: Delivery of CT was consistent with the MAGIC trial whereas more patients completed cXRT than in the MacDonald trial (73.3% vs. 64%). Outcomes of CT compared to cXRT appear to be similar in this comparative analysis with similar relapse and survival rates. Pre-operative CT results in fewer pts with a LN ratio > 0.2. Either modality can be considered in the peri-operative management of GC or GEJ adenocarcinoma. [Table: see text]

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DA-EPOCH-R in Primary Mediastinal B-Cell Lymphoma; Analysis of End of Therapy FDG-PET and Outcome

Blood ◽

10.1182/blood.v128.22.1116.1116 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1116-1116 ◽

Cited By ~ 3

Author(s):

Christopher Joseph Melani ◽

Ranjana Advani ◽

Clara C. Chen ◽

Kelsey M. Walters ◽

David Venzon ◽

...

Keyword(s):

Fdg Pet ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Patient Characteristics ◽

Mediastinal Radiation ◽

Deauville Score ◽

Kaplan Meier ◽

Pet Scans

Abstract Background: Primary mediastinal B-cell lymphoma (PMBL) is a distinct diffuse large B-cell lymphoma that occurs in adolescents and young adults. Retrospective studies suggest dose-intensive therapy is more effective than R-CHOP, and support a role for mediastinal radiation following R-CHOP. We demonstrated that DA-EPOCH-R is effective and obviates the need for mediastinal radiation, thus eliminating the risk of long-term toxicities (NEJM 2013;368:1408-16). End of therapy (EOT) FDG-PET is often performed to assess residual mass activity. The clinical value of EOT negative FDG-PET is under investigation in an international study in which FDG-PET negative patients are randomized to receive radiation or observation following immunochemotherapy (IELSG 37). All patients with an EOT positive FDG-PET receive mediastinal radiation. Herein, we investigate the predictive value of EOT FDG-PET following DA-EPOCH-R and provide updated results from the National Cancer Institute (NCI) and Stanford University Hospital publication of PMBL (NEJM 2013;368:1408-16). Methods: Ninety-two patients with newly diagnosed PMBL were treated with DA-EPOCH-R (Table 1). DA-EPOCH-R was administered for 6-8 cycles as previously described and no patients received up-front radiation. EOT FDG-PET was performed in 76 (83%) patients and scored retrospectively according to Deauville criteria with scores 4 to 5 called positive and scores 1 to 3 called negative. Patients with EOT positive FDG-PET scans were followed with serial scans to distinguish persistent disease from resolving inflammatory changes. The NCI and Stanford cohorts showed no significant differences in outcome and were therefore combined for analysis of event free survival (EFS) and overall survival (OS). Analyses of EFS and OS in patients with Deauville positive and negative EOT FDG-PET scans were also performed. Results: Patient characteristics were similar in the NCI and Stanford cohorts (Table 1). Overall, the median age was 31 years (range, 18 to 68), 59% were female, 59% had mediastinal masses > or = 10 cm and 20% of patients had stage IV disease. At a median follow-up of 5.3 years, the EFS and OS are 90% and 94%, respectively (Figure 1). Of 76 EOT FDG-PET scans performed, 25 (33%) were positive (Deauville score 4 or 5) and 51 (67%) were negative (Deauville score 1 to 3). Only 1 (2%) patient with an EOT negative FDG-PET scan relapsed (at 1 year), and 5 (20%) patients with an EOT positive FDG-PET scan had residual disease and received further therapy. EOT FDG-PET had a sensitivity and specificity of 83% and 71%, respectively, and a positive and negative predictive value of 20% and 98%. Comparison of outcome for EOT FDG-PET negative and positive patients at 5.3 years was 92% and 80% for EFS (p= 0.043), respectively, and was 94% and 91% for OS (p= 0.37) (Figure 2). Serial monitoring of false positive EOT FDG-PET scans showed reduction or occasionally stabilization of SUV, which is consistent with inflammatory causation. There were no events in the 16 patients without evaluable EOT FDG-PET scans resulting in an EFS of 100%. This EFS, however, was not significantly different than that of patients with evaluable EOT FDG-PET scans. Conclusions: DA-EPOCH-R (without radiation) is highly effective in PMBL and has an EFS of 90% with long-term follow-up. An EOT negative FDG-PET has a negative predictive value of 98%. Even among patients with an EOT positive FDG-PET, 80% are cured of disease and achieve long-term remission. These results demonstrate that EOT Deauville 4-5 FDG-PET scans following DA-EPOCH-R do not accurately identify patients with residual disease in most cases and should not be used to justify mediastinal radiation. In the absence of disease progression on CT scans, patients with EOT positive FDG-PET scans should be carefully monitored with short interval (e.g. 4-6 weeks) repeat FDG-PET scans to assess progressive SUV changes and need for biopsy before instituting further therapy. Table 1 Patient Characteristics Table 1. Patient Characteristics Figure 1 Kaplan-Meier Estimate of EFS for Combined NCI and Stanford Cohorts Figure 1. Kaplan-Meier Estimate of EFS for Combined NCI and Stanford Cohorts Figure 2 Kaplan-Meier Estimate of EFS by EOT FDG-PET Deauville Score Figure 2. Kaplan-Meier Estimate of EFS by EOT FDG-PET Deauville Score Disclosures Advani: Kyowa Hakko Kirin: Consultancy, Honoraria; Infinity: Research Funding; FortySeven: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Sutro: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Stanford University: Employment; Millennium: Research Funding; Kura: Research Funding; Celgene: Research Funding; Regeneron: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Agensys: Research Funding.

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Lymphocyte-to-Monocyte Ratio at Diagnosis and Survival in De Novo Double/Triple Hit Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.3885.3885 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3885-3885

Author(s):

Luis Porrata ◽

Kay Ristow ◽

Ellen D. McPhail ◽

William Macon ◽

Matthew J Maurer ◽

...

Keyword(s):

Prognostic Factor ◽

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphocyte To Monocyte Ratio ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract The lymphocyte-to-monocyte ratio at diagnosis (LMR-D) has been reported to be a prognostic factor for clinical outcomes in both T-cell and B-cell lymphomas. However, there are no reports testing the prognostic ability of LMR-D in patients diagnosed with de novo double/triple hit diffuse large B cell lymphoma (DLBCL). Thus, we set out to investigate if the LMR-D is a prognostic factor for survival in de novo double/triple hit lymphomas. From 10/5/1998 until 1/16/2015, thirty-four patients with de novo double/triple hit DLBCL were identified for this study. Double and triple hit were defined by interphase FISH evaluating three fusion signals to identify the BCL2 translocation and IGK/MYC D-FISH probe to identify whether the partner is IG or non-IG. Interphase fluorescence in situ hybridization (FISH) was performed on paraffin sections using probes that included 8q24 (5'MYC, 3'MYC); t (2;8), IGK/MYC; t(8,14), MYC/IGH; t(8;22), MYC/IGL; 3q27 (3'BCL6, 5'BCL'6); and 18q21 (3'BCL2, 5'BCL2). The cohort included 14 females and 20 males. The median follow-up for the cohort was 9.0 months (range: 0.4-72.6 months). Using the median for the LMR-D as the cut-off value, patients with a LMR-D ≥ 1.2 experienced superior overall survival (OS) [Hazard ratio (HR) of 0.127, 95% confidence interval (CI) of 0.019-0.530, p < 0.004] and progression-free survival (PFS) [HR of 0.107, 95 CI of 0.024-0.335, p < 0.0001]. The median follow up for OS for patients with a LMR-D ≥ 1.2 was not reached with a 5-year OS rate of 82% (95% CI of 49%-95%) compared with a median follow-up of 10 months for patients with a LMR-D < 1.2 with a 0% 5 year OS rate, p < 0.003 (Figure 1A). The median PFS for patients with a LMR-D ≥ 2 was not reached with a 5 years PFS of 74% (95%CI, of 43%-91%) compared with a median follow-up of 4.7 months for patients with a LMR-D < 1.2 and 0% 5 year PFS rate, p < 0.0001 (Figure 1B). After adjusting for the International Prognostic Index, multivariate analysis showed that the LMR-D remained an independent prognostic factor for OS [HR = 0.180, 95% CI of 0.254-0.784, p < 0.02] and for PFS [HR of 0.127, 95%CI of 0.029-0.409, p < 0.0003]. In spite of the small cohort of de novo double/triple hit DLBCL, the LMR-D was identified as a prognostic factor for clinical outcomes for this specific set of aggressive lymphomas. Further studies are warranted to confirm our findings. Table.LMR-D ≥ 1.2, N = 18Events = 2LMR-D < 1.2, N = 16Events = 8P < 0.003LMR-D ≥ 1.2, N = 18Events = 3LMR-D < 1.2, N = 16Events = 14P < 0.0001Figure 1AB Figure 1. Figure 1. Disclosures Maurer: Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Off Label Use: New agent in a combination regimen..

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A Pilot Study of Brentuximab Vedotin, Rituximab and Dose Attenuated CHP in Patients 75 Years and Older with Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2020-140384 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Patrick M. Reagan ◽

Craig A. Portell ◽

Carla Casulo ◽

Andrea M. Baran ◽

Allison Magnuson ◽

...

Keyword(s):

Older Patients ◽

Research Funding ◽

Sensory Neuropathy ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Genetics Research ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Peripheral Sensory

Older patients with hematologic malignancies are underrepresented on prospective clinical trials relative to the incidence of disease in this group (Kanapuru et al, 2020). There are few studies in diffuse large B-cell lymphoma (DLBCL) focused specifically on older patients. Rituximab and dose attenuated cyclophosphamide, doxorubicin, vincristine, and prednisone (R-miniCHOP) has been studied on a prospective trial in fit patients aged 80 years and older. Seventy-two percent of patients on this study completed 6 cycles of R-miniCHOP. The overall response rate (ORR) was 73%, and the 2-year progression free survival (PFS) was 47% (Peyrade et al, 2011). Novel regimens are needed to improve upon the efficacy of therapy while preserving tolerability. Brentuximab vedotin (BV) has demonstrated activity in relapsed and refractory DLBCL (Jacobsen et al, 2015) as well as in combination with chemoimmunotherapy (Svoboda, 2020). This study evaluates the feasibility of BV with dose attenuated chemoimmunotherapy. Methods: Patients with both CD30 positive (cut off 1%) and CD30 negative DLBCL aged 75 years and older were enrolled on the study. Patients received six, 3-week cycles of BV 1.8 mg/kg, cyclophosphamide 400 mg/m2, doxorubicin 25 mg/m2, vincristine 1 mg and prednisone 40 mg/m2 days 1-5 (BV R-miniCHP). For the first cycle patients received BV and prednisone as a prephase starting one week prior to cycle 1. All patients received pegfilgrastim. All patients underwent geriatric assessments at screening, following prephase and at the end of treatment. The primary endpoint was feasibility of this regimen in older patients. The regimen was considered feasible if 71% of patients completed 6 cycles of treatment with a 90% confidence interval (CI)=(58.0, 90.6%). Secondary endpoints included toxicity, ORR and complete response (CR) evaluated by positron emission tomography, PFS and overall survival (OS). Response assessments used the Lugano Criteria (Cheson et al, 2014). PFS and OS were estimated using the Kaplan-Meier method. Results: Twenty-two patients were enrolled and started prephase with BV and prednisone. Their baseline characteristics are summarized in the table. Seventy-seven percent (17/22) of patients completed 6 cycles of BV R-miniCHP. Reasons for not completing treatment included progressive disease in 2 patients, myocardial infarction, fatigue, and an unrelated injury in 1 patient each. Twenty-one patients were evaluable for response. ORR was 86% (18/21) in all patients, with 67% (14/21) achieving CR. In CD30 positive patients the ORR was 80% (8/10) and the CR rate was 70% (7/10). In CD30 negative patients the ORR was 91% (10/11) and the CR rate was 64% (7/11). With a median follow up of 23 months, median OS and PFS (figure) were not reached. The 2-year PFS was 60.6%, 90% CI=(40.0%, 76.1%), and the 2-year OS was 73.9%, 90% CI=(52.4%, 86.8%). The most common adverse events (AEs) were fatigue (82%), anemia (50%), diarrhea (50%), dysgeusia (45%) and peripheral sensory neuropathy (45%). Grade ≥3 AEs seen in more than 2 patients included neutropenia (23%), fatigue (18%), pneumonia (18%), hypoxia (14%), thrombocytopenia (9%) and thromboembolism (9%). Grade ≥3 peripheral sensory neuropathy was seen in 9% of patients. There were two deaths in patients receiving study treatment. These included a myocardial infarction related to treatment, and a bowel obstruction secondary to disease progression. Three other patients have died in follow up with 2 secondary to disease progression and 1 due to an unrelated event. Conclusions: The study met its primary feasibility endpoint with 77% of patients completing 6 cycles of therapy. This regimen was delivered safely in this population and toxicities were consistent with those reported in larger prospective studies with R-miniCHOP or ofatumumab and miniCHOP (Peyrade et al, 2011; Peyrade et al 2017). Peripheral neuropathy is a key AE of interest given the inclusion of BV and while nearly half of patients experienced some peripheral neuropathy, it was severe in only 9% of pts. The ORR and CR rate, as well as the 2-year PFS compare favorably to other prospective studies in a population that included patients with high clinical risk, histologic transformation, and double hit lymphoma. BV and R-miniCHP may be a feasible regimen in older patients, and warrants further study based on these preliminary data demonstrating clinical activity and tolerability. Figure 1 Disclosures Reagan: Seattle Genetics: Research Funding; Curis: Consultancy; Kite, a Gilead Company: Consultancy. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Barr:Gilead: Consultancy; Verastem: Consultancy; Abbvie/Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Morphosys: Consultancy; TG therapeutics: Consultancy, Research Funding; Merck: Consultancy. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Roche: Other: Travel expenses; Kite Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Consultancy; Astellas: Consultancy; Bayer: Consultancy.

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Single Institution Experience of Gastrointestinal Involvement of Diffuse Large B- Cell Lymphoma: Presentation, Outcomes and Patterns of Treatment Failure

Blood ◽

10.1182/blood-2018-99-117651 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2982-2982

Author(s):

Puja C. Arora ◽

Victor M. Orellana-Noia ◽

Abeer Alfaraj ◽

Wenzinger Christopher ◽

Sandra Monson ◽

...

Keyword(s):

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Response To Treatment ◽

Gi Tract ◽

Cns Involvement ◽

Single Institution ◽

Large B Cell Lymphoma ◽

Duration Of Response

Abstract Introduction Extranodal (EN) involvement of the gastrointestinal (GI) tract in diffuse large B-cell lymphoma (DLBCL) presents heterogeneously across different anatomic sites and often occurs at initial diagnosis. Rituximab, anthracycline-based combination chemotherapy, radiation, and surgery have all been studied separately and in various combinations. However, given the variability in how patients may present in these contexts, there remains no consistent standard of care or pattern of treatment failure. We hypothesized these patients have different outcomes than those lacking this EN site of involvement. Methods We conducted a single-institution, retrospective analysis of consecutive cases who presented at initial diagnosis with DLBCL involving the GI tract including the esophagus, stomach, small intestine, or portion of large intestine. We performed a search in the University of Virginia Pathology database to identify all patients age >/= 18 years with DLBCL involving the GI tract and excluded those without additional clinical information available for review. A total of 51 patients were identified and we retrospectively collected data on demographics, date of diagnosis, involvement of extranodal sites, stage, International Prognostic Index (IPI) score, treatment, response to treatment, relapse, and survival at last follow-up. Results Of the 51 DLBCL patients, 65% of patients were male and 82% were Caucasian. Median age was 65 years (range 22-92). Three patients had HIV infection and no patients had active hepatitis B or C. Sites included gastric (51%), colon (27%), small bowel (12%), esophagus (4%), and rectum (2%); 4% had multiple GI sites involved. Forty-nine percent of patients presented with abdominal pain. Other common presentations included gastric/bowel perforation (12%), GI bleed (12%), gastric/small bowel obstruction (12%). Three cases (6%) were discovered on a screening colonoscopy. Forty-three percent of patients presented as stages I-IIIE versus 57% presented as stage IVE. Fifty-five percent were IPI 0-2 while 45% were IPI 3-5. Six patients (12%) had CNS involvement at presentation. Median follow-up was 20 months (range 26 days to 17 years). Six patients were lost to follow-up prior to assessment of response, and 4 had treatment discontinued early (3 due to grade 5 infection, 1 for GI perforation leading to death). One patient was still undergoing treatment. Forty patients were available to assess for response to treatment. The majority were treated with R-CHOP (57%) or DA-R-EPOCH (29%). Sixty-eight percent (n=27) had a complete response (CR), 22.5% (n=9) a partial response (PR), and 10% (n=4) were primary refractory. Of the 27 CRs, 13 (48%) had presented as stage 1-3 and 14 (52%) had presented as stage 4; 16 (59%) had an IPI score of 0-2 and 11 (41%) had an IPI score of 3-5. Of the four patients who had primary refractory disease, 3 had multiple EN sites involved at diagnosis, including 2 with CNS involvement. Of those who had a response (including CR or PR), median duration of response was 1 year (range 4 months to 13 years). Eleven patients (28%) had a relapse: 3 in the CNS, 5 in the GI tract (3 at the same site of initial involvement, 1 with a different GI site involved, and 1 with a different GI site in addition to systemic disease), and 3 in lymph nodes alone. Time to relapse ranged 1 month to 13 years with a median of 8.4 months. Fifty-seven percent of patients were alive at time of last follow-up. Median Overall survival (OS) was 5.7 years and Median Progression Free Survival (PFS) was 5.6 years (Figure 1). Conclusion There is limited data on how patients with DLBCL involving the GI tract initially present and respond to therapy. This study encompassing almost twenty years of experience at a single institution, suggests that though patients present at all stages and as low risk vs high risk IPI, outcomes are poor compared to prior studies, especially when additional extranodal sites are involved. Duration of response can be substantial, however relapses are common and may present years later indicating ongoing follow-up is imperative. Figure 1. Figure 1. Disclosures Portell: AbbVie: Research Funding; Amgen: Consultancy; Kite: Research Funding; TG therapeutics: Research Funding; BeiGene: Research Funding; Genentech/Roche: Consultancy, Research Funding; Acerta: Research Funding; Infinity: Research Funding. Williams:Sandoz: Consultancy; Pharmacyclics: Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; Gilead: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Juno: Consultancy.

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Combination of Umbralisib, Ublituximab, and Bendamustine Is Safe and Highly Active in Patients with Advanced Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Blood ◽

10.1182/blood-2018-99-118917 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4197-4197 ◽

Cited By ~ 1

Author(s):

Matthew A. Lunning ◽

Philip Bierman ◽

R. Gregory Bociek ◽

Marshall T. Schreeder ◽

Tanya Siddiqi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Employment Equity ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Ecog Ps

Abstract Introduction: Umbralisib (UMB) is a next generation, once daily, PI3Kδ/CK1ε inhibitor, active in patients with relapsed or refractory (rel/ref) hematologic malignancies that, in long-term follow-up, has demonstrated a uniquely differentiated safety profile from prior PI3Kδ inhibitors (Davids, 2018). Ublituximab (UTX) is a novel glycoengineered mAb targeting a unique epitope on the CD20 antigen. Bendamustine (Benda) is an active chemotherapy agent in pts with lymphoma. The combination of UMB + UTX (U2) is tolerable and active in patients with rel/ref hematologic malignancies and registration directed trials for patients with CLL & NHL are ongoing. This Phase 1 trial evaluates the safety and efficacy of U2 + Benda in patients with advanced diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Methods: Eligible patients had rel/ref DLBCL or FL with an ECOG PS ≤ 2 w/o limit to number of prior therapies. ANC of ≥ 750 and Platelets ≥ 50,000 were required; no growth factor support was permitted in Cycle 1 (cohort escalation group only). Patients refractory to prior PI3Kδ, Benda, or anti-CD20's were eligible. UTX was dosed on Days 1, 8, 15 of Cycle 1, Day 1 of Cycle 2-6, followed by Cycle 9 & 12. UMB was started at 800 mg QD with a -1 dose reduction cohort at 600 mg if not tolerated in ≥ 2/6 patients. Benda was dosed at 90 mg/m2 on Days 1 & 2 of Cycles 1-6 only. Primary endpoints included safety and efficacy (Cheson 2007). Results: Thirty-nine patients were evaluable for safety: 26 DLBCL and 13 FL. Med age 67 yo (range 31-81); 23 M/16 F; median prior treatment regimens = 2 (range 1-6); 22 pts (56%) were refractory to prior treatment and 6 patients had progressed post-transplant; ECOG PS 0/1/2 (12/25/2). Initially 2/4 patients at 800 mg UMB experienced AE's in Cycle 1 that led to treatment interruption (rash, neutropenia) thus the 600 mg dose of TGR-1202 was explored. No additional Cycle 1 treatment delays were reported at the 600 mg dose level, which was later expanded and the 800 mg UMB dose was evaluated with the use of growth factor support in cycle 1 permitted. The most common AE's regardless of causality included diarrhea (54%; G3/4 15%), nausea (49%; G3/4 5%), vomiting (38%; G3/4 0%), neutropenia (33%; G3/4 33%) and pyrexia (31%; G3/4 0%). Thirty-eight patients (25 DLBCL/13 FL) were evaluable for efficacy (1 DLBCL patient came off study for G4 neutropenia prior to first assessment). ORR in the respective groups is shown in Table 1. The median time to response was 8 weeks. The median DOR was 9.6 months (95% CI: 2.5-NR) for patients with DLBCL, and was not reached (95% CI: 8.0-NR) for patients with FL, at a median duration of follow-up for responders of 11.5 months (range 2.9 - 30+ mos). Conclusions: The combination of U2 + bendamustine has exhibited manageable toxicity with significant activity in advanced DLBCL and FL patients, including an encouraging CR rate in advanced patients. Based upon the early activity of the triplet, a registration directed study is underway for patients with rel/ref DLBCL (UNITY-NHL). Disclosures Lunning: Gilead: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; Bayer: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Genzyme: Consultancy; Kite: Consultancy; Juno: Consultancy; Genentech: Consultancy; Portola: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy. Siddiqi:Juno Therapeutics: Other: Steering committee. Flowers:Abbvie: Research Funding; TG Therapeutics: Research Funding; Gilead: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Consultancy; Pharmacyclics: Research Funding; V Foundation: Research Funding; Abbvie: Consultancy, Research Funding; Bayer: Consultancy; Karyopharm: Consultancy; Burroughs Wellcome Fund: Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Gilead: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Pharmacyclics/ Janssen: Consultancy; Spectrum: Consultancy; Janssen Pharmaceutical: Research Funding; Denovo Biopharma: Consultancy; Acerta: Research Funding. Cohen:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Cutter:TG Therapeutics, Inc.: Consultancy. Pauli:TG Therapeutics, Inc.: Consultancy. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics: Employment, Equity Ownership. Weiss:TG Therapeutics: Employment, Equity Ownership. Vose:Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Roche: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Acerta Pharma: Research Funding; Epizyme: Honoraria; Celgene: Research Funding.

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