scholarly journals Baseline Hypoalbuminemia Does Not Appear to be an Adverse Prognostic Factor in Patients with Relapse/Refractory B-Cell Lymphomas Treated with Axicabtagene Ciloleucel (axi-cel)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5343-5343
Author(s):  
Megan Melody ◽  
Sangeetha Gandhi ◽  
Zaid Abdel Rahman ◽  
Paula A Lengerke Diaz ◽  
Nicole Gannon ◽  
...  
Keyword(s):  
Serum Albumin ◽  
B Cell ◽  
Mayo Clinic ◽  
Research Funding ◽  
Response Rate ◽  
Normal Serum ◽  
Advisory Board ◽  
Genetics Research ◽  
Significant Difference

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

scholarly journals P0341RITUXIMAB IN THE TREATMENT OF PRIMARY MEMBRANOUS NEPHROPATHY - A COMPARATIVE STUDY OF THREE REGIMEN

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Harbir Singh Kohli ◽  
Raja Ramachandran ◽  
Manish Rathi ◽  
Ranjana Minz ◽  
Ritambhra Nada Duseja
Keyword(s):  
Targeted Therapy ◽  
Adverse Events ◽  
Serum Albumin ◽  
Cumulative Dose ◽  
Membranous Nephropathy ◽  
Response Rate ◽  
Secondary Outcome ◽  
Therapy Initiation ◽  
Significant Difference

Abstract Background and Aims Different rituximab dosing schedules have been used to manage primary membranous nephropathy (PMN). Better response rate and toxicity needs to be balanced to arrive at correct dose. The dosing schedules in PMN as of now are an on the lines of the management of lymphoma or rheumatoid arthritis. In the current study, we report the 1-year outcome of patients treated with three dosing schedules of rituximab in PMN. Method The current report is a study of patient of PMN treated with three different dosing schedules of rituximab treatment. The study included PMN patients with nephrotic syndrome (proteinuria&gt;3.5 g/day and serum albumin of &lt; 3.5 g/dL). Patients with secondary membranous nephropathy and a history of prior exposure of immunosuppressive therapy in the last three months were excluded from the study. The three dosing schedules of rituximab were 1 g (on day 0,15) (regimen 1), 375 mg/m2 (weekly for four weeks) (regimen 2) or CD19 targeted rituximab therapy (375 mg/m2 as the initial dose and additional dose 100 mg, when the CD19 cell count was&gt; 5/ul or &gt;1%, done every month for 12 months) (regimen 3). Serum PLA2R autoantibodies were done before rituximab therapy and at six months of therapy initiation. Primary outcomes: Remission at the end of 12 months of therapy initiation. Secondary outcome: Complete remission (CR) and partial remission (PR), remission with different treatment schedules and adverse events. Definition: CR: reduction of proteinuria to &lt;0.5 g/d and with creatinine clearance of &gt;60 ml/min/1.73m2 and serum albumin &gt; 3.5 g/dl. PR: reduction of proteinuria to 0.5–3.5 g/day and stable serum creatinine. A p-value of &lt;0.05 was considered significant. Results The study included 87 patients of PMN. The mean age of the patients was 33.36±15.38 (range 15-61) years. Thirty-two (36.4%) and 56 (63.6%) patients received rituximab as the first-line therapy and for relapsing/resistant disease, respectively. Forty, 15 and 33 patients received regimen 1, 2 and 3, respectively. The median proteinuria, serum albumin and creatinine at the baseline before rituximab therapy was 5.90 (IQR 4.20,9.75) gm, 2.50 (IQR 2.15,3.25) g/dl and 0.88 (IQR 0.77,1.09) mg/dl, respectively. At the end of 12 months of follow-up, 55 (56.8%) patients received remission. Nineteen (21.6%) and 32 (36.3%) patients achieved CR and PR, respectively. In regimen 1, 12 (30%) and 13 (32.5%) patients achieved CR and PR, respectively. In regimen 2, 2 (13.3%) and 5 (33.3%) patients achieved CR and PR, respectively. In regimen 3, 5 (15.6%) and 14 (43.7%) patients achieved CR and PR, respectively. One patient in the CD19 targeted therapy (regimen 3) was lost to follow-up after the 1st dose; all but one patient in the received regimen three as a second-line treatment. There was a significant association of anti-PLA2R to clinical response (p&lt;0.05). There was no difference in the response rate among the three groups (p&gt;0.05). A total of 7 (7.9%) patients had severe adverse events, there was no difference in the 3 regimens. (p&gt;0.05) The cumulative dose in regimen 3 was significantly less as compared to regimen 1 & 2 (p&lt;0.01) Conclusion Rituximab induces remission in two-thirds of the patients with PMN. There is no significant difference in the remission rates between different rituximab regimens. CD19 targeted therapy is equally effective with lower cumulative dose.

Phase I/II Trial of Ofatumumab/Lenalidamide for Patients with Relasped/Refractory B-Cell Non-Hodgkin Lymphoma: High Response Rate in Indolent Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3692-3692
Author(s):  
Julie M Vose ◽  
Fausto R. Loberiza ◽  
R. Gregory Bociek ◽  
Philip Bierman ◽  
James O. Armitage
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
High Response Rate ◽  
Indolent Lymphoma ◽  
Non Hodgkin Lymphoma

Abstract Abstract 3692 Introduction: Lenalidomide and ofatumumab have demonstrated clinical activity as single agents in a variety of types of non-Hodgkin lymphoma (NHL). This trial is a phase I/II trial combining these two agents for treatment of patients with relapsed and refractory B-cell NHL. Methods: Patients with relapsed and refractory B-cell NHL of any histology were enrolled on a phase I/II trial combining lenalidomide and ofatumumab. Nine patients were on the phase I part of the trial and received a fixed dose of ofatumumab 1000 mg weekly × 8 doses along with lenalidomide 15 mg (N=3), or10 mg (N=6) for 21/28 days until the time of progression. The phase II portion of the study has 28 patients on the study with adequate follow-up at the time of analysis. The phase II doses were ofatumumab 1000 mg weekly × 8 along with lenalidomide 10 mg on 21/28 days. The lenalidomide was dose adjusted according to standard dose reduction criteria. All patients were on either a daily aspirin or other anticoagulation for thrombosis (DVT) prophylaxis. Results: Thirty seven evaluable patients had adequate follow-up at the time of the analysis. The patients had a median age of 65 years (range 36–81), 76% were male, and 89% have an ECOG performance status of 0–1. The majority of patients had a relapsed indolent lymphoma with 12/37 (32%) follicular lymphoma (FL), 6/37 (16%) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 7/37 (19%) mantle cell lymphoma (MCL), one unclassifiable indolent lymphoma (3%), and 11/37 (30%) diffuse large B-cell lymphoma (DLBLC). The median duration of follow-up of surviving patients was 13 months (range 4–24). The complete response (CR) rate was 2/37 (5%) (one each FL and DLBCL) and the partial response (PR) rate was 13/37 (35%) for an overall response rate (ORR) of 15/37 (40%). The 1 year progression-free survival (PFS) was 41% (95% CI; 23–58) and the 1-year overall survival (OS) was 68% (95% CI; 49–82). In an analysis of response by patient variables, those significant included the patients with an FL histology (ORR 83%) vs. DLBCL (ORR 18%) or other(SLL, MCL, unclassifiable) (ORR 21%) (p= 0.001) and lactic dehydrogenase (LDH) normal (ORR 56%) vs. elevated (ORR 14%) (p= 0.01). In an analysis of variables for PFS, the variables with significance include diagnosis of FL (1-year PFS 67%) vs. DLBCL (9%) and SLL, MCL, unclassifiable (45%) (p=0.002), LDH normal (1-year PFS 55%) vs. elevated LDH (1-year PFS 19%), and number of prior chemotherapies 1–2 (1-year PFS 58%) vs. > 3 (1-year PFS 19%). Higher grade toxicities included grade 4 neutropenia in 9/37 (24%), one each of grade 4 bacteremia, one grade 4 DVT, stroke, and acute renal failure. Conclusions: The combination of lenalidomide and ofatumumab was well tolerated by most patients. The patients with indolent NHL had a high response rate of 83% and a 1-year PFS of 67%. Disclosures: Vose: Glaxo Smith Kline: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidamide and Ofatumumab will be discussed for use in indolent and aggressive non-Hodgkin lymphoma.

Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: Long Term Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 292-292 ◽  
Author(s):  
Joseph M Connors ◽  
Stephen Ansell ◽  
Steven I. Park ◽  
Michelle A. Fanale ◽  
Anas Younes
Keyword(s):  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Brentuximab Vedotin ◽  
Advanced Stage ◽  
Newly Diagnosed ◽  
Genetics Research

Background: The ABVD regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine is a common standard of care for the frontline treatment of advanced stage Hodgkin lymphoma (Santoro 1987; Duggan 2003) and is curative for the majority of patients; however, up to 30% of patients require a secondary therapy. Hodgkin Reed-Sternberg cells of classical HL (cHL) typically express CD30. In a pivotal phase 2 trial brentuximab vedotin (A, ADCETRIS®), comprised of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) induced an objective response rate (ORR) of 75% and complete response rate (CR) of 34% in highly treatment-refractory patients with cHL (Younes 2012). Methods: We conducted a phase 1, open-label, multicenter study to evaluate the safety and efficacy of A when administered in combination with standard therapy (ABVD) or the same regimen without bleomycin (AVD) (Younes 2013). Adult patients with newly diagnosed advanced stage (II bulky, II B, III or IV; 80% stage III or IV) received doses of 0.6, 0.9, or 1.2 mg/kg A with standard doses of ABVD or 1.2 mg/kg with AVD, depending on cohort assignment on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Previously we reported that among patients assessable for response 95% of patients given ABVD+A achieved a CR, as did 96% of patients given AVD+A. None of 26 patients given AVD+A but 11 of 25 (44%) given ABVD+A experienced pulmonary toxicity, including 2 deaths, establishing that A cannot be safely combined with bleomycin. In this current study we provide the long term survival and safety data on patients enrolled in the phase 1 trial. Results: In total 51 patients were assigned to either ABVD+A (n=25) or AVD+A (n=26). 1 patient who withdrew from the trial during the first cycle of ABVD+A is excluded from this analysis and 1 patient who received 3 cycles of ABVD+A, then withdrew, then received 3 cycles of ABVD alone and 2 patients who died during treatment (pulmonary toxicity) are included (total n=50). Median follow-up from diagnosis for the 24 patients treated with ABVD+A is 41 months (range 9-51 months) and for the 26 patients treated with AVD+A, 31 months (range 9-35 months). All 26 patients treated with AVD+A have been followed longer than the longest time to relapse (7 months). 45 patients remain in first CR and 5 treatment failures have occurred: 4 in the ABVD+A cohort (2 toxic deaths; 2 relapses (9 and 23 months from diagnosis)) and 1 after AVD+A (7 months from diagnosis). 3y-failure-free survival (3y-FFS) is 83% and 96% for ABVD+A and AVD+A, respectively, and 3y-overall survival (3y-OS), is 92% and 100%. No additional toxic deaths have occurred in follow-up. Conclusions: These updated outcomes reflecting the impact of adding brentuximab vedotin (1.2 mg/kg) to standard doses of AVD for classical Hodgkin lymphoma, demonstrating 96% 3y-FFS and 100% 3y-OS with no major unexpected toxicity, strongly support the current large international trial comparing AVD-A (AVD+1.2mg/kg brentuximab vedotin) to standard ABVD (ECHELON-1, clinicaltrials.gov NCT01712490), which may identify a new, less toxic gold standard treatment for advanced stage classical Hodgkin lymphoma. Disclosures Connors: Seattle Genetics: Research Funding. Off Label Use: brentuximab vedotin in phase 1 trial. Ansell:Seattle Genetics: Research Funding. Park:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding. Fanale:Seattle Genetics: Research Funding. Younes:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding.

Phase II Study of the Salvage Mini-Hyper-CVD in Combination with Inotuzumab Ozogamicin (INO) for Adult Patients with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1606-1606 ◽  
Author(s):  
Koji Sasaki ◽  
Elias J. Jabbour ◽  
Susan M. O'Brien ◽  
Farhad Ravandi ◽  
Deborah A Thomas ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Conditioning Regimen ◽  
Advisory Board ◽  
Historical Cohort ◽  
Platelet Recovery ◽  
Low Intensity

Abstract Background: Outcome of patients with R/R ALL is poor. INO is a CD22 monoclonal antibody bound to a calecheamicin, and has shown single-agent activity in R/R ALL with a response rate of 58% and median survival of 6.3 months. The addition of targeted therapy to effective low-intensity chemotherapy might further improve clinical outcome. The aims of this study are to evaluate response rate, progression-free survival (PFS), overall survival (OS), and to assess the safety of this regimen. Methods: Patients ≥18 years with R/R ALL were eligible. The chemotherapy was lower intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). Rituximab and intrathecal chemotherapy were given for first 4 courses. INO was given on Day 3 of each of the first 4 courses. Patients received INO at 1.8 mg/m2 for cycle 1 followed by 1.3 mg/m2 for subsequent cycles. After the occurrence of veno-occlusive disease (VOD), the dose of INO was modified to 1.3 mg/m2 for Cycle 1 followed by 1.0 mg/m2 for subsequent cycles starting at the Patient #48. Results: Fifty-seven patients (29 men, 28 women) have been enrolled. Patient characteristics and outcome are summarized in Table 1. Median age is 34 years (range 9-87). Median follow-up is 15 months (range, 2-34). The overall response rate was 45 (79%): 31 (53%) CR, 13 (23%) CR without platelet recovery (CRp), and 1 (2%) CR with incomplete count recovery (CRi). Grade 3/4 toxicities included infections during induction (52%), infections during consolidation (73%), prolonged thrombocytopenia (79%), hyperglycemia (50%), hypokalemia (35%), hyperbilirubinemia (24%), elevated AST/ALT (21%), hemorrhage (18%), and VOD (11%; n=6). Of 6 patients who developed VOD, all 6 had allogeneic stem cell transplantation (allo-SCT) prior to or post INO therapy; three had prior allo-SCT (conditioning regimen; 2 fludarabine/clofarabine; 1 cyclophosphamide/total body irradiation); 4 had allo-SCT after INO therapy (conditioning regimen; 2 fludarabine/busulfan/clofarabine; 1 fludarabine/melphalan; 1 fludarabine/busulfan); 1 had chimeric antigen receptor T-cell therapy. Twenty-seven (47%) patients proceeded to receive allo-SCT. At the last follow-up, 25 (44%) patients are alive. Thirty-two (56%) patients died: 7 early death; 5 refractory disease; 7 post relapse after subsequent salvage, 3 in CR/CRp (1 sepsis; 2 unknown), 10 post allo-SCT (1 VOD; 3 transplant complications; 5 relapse; and 1 unknown). The 2-year PFS and OS rates were 52% and 34%, respectively (Figure 1). Median OS for patients with S1 was not reached with 2-year OS of 53%; patients with S2, 6 months with 2-year OS of 0%; patients with ≥S3, 5.6 months with 2-year OS of 0% (p=0.005). Patients who were treated with mini-hyper-CVD plus INO plus/minus rituximab had a tendency of higher PFS rates, and improved OS compared to a historical cohort with single-agent INO in R/R ALL (2-year PFS; 52% vs. 36%; p=0.20: 2-year OS; 44% vs. 25%; p=0.01). Conclusions: The combination of INO with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with R/R ALL. The risk of VOD should be considered carefully for patients with previous liver damage and transplant candidate. Lower dose schedule of INO are being explored. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Burger:Pharmacyclics: Research Funding. Jain:Pharmacyclics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Servier: Consultancy, Honoraria; Infinity: Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Celgene: Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

scholarly journals Prevalence of Low Count (LC) Monoclonal B Cell Lymphocytosis (MBL) and Serious Infections in a Population-Based Cohort of U.S. Adults Participating in a Large Bio-Repository

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 831-831
Author(s):  
Tait D. Shanafelt ◽  
Neil E. Kay ◽  
Curtis A. Hanson ◽  
Sameer A. Parikh ◽  
Sara J Achenbach ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cell ◽  
Mayo Clinic ◽  
Research Funding ◽  
Olmsted County ◽  
Sample Collection ◽  
Serious Infection ◽  
Clinical Records ◽  
The Relationship

Abstract Background: There is little prospective, longitudinal data on the health outcomes of low count MBL in the U.S. adult population. We screened for MBL in asymptomatic adults with normal blood counts using highly sensitive flow-cytometry in a clinic-based cohort of participants from the Mayo Clinic Biobank and explored the relationship between MBL and risk of hospitalization with infection. Methods: The Mayo Clinic Biobank is a large scale biorepository of 50,000 adults (age&gt;18) seen in primary care-based clinics. All consented participants completed a health history questionnaire and provided blood samples. For the present study, we focused on the study participants from Olmsted County, Minnesota, 40 years of age or older who had stored PBMC. We used these PBMC to screen for MBL using an 8 color (CD38, CD45, Kappa, Lambda, CD19, CD23, CD5 and CD20) flow cytometry assay validated to consistently detect clonal B-cell events to the 0.005% level (1/20,000 events). The sensitivity of this approach of collecting 500,000 events from isolated PBMC is 2-3-fold higher than collecting 500,000 events from whole blood due to the increased concentration of lymphocytes in these samples. Infections associated with hospitalization were considered serious or life-threatening infections. Every hospitalization at both Mayo Clinic and Olmsted Medical Center hospitals in Olmsted County, MN following the sample collection was reviewed to document hospitalization with infection. Data on hospitalization with infection was abstracted from clinical records using our previously published approach (Moriera, Leukemia 27:136). This approach allows medical record validation and review of detailed clinical and treatment information related to infection. For this analysis, follow-up began at date of sample collection and ended at the earliest of death, migration from Olmsted County, or 12/31/2016. The individual abstracting information on hospitalization for infection was blinded to the results of MBL screening. Chi-square tests were used to assess associations between MBL status and demographic characteristics. Cox regression models were used to determine association with risk of hospitalization with infection accounting for the competing risk of death using Fine Gray models. Results : We screened for MBL in 1045 Olmsted County residents age 40 and older. Of these, 984 (94%) had interpretable results. 119 of these 984 (12%) had a clonal B-cell population detected including 106 (11%) with CLL phenotype (CD5, CD19, CD20 [dim], CD23, kappa or lambda light chain restriction [dim]).This analysis focused on the 106 individuals with CLL-like MBL clones (mean age 69 years, 55% male) and the 865 individuals with normal immunophenotype (mean age 61 years, 40% male). The presence of CLL phenotype MBL was strongly associated with age. MBL was detected in 3% of patients age 40-49 years, 7% of those 50-59, 10% of those 60-69, 20% of those 70-79, and 27% of those age 80+ (p&lt;0.001). MBL was also more common among men (women 8%; men 14%; p=0.003). After a median follow-up of 7 years from biobank enrollment, 76 of the 971 participants were hospitalized with infection in Olmsted County at least once. The estimated cumulative incidence of infections at 7 years was 19% for LC MBL and 9% for those without MBL (Figure). The most frequent site of infections for which these individuals were first hospitalized were pneumonia (14 individuals; 18%), cellulitis (20 individuals; 26%), urinary tract infection (21 individuals; 26%), and blood stream infection (6 individuals; 8%). An association between LC MBL and hospitalization with infection was observed with the unadjusted HR for hospitalization with infection among the 106 Olmsted County residents with LC MBL relative to the 865 Olmsted County residents with normal immunophenotype is 2.41 (95%CI: 1.39-4.19; p=0.002). After adjusting for age and sex, the HR is 1.65 (95% CI: 0.95-2.88; p=0.08). Conclusions: We report one of the first studies to systematically explore the relationship between LC MBL and the risk of serious infection. It appears that individuals with LC MBL may be at increased risk for serious infection. If this observation is confirmed, it would suggest that 5-10% of adults over age 40 (6-12 million U.S. adults) have a largely unstudied condition with potentially serious health implications. Figure 1 Figure 1. Disclosures Shanafelt: Hospira: Research Funding; AbbVie: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Jannsen: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding. Kay: Gilead: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Tolero Corporation: Research Funding. Parikh: Pharmacyclics: Research Funding; AstraZeneca: Honoraria; Pharmacyclics: Honoraria.

scholarly journals A Multicenter, Open Label Phase I/II Study of Carfilzomib, Pomalidomide and Dexamethasone in Relapsed and/or Refractory Multiple Myeloma (MM) Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1145-1145 ◽  
Author(s):  
Sara Bringhen ◽  
Valeria Magarotto ◽  
Anna Marina Liberati ◽  
Angelo Belotti ◽  
Alessandra Larocca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Research Funding ◽  
Low Dose ◽  
Response Rate ◽  
Primary Objective ◽  
Advisory Board ◽  
Level 1

Abstract Background: Survival rates of multiple myeloma (MM) patients (pts) has improved over the past few years, but patients inevitably relapse and become more resistant to subsequent treatments. Carfilzomib and Pomalidomide were both approved for the treatment of relapsed/refractory MM (RRMM). Combinations including a proteasome inhibitor (PI) plus an immunomodulator (IMiD), such as Bortezomib-Lenalidomide-Dexamethasone (VRD) or Carfilzomib-Lenalidomide-Dexamethasone (CRD), showed a very high response rate with an acceptable toxicity. Moreover, in the CHAMPION1 study (Berenson et al Blood 2016), the weekly infusion of Carfilzomib showed to be as effective as the twice schedule. In this phase I/II study we assessed for the first time weekly Carfilzomib plus Pomalidomide and low dose Dexamethasone (wKPd) for the treatment of RRMM. Here we report preliminary results. Methods: the primary objective of the phase I part of the trial was to determine the maximum tolerated dose (MTD) of wKPd combination. The primary objective of the phase II was to determine the rate of partial response (PR). Patients with RRMM, who received 1-3 prior lines of treatments and were refractory to Lenalidomide were eligible. Treatment consisted of 28-day cycles of oral Pomalidomide at fixed dose of 4 mg on days 1-21 (1 week off), oral or intravenous (iv) Dexamethasone 40 mg on days 1,8,15,22 and iv Carfilzomib at escalating doses on days 1,8,15. Escalation started at the dose of 36 mg/m2 (0 level) and used a standard 3+3 schema based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment was continued until relapse or intolerance. Results: A total of 57 patients were enrolled in 6 Italian centers. Fifty-two patients could be evaluated for this analysis (5 patients did not complete the first cycle yet). The median age was 62 years with a median time from diagnosis of 4 years. 17/39 (44%) of patients were considered high risk according to cytogenetic abnormalities [at least one among t (4;14) t (14;16) and deletion chromosome 17 (del17) detected by FISH]. In the phase I of the trial 15 patients were enrolled. The first 3 patients at the dose level 0 of Carfilzomib did not experience any DLT. In the next cohort with Carfilzomib 20/45 mg/m2 a G3 hypertension and a sudden death occurred. According to the protocol, 3 more patients were enrolled at dose level 0: 1 patient experienced G3 atrial fibrillation, 2 patients ≥ G3 hypertension. Considering the serious adverse events (SAEs) occurred, the trial was temporary stopped to evaluate the benefit of continuing the study. All the DLTs were cardiologic and occurred in patients with a prior history of cardiac disease. As per protocol, they were evaluated with ECG and echocardiogram before the enrolment and were considered eligible for the study. The safety committee established new procedures for the evaluation of cardiac function of potentially eligible patients, including 24 h continuing pressure monitoring before the enrolment and serial measurement of blood pressure during and after Carfilzomib infusions. Six more patients were enrolled at dose level -1 (Carfilzomib 20/27 mg/m2) and none experienced a DLT. The MTD was established at dose level -1 with Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg and Dexamethasone 40 mg. In the phase II portion of the trial, 42 patients were enrolled. Considering both phase I and II portions of the study, the most frequent drug related, grade ≥ 3 AEs were hematologic (65% of neutropenia and 13% of thrombocytopenia) and cardiologic (17%, mainly hypertension). We recorded only 4% of infection and ≥ G3 peripheral neuropathy. The overall response rate (ORR) of phase I/II portions was 58% (30/52) including 25% (13/52) of ≥ very good partial remission (VGPR). The ORR of high risk patients was 44% (7/16) including 19% (3/16) of ≥ VGPR. With a median follow-up of 10 months, median progression free survival (PFS) was 9.5 months and the median overall survival was not reached. Conclusions: This is the first phase I/II trial that combined weekly Carfilzomib with Pomalidomide and Dexamethasone. This combination was highly effective in RRMM. After a median follow-up of 10 months, wKRd showed a double median PFS in comparison with Pomalidomide-low dose dexamethasone (Sanmiguel et al Lancet Oncology 2013): 9.5 vs 4 months respectively, confirming the efficacy of combining a PI with an IMiD. An updated analysis will be presented at the meeting. Disclosures Bringhen: BMS: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Larocca:Celgene: Honoraria; Janssen-Cilag: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Gaidano:Karyopharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Oliva:Amgen: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Boccadoro:Janssen: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Abbivie: Honoraria; Mundipharma: Research Funding; SANOFI: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding.

scholarly journals A Phase II Trial of Nivolumab and Ibrutinib for Patients with Relapsed or Refractory Central Nervous System Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4086-4086
Author(s):  
Jason R. Westin ◽  
Nathan H. Fowler ◽  
Loretta J. Nastoupil ◽  
Sattva S Neelapu ◽  
Hun Ju Lee ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Single Agent ◽  
Advisory Board ◽  
Cns Lymphoma ◽  
Advisory Committees

Background: Central Nervous System (CNS) lymphoma is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL). CNS lymphoma has a unique genomic profile which has similarities to the activated B-cell (ABC) subtype of DLBCL, which may speak to potential targets for therapy. These aberrancies include near uniform reliance on Toll-Like Receptor signaling, mutations of MYD88, and frequent translocation or copy number alterations of 9p24 which codes for programmed death receptor ligand 1 (PD-L1). Mutations of MYD88 may predict for response to Bruton's tyrosine kinase (BTK) inhibitors in patients with systemic DLBCL. Expression of PD1 or PD-L1, which corresponds to response with PD-targeted therapy in solid tumors, has been found on up to 90% of CNS lymphoma cases, and 60% of specimens had tumor infiltrating lymphocytes which were PD1+ (Berghoff, Clin Neuropath 2014). In addition, the majority of CNS lymphoma cases have a copy gain of 9p24.1, associated with increased expression of PD-L1 (Chapuy, Blood 2016). This suggests a potential ongoing immune reaction against CNS lymphoma, but the microenvironment and tumor conspire to render the immune response ineffective. Ibrutinib is a BTK inhibitor which is FDA approved for multiple B-cell malignancies and is known to achieve therapeutic concentration in the cerebral spinal fluid (CSF), with activity in CNS lymphoma as a single agent and in combination with other agents. Nivolumab is a PD1 inhibitor which is FDA approved for multiple malignancies, with impressive anecdotal evidence of single agent activity in CNS lymphoma. Ibrutinib and nivolumab have been combined in other studies with modest toxicities. Study Design and Methods: We are conducting a phase II, open label, single center clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Patients are eligible if they have CNS lymphoma relapsed after or were refractory to at least 1 prior line of therapy with adequate organ and bone marrow function, are aged 18y or greater, have not received prior ibrutinib or PD1 inhibitor, and do not require persistent high dose steroids. The trial has two cohorts which will be sequentially enrolled. Cohort A begins with ibrutinib 560mg oral daily for a single 28-day cycle, followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B begins with the ibrutinib and nivolumab combination during the first cycle. Patients who have at least a partial response at the conclusion of the planned 6 cycles of combined ibrutinib and nivolumab may continue therapy for up to 2 years total or until progression of disease or unacceptable toxicity occurs. Neurocognitive assays and patient reported outcome instruments are being utilized. The primary objective is to determine the best overall response rate during the first 24 weeks of therapy. Secondary objectives will include the response rate of ibrutinib as a lead in prior to the combination, the complete response rate, landmark survival outcomes, and the safety of the combination. Exploratory analyses include assays of the blood and CSF for ctDNA and immune profiling. The first patient was treated in February 2019, with a planned total of 40 patients to be enrolled. Disclosures Westin: MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Bayer: Honoraria. Neelapu:Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Research Funding; Cellectis: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ibrutinib and nivolumab are not yet indicated for CNS lymphoma

scholarly journals Outcomes and Predictors of Relapse with Use of Hypomethylating Agents in Combination with Venetoclax Prior to Allogeneic Transplant in Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2327-2327
Author(s):  
Imran Nizamuddin ◽  
Timothy Seijung Oh ◽  
Yazan Numan ◽  
Max Farber Kelsten ◽  
Madelyn Burkart ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Board ◽  
Intermediate Risk ◽  
Hypomethylating Agents ◽  
Significant Difference ◽  
Acute Myeloid

Abstract Introduction The treatment of acute myeloid leukemia (AML) has evolved tremendously. Recently, venetoclax with hypomethylating agents (HMA/ven) demonstrated durable responses in the frontline and relapsed/refractory (R/R) settings. This regimen is now standard of care for older adults or those unfit for intensive induction chemotherapy (DiNardo CD, N Engl J Med, 2020). Our institution also often uses HMA/ven to treat fit patients (pts) with high risk disease characteristics. Because HMA/ven was studied in transplant-ineligible pts, outcomes following potentially curative allogeneic hematopoietic stem cell transplantation (HSCT) remain unknown. This retrospective study aims to describe characteristics and outcomes of pts treated with HMA/ven who proceeded to HSCT. Methods Adult pts diagnosed with AML and treated with HMA/ven either in the frontline or R/R setting between 1/2010 and 2/2020 at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University were identified. Hypomethylating agents included either azacitadine or decitabine. Data were collected and analyzed based on demographics, laboratory and clinical characteristics, and disease and toxicity outcomes. Efficacy endpoints included complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with incomplete platelet recovery (CRp). Survival curves for overall survival (OS) and leukemia-free survival (LFS) were calculated using the Kaplan-Meier method. Univariate analyses were performed to determine impact of clinical variables on outcomes (significance defined as p≤0.05). Cohorts were compared using χ 2 or Fisher's exact test for categorical variables and the unpaired t-test for continuous variables. Results Clinical and demographic features at time of diagnosis are listed in Table 1. In total, 257 pts received HMA/ven. Of these, 36 pts received a HSCT, which was the population analyzed in this study. In the front-line setting 11 (31%) pts received HMA/ven and 25 (69%) pts received HMA/ven for R/R disease. 25 (69%) pts received azacitadine and 11 (31%) pts received decitabine (5 days, n=5, 14%; 10 days, n=6, 17%). Based on ELN guidelines, 23 (64%) pts had adverse risk disease at diagnosis. Response to HMA/ven in the pre-transplant setting is shown in Table 2. Of 35 evaluable pts, 34 achieved remission (CR, n=32, 91%; CRi, n=1, 3%; CRp, n=1, 3%). Table 3 shows outcomes following HSCT. 14 (39%) pts relapsed post HSCT and 13 (36%) pts received treatment for relapse. With a median follow-up of 11.6 months, median LFS from time of transplantation was 11.2 months. Median OS was not reached over follow up period but estimated to be 25.4 months. There was a significant difference in rates of relapse based on ELN classification at diagnosis (p=0.0296). In comparison, presence of complex/monosomal karyotypes (p=0.593), blast percentage at diagnosis (p=0.456), donor type (p=0.484), and number of previous lines of therapy (p=0.822) did not predict for relapse. Median LFS in adverse and favorable/intermediate risk ELN groups was 5.8 and 19.8 months, respectively. Median OS in adverse and favorable/intermediate risk ELN groups was 25.4 and 29.5 months, respectively. Following transplant, 10 (28%) pts received maintenance therapy with a median of 5 cycles (range 1-14); 8 pts (22%) received HMA/ven maintenance following HSCT. There was no significant difference in relapse rates between those who received maintenance therapy (n=6, 43%) and those who did not (n=8, 57%) (p = 0.107). Median time to relapse from HSCT was 4.42 months in those who received maintenance therapy compared to 2.98 months in those who did not receive maintenance therapy (p=0.370). Following relapse, 10 (28%) pts were retreated with HMA/ven, but less than half (n=4, 40%) had a response. To date, 22 (61%) pts are alive with the majority (n=19, 86%) in remission. 14 (39%) pts died with half in remission at the time of death. Conclusions Our study showed that HMA/ven can feasibly be used not only to bridge to transplant, but to achieve durable remissions post HSCT. For those pts that relapsed post HSCT, duration of remission was very short. ELN classification was the only factor that informed relapse risk. Prospective studies must be done to understand which cytogenetic and molecular subgroups benefit the most from HMA/ven prior to transplant. Figure 1 Figure 1. Disclosures Abaza: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Altman: Biosight: Consultancy, Other: Travel fees, Research Funding; Fujifilm: Research Funding; Kura: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Daiichi Sankyo: Consultancy; ALZ Oncology: Research Funding; Theradex: Consultancy, Other: Advisory boards; Syros: Consultancy; Amgen: Research Funding; Aprea: Research Funding; Boehringer Ingelheim: Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; GlycoMimetics: Other: Participation on an advisory board; AbbVie: Consultancy, Other: Advisory Board, Research Funding; BMS: Research Funding; Kura Oncology: Consultancy. Dinner: Pfizer: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria.

scholarly journals Central Nervous System Involvement in Peripheral T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5293-5293
Author(s):  
Sangeetha Gandhi ◽  
N. Nora Bennani ◽  
Sonia Fortin ◽  
Thomas M. Habermann ◽  
Patrick Johnston ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Advisory Board ◽  
T Cell Lymphoma ◽  
High Dose ◽  
Cns Involvement ◽  
Advisory Committees ◽  
Genetics Research

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

scholarly journals MLL1 Modulates IgM and Inflammatory Cytokines in Waldenstrom's Macroglobulinemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3966-3966
Author(s):  
Mona Karbalivand ◽  
Weiguo Han ◽  
Luciana L Almada ◽  
Stephen M Ansell ◽  
Martin Fernandez-Zapico ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Inflammatory Cytokines ◽  
Mayo Clinic ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Primary Response ◽  
Low Grade ◽  
Genetics Research ◽  
Ccl2 Expression

Waldenström macroglobulinemia (WM) is a low-grade B-cell lymphoma associated with the accumulation of lymphoplasmacytic cells in the bone marrow (BM) and a high level of monoclonal IgM protein in the serum. Genome-wide studies revealed genomic alternations in WM, with the most prevalent being a point mutation in the myeloid differentiation primary response gene 88 (MyD88) resulting in an amino acid substitution (L265P) that is present in over 90% of WM patients. MyD88 is an effector of Toll-like receptor (TLR) signaling pathway that mediates inflammatory cytokine expression and secretion upon activation. Here, we found that activation of the TLR-MyD88 pathway in WM cells carrying the MyD88 L265P somatic mutation increases the expression of IL-6 and CCL2, two cytokines known to participate in the pathobiology of several neoplasms including B cell malignancies. Furthermore, IL-6 has been shown to modulate IgM secretion and malignant B cell growth in WM. We demonstrate that an active ERK1/2 pathway, which is elevated in WM patient samples, is required to maintain IL-6 and CCL2 expression in BCWM.1 (p=0.0339) and RPCI-WM1 (p=0.0005) cells. Further characterization identified a change in the chromatin landscape in response to TLR-MyD88 activation in WM cells. We found increased levels of trimethylation of histone 3 lysine 4 (H3K4me3) at the promoters of the inflammatory cytokines IL-6 and CCL2 by chromatin immunoprecipitation (ChIP) assay followed by qPCR (ChIP-qPCR). The H3K4me3 modification is catalyzed by six related homologs of the yeast histone methyltransferase (HMT) family. Further analysis identified the Mixed-lineage leukemia 1 (MLL1) as the enzyme bound to these promoters in response to TLR-MyD88 stimulation of WM cells. Analysis of WM cell lines and primary WM patient cells showed that MLL1 and its binding partner, menin, are expressed at significantly higher levels in CD19+CD138+cells from WM patients compared to CD19+B cells from peripheral blood of healthy donors (p<0.001). We also found an increase in H3K4me3 deposition on IL-6 and CCL2 promoters during early (1-3 hr) and late (12-24 hr) kinetics following TLR-MyD88 stimulation. This also coincided with increased deposition of MLL1 on these cytokine promoters by ChIP-qPCR. Disruption of menin-MLL1 using the MI-2 or MI-503 menin-MLL1 inhibitors significantly reduced IL-6 and CCL2 expression in WM cell lines (BCWM.1 p=0.039; RPCI-WM1 p=0.0041). This also results in significantly reduced IgM expression (p<0.0001) and secretion at inhibitor dose (5 μM) that has no effect on cell proliferation. Finally, MLL1 knockdown using RNAi significantly reduces IgM expression in BCWM.1 (p<0.0001), MWCL (p=0.0016) and RPCI-WM1 (p<0.0001) and IgM secretion in BCWM.1 (p<0.0001) and MWCL-1 (p<0.0001). Taken together, these results identify a novel role for menin-MLL1 in regulating inflammatory cytokines and IgM expression and secretion in WM and provide the rationale for targeting these molecules in WM patients. Disclosures Ansell: Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding.

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