Abexinostat (S78454/PCI-24781), an Oral Pan-Histone Deacetylas (HDAC) Inhibitor in Patients with Refractory or Relapsed Hodgkin's Lymphoma, Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia. Results of a Phase I Dose-Escalation Study in 35 Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3643-3643 ◽  
Author(s):  
Franck Morschhauser ◽  
Louis Terriou ◽  
Bertrand Coiffier ◽  
Gilles Salles ◽  
Ioana Kloos ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees

Abstract Abstract 3643 Background. Abexinostat is a new hydroxymate-based pan-HDAC inhibitor of class I and II that induces apoptosis and cell cycle arrest in various human tumor cell lines and inhibits tumor growth in several lymphoma xenograft models. Aim. The primary objective of the Phase I was to assess the safety profile and to determine the recommended Phase 2 dose (RP2D) as well as the optimal administration schedule of abexinostat in patients with refractory or relapsed lymphoma or chronic lymphocytic leukemia. The secondary objectives included assessment of pharmacokinetic and pharmacodynamic profiles and preliminary antitumor activity. Methods. Eligibility criteria included ECOG ≤ 1 and adequate hematological, renal and hepatic functions. This study used a 3+3 cohort expansion design to reach the RP2D. Three different 3-week schedules of abexinostat were tested: schedule 1 (S1) with 14 days of treatment (day 1 – day 14); schedule 2 (S2) with 10 days of treatment (day 1 – day 5 and day 8 – day 12); schedule 3 (S3) with 12 days of treatment (day 1 – day 4, day 8 – day 11 and day 15 – day 18). The schedules were evaluated at different dose levels of abexinostat b.i.d. (4 h apart): S1 at 30 mg/m2, and all 3 schedules at both 45 mg/m2 and 60 mg/m2. The following were considered DLTs if they occurred in cycle 1: ≥ grade 3 non-hematologic toxicity, prolongation of QTc interval and febrile neutropenia; grade 4 neutropenia or thrombocytopenia; and next cycle postponed by > 1 week. Results. A total of 35 patients were included. The median age was 61 (21–83). The sex ratio M/F was 22/13. The median number of prior therapies was 5 (2–11). Lymphoma subtypes were Hodgkin's lymphoma (HL) (n=11), follicular lymphoma (FL) (n=7), diffuse large B-cell lymphoma (DLBCL) (n=6), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) (n=4), marginal zone B-cell lymphoma (MZL) (n=3), mantle cell lymphoma (MCL) (n=3) and peripheral T-cell lymphoma (n=1). One DLT (thrombocytopenia) was observed in S2 at 45 mg/m2. At 60 mg/m2, 2 DLTs were observed in each schedule: thrombocytopenia in S1 and S2 (2 each), thrombocytopenia and febrile neutropenia (1 each) in S3. Grade 3 and 4 toxicities were exclusively hematologic: thrombocytopenia (G3: 31.4% patients, G4: 25.7% patients), neutropenia (G3: 11.4% patients, G4: 5.7% patients), febrile neutropenia (G3: 2.9% patients, G4: 2.9% patients), anemia (G3: 2.9% patients, G4: 2.9% patients) and leukopenia (G3: 2.9% patients). The other frequent drug-related adverse events were grade 1 and 2: asthenia (34.3% patients), gastro-intestinal disorders (60% patients) and dry skin (17.1% patients). No prolonged QTc intervals were observed in any schedule. A dose reduction occurred in 28.6% patients in S1, 33.3% in S2 and 37.5% in S3. S1 was selected for Phase 2 since it allowed a full week for platelets recovery, a longer drug exposure than S2 and a safety profile similar to the 2 other schedules. Cmax was reached after each administration with median tmax between 0.5 h and 1 h for each schedule and at each dose level. The median apparent terminal elimination half-life was around 4 h. These results are consistent with the limited accumulation of abexinostat with these dose regimens. There is no evidence of time dependent pharmacokinetics. No correlations have been demonstrated so far between histones H3 acetylation in peripheral blood mononuclear cells and PK parameters or clinical activity. Eight out of 29 (27.5%) evaluable patients achieved objective response: 2 complete responses (2 FL) and 6 partial responses (1 FL, 1 CLL, 1 MZL and 3 HL). At the time of data cut off, all but 1 (HL) responses were ongoing between cycle 6 and cycle 22 (median 13.5 cycles). One stable disease (1 MZL) was observed and was still ongoing after cycle 9. Nineteen patients withdrew for progressive disease, including 9 patients who withdrew after at least 2 cycles (4 HL, 2 DLBCL, 1 MCL, 1 MZL and 1 FL). Conclusion. Abexinostat is well tolerated and demonstrates promising durable responses (including CRs) in indolent lymphomas and Hodgkin's lymphoma patients. Enrollment in the Phase II part of the study is ongoing following S1 (3-week cycles – 14 days of treatment) at the RP2D (45 mg/m2b.i.d.). Disclosures: Terriou: Servier: Honoraria; Pfizer: Consultancy; Amgen: Honoraria; GSK: Honoraria. Coiffier:Servier: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kloos:Institut de recherches internationales Servier: Employment. Tavernier:Institut de recherches internationales Servier: Employment. Depil:Institut de recherches Internationales Servier: Employment. Ribrag:Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; astrazeneca: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees; bayer: Research Funding; sanofi: Research Funding.

scholarly journals Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5468-5468
Author(s):  
Shuo Ma ◽  
Rebecca J Chan ◽  
Lin Gu ◽  
Guan Xing ◽  
Nishan Rajakumaraswamy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Clinical Outcomes ◽  
Research Funding ◽  
Treatment Interruption ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Localized gastric diffuse large B-cell lymphoma and Hodgkin's lymphoma as secondary neoplasms in two patients with chronic lymphocytic leukemia

2006 ◽  
Vol 47 (10) ◽  
pp. 2244-2246 ◽  
Author(s):  
Monika Prochorec-Sobieszek ◽  
Mirosław Majewski ◽  
Anna Sikorska ◽  
Kinga Kos ◽  
Sławomir Huszcza ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Secondary Neoplasms ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Safety and Efficacy of Obinutuzumab Plus Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia: Subgroup Analysis of the Green Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 493-493 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Osman Ilhan ◽  
Darius Woszczyk ◽  
Christoph Renner ◽  
Eva Mikuskova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Grade 3

Abstract Background The glycoengineered type II anti-CD20 monoclonal antibody obinutuzumab (GA101; GAZYVA/GAZYVARO; G) combined with chlorambucil (Clb) has superior efficacy to Clb monotherapy and to rituximab plus Clb with an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL), as shown in the CLL11 study (Goede V, et al. NEJM 2014). GREEN is an ongoing, non-randomized, multi-cohort phase IIIb study (NCT01905943) investigating the safety (primary objective) and efficacy of G alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL and assessing various strategies (cohorts 1-3) for reducing the rate of infusion-related reactions (IRRs) during the first infusion of G (Bosch F, et al. Blood 2014). We report safety and efficacy data from a subgroup of previously untreated patients in cohort 1 who received G-bendamustine (G-B). Methods Subjects were aged ≥18 years withdocumented CLL (except one case of SLL), an ECOG performance status of 0-2, and adequate hematologic function. Non-fit patients were those with a CrCl of <70 mL/min, and/or a CIRS score of >6. Fit patients comprised all others. Treatment was six 28-day cycles of G-B, where G was administered IV on D1/D2 of C1 (split dose: 25mg D1/975mg D2), and 1000mg on D8 and D15 of C1 and D1 C2-6. B was administered ≥30 minutes after G on D1 and D2 of each cycle at 90mg/m2 IV, or at 70mg/m2 in non-fit patients at the investigator's discretion. Safety endpoints included incidence, type and severity of AEs. Efficacy endpoints included ORR (investigator-assessed) and minimal residual disease (MRD) measured 3 months post-treatment. ORR was strictly assessed per International Workshop Group criteria (iwCLL 2008). Patients with missing response assessment components had their responses downgraded mandatorily. MRD negativity was defined as <1x10-4 malignant B cells in peripheral blood or bone marrow aspirate, measured in a central laboratory by 4-color flow cytometry. The population comprised all patients from cohort 1 of GREEN who received at least a partial dose of both G and B, and was based on a data cut-off of 26 March 2015. Results With a planned overall sample size of 950 patients in GREEN, the G-B subgroup in cohort 1 comprised 158 patients (157 CLL, 1 SLL; 74 fit, 84 non-fit). Median age was 67.6 years, 15.8% of patients had a CIRS score of >6, and 44.9% had a CrCl of <70 mL/min; 31.6% of patients had Binet stage A disease, 38% Binet B, and 30.4% Binet C. 7.0% of patients' disease displayed 17p deletion, 16.5% 11q deletion, and 58.2% unmutated IGHV. 91.1% of patients receiving B and 93.0% of those receiving G took ≥90% of the recommended total dose. The safety profile of G-B was as expected. 50% of patients developed grade 3-5 neutropenia and 12.7% developed a grade 3-5 infection. Other common grade 3-5 AEs included thrombocytopenia (12.7%) and tumor lysis syndrome (TLS; 10.1%). The most common serious AEs were neutropenia (10.8%), pyrexia (7.6%), febrile neutropenia (7.0%), and TLS (5.1%). There were nine deaths - one due to progression, and eight due to AEs (considered related to study drug by the investigator: 1 infection, 1 sudden death, 1 acute hepatic failure, and 1 febrile neutropenia combined with TLS; considered unrelated: 2 infections and 2 secondary neoplasms). IRRs occurred in 55.7% of patients (15.2% grade 3-5, none fatal). Overall, 26 patients (16.5%) prematurely discontinued treatment due to ≥1 adverse event. The ORR was 78.5% (124/158). The rate of CR (including incomplete CR [CRi]) was 32.3% (51/158), PR 46.2% (73/158), SD 10.8% (17/158), and PD 0.6% (1/158); 10.1% (16/158) of patients had missing data. Response rates were similar in non-fit (34.5% CR/CRi, 41.7% PR, 10.7% SD, and 1.2% PD) and fit (29.7% CR/CRi, 51.4% PR, 10.8% SD, and 0% PD) patients. In an intent-to-treat analysis including all missing (not taken or evaluable) MRD results, MRD negativity was 58.9% (93/158, including 56 missing) in blood and 27.8% (44/158, including 95 missing) in bone marrow. With a median observation time of 11.2 months, PFS data were immature and the median was not reached. Conclusions Treatment with G-B in previously-untreated CLL patients is generally well tolerated and the observed toxicities are manageable and not unexpected. G-B achieves a promising rate of CRs and a high rate of MRD-negative remissions, and may offer a new treatment option for fit and non-fit patients with CLL. Disclosures Stilgenbauer: Gilead: Honoraria, Research Funding. Off Label Use: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). This abstract reports on obinutuzumab alone or in combination with chemotherapy for previously untreated or relapsed/refractory CLL. Renner:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Böttcher:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Celgene: Research Funding; Beckton Dickinson: Honoraria. Tausch:Gilead: Other: Travel support. Moore:Roche: Employment. Tyson:Roche: Employment, Equity Ownership. Adamis:Roche: Employment. Leblonde:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Speakers Bureau. Bosch:Roche: Consultancy, Research Funding, Speakers Bureau. Foà:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3904-3904 ◽  
Author(s):  
Thomas J. Kipps ◽  
Lode J. Swinnen ◽  
William G. Wierda ◽  
Jeffrey Alan Jones ◽  
Steven E. Coutre ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Progressive Disease ◽  
Phase 1 ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Anti Tumor Activity

Abstract Abstract 3904 Background: Navitoclax (ABT-263), a novel, orally bioavailable, small molecule, binds with high affinity (Ki ≤1nM) to Bcl-2, Bcl-xL, and Bcl-w, promoting apoptosis. In vitro, navitoclax shows potent targeted cytotoxicity (EC50≤1 μM) against T and B lymphoid malignancies that overexpress Bcl-2. In preclinical models of B-cell lymphoma, navitoclax enhanced efficacy of rituximab (R) when used alone or in combination with chemotherapy. Based on phase 1 trial data, oral navitoclax monotherapy was well-tolerated and had anti-tumor activity in patients (pts) with chronic lymphocytic leukemia (CLL). Thrombocytopenia was the dose-limiting toxicity (DLT). We examined whether navitoclax could be used safely in combination with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) for treatment of pts with CLL. Methods: This ongoing, phase 1 dose-escalation study is evaluating the safety and pharmacokinetics (PK) of oral navitoclax used in combination with FCR (Arm A) or BR (Arm B) for treatment of pts with relapsed/refractory CLL. Secondary objectives are efficacy endpoints (PFS, ORR, TTP, OS, duration of response). Eligible pts had measurable disease, ECOG performance score ≤1, ANC ≥1000/μL, platelets ≥100,000/mm3, and hemoglobin ≥9.0 g/dL. Preliminary results are reported. Enrolled pts (6 pts/cohort) were assigned to Arm A or Arm B based on physician preference. In both arms, R was 375 mg/m2 on Day 1 of Cycle 1; and 500 mg/m2 on Day 2 of Cycle 2 and on Day 1 of subsequent 28-day cycles. In Arm A, F 25 mg/m2 and C 175 mg/m2 were dosed on Days 2–4 in Cycles 1 and 2, and on Days 1–3 in subsequent cycles. In Arm B, B was dosed at 70 mg/m2 on Days 2 and 3 of Cycles 1 and 2, and on Days 1 and 2 in subsequent cycles. Oral navitoclax was administered once daily (starting dose of 110 mg) pre-chemotherapy on Days 3–5 of Cycle 1 and Days 1–3 of subsequent cycles. Dose escalation decisions were made independently in each arm via a continuous reassessment method, and the objective was to identify a dose of navitoclax in combination with chemotherapy in which <33% of subjects experienced DLTs. Tumor responses were evaluated using NCI-WG 1996 criteria. Adverse events (AE) were graded by NCI CTCAE V3. Pts continued on navitoclax monotherapy up to the recommended phase 2 dose of 250 mg daily for 1 year or until progressive disease or intolerable toxicity. Results: As of July 2011, 28 pts (median age 59 yr [39–80]) have enrolled; 5 in Arm A (FCR+navitoclax; 110 mg) and 23 in Arm B (BR+navitoclax; 110–250 mg). The median number of prior therapies was 2 (range 1–13). In Arm A, 1 pt had a DLT of febrile neutropenia (110 mg). In Arm B, 5 pts had DLT; 1 had elevated ALT and AST (110 mg), 1 had grade 4 febrile neutropenia (200 mg), and 3 had grade 4 thrombocytopenia (250 mg). Overall, the most common (>20%) navitoclax-related AEs of any grade were nausea (73%), fatigue (50%), neutropenia (50%), cough (39%), vomiting (35%), chills (31%), diarrhea (31%), constipation (27%), headache (27%), anemia (23%), and thrombocytopenia (23%). The most common (>19%) grade 3/4 navitoclax-related AE was neutropenia (35%) and thrombocytopenia (19%); but only 2 of the latter pts had hemorrhagic events (Grade 1 epistaxis) unlikely related to navitoclax. Of the 28 pts evaluated for safety, 6 remain active and 22 discontinued (DC); 1 due to AE, 1 due to AE and progressive disease (PD), 3 due to PD, 6 withdrew consent, 3 due to physician discretion, 4 completed therapy, 2 proceeded to transplant, and 2 due to toxicity. Preliminary best anti-tumor responses were assessed in 20 pts. Of the 16 pts assessed in Arm B (BR), 6 achieved complete responses (CR), 7 partial responses (PR), 2 stable disease (SD) and 1 with PD. The ORR was 81% (13/16). In this arm, 3/5 pts with 17p deletion achieved PR. Of the 4 pts assessed in Arm A (FCR), 2 achieved PR, 1 SD and 1 with PD. Preliminary PK results suggest that there is no apparent PK interaction between navitoclax and bendamustine. Conclusions: The combination of navitoclax with BR appears well-tolerated and to have anti-tumor activity. The maximum tolerated dose of navitoclax has been reached at 250 mg for Arm B, but not for Arm A where escalation continues. To date, we have not observed unacceptable myelotoxicity when this bcl-2 antagonist was used in combination with standard cytotoxic chemo-immunotherapy regimens for treatment of pts with CLL. Disclosures: Kipps: Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbott Industries: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; GSK: Research Funding; Gilead Sciences: Consultancy, Research Funding; Amgen: Research Funding. Off Label Use: R05429083 is a novel humanized antibody direct against the standard region of CD44. R05429083 is currently intensive pre-clinical studies and fist dosing of cancer patients has started in Europe in 2011. Swinnen:Abbott Laboratories: Research Funding. Yang:Abbott Laboratories: Employment. Cui:Abbott Laboratories: Employment, Stock Holder at Abbott Laboratories. Busman:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Enschede:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock. Humerickhouse:Abbott Laboratories: Employment, Owns Abbott Laboratories Stock.

scholarly journals Ibrutinib in Association with R-DHAP/Ox for Patients with Relapsed/Refractory B-Cell Lymphoma: Preliminary Results of the Biblos Phase Ib Lysa Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5384-5384 ◽  
Author(s):  
Christophe Bonnet ◽  
Thierry Lamy ◽  
Christophe Fruchart ◽  
Steven Le Gouill ◽  
Katharina Gunzer ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
Advisory Committees ◽  
Cutaneous Eruption ◽  
Phase Ib ◽  
Hemorrhagic Events

Abstract Background: Ibrutinib is a first-in-class selective, irreversible inhibitor of Bruton's tyrosine kinase (BTK) approved for the treatment of patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) and R/R chronic lymphocytic leukemia. In heavily pretreated MCL, in monotherapy, an ORR of 68% was observed in a phase II study (Wang, 2013). Toxicity is mainly hematological and gastrointestinal. Safety profiles for combination of ibrutinib with R-CHOP or R-benda are acceptable and these combinations are under evaluation in phase III randomized studies (Younes, 2014; Maddocks 2015). We present here preliminary data of a phase Ib study evaluating the safety and tolerability of ibrutinib in association with R-DHAP or R-DHAOx for patients with B-cell lymphoma after first or second treatment failure who are candidates for autologous stem cell transplantation (ASCT). Patients & methods: Eligible patients were planned to receive 3 cycles, given every 21 days, of rituximab 375 mg/m² on day 1, dexamethasone 40 mg on days 1 to 4, cytarabine 2 g/m² bid on day 2 and cisplatin 100 mg/m² on day 1 (R-DHAP) or oxaliplatin 130 mg/m² on day 1 (R-DHAOx) in association with escalating doses of ibrutinib. The starting dose (dose level 1, DL1) was 420 mg/day on days 1 to 21. The dose-variation scheme followed a traditional "3+3" design (DL-1: 280 mg/day on days 1 to 21; DL2: 560 mg/day on days 1 to 21). Dose-limiting toxicities (DLT) were considered during the first cycle. DLT were defined as: non-hematological toxicity grade (Gr) 3-4 excluding alopecia, diarrhea and/or nausea/vomiting and/or fatigue/asthenia for less than 7 days; any Gr ≥ 2 hemorrhagic events; any Gr≥ 1 intracranial hemorrhage and any Gr≥ 4 hematological toxicity lasting more than 7 days. Results: Between May 2014 and July 2015, 25 patients have been treated (R-DHAP: 13, 1 non evaluable for DLT; R-DHAOx: 12). In the DL1 cohort (420 mg/day), DLTs assessed as related to ibrutinib were observed in 3/6 patients receiving R-DHAOx (Gr3 cutaneous eruption, Gr3 febrile neutropenia and prostatic infection, Gr4 thrombocytopenia) and in 3/6 patients receiving R-DHAP (Gr4 cutaneous eruption, Gr4 thrombocytopenia and Gr4 sepsis). According to protocol, ibrutinib dose was decreased to 280 mg/day. Thirteen patients were treated at DL-1 with 1 patient experiencing DLT in each cohort (1/6 evaluable patients in R-DHAP group: Gr4 thrombocytopenia and Gr4 gastric hemorrhage, Gr3 atrial fibrillation; 1/6 patient in R-DHAOx group: Gr3 epigastric pain). Six (50%) patients treated with ibrutinib at the dose of 420 mg and 10 (77%) of those treated at the dose of 280 mg received more than 80% of the planned dose before ASCT. All 25patients experienced one or more adverse events (AE). Diarrhea occurred in 8% of patients. All 25 patients presented Gr3-4 hematological adverse events (neutropenia: 17 patients, including 7 with febrile neutropenia; thrombocytopenia: 25). Three patients presented serious hemorrhagic events. Four patients developed cutaneous eruptions (all of them received prophylactic sulfamethoxazole-trimethoprim). There was 1 death attributable to cardiac toxicity (assessed as unrelated to ibrutinib). Nine patients discontinued ibrutinib (7 due to toxicities, including DLTs, and 2 due to patient's decision). Response to treatment (Cheson 2007 criteria) is currently evaluable in 16 patients (64%). Fourteen responded to the treatment: 8 CR (50%) and 6 PR (37%). Stem cells were harvested in 16 patients and all of them underwent ASCT (CD34+ cells > 3.0x106/kg in 94% of the collected patients after one sole apheresis). Conclusion: Our preliminary result show thatthe DHAP/Ox plus ibrutinib (administered continuously from D1-21) regimen led to several dose-limiting toxicities. Because the dose of 280 mg might be insufficient to improve the quality of response, the protocol was amended in October 2015 in order to change the schedule of Ibrutinib. A new escalation phase using ibrutinib only from day 5 to day 18 is currently ongoing. Pharmacokinetics analyses are also performed. Disclosures Bonnet: JANSSEN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SERVIER: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees. Karlin:takeda: Consultancy; amgen: Consultancy, Honoraria; janssen-cilag: Consultancy, Honoraria; celgene: Consultancy, Honoraria; Bristol: Consultancy. Dupuis:janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Salles:Roche/Genentech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria.

R-CHOP, Followed by High Dose Therapy and Autologous Stem Cell Rescue (HDT/ASCR), and R-Hypercvad Have Equivalent Progression-Free Survival and Are Superior to R-CHOP Alone in Younger Patients with Mantle Cell Lymphoma: a Comparative Effectiveness Analysis From the National Comprehensive Cancer Network (NCCN) Non-Hodgkin's Lymphoma Outcomes Database Project.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 403-403 ◽  
Author(s):  
Ann LaCasce ◽  
Jonathan L. Vandergrift ◽  
Maria A. Rodriguez ◽  
Allison L. Crosby ◽  
Eva M. Lepisto ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Advisory Committees ◽  
Non Hodgkin's Lymphoma ◽  
Mantle Cell

Abstract Abstract 403 Background: Mantle Cell Lymphoma (MCL) is an uncommon histology of non-Hodgkin's lymphoma (NHL) with an unfavorable prognosis for which optimal initial therapy has not been clearly defined. Despite a number of single center studies and uncontrolled trials examining first-line therapy options in MCL, no randomized clinical trials or observational studies have directly compared initial therapeutic options in a single cohort of patients. The role of aggressive induction therapy versus sequential standard chemotherapy remains uncertain, particularly in younger patients. We therefore used the NCCN NHL Outcomes Database to compare R-HyperCVAD, R-CHOP followed by HDT/ASCR and R-CHOP alone as first-line therapy. Our endpoints were progression-free survival (PFS) and overall survival (OS). Methods: The NCCN Non-Hodgkin's Lymphoma Outcomes Database is a prospective cohort study collecting comprehensive clinical, treatment, and outcome data for patients seen at 7 participating NCCN centers. Overall, 229 patients <65 years old with newly diagnosed MCL presented at NCCN institutions between August 2000 and February 2009. Patients were excluded if they (1) were enrolled in clinical trial (n=27), (2) did not receive Rituximab therapy (n=27), (3) did not receive either R-HyperCVAD or R-CHOP induction therapy (n=10), or (4) received both R-CHOP and R-HyperCVAD as induction (n=9). Induction therapy was determined as the initial chemo-immunotherapy received within 180 days of diagnosis. HDT/ASCR consolidation was defined as a transplant after achieving remission. In the R-CHOP+ HDT/ASCR group, ASCR was initiated within 100 days of induction therapy for 90% of patients. The maximum time from induction to ASCR was 172 days. In total, 156 patients were included in the final analysis. Median follow-up was 30 months. Results: Overall, 28 (18%) patients received R-CHOP alone, 29 (19%) received R-CHOP+HDT/ASCR, and 99 (63%) received R-HyperCVAD. No significant differences were observed between therapy groups with regards to co-morbidity (p=0.419), ECOG performance status (p=0.216), B symptoms (p=0.685), bulky disease (p=0.647), IPI risk group (p=0.247), or bone marrow involvement (p=0.651). No difference in PFS (p=0.546) was observed between the R-HyperCVAD and R-CHOP+HDT/ASCR arm (figure 1a). R-CHOP without consolidation had significantly poorer PFS than both R-HyperCVAD (p=0.001) and R-CHOP+HDT/ASCR (p=0.001). No significant differences in OS were observed between the three groups. However, there was a strong trend favoring R-HyperCVAD over R-CHOP (p=0.082, figure 1b). Conclusion: R-CHOP was inferior to both R-HyperCVAD and R-CHOP+HDT/ASCR, which had equal PFS and OS in patients with de novo mantle cell lymphoma. Even with these aggressive induction regimens in younger patient populations, the median PFS in these cohorts was only 3 years. Future trials should focus on incorporating novel agents rather than comparing efficacy of current suboptimal regimens. Disclosures: Czuczman: NCCN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nademanee:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blayney:American Society of Clinical Oncology: Membership on an entity's Board of Directors or advisory committees; BlueCross Blue Shield of Michigan: Research Funding; NCCN: Honoraria; University of Michigan Health System: Employment. Friedberg:Genentech: Membership on an entity's Board of Directors or advisory committees.

Correlations Between Ofatumumab Exposure and Treatment Outcomes for Patients with Chronic Lymphocytic Leukemia (CLL) Treated with Frontline Ofatumumab, Fludarabine, and Cyclophosphamide Chemoimmunotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1793-1793 ◽  
Author(s):  
William G. Wierda ◽  
Roxanne C. Jewell ◽  
Thomas J. Kipps ◽  
Jan Dürig ◽  
Laimonas Griskevicius ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Mass ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Multivariable Analyses

Abstract Abstract 1793 Introduction: Results: Seven pts (4 male) with a medianLittle is known about the pharmacokinetics (PK) and pharmacodynamics of CD20 monoclonal antibody (mAb) with chemotherapy in patients (pts) with CLL. Ofatumumab (O) is a human mAb targeting a membrane-proximal small-loop epitope on CD20 and mediates efficient complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Safety and efficacy of O at 2 dose levels in combination with fludarabine and cyclophosphamide (FC) were evaluated in previously untreated pts with CLL. Relationship between O PK, baseline characteristics, and clinical outcomes were studied. Pts and Methods: Pts with active CLL were randomized to O 500 mg (n=31) or 1000 mg (n=30) on Day 1 with F 25 mg/m2 and C 250 mg/m2 on Days 2–4 (Course 1) or Days 1–3 (Courses 2–6) every 4 weeks for 6 courses. O dose at Course 1 was 300 mg for both groups. Response (1996 NCI-WG criteria) was assessed by an Independent Review Committee up to 3 months after last course. Serial blood samples were collected at Courses 1 and 6 for noncompartmental PK analyses; pre- and post-infusion samples were collected at other courses. Relationship between PK parameters and baseline pt characteristics and disease factors was evaluated by univariable and multivariable analyses. Associations between PK and complete response (CR), overall response (OR), or progression-free survival (PFS) were explored using univariable regression analyses. Results: 22/31 (71%; 500 mg) and 19/30 (63%; 1000 mg) of pts received all 6 O doses; 2 pts at 1000 mg did not receive FC for Course 6. CR (primary endpoint) rates of 32% and 50% and OR rates of 77% and 73% were observed in the 500 mg and 1000 mg groups, respectively. O PK parameters are summarized (Table). O PK at Dose 6 appeared proportional to dose. Factors associated with PK in multivariable analyses are shown (Table). The factor most associated with PK at Dose 1 was sex, with higher Cmax/AUC and lower CL and Vss/longer t½ in women vs. men. PK at Dose 6 was not consistently associated with any factor tested. Median Cmax and Cmin values were similar at first dose between pts who had CR, partial response (PR)/nPR, and stable disease (SD)/progressive disease (PD; Figure); at later doses, median Cmax and Cmin values appeared different between CR and the other groups, although number of subjects decreased over time, especially in the SD/PD group. Based on univariable analyses, higher Cmax and Cmin at Dose 3 and higher Cmax and AUC at Dose 6 were associated with increased likelihood of CR (P<.05); higher Cmin before Dose 6 was associated with increased likelihood of OR and longer PFS. Conclusions: PK of O in combination with FC appeared proportional to dose after repeated dosing. Higher concentrations at Doses 3 and 6 were associated with CR. O PK was similar at first dose and different at later doses between patients who had CR, PR/nPR, and SD/PD, suggesting that response to O-FC treatment leads to clearance differences due to decreased B-cell mass and thus concentration differences with continued dosing. Further analyses of associations between disease-related factors, PK, and treatment response will be performed at study completion. Disclosures: Wierda: GlaxoSmithKline: Research Funding; Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Abbott: Research Funding. Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia, and is currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma), as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Jewell:GlaxoSmithKline: Employment. Kipps:Gilead Sciences: Consultancy, Research Funding; GSK: Research Funding; Genentech: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbot Industries: Research Funding; Celgene: Consultancy, Research Funding; Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Dürig:Santaris Pharma: Consultancy, Research Funding; GSK: Speakers Bureau; Roche: Speakers Bureau; Celgene: Research Funding. Stilgenbauer:Genmab: Research Funding; GSK: Consultancy, Honoraria, Research Funding. Smolej:Roche: Honoraria, Travel Grants; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants; Genzyme: Honoraria, Travel Grants. Hernandez-Ilizaliturri:Genmab: Research Funding; Celgene: Honoraria; Amgen: Research Funding. Fang:PharStat: Employment; GSK: Consultancy; Gilead Sciences: Consultancy; Pharmasset Inc: Consultancy. Gorczyca:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment.

scholarly journals Impact of Interim FDG-PET (iPET) in the Outcomes of Patients with Aggressive B-Cell Lymphomas Receiving DA-EPOCH-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2898-2898
Author(s):  
Vania Phuoc ◽  
Leidy Isenalumhe ◽  
Hayder Saeed ◽  
Celeste Bello ◽  
Bijal Shah ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Fdg Pet ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
End Of Treatment

Introduction: 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) remains the standard of care for baseline and end of treatment scans for aggressive non-Hodgkin lymphomas (NHLs). However, the role of interim FDG-PET remains not as well defined across aggressive NHLs, especially in the era of high-intensity chemoimmunotherapy. Interim FDG-PET (iPET) can serve as an early prognostic tool, and prior studies evaluating the utility of iPET-guided treatment strategies primarily focused on diffuse large B-cell lymphomas (DLBCL) and frontline R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Classification criteria systems assessing response also differ between studies with no clear consensus between use of Deauville criteria (DC), International Harmonization Project (IHP), and the ΔSUVmax method. Methods: This study evaluates our institutional experience with iPET during treatment with DA-EPOCH ± R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin with or without Rituximab) in aggressive NHLs. We retrospectively evaluated 70 patients at Moffitt Cancer Center who started on DA-EPOCH ± R between 1/1/2014 to 12/31/2018 for aggressive NHLs. Response on interim and end-of-treatment (EOT) scans were graded per DC, IHP, and ΔSUVmax methods, and progression free survival (PFS) probability estimates were calculated with chi-square testing and Kaplan Meier method. PFS outcomes were compared between interim negative and positive scans based on each scoring method. Outcomes were also compared between groups based on interim versus EOT positive or negative scans. Results: We identified 70 patients with aggressive NHLs who received DA-EPOCH ± R at our institute. The most common diagnoses were DLBCL (61%) followed by Burkitt's lymphoma (10%), primary mediastinal B-cell lymphoma (9%), plasmablastic lymphoma (7%), gray zone lymphoma (6%), primary cutaneous large B-cell lymphoma (1%), primary effusion lymphoma (1%), and other high-grade NHL not otherwise specified (3%). Of the 43 patients with DLBCL, 21/43 (49%) had double hit lymphoma (DHL) while 7/43 (16%) had triple hit lymphoma (THL), and 3/43 (7%) had MYC-rearranged DLBCL while 2/43 (5%) had double expressor DLBCL. Thirty nine out of 70 (56%) were female, and median age at diagnosis was 58.39 years (range 22.99 - 86.86 years). Most patients had stage IV disease (49/70, 70%), and 43/70 (61%) had more than one extranodal site while 45/70 (64%) had IPI score ≥ 3. Forty-six out of 70 (66%) received central nervous system prophylaxis, most with intrathecal chemotherapy (44/70, 63%). Fifty-five out of 70 (79%) had iPET available while 6/70 (9%) had interim computerized tomography (CT) scans. Fifty-six out of 70 (80%) had EOT PET, and 4/70 (6%) had EOT CT scans. Sustained complete remission occurred in 46/70 (66%) after frontline DA-EPOCH ± R (CR1), and 12/70 (17%) were primary refractory while 5/70 (7%) had relapse after CR1. Four of 70 (6%) died before cycle 3, and 3/70 (4%) did not have long-term follow-up due to transition of care elsewhere. Median follow-up was 15.29 months (range 0.85 - 60.09 months). There was significantly better PFS observed if iPET showed DC 1-3 compared to DC 4-5 (Χ2=5.707, p=0.0169), and PFS was better if iPET was negative by IHP criteria (Χ2=4.254, p=0.0392) or ΔSUVmax method (Χ2=6.411, p=0.0113). Comparing iPET to EOT PET, there was significantly better PFS if iPET was negative with EOT PET negative (iPET-/EOT-) compared to iPET positive with EOT negative (iPET+/EOT-), and iPET+/EOT+ and iPET-/EOT+ had worse PFS after iPET-/EOT- and iPET+/EOT- respectively. This pattern in iPET/EOT PFS probability remained consistent when comparing DC (Χ2=30.041, p<0.0001), IHP (Χ2=49.078, p<0.0001), and ΔSUVmax method (Χ2=9.126, p=0.0104). These findings fit clinical expectations with positive EOT scans indicating primary refractory disease. There was no significant difference in PFS when comparing DLBCL versus non-DLBCL (Χ2=3.461, p=0.0628) or DHL/THL versus non-DHL/THL diagnoses (Χ2=2.850, p=0.0914). Conclusion: Our findings indicate a prognostic role of iPET during treatment with DA-EPOCH ± R for aggressive NHLs. Significant differences in PFS were seen when graded by DC, IHP, and ΔSUVmax methods used in prior studies and when comparing interim versus EOT response. Larger studies are needed to confirm these findings. Disclosures Bello: Celgene: Speakers Bureau. Shah:Novartis: Honoraria; AstraZeneca: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Sokol:EUSA: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

IKZF3 Overexpression Phenocopies Gain-of-Function Mutation in Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-9
Author(s):  
Shanye Yin ◽  
Gregory Lazarian ◽  
Elisa Ten Hacken ◽  
Tomasz Sewastianik ◽  
Satyen Gohil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Dna Binding ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Bcr Signaling ◽  
Experimental Group

A hotspot mutation within the DNA-binding domain of IKZF3 (IKZF3-L162R) has been identified as a putative driver in chronic lymphocytic leukemia (CLL); however, its functional effects are unknown. We recently confirmed its role as a CLL driver in a B cell-restricted conditional knock-in model. IKZF3 mutation altered mature B cell development and signaling capacity, and induced CLL-like disease in elderly mice (~40% penetrance). Moreover, we found IKZF3-L162R acts as a gain-of-function mutation, altering DNA binding specificity and target selection of IKZF3, and resulting in overexpression of multiple B-cell receptor (BCR) genes. Consistent with the murine data, RNA-sequencing analysis showed that human CLL cells with mut-IKZF3 [n=4] have an enhanced signature of BCR-signaling gene expression compared to WT-IKZF3 [n=6, all IGHV unmutated] (p&lt;0.001), and also exhibited general upregulation of key BCR-signaling regulators. These results confirm the role of IKZF3 as a master regulator of BCR-signaling gene expression, with the mutation contributing to overexpression of these genes. While mutation in IKZF3 has a clear functional impact on a cardinal CLL-associated pathway, such as BCR signaling, we note that this driver occurs only at low frequency in patients (~3%). Because somatic mutation represents but one mechanism by which a driver can alter a cellular pathway, we examined whether aberrant expression of IKZF3 could also yield differences in BCR-signaling gene expression. We have observed expression of the IKZF3 gene to be variably dysregulated amongst CLL patients through re-analysis of transcriptomic data from two independent cohorts of human CLL (DFCI, Landau et al., 2014; ICGC, Ferreira et al., 2014). We thus examined IKZF3 expression and BCR-signaling gene expression, or the 'BCR score' (calculated as the mean expression of 75 BCR signaling-associate genes) in those cohorts (DFCI cohort, n=107; ICGC cohort, n=274). Strikingly, CLL cells with higher IKZF3 expression (defined as greater than median expression) had higher BCR scores than those with lower IKZF3 expression (&lt;median) (p=0.0015 and p&lt;0.0001, respectively). These findings were consistent with the notion that IKZF3 may act as a broad regulator of BCR signaling genes, and that IKZF3 overexpression, like IKZF3 mutation, may provide fitness advantage. In support of this notion, our re-analysis of a gene expression dataset of 107 CLL samples (Herold Leukemia 2011) revealed that higher IKZF3 expression associated with poorer prognosis and worse overall survival (P=0.035). We previously reported that CLL cells with IKZF3 mutation appeared to increase in cancer cell fraction (CCF) with resistance to fludarabine-based chemotherapy (Landau Nature 2015). Instances of increase in mut-IKZF3 CCF upon treatment with the BCR-signaling inhibitor ibrutinib have been reported (Ahn ASH 2019). These studies together suggest an association of IKZF3 mutation with increased cellular survival following either chemotherapy or targeted treatment. To examine whether higher expression of IKZF3 was associated with altered sensitivity to ibrutinib, we performed scRNA-seq analysis (10x Genomics) of two previously treatment-naïve patients undergoing ibrutinib therapy (paired samples, baseline vs. Day 220). We analyzed an average of 11,080 cells per patient (2000 genes/cell). Of note, following ibrutinib treatment, remaining CLL cells expressed higher levels of IKZF3 transcript compared to pretreatment baseline (both p&lt;0.0001), whereas no such change was observed in matched T cells (n ranging between 62 to 652 per experimental group, p&gt;0.05), suggesting that cells with high expression of IKZF3 were selected by ibrutinib treatment. Moreover, we showed that ibrutinib treatment resulted in consistent upregulation of BCR-signaling genes (e.g., CD79B, LYN, GRB2, FOS, RAC1, PRKCB and NFKBIA) (n ranging between 362 to 1374 per experimental group, all p&lt;0.0001), which were likewise activated by mutant IKZF3. Altogether, these data imply that IKZF3 mutation or overexpression may influence upregulation of BCR-signaling genes and enhance cellular fitness even during treatment with BCR-signaling inhibitors. We highlight our observation that IKZF3 mutation appears to be phenocopied by elevated IKZF3 expression, and suggest that alterations in mRNA or protein level that mimic genetic mutations could be widespread in human cancers. Disclosures Kipps: Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees. Wu:BionTech: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding.

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