scholarly journals Time-Limited Venetoclax and Ibrutinib for Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Who Have Undetectable MRD - Primary Analysis from the Randomized Phase II Vision HO141 Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 69-69
Author(s):  
Carsten Utoft Niemann ◽  
Julie Dubois ◽  
Christian Brieghel ◽  
Sabina Kersting ◽  
Lisbeth Enggaard ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Steering Committee ◽  
Lymphocytic Leukemia ◽  
Similar Proportion ◽  
Treatment Cessation ◽  
Bleeding Events ◽  
Advisory Committees

Abstract Background: For patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL), targeted time-limited treatment options are warranted. Thus far, therapeutic options are based on a (one-size-fits-all) fixed treatment duration or treatment until progression independent of individualized responsiveness. Post-treatment minimal residual disease (MRD) predicts outcome for patients receiving venetoclax-based therapy. Aim: To evaluate Progression-Free Survival (PFS) for patients with R/R CLL 12 months after MRD guided treatment cessation of venetoclax + ibrutinib (V+I) treatment (arm B) with the option to reinitiate V+I based on MRD reappearance. Methods: Patients (BTK inhibitor naïve) received ibrutinib lead-in (420 mg daily) for two (28-day) cycles. Venetoclax ramp-up was initiated during cycle 3, reaching 400 mg daily at cycle 4 with continued V+I during cycle 4-15. Patients reaching at least partial remission (PR) and undetectable (u)MRD (<10 -4) in blood (PB) and bone marrow (BM, by central 8-color flow cytometry) at cycle 15 day 15 were randomized 1:2 between ibrutinib maintenance (arm A) or treatment cessation (arm B). Patients later becoming MRD positive (>10 -2) in arm B reinitiated V+I. MRD positive patients at cycle 15 remained on ibrutinib until progression. Results: 225 patients were enrolled: median age 68 years (range 36-87), median CIRS score 2 (range 0-12), Binet stage B/C 84%, IGHV unmutated: 64%, TP53 aberrations (deletions and/or mutations): 24%. Planned treatment until randomization was completed by 194 (86%) patients, 8 patients went off protocol due to toxicity, 5 (2%) patients died during the first two cycles of ibrutinib lead-in (unknown cause, myocardial infarction, intracranial hemorrhage, Richter's transformation and tick-borne viral encephalitis), 15 patients went off protocol due to refusal to continue or other reasons and 3 patients progressed. At cycle 15, 81 (36%) patients achieved uMRD in both PB (112, 50%) and BM (84, 37%) and overall responses were 86%, of which 145 pts (64%) CR(i). Patients with uMRD were randomized to ibrutinib maintenance arm A (n 24 11%) or observation arm B (n 48 21%). Patients who did not achieve uMRD (n 125, 56%) continued ibrutinib maintenance without randomization while 5 patients went off protocol. The primary endpoint of the trial was met; PFS was achieved for 47 (98%) of 48 patients randomized to observation arm B at 12 months after randomization (27 months after starting therapy). One patient died during observation due to myelodysplastic syndrome and 1 patient, without sign of progression, reinitiated per protocol due to MRD positivity. A similar proportion of uMRD patients randomized to ibrutinib maintenance (arm A) or observation (arm B) remained uMRD after 12 months (month 27 after treatment start); 75% and 71%, respectively; see figure. No difference in blood uMRD at cycle 15 was seen neither between TP53 aberrated/wildtype (uMRD: 46%, 52%) nor between IGHV unmutated/mutated patients (uMRD: 50%, 50%). The most frequent adverse event (AE, only grade ≥2) was infections with 68 (30%) grade 2 and 62 (28%) grade ≥3 during the first 15 cycles, while 14 (58%) and 6 (12%) infections appeared after randomization in the treatment arm A and observation arm B, respectively. Atrial fibrillation was reported for 29 (13%) patients during the first 15 cycles, for 4 (3%) during ibrutinib maintenance (arm A + non-randomized) while no patients were reported with atrial fibrillation in arm B. Hypertension was reported for 23 (10%) patients during the first 15 cycles and for 10 (7%) patients during ibrutinib maintenance while no events were reported in arm B. One fatal bleeding event was reported in addition to 32 (14%) grade 2-3 bleeding events during the first 15 cycles; 12 (9%) grade 2-3 bleeding events were reported during ibrutinib maintenance, while no events were reported in arm B. Laboratory tumor lysis grades 2-3 was reported for 11 (5%) of patients. Conclusion: MRD guided time-limited treatment with ibrutinib and venetoclax in the setting of R/R CLL is feasible and demonstrates a favorable benefit-risk profile. No new safety signals were detected. No patients progressed after treatment cessation while patients becoming MRD positive successfully reinitiated therapy, thus proving MRD-guided cessation and reinitiation of targeted therapy feasible in CLL. Figure 1 Figure 1. Disclosures Niemann: CSL Behring, Genmab, Takeda, Octapharma: Consultancy; Abbvie, AstraZeneca, Janssen: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding. Dubois: Abbvie: Research Funding; Genentech: Research Funding; Roche: Research Funding. Brieghel: AstraZeneca: Consultancy. Kersting: Cellgene: Other: travel grant. Enggaard: Abbvie: Consultancy; Janssen: Consultancy. Mellink: Financial support related to microarray analysis of Murano samples: Research Funding; Genome Diagnostics Laboratory, AUMC: Current Employment; Cytogenetic Field: Consultancy. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Frederiksen: Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding. Janssens: Sanofi: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Trael Grant, Speakers Bureau; Beigene, AstraZeneca: Consultancy, Speakers Bureau. Mattsson: Gilead: Research Funding. Bellido: Janssen: Other: educational funding. Tran: Novartis, Janssen, Abbvie, Takeda, CSL Bering: Consultancy; Astra Zeneca: Consultancy. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding. OffLabel Disclosure: The combination of ibrutinib and venetoclax is not registered for treatment of CLL, both drugs are separately registered for treatment of CLL

scholarly journals Tocilizumab to Prevent Infusion-Related Events in Patients with Chronic Lymphocytic Leukemia and Co-Morbidities Treated with Obinutuzumab and Chlorambucil: Results from the Randomized Phase Ib GALACTA Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4419-4419
Author(s):  
Ciara Louise Freeman ◽  
Sebastian Böttcher ◽  
Javier De la Serna ◽  
Julio Delgado ◽  
Franca Falzetti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Intensive Therapy ◽  
Lymphocytic Leukemia ◽  
Similar Proportion ◽  
Advisory Committees ◽  
Phase Ib ◽  
Amyloid A ◽  
Equity Ownership

Abstract Introduction: In the CLL11 study, obinutuzumab (G) plus chlorambucil (Clb; G-Clb) significantly improved outcomes relative to rituximab plus Clb and Clb alone in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities, but was associated with an increased incidence and severity of infusion-related reactions (IRRs), cytopenias and treatment discontinuations (Goede et al. N Engl J Med 2014; Goede et al. EHA 2018). IRRs have been associated with the release of pro-inflammatory cytokines, including interleukin-6 (IL-6; Freeman et al. Blood 2015). Tocilizumab (TCZ) is a monoclonal antibody that blocks downstream signaling by IL-6. It has regulatory approval (FDA/EMA) for the treatment of chimeric antigen receptor T-cell induced cytokine release syndrome, and could potentially be used to limit the IRRs associated with G administration. GALACTA was a randomized, double-blind, Phase Ib trial in previously untreated pts with CLL and co-morbidities (NCT02336048). Its primary objective was to determine the safety and tolerability of TCZ prior to G-Clb. Secondary endpoints included pharmacokinetics and pharmacodynamics of TCZ in this population, and impact on the efficacy of the G-CIb combination. Methods: Previously untreated CLL pts who were unsuitable for more intensive therapy (CIRS score >6 or creatinine clearance <70mL/min) were randomized 2:1 to receive a single IV infusion of TCZ 8mg/kg or placebo (PLB) prior to G on day (D) 1 of cycle (C) 1 of G-Clb. Pts were stratified prior to randomization by absolute lymphocyte count (ALC; >50x109/L) and mean fluorescence intensity of CD20 on CLL-gated cells. G-CIb was administered as: G 1000mg IV on D1/D2 (100mg/900mg), D8 and D15 of C1, and D1 of C2-6; Clb 0.5mg/kg PO on D1 and D15 of C1-6. Prior to the first G dose in C1, standard premedication (antipyretic, antihistamine, corticosteroids) was administered in addition to TCZ or PLB. IRR was defined as any adverse event (AE) occurring during or within 24 hours of G infusion and judged by the investigator as related to G. Results: A total of 38 pts were enrolled between June 26, 2015 and Jan 22, 2018; 25 were randomized to TCZ and 13 to PLB. Median age was 74 years (range 54-87), 63% were male, 95% had ECOG PS 0-1, and 95% had Binet stage B/C disease. Baseline characteristics were well balanced, with the exception of more males in the TCZ arm (72%) than the PLB arm (46%). Despite a similar proportion of baseline ALC ≤50 versus >50x109/L in the two treatment arms, more pts in the TCZ arm had levels which were >100x109/L (15% in PLB vs 28% in TCZ). At the time of analysis, 25 pts had completed all 6 cycles, 6 remained on treatment, and 7 had discontinued. IRRs occurred in 18/25 (72%) pts in the TCZ arm and 10/13 (77%) in the PLB arm. Grade ≥3 IRRs occurred in 11/25 (44%) pts in the TCZ arm and 4/13 (31%) pts in the PLB arm. Four pts discontinued treatment due to IRRs: 3 (12%) in the TCZ arm and 1 (8%) in the PLB arm. Similar to previous reports, cytokine levels peaked on D1 after 100mg G had been administered. Serum amyloid A (Figure 1) and C-reactive protein (CRP) (Figure 2) were sub-optimally reduced in the TCZ arm. Of the 19 pts with measurable TCZ levels, no marked differences in exposure were seen based on IRR intensity. However, TCZ exposure was lower on average than in rheumatoid arthritis pts of equivalent weight treated with the same dose (mean Cmax 154 vs 193µg/mL), and TCZ-treated pts that developed IRRs had comparatively less suppression of CRP than those who did not. Conclusions: Preliminary results suggest that use of a single 8mg/kg dose of TCZ prior to the first dose of G was feasible, but did not appear to prevent IRRs in this pt population. The study was primarily designed to assess the safety of the combination, and was underpowered to detect meaningful differences between groups in IRR severity. TCZ-treated pts who developed IRRs had higher baseline risk than those who did not, and the TCZ dose may have been insufficient, resulting in the lack of efficacy. Whether inhibition of this pro-survival cytokine enhances the cytotoxic potential of the regimen is not yet determined; updated results will be presented at the meeting. Disclosures Freeman: Seattle Genetics: Honoraria; Abbvie: Honoraria. Böttcher:Celgene: Research Funding; Genentech: Research Funding; AbbVie: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. De la Serna:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gobbi:Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Di Bernardo:Roche: Employment. Mallalieu:Roche: Employment, Equity Ownership. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Knapp:Roche: Employment. Gribben:Janssen: Honoraria, Research Funding; Abbvie: Honoraria; Acerta Pharma: Honoraria, Research Funding; TG Therapeutics: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Medical Research Council: Research Funding; Novartis: Honoraria; Kite: Honoraria; Cancer Research UK: Research Funding; Pharmacyclics: Honoraria; Unum: Equity Ownership; Roche: Honoraria; Wellcome Trust: Research Funding; NIH: 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.

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.

Increased Activity of Aldehyde Dehydrogenase, a Stem/Progenitor Cell Marker, in Chronic Lymphocytic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3867-3867
Author(s):  
Raymond P. Wu ◽  
Christina C.N. Wu ◽  
Tomoko Hayashi ◽  
Laura Z. Rassenti ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Progenitor Cell ◽  
Lymphocytic Leukemia ◽  
Cell Marker ◽  
Aldh Activity ◽  
Advisory Committees ◽  
Aldefluor Assay

Abstract Abstract 3867 Introduction: Despite their mature appearance, the B cells from chronic lymphocytic leukemia (CLL) possess immature characteristics both functionally and biochemically. CLL B cells display known biochemical markers characteristic of cells early in the blood lineage, including ROR1, Wnt16, and LEF1. In addition, CLL B cells have higher levels of Reactive Oxygen Species (ROS) and of the oxidant-induced transcription factor Nrf2 [NFE2L2], compared to normal peripheral blood mononuclear cells (PBMC). Intracellular ROS status has been suggested to be a marker of cancer stem/progenitor cells possibly due to their high expression of oncogenes. Downstream targets of Nrf2 include the Aldehyde dehydrogenase [ALDH] enzymes, which are believed to play a crucial role in stem cell biology because they protect the cells against oxidative stress caused by accumulation of aldehydes. Here, we use ALDH activity to visualize populations of CLL B cells that may have stem/progenitor properties. Materials and Methods: Isolated PBMC from normal donors and CLL patients with aggressive and indolent disease were stained for ALDH activity with an Aldefluor assay kit (StemCell Technologies). The ALDH inhibitor, diethylaminobenzaldehyde (DEAB), was used to confirm that the fluorescent activity was due to ALDH activity. At the end of the Aldefluor assay, the cells were stained for cell surface markers, CD19, CD5, CD38 and CD34. 50,000 total events were collected for FACS analysis. Normalized Mean Fluorescence Intensity (MFI) values were calculated by dividing each MFI value to average MFI value of normal CD19+ cells for each experiment. Data analyses were performed by FlowJo software and Prizm. P-values were calculated by One-Way ANOVA analysis with Post-Bonferroni's multiple comparison test. Results: We examine the level of ALDH expression and activity in CD19+ cells of healthy donors (n = 9), CLL samples that expressed unmutated IgVH and that were ZAP-70 positive (defined as “aggressive”, n = 14) or samples that expressed mutated IgVH and were ZAP-70 negative (defined as “indolent”, n=12). CLL B cells from patients with aggressive disease had significantly higher ALDH activities compared to normal B cells (p < 0.001) and indolent CLL B cells (p < 0.05) (Figure1). Indolent CLL B cells also have higher level of ALDH activities compared to normal B cells (p < 0.01) (Figure1). Treatment with the ALDH inhibitor, DEAB, suppressed the increased fluorescence observed in CLL B cells. In addition, ALDH high CLL B cells are CD34 negative. These data show that CLL B cells express a marker known to be associated with stem/progenitor cells, but these populations are different from CD34 positive hematopoietic stem cells. In addition, our data show that a stem/progenitor cell marker is associated with the pathogenesis of CLL. Disclosures: Kipps: Igenica: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Abbot 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.

Head-To-Head Comparison Of Obinutuzumab (GA101) Plus Chlorambucil (Clb) Versus Rituximab Plus Clb In Patients With Chronic Lymphocytic Leukemia (CLL) and Co-Existing Medical Conditions (Comorbidities): Final Stage 2 Results Of The CLL11 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 6-6 ◽  
Author(s):  
Valentin Goede ◽  
Kirsten Fischer ◽  
Raymonde Busch ◽  
Anja Engelke ◽  
Barbara Eichhorst ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Final Stage ◽  
Research Funding ◽  
Observation Time ◽  
Lymphocytic Leukemia ◽  
Type Ii ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Stage 1

Abstract Introduction CLL11 is a large randomized phase 3 trial investigating first-line chemoimmunotherapy in CLL patients with comorbidities, i.e. patients typically treated in daily practice. Here, we present: (i) The final stage 2 analysis with efficacy and safety results of the head-to-head comparison between GA101 plus Clb (GClb) and rituximab plus Clb (RClb); at the pre-planned interim analysis, the primary endpoint was met early and the results were released by the independent data monitoring board. (ii) An update on the stage I analysis (GClb vs. Clb and RClb vs. Clb comparisons) with longer observation time; the final stage 1 analysis recently showed that GClb or RClb has superior efficacy to chemotherapy with Clb alone. Methods Treatment-naïve CLL patients with a Cumulative Illness Rating Scale (CIRS) total score >6 and/or an estimated creatinine clearance (CrCl) <70 mL/min were eligible. Patients received Clb alone (0.5 mg/kg po d1, d15 q28 days, 6 cycles), GClb (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 of cycle 1, 1000 mg d1 cycles 2-6), or RClb (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6). Primary endpoint was investigator-assessed progression-free survival (PFS). Response rates, minimal residual disease (MRD), and overall survival (OS) were key secondary efficacy endpoints. Results Final results of the stage 2 analysis: Median observation time was 19 months. The GClb and RClb treatment arms were well balanced for baseline characteristics. Median age, CIRS score, and CrCl at baseline were 73 years, 8, and 63 mL/min respectively. Key efficacy and safety results are shown in the table. The PFS benefit of GClb over RClb was supported by all pre-planned subgroup analyses (including the cytogenetic subgroups 17p-, 11q-, 12+, 13q-). The number of patients with MRD negative blood samples at end-of-treatment was more than 10-fold higher with GClb compared with RClb (63/214 [29.4%] vs. 6/243 [2.5%]). Grade 3-4 infusion-related reactions with GClb occurred at first infusion only. Updated results of the stage 1 analysis: Median observation time was 23 months. Confirming the primary stage 1 results, GClb or RClb compared with Clb alone was associated with statistically significant and clinically meaningful improvement in PFS (GClb vs. Clb: HR 0.18, CI 0.13-0.24, p<.0001, RClb vs. Clb: HR 0.44, CI 0.34-0.57, p<.0001). The updated median PFS in GClb, RClb and Clb were 26.7, 16.3 and 11.1 months, respectively. Updated OS analysis demonstrated a benefit of GClb over Clb (HR 0.41, CI 0.23-0.74, p=0.002). OS analysis for RClb over Clb showed HR 0.66, CI 0.39-1.11, p=0.113. At the data cut-off, 9%, 15%, and 20% of the patients in the GClb, RClb, and Clb arms, respectively, had died. OS medians were not reached. Conclusions GA101, a novel, glycoengineered, type II CD20 antibody, in combination with Clb (GClb regimen) demonstrated statistically significant and clinically meaningful prolongation of PFS, and higher complete response rate and MRD negativity rate compared with RClb in previously untreated CLL patients with comorbidities. Infusion-related reactions and neutropenia were more common with GClb without an increase in infections. Furthermore, GClb vs. Clb alone demonstrated a prolongation of OS. Overall, GClb is superior to RClb and a highly active treatment in this typical CLL patient population. Disclosures: Goede: Mundipharma: Honoraria; F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: GA101 is a novel, glycoengineered, type II anti-CD20 monoclonal antibody that is designed to enhance direct cell death and antibody-dependent cellular cytotoxicity. It is being investigated in chronic lymphocytic leukemia, Non-Hodgkin’s Lymphoma and other hematologic indications. Fischer:Mundipharma: Travel grants, Travel grants Other; F. Hoffmann-La Roche: Travel grants Other. Engelke:F. Hoffmann-La Roche: Travel grants Other. Eichhorst:Mundipharma: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Consultancy; F. Hoffman-La Roche: Honoraria, Research Funding. Wendtner:F. Hoffmann-La Roche: Consultancy, Research Funding. Dilhuydy:F. Hoffmann-La Roche: Consultancy. Opat:F. Hoffmann-La Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Alexion Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Owen:F. Hoffmann-La Roche: Honoraria. Kreuzer:F. Hoffmann-La Roche: Consultancy, Honoraria. Langerak:F. Hoffmann-La Roche: Research Funding. Ritgen:F. Hoffmann-La Roche: Research Funding. Stilgenbauer:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding. Asikanius:F. Hoffmann-La Roche: Employment. Humphrey:F. Hoffmann-La Roche: Employment. Wenger:F. Hoffmann-La Roche: Employment, Ownership interests (including stock options) in a start-up company, the stock of which is not publicly traded Other. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

Preliminary Safety Results from the Phase IIIb GREEN Study of Obinutuzumab (GA101) Alone or in Combination with Chemotherapy for Previously Untreated or Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3345-3345 ◽  
Author(s):  
Francesc Bosch ◽  
Thomas Illmer ◽  
Mehmet Turgut ◽  
Agostino Cortelezzi ◽  
Susan F. Lasserre ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Safety Profile ◽  
Research Funding ◽  
Safety Data ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Phase Iiib ◽  
Unfit Patients ◽  
Grade 3

Abstract Background: The novel, glycoengineered type II anti-CD20 monoclonal antibody, obinutuzumab (GA101) has demonstrated superior efficacy to chlorambucil (Clb) monotherapy and to Clb in combination with rituximab (R-Clb) with an acceptable safety profile in CLL. However, an increased rate of infusion-related reactions (IRRs) has been observed with the obinutuzumab(G)-Clb combination compared with R-Clb during the first cycle of treatment. The GREEN study (NCT01905943) is an ongoing phase IIIb, multicenter, open-label trial investigating the safety and efficacy of obinutuzumab alone or in combination with chemotherapy in patients with previously untreated or relapsed/refractory CLL. We report safety data from cohort 1, which aimed to reduce IRRs on the first day of obinutuzumab administration in previously untreated patients using a lower dose and slower infusion rate than in previous studies. Methods: Subjects aged ≥18 years withdocumented CLL, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate hematologic function are enrolled. Treatment includes obinutuzumab (1000mg) administered intravenously on days (D) 1 (25mg) and 2 (975mg), D8, and D15 of cycle (C) 1, and on D1 of C2–6, alone (any patient: n=18) or in combination with 28-day cycles of chemotherapy: fludarabine plus cyclophosphamide (FC; n=46) for fit patients (cumulative illness rating scale [CIRS] ≤6 and creatinine clearance [CrCl] ≥70mL/min), Clb (n=8) for unfit patients (CIRS >6 and/or CrCl <70mL/min) or bendamustine (B; n=86) for fit/unfit patients. The primary outcome is safety, including the frequency, type and severity of adverse events (AEs). The present analysis focuses on IRRs, defined as treatment-related AEs occurring during or within 24 hours of infusion. Results were assessed to determine if a low obinutuzumab dose (25mg) and slow infusion rate (12.5mg/hour) on D1 (the current recommended C1D1 regimen is 100mg at 25mg/hour) could reduce IRRs. Analysis was based on a data cut-off of 28 April 2014, planned for when the first 150 previously untreated patients had completed cohort 1. Results: Of 158 subjects eligible for the IRR analysis (Table), median age was 65.0 (34.0–83.0) years and the majority were males (65.2%) with Binet stage B (52.5%) or C (31.0%) CLL. Median observation time was 2.09 (0.2–6.0) months and median exposure time was 1.0 (0.0–4.8) month. IRRs occurring in ≥10% of patients were chills (14.6%) and pyrexia (15.2%). Serious IRRs in ≥1% of patients were tumor lysis syndrome (TLS; 3.8%) and pyrexia (1.3%). Grade ≥3 IRRs experienced by ≥1% of patients were TLS (5.7%), hypertension (1.3%) and hypotension (1.3%). IRRs were most frequent in C1D1 (Fig). In the overall safety population (n=172; previously untreated patients) the most frequently reported serious AEs of special interest included IRR (8.1%) and neutropenia (11.0%). AEs of particular interest, thrombocytopenia, cardiac, and hemorrhagic events, were experienced by 16.3%, 3.5% and 3.5% of patients, respectively. Table. Table. Conclusions: Preliminary safety data from the GREEN study, assessing the use of obinutuzumab alone or in combination with chemotherapy (B, FC or Clb) in subjects with untreated CLL, are in line with the known safety profile of obinutuzumab in similar populations. Although there is limited exposure time available for subjects in GREEN, IRRs seemed to be more manageable and a lower proportion of subjects with IRRs grade ≥3 was observed compared with previous studies. No new safety signals were reported. However, since the number of discontinuations during C1 was comparable with previous obinutuzumab studies, the decision was taken to further improve IRR rates by assessing additional dexamethasone premedication in cohort 2. Final safety data from the study will be presented at a later timepoint. Figure 1 Figure 1. Disclosures Bosch: Roche: Consultancy, Research Funding, Speakers Bureau. 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.. Lasserre:F. Hoffmann–La Roche: Employment. Truppel-Hartmann:F. Hoffmann–La Roche: Employment. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Roche-Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Roche: Consultancy, Honoraria, Research Funding.

Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 233-233 ◽  
Author(s):  
Susan M. O'Brien ◽  
Richard R. Furman ◽  
Steven E. Coutre ◽  
Ian W. Flinn ◽  
Jan Burger ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones: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; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

Presence of a Translocation Is Associated with Short Time to Treatment from Diagnosis in IGHV Mutated Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4372-4372 ◽  
Author(s):  
Nyla A. Heerema ◽  
Qiuhong Zhao ◽  
Amy S. Ruppert ◽  
Heather Breidenbach ◽  
Jeffrey Jones ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Statistical Significance ◽  
Patient Characteristics ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Final Model ◽  
Time To Treatment ◽  
Short Time

Abstract Chronic Lymphocytic Leukemia (CLL) has a varied clinical course; some patients experience a long survival and others succumb to disease in a short time. Clinical factors correlated with either time to first treatment (TFT) and/or overall survival include Rai stage, IGHV somatic hypermutation status, fluorescence in situ hybridization (FISH) abnormalities, especially del(17p), karyotypic complexity and the presence of a cytogenetic translocation. Previous studies have included patients both at diagnosis and at various times throughout their diseases, and many included limited numbers of patients, precluding extensive analyses of relationships between the prognostic factors and their relative impact on clinical outcome. We sought to identify which factors determined within a short time of diagnosis (i.e., 1 year) were prognostic for TFT in untreated CLL patients. We identified 329 untreated CLL patients who had stimulated karyotypic and FISH analyses within 1 year of diagnosis seen at The Ohio State University (OSU). Patient characteristics and outcome were obtained from patient records. The studies were approved by the OSU IRB and were conducted according to the Declaration of Helsinki. A complex karyotype was defined as ≥ 3 unrelated aberrations by karyotype. Patient characteristics are given in Table 1. Translocations occurred in 87 (26.4%) patients: 38 balanced and 49 unbalanced translocations. Initial statistical analyses showed no large difference in TFT between balanced and unbalanced translations, so they were combined for final analyses. 144 patients (49 with and 95 without a translocation) had unmutated IGHV, and 144 patients (22 with and 122 without a translocation) had mutated IGHV. IGHV data were not available for 41 patients. TFT was calculated from date of diagnosis to date of first treatment. Untreated patients were censored at last known untreated date. Kaplan-Meier curves estimated TFT probability, and proportional hazard models were used to examine the association between potential risk factors and TFT. Using backward selection, variables with statistical significance when adjusting for all other covariates were included in the final model. To evaluate potential effect modifications, pairwise interactions among all the variables in the final model were examined and retained if statistically significant. Stata 14 (College Station TX) was used, and all tests were two-sided with statistical significance set at p<0.05. Median follow-up for censored patients was 30 months (range 0.03-102 months). Median TFT for the entire cohort was 47 months (95% confidence interval (CI) 40-63 months). In a univariable model, the following factors were significant: presence of a translocation (hazard risk (HR) 2.69, CI 1.91-3.78, p<0.001), Rai stage III/IV (HR 3.73, CI 2.32-5.99, p<0.001), complexity (HR 2.92, CI 1.98-4.31, p<0.001), unmutated IGHV (HR 3.54, CI 2.42-5.17, p<0.0001), del17p (HR 2.10, CI 1.31-3.37, p=0.002), del11q (HR 2.91,CI 1.92-4.40, p<0.001). In the multivariable model, there was significant effect modification of IGVH status on the relationship between translocation and TFT (p<0.001). In IGHV mutated patients, those with a translocation had over 5 times the risk of starting treatment relative to those without a translocation (HR 5.30, CI 2.76-10.17); however, in IGHV unmutated patients, a translocation did not significantly increase the risk of starting treatment (HR 1.32, CI 0.86-2.03). Independent of IGHV and translocation, Rai Stage (HR 2.07, CI 1.24-3.45, p=0.01) and del11q (HR 1.68, CI 1.09-2.60, p=0.02) were the only variables that remained statistically significant. Notably, once these variables were accounted for in the model, complexity did not provide additional significant prognostic information (p=0.12), perhaps due to its strong association with a translocation (p<0.001). In summary, the presence of a translocation in IGHV mutated patients appeared to negate the improved prognosis associated with mutated IGHV, but the presence of a translocation did not have an effect on TFT in high-risk IGHV unmutated patients (Figure 1). Table 1 Table 1. Figure 1 Time to Treatment for patients with vs without a translocation and with mutated vs unmutaed IGVH Figure 1. Time to Treatment for patients with vs without a translocation and with mutated vs unmutaed IGVH Disclosures Jones: Pharmacyclics, LLC, an AbbVie Company: 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. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Woyach:Morphosys: Research Funding; Acerta: Research Funding; Karyopharm: Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

scholarly journals Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 327-327 ◽  
Author(s):  
Susan O'Brien ◽  
Jeffrey A. Jones ◽  
Steven Coutre ◽  
Anthony R. Mato ◽  
Peter Hillmen ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Previously Treated ◽  
Grade 3

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

scholarly journals A Study of Ribonucleotide Reductase mRNA Expression and Its Prognostic Role in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4678-4678
Author(s):  
Sevastianos Chatzidavid ◽  
Christina-Nefeli Kontandreopoulou ◽  
Panagiotis T Diamantopoulos ◽  
Nefeli Giannakopoulou ◽  
Panagiota Katsiampoura ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mrna Expression ◽  
Board Of Directors ◽  
Ribonucleotide Reductase ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Line Treatment ◽  
Prognostic Role ◽  
Advisory Committees ◽  
Trisomy 12

Abstract Background Ribonucleotide Reductase (RNR) is responsible for converting ribonucleotides to deoxyribonucleotides required for DNA replication and repair. RNR consists of two subunits, termed subunit 1 (RRM1) and 2 (RRM2). Imbalance in the regulation of RNR activity and control of dNTPs' pool leads to genomic instability and increases mutation rate. RNR expression has been associated with prognosis in pancreatic, non-small-cell lung, breast, and biliary tract cancer. However, RNR expression in chronic lymphocytic leukemia (CLL) and its possible prognostic role have not been investigated yet. Aim In this study we evaluate the possible prognostic role of RNR expression in CLL. Method The study comprised patients with immunophenotypically confirmed disease at the time of sample collection. Peripheral whole blood samples were collected from 84, 27, 15, and 9 patients before treatment, after one, two, and three lines of treatment respectively. RNA extraction and reverse transcription were carried out using standard protocols. A Taqman based real-time PCR was performed on a CFX96 RT-PCR system (Bio-Rad Laboratories, Hercules, CA, USA). For both the housekeeping and target genes, a Taqman primer/probe mix was used according to the manufacturer's instructions (Applied Biosystems, Foster City, CA, USA). RRM1 and RRM2 mRNA levels were expressed as an RRM1-2/GAPDH ratio. Western blot analysis was performed to quantify the RRM1 protein levels in a random sample of 41 patients. Antibodies used were: RRM1 #3388, β-actin #4967 and anti-rabbit IgG HRP-conjugated #7074 (Cell Signaling Technology, Danvers, MA, USA). Detection was done using the ECL western blotting reagents. Statistical analysis was conducted to study the possible correlations between the variables. All reported p values are two-tailed. Statistical significance was set at p&lt;0.05 and analyses were conducted using SPSS statistical software (version 22.0). Results From 135 CLL patients included in the study 56.3% were female and the median age at diagnosis was 64 years. Peripheral blood was collected in 84 treatment-naïve patients (62.2%). Median follow up was 6.66 years (3.47 ─ 11.13) and median time from diagnosis until 1st line treatment was 23.1 months (IQR: 5.8 - 56.5 months). Out of 135 patients, 69 (51,1%) received 1 st line treatment and 35 patients (25,9%) 2 nd line treatment with median time between the two treatment lines being 26.5 months (IQR: 7.8 - 40.8 months). Furthermore, 48.5%, 33.8%, 12.3%, 3.1% and 2.3% of the patients had Rai score 0, I, II, III, IV respectively. The median mRNA expression of RRM1 was 0.04 (IQR: 0 - 0.09) and of RRM2 was 0.01 (IQR: 0 - 0.1). RRM1 mRNA expression was significantly higher in patients without anemia (p=.025) and without lymphadenopathy (p=.002). Higher values of ESR (r=-.30; p=.028), LDH (r=-.20; p=.026) and Rai score (r=-.18; p=.037) were associated with lower expression of RRM1 mRNA. In addition, TP53 gene deletion detected by FISH was associated with higher RRM1 mRNA expression (p=.036). Significantly higher RRM2 mRNA expression was reported in patients without lymphadenopathy (p=.021) and Rai score 0 (p=.003). Moreover, higher was the expression of RRM2 mRNA in cases with Trisomy 12 (p=.050). In samples collected before treatment, higher values of RRM1 mRNA expression were statistically significantly associated with lower RAI score (r=-.30; p=.005) and longer time periods between the first two lines of treatment (r=.95; p=.050). Western blot analysis confirmed detection of RRM1 protein but statistical correlation was not carried out due to lack of material from the whole group of patients. Conclusion For the first time, mRNA expression of RRM1 and RRM2 is studied in patients with CLL. These results show RNR involvement in the pathophysiology of CLL. RRM1 and RRM2 mRNA higher expression found in 17p deletion and trisomy 12 cases respectively may be consistent with the existence of a methylation-depended mechanism proposed by other studies. Therefore, these results demonstrate RNR's potential role as a prognostic factor, and make it a probable therapeutic target. A study including a larger number of cases could further confirm our results. Figure 1 Figure 1. Disclosures Kyrtsonis: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Genesis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees. Panagiotidis: Abbvie: Research Funding; Pfizer: Research Funding; Janssen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Sandoz: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Research Funding; Astellas: Research Funding. Viniou: Sandoz: Research Funding; Takeda: Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Roche: Research Funding; Astellas: Research Funding; Celgene: Research Funding.

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