Impact of Deletion6q23 Identified By FISH in Patients with Chronic Lymphocytic Leukemia

Background: Cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH) are known to differentially impact prognosis in patients with chronic lymphocytic leukemia (CLL). Deletion6q23 (del6q23) has been reported in ~2-3% of CLL patients at diagnosis; however, its prognostic significance remains indeterminate. Methods: We identified previously untreated CLL patients from the Mayo Clinic CLL Database seen between 1/1995 - 2/2020 who had FISH performed. The clinical characteristics, concomitant cytogenetic abnormalities, time to first therapy (TTFT), and overall survival (OS) were compared between patients with del6q23 to those without this abnormality. TTFT was analyzed from FISH date until treatment or last known untreated date, accounting for competing risk of death. OS was analyzed using Kaplan-Meier methods from FISH date. In a matched (CLL-IPI risk score and sex) analysis, Cox regression analysis was used to determine the association between TTFT/OS and presence of del6q23. The Mayo Clinic IRB approved this study. Results: A total of 3101 CLL patients were identified; their median age at diagnosis was 64 years and 66% were male. Of these patients, 42 (1.3%) had evidence of del6q23 by FISH. Compared to patients without del6q23, patients with del6q23 carried a more adverse clinical and cytogenetic profile at the time of diagnosis including advanced Rai stage (22% Rai III/IV vs. 9% Rai III/IV; P = 0.002), unmutated IGHV genes (91% vs. 43%; P < 0.001), and high/very high risk CLL-IPI (50% vs. 27%; P < 0.001). Del6q23 was the sole abnormality in 13 patients (31%). Of the remaining patients, del6q23 was concomitantly present with del13q in 8 patients (19%), and with either del11q or del17p in 21 patients (50%). Of the 42 patients with del6q23, 29 received first line therapy: chemoimmunotherapy in 16 patients, BTK inhibitor in 7 patients, and an anti-CD20 monoclonal antibody alone in 6 patients. The median follow-up of the entire cohort was 7.3 years. The median TTFT in patients with del6q23 was 0.7 years while the 5-year OS was 76%. Patients with del6q23 demonstrated significantly shorter TTFT and reduced OS when compared to patients without del6q23 (Figures 1A and 1B). The shorter TTFT was also evident for patients with del6q23 compared to patients without del6q23 divided according to the Dohner risk category (Figure 2A), although there was no difference in OS between these groups of patients (Figure 2B). Because del6q23 patients were enriched for other unfavorable prognostic markers, we identified four control patients without del6q23, matched by CLL-IPI risk score and sex, to each treatment-naïve patient with del6q23. Patients with del6q23 showed a borderline statistically significant shorter TTFT (median 0.7 years versus 3.9 years; P = 0.07) and a nonsignificant association with OS (median 10.9 years versus 10.3 years; P = 0.28). Conclusion: Del6q23 by FISH in previously untreated CLL represents an uncommon abnormality. When compared to patients without del6q23, patients with del6q23 tend to have more adverse clinical and cytogenetic profiles at baseline, which likely confer a worse prognosis as reflected by shorter TTFT compared to patients without this abnormality. Figure Disclosures Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Astra Zeneca: Research Funding. Wang:Novartis: Research Funding; Innocare: Research Funding; Incyte: Research Funding. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Kay:Sunesis: Research Funding; Abbvie: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; MEI Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Kenderian:Juno: Research Funding; Gilead: Research Funding; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding; Mettaforge: Patents & Royalties; Tolero: Research Funding; BMS: Research Funding. Parikh:Ascentage Pharma: Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria.

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Impact of Individual Comorbidities on Treatment Outcomes in Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2018-99-113917 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4848-4848

Author(s):

Max J. Gordon ◽

Michael C Churnetski ◽

Hamood Alqahtani ◽

Xavier Issac Rivera ◽

Adam Kittai ◽

...

Keyword(s):

Random Forest ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Cox Model ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Risk Of Death ◽

Oncology Research ◽

The Impact

Abstract Introduction: Chronic lymphocytic leukemia (CLL) is a common leukemia which tends to occur late in life. Comorbidities are common, and the iwCLL guidelines recommend their assessment in patients (pts) enrolled on clinical trials. The Cumulative Illness Rating Scale (CIRS) is a rigorous tool designed to evaluate the burden of comorbidities, which has been employed in therapeutic studies. Our group and others demonstrated that CIRS score predicts survival in pts with CLL treated with either chemo-immunotherapy (CIT) or novel kinase inhibitors (KI; ibrutinib) (Manda et al, 2016 & Gordon et al, 2018). However, CIRS has not become part of common clinical practice, in part due to complexities in scoring. It is also unknown whether all of the 14 organ systems included in the score carry equal weight to determine prognosis. Here we report the impact of specific comorbidities from a multicenter retrospective cohort of CLL pts treated with either CIT or KI. Methods: We conducted a retrospective analysis of pts with CLL treated at five US academic medical centers between 2000 and 2017. CIRS score was calculated as in Salvi et al, 2008. Random forest (RF) was used to assess specific comorbidities' impact on overall survival (OS) and event-free survival (EFS, defined as time to new therapy, disease progression or death). We adapted two separate approaches to investigate the RF variable selection process: variable Importance (VIMP), a property related to variable misspecification, and Minimal Depth (MD), a property derived from the construction of trees within the forest. Best variables were those selected consistently as top 3 in both VIMP and MD on the 500 RF repetitions. Because hepatic and renal comorbidities were rare they were excluded. OS and EFS were assessed by Kaplan-Meier estimates and Cox proportional hazard model adjusted for performance status and age. Significance was assessed with log-rank test. Results: 398 pts were included in the final analysis. The median age was 63 years (range, 30-93). 50% of pts (n=198) had a high CIRS score (≥7). 184 pts (46%) had comorbidities assessed in relapsed setting. For all pts, the most common treatments included ibrutinib (n=145; 37%), fludarabine-containing regimens (n=104; 26%) and bendamustine (n=39; 10%). Complex karyotype was observed in 3.5% (n=14) and 10.6% (n=42) of pts had del(17p). Pts with comorbidities (CIRS ≥7) demonstrated shortened survival following therapy, with 5-year OS of 64% vs 89% (p<0.0001) and median EFS of 24 vs 49 months (p<0.0001). Pts treated with CIT had lower CIRS scores compared pts on KIs (6.5 vs 8.7, p<0.001), however there was no difference in CIRS between pts treated with high vs. low intensity CIT (e.g. FCR/BR vs chlorambucil/rituximab [n=59]; CIRS 6.8 vs 6.6, p=0.78), indicating comorbidities are not consistently taken into account when selecting therapy. Random forest variable selections identified vascular comorbidities (e.g. DVT/PE) as the most influential risk factor for OS with CIT treatment, while HEENT and cardiac comorbidities were most impactful to OS for patients treated with KI. For EFS, the most influential comorbidities were cardiac and vascular for the CIT treatment group and endocrine and HEENT for patients treated with KI. Across EFS and OS, the most frequently selected variables in CIT were cardiac, hypertension, vascular and neurologic. We constructed a simplified scoring system assigning 1 point for each category. Comparing scores of 0, 1 and 2-4 (n=100, n=82, n=60), 5-year OS was 87%, 82% and 66%, respectively (p<0.0001). In an adjusted Cox model OS decreased between risk groups (HR=1.78; 95% CI, 1.2-2.6; p=0.004). Cardiac, vascular, HEENT and endocrine were the most frequently selected in pts receiving KI. Comparing scores of 0, 1 and 2-4 (n=50, n=51, n=55), 2-year OS was 98%, 87% and 81%, respectively (p=0.034). There was a trend towards increased risk of death in the adjusted cox model (HR=1.63; 95% CI, 0.80-3.34; p=0.19). Conclusion: Comorbidities impact survival in CLL whether treated with CIT or KI. Which comorbidities are most prognostic may vary by treatment type. Vascular and cardiac comorbidities appear to be the most relevant in CLL pts treated with CIT. Meanwhile, cardiac, endocrine and HEENT had greater impact when pts were treated with KI. A simplified CIRS score is predictive of outcomes in both treatment subgroups. Disclosures Choi: Gilead: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy; Genentech: Speakers Bureau. Cohen:Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy. Persky:Genentech: Honoraria; Morphosys (IDMC): Consultancy; Spectrum: Research Funding; Merck: Research Funding. Danilov:Aptose Biosciences: Research Funding; Verastem: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding.

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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 ◽

10.1182/blood-2019-124541 ◽

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.

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Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽

10.1182/blood.v128.22.3306.3306 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3306-3306

Author(s):

Yi L. Hwa ◽

Qian Shi ◽

Shaji Kumar ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Research Funding ◽

Beta Blockers ◽

Multivariable Analysis ◽

Advisory Committees ◽

Risk Of Death ◽

Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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

Blood ◽

10.1182/blood-2020-137085 ◽

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<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 (<median) (p=0.0015 and p<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<0.0001), whereas no such change was observed in matched T cells (n ranging between 62 to 652 per experimental group, p>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<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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Increased Activity of Aldehyde Dehydrogenase, a Stem/Progenitor Cell Marker, in Chronic Lymphocytic Leukemia,

Blood ◽

10.1182/blood.v118.21.3867.3867 ◽

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.

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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 ◽

10.1182/blood.v122.21.6.6 ◽

2013 ◽

Vol 122 (21) ◽

pp. 6-6 ◽

Cited By ~ 10

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.

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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 ◽

10.1182/blood.v124.21.3345.3345 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3345-3345 ◽

Cited By ~ 7

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.

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

Blood ◽

10.1182/blood.v128.22.233.233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 233-233 ◽

Cited By ~ 53

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.

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

Blood ◽

10.1182/blood.v128.22.4372.4372 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4372-4372 ◽

Cited By ~ 1

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.

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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 ◽

10.1182/blood.v124.21.327.327 ◽

2014 ◽

Vol 124 (21) ◽

pp. 327-327 ◽

Cited By ~ 27

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.

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