scholarly journals Mechanisms of Adaptation to Ibrutinib in High Risk Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 585-585 ◽  
Author(s):  
Valeria Spina ◽  
Gabriela Forestieri ◽  
Antonella Zucchetto ◽  
Alessio Bruscaggin ◽  
Tamara Bittolo ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Nuclear Localization ◽  
Peripheral Blood ◽  
Research Funding ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Adaptation Process ◽  
Over Time ◽  
Stimulation Of

Abstract Introduction. Ibrutinib inhibits the BTK molecule downstream the B-cell receptor (BCR). Though highly active in high risk chronic lymphocytic leukemia (CLL), the most typical response achievable in patients is a minimal residual disease (MRD) positive partial remission (PR) which is maintained until the development of genetically driven resistance caused by the acquisition of mutations in the BTK or PLCG2 genes. The study aims at characterizing the adaptation process allowing residual CLL cells to persist despite BTK inhibition. Methods. The IOSI-EMA-001 study (NCT02827617) is an observational study consisting in the prospective and longitudinal collection of peripheral blood samples and clinical data from high risk CLL patients treated with ibrutinib. Peripheral blood CLL cells longitudinally drawn from patients before treatment start and at fixed timepoints under ibrutinib were monitored by: i) next generation flow cytometry approaches for changes in proliferation rate, surfaceome, and pathway activation; and ii) CAPP-seq targeted deep next generation (sensitivity ~10-3) for clonal evolution. Results. The study cohort comprised 31 high risk CLL patients, including 15 treatment naïve, 16 relapsed, 80% IGHV unmutated, 42% 17p deleted and 55% TP53 mutated. Median duration of ibrutinib treatment was 45 weeks (24-72 weeks). All patients obtained a MRD positive PR that was maintained in all but one who progressed with a PLCG2 mutation (VAF 3%). Compared to baseline, under ibrutinib therapy CLL cells slowed down their proliferation, as suggested by the decreased expression of Ki-67, the reduction of the proliferating fraction (CXCR4dimCD5bright), and the increase of the resting fraction (CXCR4brightCD5dim). Compared to baseline, under ibrutinib therapy CLL cells also upregulated BCR and adhesion/homing proteins, and decreased the expression of BCR inhibitor proteins. Upon stimulation of the BCR with anti-IgM, the downstream path through pBTK and pPLCG2 was inhibited by ibrutinib, while conversely the downstream path through pAKT and pERK was still inducible throughout all the assessed timepoints. The proportion of CLL cells harboring nuclear localization of NF-kB progressively increased over time under ibrutinib. NF-kB nuclear localization was inducible throughout all the assessed timepoints by CD40L stimulation of the non-canonical NF-kB pathway, but not by anti-IgM stimulation of the BCR/canonical NF-kB pathway. Overall, 880 individual mutations were longitudinally discovered and monitored across a total of 121 sequential timepoints collected during ibrutinib treatment. Clonal evolution was observed in (67.7%) cases, a proportion rate previously documented in CLL treated with chemoimmunotherapy. Clonal evolution appeared to be heterogeneous involving different genes without a stereotypic targeting. Consistently, none of the main driver gene mutations was homogeneously selected or suppressed by ibrutinib suggesting that the biological adaptation of CLL cells under ibrutinib is not genetically driven. Clonal evolution propensity was not associated with any of the biomarkers of the disease, and it did not decrease over time under ibrutinib. Conclusions. Taken together these results suggest that residual CLL cells persisting under ibrutinib therapy adapt their phenotype by upregulating adhesion molecules, chemokine receptors and BCR molecules, and by maintaining a competence of BCR signaling through the PI3K/AKT/ERK pathway. The progressive selection of CLL cells having NF-kB in the nucleus, likely due to the BTK independent non-canonical NF-kB pathway, might explain their survival despite ibrutinib therapy. Finally, clonal evolution is not suppressed by ibrutinib chemotherapy, and despite does not seem to be directly involved in such adaptation process, may ultimately favor the acquisition of BTK and PLCG2 ibrutinib resistance mutations. Disclosures Zucca: Celltrion: Consultancy; AstraZeneca: Consultancy. Ghia:Sunesis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie, Inc: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding. Montillo:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Tedeschi:Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy; AbbVie: Consultancy. Gaidano:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria.

Detailed Safety Analysis of Venetoclax Combined with Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2033-2033 ◽  
Author(s):  
Danielle M. Brander ◽  
Michael Y. Choi ◽  
Andrew W. Roberts ◽  
Shuo Ma ◽  
L. Leanne Lash ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Advisory Committees ◽  
Grade 3 ◽  
Over Time

Abstract Background: Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor FDA-approved for patients with del(17p) chronic lymphocytic leukemia (CLL) and who have received ≥1 prior therapy. Based on preclinical evidence of synergy, VEN plus rituximab is being assessed in an ongoing Phase 1b study. Methods: Patients with relapsed/refractory (R/R) CLL received daily VEN with stepwise ramp-up over 3-4 weeks to reach daily doses of 200-600mg. After 1 week at the target dose, monthly rituximab was added for 6 doses. Responses and progression were assessed by iwCLL criteria with CT scan and bone marrow biopsy. Bone marrow assessments were done at screening, completion of combination therapy (month 7), and 2 months after clinical/radiologic criteria of iwCLL response were met. Minimal residual disease (MRD) was assessed in peripheral blood and marrow aspirates using ≥4 color flow cytometry (min sensitivity: 0.01%). Data cutoff was 04March2016, with analysis focusing on updated safety of cytopenias experienced on the course of treatment. Results: Forty-ninepatients enrolled (48 CLL/1 SLL). Patients had received a median of 2 prior therapies (range: 1-5) and disease in 25 (51%) was considered refractory to the most recent therapy. Median time on study was 28 (<1-42) months, with 31 patients active on study. Eighteen patients discontinued: 11 due to disease progression, 3 due to toxicity (peripheral neuropathy [1], MDS [1], and death due to TLS [1]), 3 withdrew consent, and 1 was lost to follow up. Across all doses, the most common AEs of any grade were diarrhea (57%), neutropenia (55%), upper respiratory tract infection (55%), and nausea (51%). Peripheral blood cytopenias were the most common Grade 3/4 AEs (neutropenia [53%], thrombocytopenia [16%], anemia [14%], febrile neutropenia [12%], and leukopenia [12%]). Twenty-seven (55%) patients had a history of neutropenia, of whom 6 were receiving G-CSF support prior to starting VEN. Overall, in the first month of therapy, 15 (31%) experienced an AE of neutropenia (any grade). Thereafter, the rate of new AEs of neutropenia decreased over time. While there was individual patient variability, mean ANC was stable over time. Overall, 26 (53%) patients had Grade 3/4 neutropenia. Neutropenia was generally well tolerated and managed by G-CSF support in 24 patients, in addition to ≥1 dose modification in 11 of the 24 patients. Of 8 (16%) patients who experienced grade 3 infections, 2 were while neutropenic. There were no grade 4 infections. Among the 11 (22%) patients who developed any-grade thrombocytopenia, none occurred within 2 weeks of a reported bleeding-related AE. One patient had thrombocytopenia overlapping with disease progression on therapy. Objective response rate for all patients was 86% (n=42), with 51% (n=25) who had complete response (CR/CRi; 12 achieved CR/CRi by month 7). At the completion of combination therapy (month 7), 39 patients had evaluable bone marrow assessments. Thirty (77%) had no histologic evidence of CLL in the bone marrow and 22 patients (56%) had attained bone marrow MRD-negativity. In longer follow up at any point during treatment for all 49 patients, 37 (75%) patients achieved complete marrow clearance and 28 (57%) achieved marrow MRD-negativity. Conclusions: Transient manageable neutropenia was the most common AE, with first onset usually seen within the first month of treatment and the onset of new neutropenia AEs decreased over time. No patients discontinued the study due to cytopenias. Patients were able to continue on study and high rates of response to treatment were observed. VEN given with rituximab achieved rapid and profound reductions in disease burden in peripheral blood and bone marrow. 77% of evaluable patients achieved morphologic clearance by month 7, and 57% were MRD-negative at any point on study. Figure 1 Figure 1. Disclosures Brander: TG Therapeutics: Research Funding; Gilead: Honoraria. Roberts:AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; AbbVie: Research Funding. Lash:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Final Results from the Multicenter, Open-Label, Phase II GIBB Study of Obinutuzumab+Bendamustine in Previously Untreated Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4317-4317
Author(s):  
Jeff P. Sharman ◽  
John M Burke ◽  
Habte A Yimer ◽  
Michael A. Boxer ◽  
Sunil Babu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Peripheral Blood ◽  
Research Funding ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Induction Treatment ◽  
Open Label ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Over Time

Background: Bendamustine+rituximab (BR) is an effective chemoimmunotherapy for newly diagnosed chronic lymphocytic leukemia (CLL) and is the most commonly used chemoimmunotherapy in CLL patients requiring therapy (Seymour et al. Cancer. 2019). In a phase III study, the anti-CD20 antibody obinutuzumab (G) showed improved survival in combination with chlorambucil (clb) compared with rituximab (R)+clb, suggesting that G may be a better anti-CD20 monoclonal antibody to combine with bendamustine (B). Here, we report the final study results for the phase II, single-arm, open-label GIBB study (NCT02320487), in which the combination of bendamustine+obinutuzumab (BG) was evaluated in previously untreated patients with CLL. This is also one of the first studies to characterize the evolution of minimal residual disease (MRD) status over time in previously untreated CLL patients receiving chemoimmunotherapy. Methods: Newly diagnosed patients requiring treatment for CLL had ECOG PS 0-2, and adequate cell counts and organ function. BG treatment was given IV over six 28-day (d) cycles and included obinutuzumab (cycle 1: 100 mg d1, 900 mg d2, and 1000 mg on d8 and d15, and cycles 2-6: 1000 mg d1 of each cycle) plus bendamustine (90 mg/m2 cycle 1: d2 and d3; and cycles 2-6: d1 and d2). The primary end point was complete response (CR), including CR and incomplete CR (CRi), per 2008 iwCLL guidelines after induction treatment. Secondary end points included progression-free survival (PFS) and overall survival (OS). MRD negativity (MRD−) was defined as < 1 cell per 10,000 leukocytes (ie, 10−4) and was measured at baseline, end of treatment (28 d after cycle 6), clinical response assessment, and every 6 months thereafter for ≤ 2 years. Results: Overall, 102 patients were enrolled on this study. Patients had a median age of 61 years (range, 35-90), and 97% had ECOG PS of 0-1. Of 74 patients evaluated for IgVH status, 49 patients (66%) had unmutated IgVH. Overall, 79% of patients completed 6 cycles of BG. 50% of patients achieved a CR/CRi (95% CI, 40%-60%), which contributed to an 89% overall response rate (95% CI, 82%-95%). At a median follow-up of 34.3 mo, median PFS was 35.5 mo (95% CI, 35.0 mo to not reached) and median OS was not reached (Figure 1). Seven patients died during the study (3 from cardiac events not attributed to treatment by investigators and 4 from other non-progressive disease causes). The most common grade 3/4 treatment-emergent adverse events (> 5%) were neutropenia (25%), infusion-related reactions (9%), anemia (8%), thrombocytopenia (8%), pneumonia (6%), and tumor lysis syndrome (6%). The rate of grade 3/4 febrile neutropenia was 5%. Achievement of MRD− in evaluable peripheral blood and bone marrow at the clinical response assessment was shown in 33/74 (45%; 95% CI, 33%-57%) and 30/51 (59%; 95% CI, 44%-72%) patients, respectively. In the 79 patients (77%) who achieved MRD− in peripheral blood throughout the study, the median duration of MRD− response was 28.9 mo (95% CI, 23.0 to not reached). Of these 79 MRD− patients, 28 became MRD+, and the median time from identification of MRD+ status to progressive disease/death was 10.5 mo (95% CI, 6.3-17.9). An exploratory Cox proportional multivariate analysis identified 2 factors that were significantly associated with longer durations of MRD− responses: mutated (vs unmutated) IgVH with a HR = 0.13 (95% CI, 0.03-0.61), and CD38 ≥ 30% (vs < 30%) with a HR = 0.35 (95% CI, 0.14-0.92). When stratified by IgVH status, the PFS distributions for IgVH mutated and unmutated groups were similar (Figure 1). Median OS was not reached in all patients and irrespective of IgVH status. Conclusions: Final results for the GIBB study showed that the BG combination was an effective regimen for previously untreated patients with CLL, with no unexpected safety signals. Complete response and MRD− in peripheral blood were achieved in approximately half of all patients after induction treatment and persisted over time. IgVH mutated status was associated with a longer duration of MRD− and median PFS. In summary, BG is a clinically active CLL regimen with durable MRD− rates over time; overall outcomes are consistent with other firstline studies of anti-CD20 antibody and bendamustine combinations. Disclosures Sharman: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Yimer:Amgen: Consultancy; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Boxer:Rigel: Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Arizona Oncology: Employment; Incyte: Speakers Bureau; Gerson Lerman: Consultancy; Best Doctors: Consultancy; Abbvie: Honoraria, Speakers Bureau. Babu:Fort Wayne Medical Oncology & Hematology: Employment; Bristol Myers Squibb: Consultancy, Research Funding; Fort Wayne Medical Oncology & Hematology: Equity Ownership; Abbvie: Research Funding; Eli Lilly: Honoraria, Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Incyte: Research Funding; AstraZeneca: Honoraria; Lutheran Hospital, Fort Wayne, Indiana: Membership on an entity's Board of Directors or advisory committees. Li:Roche: Equity Ownership; Genentech: Employment. Mun:Genentech: Employment, Equity Ownership. Danilov:Curis: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Abbvie: Consultancy; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Seattle Genetics: Consultancy; Janssen: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Yes, this was an investigational clinical study of the combination therapy of obinutuzumab and bendamustine in previously untreated patients with chronic lymphocytic leukemia.

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.

scholarly journals TP53 Clonal and Subclonal Architecture in Chronic Lymphocytic Leukemia Patients Under Ibrutinib Treatment

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3119-3119
Author(s):  
Ilaria Del Giudice ◽  
Luciana Cafforio ◽  
Luca Vincenzo Cappelli ◽  
Caterina Ilari ◽  
Sara Raponi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Member ◽  
Clonal Evolution ◽  
Single Agent ◽  
Variant Calling ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
Bioinformatics Pipeline ◽  
Time Points ◽  
Over Time

Abstract Introduction. Ibrunitib (IBR) is active in chronic lymphocytic leukemia (CLL) patients (pts) with TP53 aberrations. Few data describing the dynamics of TP53 mutated clones under IBR are available. We analyzed a cohort of 40 treatment-naïve and relapsed CLL pts treated with IBR to investigate the dynamics of clonal and subclonal TP53 mutations (TP53-mut). Methods. Forty pts (Table) underwent a longitudinal TP53 monitoring (117 samples) by ultra-deep sequencing (UDS): 26 received IBR + rituximab (IBR+RTX) in first line as part of the GIMEMA LLC 1114 protocol (IBR exposition: 8 months in 7 pts and 14 months in 19 pts) (cohort 1), while 14 received IBR single agent after a median of 1.5 (range: 1-4) chemo-immunotherapy lines (IBR exposition: 2.1 to 4 years in 12 pts) (cohort 2). Samples were analyzed by UDS on a MiSeq sequencer (Illumina, Inc.) to obtain a 5000X coverage/base. For variant calling, the MiSeq Reporter software and an in-house bioinformatics pipeline were applied. All mutations were checked on the IARC TP53 database and those with a variant allele frequency (VAF) <10% (i.e. subclonal) were confirmed in an independent UDS run. VAF was corrected to cancer cell fraction (CCF) by the proportion of CD19+/CD5+ cells. Results. In cohort 1, 12/26 pts were evaluated at 3 time-points: baseline (T0), +8 (T8) and +14 (T14) months from IBR+RTX, and 14 at T0 and either T8 or T14. At T0, 19/26 pts showed a mean number of 1.5 (range: 1-5) clonal/subclonal TP53-mut/pt, for a total of 28 mutations. Of those, 20/28 (71.4%) were clonal (mean VAF: 57.8%; range: 18-94.8%) and 8/28 (27.6%) were subclonal (mean VAF: 4.4%; range: 1.2-9.2%; VAF≤5% in 6). Seven/26 pts resulted wild-type (WT). Under IBR+RTX, of the 28 TP53-mut corrected to CCF (21 clonal and 7 subclonal), 12 (9 clonal + 3 subclonal) (42.8%) persisted stable, 9 (32.1%) clonal mutations decreased, 6 (21.4%) were lost, one evolved to clonal. No novel clonal or subclonal TP53-mut arose during IBR+RTX. According to CCF, the pts followed 5 patterns: 1) clonal TP53-mut present from T0 and persisting clonal with a stable (n=6) or decreasing CCF (n=7); 2) clonal TP53-mut disappearing during treatment (n=1); 3) subclonal TP53-mut evolving to clonal (n=1, CCF 8% at T0 and 17.5% at T14); 4) subclonal TP53-mut persisting subclonal (n=1); 5) absence of any detectable TP53-mut in all time-points (n=7). In addition, 3 cases showed coexisting clonal and subclonal TP53-mut at T0: in one case 3 TP53-mut remained stable; in another one, 4 TP53-mut, including one clonal, were lost, and one clonal decreased in CCF; in the last case, 1 TP53-mut decreased, 1 remained stable and 1 subclonal disappeared. In cohort 2, before IBR, 10/14 pts showed a mean of 3.1 (range: 1-11) clonal/subclonal TP53-mut/pt, for a total of 31 mutations. Of those, 11/31 (35.5%) were clonal (mean VAF: 31.9%; range: 10.5-78.8%) and 20/31 (64.5%) were subclonal (mean VAF: 2.9%; range: 0.9-6.8%). Four/14 pts were WT. Under IBR, 16/31 (6 clonal+10 subclonal) (51.5%) TP53-mut persisted stable, 2 (6.5%) clonal decreased, 11 (2 clonal+9 subclonal) (35.5%) were lost, 2 (6.5%) subclonal evolved to clonal; 2 novel subclonal mutations emerged. No mutation was identified in the 4 WT pts over time. In both cohorts, most of TP53-mut remained stable (42.8% vs 51.5% in cohort 1 and 2, respectively) or decreased (32.1% vs 6.5%) and 17 (5 clonal and 12 subclonal) were lost (21.4% vs 35.5%) (p=NS). Although the lymphocyte count significantly decreased during IBR+RTX/IBR exposure (cohort 1: 47.1 x 109/L vs 7.5 x 109/L, p<0.0001; cohort 2: 48.5 x 109/L vs 15.3 x 109/L, p=0.015), the mean CCF of the existing mutations remained stable on treatment (cohort 1: 48.1% vs 40.1%, p=0.42; cohort 2: 16.9 % vs 13.02%; p=0.5). Conclusions. Both when used front-line or as a subsequent line of therapy, IBR appears to decrease the TP53 clonal and subclonal numerosity and complexity. Clonal evolution and the occurrence of novel mutations are rare and occur mostly in pre-treated pts. The significant decrease of lymphocytosis with stable CCF, prove the IBR effectiveness both on TP53 mutated and WT CLL cells, regardless of previous therapies. A longer follow-up will better clarify the dynamics of clonal and subclonal TP53-mut and whether the persistent clones may survive over time and give rise to subsequent relapses. Figure. Figure. Disclosures Mauro: abbvie: Other: board member; janssen: Other: board member. Foà:GILEAD: Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau.

scholarly journals Role of Histone Deacetylase-Mediated Gene Silencing in Chronic Lymphocytic Leukemia Progression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2705-2705 ◽  
Author(s):  
Lara Rizzotto ◽  
Arianna Bottoni ◽  
Tzung-Huei Lai ◽  
Chaomei Liu ◽  
Pearlly S Yan ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Clonal Evolution ◽  
Lymphocytic Leukemia ◽  
Low Risk ◽  
Gene Promoters ◽  
Rna Seq ◽  
Hdac Inhibition ◽  
Protein Coding ◽  
Protein Coding Genes

Abstract Chronic lymphocytic leukemia (CLL) follows a variable clinical course mostly dependent upon genomic factors, with a subset of patients having low risk disease and others displaying rapid progression associated with clonal evolution. Epigenetic mechanisms such as DNA promoter hypermethylation were shown to have a role in CLL evolution where the acquisition of increasingly heterogeneous DNA methylation patters occurred in conjunction with clonal evolution of genetic aberrations and was associated with disease progression. However the role of epigenetic mechanisms regulated by the histone deacetylase group of transcriptional repressors in the progression of CLL has not been well characterized. The histone deacetylases (HDACs) 1 and 2 are recruited onto gene promoters and form a complex with the histone demethylase KDM1. Once recruited, the complex mediate the removal of acetyl groups from specific lysines on histones (H3K9 and H3K14) thus triggering the demethylation of lysine 4 (H3K4me3) and the silencing of gene expression. CLL is characterized by the dysregulation of numerous coding and non coding genes, many of which have key roles in regulating the survival or progression of CLL. For instance, our group showed that the levels of HDAC1 were elevated in high risk as compared to low risk CLL or normal lymphocytes and this over-expression was responsible for the silencing of miR-106b, mR-15, miR-16, and miR-29b which affected CLL survival by modulating the expression of key anti-apoptotic proteins Bcl-2 and Mcl-1. To characterize the HDAC-repressed gene signature in high risk CLL, we conducted chromatin immunoprecipitation (ChIP) of the nuclear lysates from 3 high risk and 3 low risk CLL patients using antibodies against HDAC1, HDAC2 and KDM1 or non-specific IgG, sequenced and aligned the eluted DNA to a reference genome and determined the binding of HDAC1, HDAC2 and KDM1 at the promoters for all protein coding and microRNA genes. Preliminary results from this ChIP-seq showed a strong recruitment of HDAC1, HDAC2 and KDM1 to the promoters of several microRNA as well as protein coding genes in high risk CLL. To further corroborate these data we performed ChIP-Seq in the same 6 CLL samples to analyze the levels of H3K4me2 and H3K4me3 around gene promoters before and after 6h exposure to the HDACi panobinostat. Our goal was to demonstrate that HDAC inhibition elicited an increase in the levels of acetylation on histones and triggered the accrual of H3K4me2 at the repressed promoter, events likely to facilitate the recruitment of RNA polymerase II to this promoter. Initial analysis confirmed a robust accumulation of H3K4me2 and H3K4me3 marks at the gene promoters of representative genes that recruited HDAC1 and its co-repressors in the previous ChIP-Seq analysis in high risk CLL patients. Finally, 5 aggressive CLL samples were treated with the HDACi abexinostat for 48h and RNA before and after treatment was subjected to RNA-seq for small and large RNA to confirm that the regions of chromatin uncoiled by HDACi treatment were actively transcribed. HDAC inhibition induced the expression of a large number of miRNA genes as well as key protein coding genes, such as miR-29b, miR-210, miR-182, miR-183, miR-95, miR-940, FOXO3, EBF1 and BCL2L11. Of note, some of the predicted or validated targets of the induced miRNAs were key facilitators in the progression of CLL, such as BTK, SYK, MCL-1, BCL-2, TCL1, and ROR1. Moreover, RNA-seq showed that the expression of these protein coding genes was reduced by 2-33 folds upon HDAC inhibition. We plan to extend the RNA-seq to 5 CLL samples with indolent disease and combine all the data to identify a common signature of protein coding and miRNA genes that recruited the HDAC1 complex, accumulated activating histone modifications upon treatment with HDACi and altered gene and miRNA expression after HDAC inhibition in high risk CLL versus low risk CLL. The signature will be than validated on a large cohort of indolent and aggressive CLL patients. Our final goal is to define a signature of coding and non coding genes silenced by HDACs in high risk CLL and its role in facilitating disease progression. Disclosures Woyach: Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding.

BCR-Assosiated Kinase Inhibition in Relapsed/Refractory Chronic Lymphocytic Leukemia. Real World Experiences of a German Regional Clinical Register

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Dietrich Kaempfe ◽  
Roshanak Bob ◽  
Joerg Brenn ◽  
Thomas Haverkamp ◽  
Agnes Knopp ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Real Life ◽  
Treatment Protocol ◽  
Lymphocytic Leukemia ◽  
Clinical Registry ◽  
Kinase Inhibition ◽  
Ample Evidence ◽  
Co Morbidity

Background: The advent of B-cell-receptor associated kinase inhibition (BCR-KI) inaugurated a novel therapeutic principle in chronic lymphocytic leukemia (CLL). First-in-class Ibrutinib (Ib) and Idelalisib (Id) received marketing authorization from the EMA for the treatment of relapsed/refractory (r/r) CLL in 2012 and 2014, respectively. In spite of ample evidence from trials, real life data are scarce. Methods: Our clinical registry has been previously described in detail [https://doi.org/10.1182/blood-2018-99-110618]. It comprises of 168 unselected CLL patients (pts.), who were observed between 10/2014 and 08/2020. 65 of them required treatment during this period: 39 x 1st line only and 26 x &gt; 2nd line. 18 of these 26 r/r CLL pts were treated either with Ib (11 x) or Id (7 x). Treatment was started according to iwCLL guidelines. The type of BCR-KI was chosen based on an individual's performance status, previous treatment and co-morbidity. Median 1st line-treatment (as a rule immunochemotherapy) started 27.5 months (m) after diagnosis (range: 0.5 m to 87.5 m). Time from 1st line therapy to BCR-KI treatment ('Ctx effected time') was 13.0 to 128.1 m (median 50.5 m), in total (18 pts.) 1052.5 m, i.e. 87.7 years (y). 17 of 18 pts. had received Rituximab (R) as part of a pre-BCR-treatment protocol. Estimated charges per month are 9.000 € in Id + R, 7.000 € in R + chemotherapy (ctx, i.e. Fludara or Bendamustin mostly) and 4.500 € in Ib or Id mono or R + Chlorambucil (Clb) respectively. Results: Patients described herein differed according to age at start of BCR-KI (44.4 to 86.8 y, median 76.0 y), sex (10 m, 8 f), types and lines (1 to 6, median 2) of prior treatment. Indications for BCR-KI were increasing tumor burden (17 x, 1 x combined with pleural effusion) and persistent hemolysis (1 x). Genetic high risk features comprised of at least one of the following: IGHV unmutated status, mutation and/or deletion of TP53 gene, deletion of 11q, and complexe karyotype. These features were present in 17 of 18 pts. (median 3 features). In particular, unmutated IGHV was found in 13/18 r/r pts who received BCR-KI (total cohort of r/r pts, 21/26). Overall response rate was 78% (Ib 8/11; Id 6/7). Time to next therapy or death (`KI effected time`) varies from 1.1 m to 69.1 m - in total 286.9 m until now. 4 pts. continued BCR-KI from 30 to 67 months. This was always the longest period of unchanged therapy in these 4 pts. Shorter `KI effected time` in the other 14 pts. was associated with higher treatment line and treatment interruptions. 2 responding pts. (without side effects) stopped BCR-KI and stayed in ongoing hematological remission for 11 and 25 months after cessation of treatment. Adverse drug reactions occurred in 6 pts. (Ib 4 x, Id 2 x). 5 pts. died on BCR-KI, but there was no therapy related death. Approximate costs per month in Germany are 1700 € in `Ctx effected time` (1.800.000 € per 1052,9 m) and 4.700 € in `KI effected time` (1.350.000 € per 286,9 m). Of note, one pt. on Id showed clinical progression associated with genetic evolution after 67 months of BCR-KI. He promptly responded to venetoclax. Discussion: In real live many r/r CLL pts. are elderly and present a broad spectrum of different clinical features. A clinical registry can reflect this and may add to our knowledge from multicenter studies. Remarkably almost all of our unselected r/r CLL pts. revealed genetic high risk features, in particular unmutated IGHV status, making them ideal candidates for targeted treatment strategies. These strategies take advantage of the fact that BCR-KI has been demonstrated to be well tolerated and effective in elderly and pre-treated pts. Undoubtedly BCR-KI increases the total costs of therapy, but affords a prolongation of overall survival. Remaining open questions include optimal treatment sequences, combination partners for BCR-KI as well as thorough analysis in the quality of molecular remissions. Disclosures Böttcher: Janssen: Honoraria, Research Funding; Celgene: Research Funding; AbbVie: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria.

Anti-CXCL12/SDF-1 Spiegelmer® Nox-A12 Alone and In Combination With Bendamustine and Rituximab In Patients With Relapsed Chronic Lymphocytic Leukemia (CLL): Results From A Phase IIa Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1635-1635 ◽  
Author(s):  
Marco Gobbi ◽  
Michael Steurer ◽  
Federico Caligaris-Cappio ◽  
Marco Montillo ◽  
Ann Janssens ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Additional Patient ◽  
Dose Titration ◽  
Advisory Committees ◽  
Therapeutic Concept ◽  
Design For All

Abstract Background NOX-A12 is a novel, potent, L-stereoisomer RNA aptamer (Spiegelmer(®)) that binds and neutralizes CXCL12/SDF-1, a chemokine which attracts and activates immune- and non-immune cells via interaction with its receptors, CXCR4 and CXCR7. The signaling of CXCL12 has been shown to play an important role in the pathophysiology of chronic lymphocytic leukemia (CLL), especially in the interaction of leukemic cells with tissue microenvironment. The therapeutic concept of NOX-A12 is to mobilize these bone marrow- and tissue-resident CLL cells into the blood, thereby removing CLL cells from the nurturing milieu and sensitizing them to cytotoxic drugs such as bendamustine and rituximab (BR). Methods To date, 19/33 planned patients have been enrolled into a multicenter Phase IIa study of NOX-A12 alone and in combination with BR in relapsed CLL patients. Here we report interim data on PK, PD and preliminary efficacy of a pilot group consisting of 3 cohorts of 3 patients each. In the pilot phase, cohorts received single doses of 1, 2 or 4 mg/kg NOX-A12 alone, respectively, two weeks prior to 6 cycles of combined treatment of NOX-A12 with BR repeated every 28 days. During combination therapy, NOX-A12 was administered 1-2 hours prior to rituximab following a dose titration design for all patients: NOX-A12 doses were increased from 1 mg/kg to 2 mg/kg and 4mg/kg at cycles 1, 2 and 3, respectively. During cycles 4-6, doses of NOX-A12 were kept at the highest individually titrated dose. Bendamustine (70 - 100 mg/m², according to SPC) was given on day 2 and 3 (cycle 1) or 1 and 2 (cycle 2-6), combined with 375 mg/m2 rituximab on day 1 for the first cycle and 500 mg/m2 for subsequent cycles. Tumor response was assessed according to NCI-WG 1996 criteria (updated by iwCLL 2008). Results In total, 10 patients were enrolled in the pilot group (one additional patient was enrolled due to one patients' under dosing). The median age was 69 years (range 57-77) with 8 women and 2 men being included. Median prior therapies were 2 (range 1-2), whereby all patients were bendamustine naïve and 6 patients had received rituximab treatment prior to enrolment. 2, 4 and 4 patients presented at screening with Binet stage A, B, and C, respectively. 8 patients showed at least 1 cytogenetic aberration at the beginning of treatment. Tumor assessments before enrolment and at end of cycles 3 and 6 were evaluated. Plasma profiles of NOX-A12 in the patient population of the pilot group (Figure 1) were similar to those of healthy volunteers in which a plasma half-life of approximately 38 h was observed. After single doses of NOX-A12, the exposure was dose-linear with peak plasma concentrations of 1.7, 3.5, and 6.7 µM in the corresponding cohorts. CLL cells in the peripheral blood were found to be increased throughout the observational period of 3 days (Figure 2). In all patients presenting with lymphadenopathy, the lymph node size decreased markedly. NOX-A12 as single agent was safe and very well tolerated. All patients responded to the combination treatment of NOX-A12 and BR (ORR 100%); one patient had to be withdrawn from treatment due to multiple infections during cycle 4 having achieved a partial response (PR). At the end of cycle 6, seven patients (78%) showed a PR and two patients (22%) achieved a complete remission (CR). In combination with BR, NOX-A12 was equally safe and well tolerated. Conclusions Proof of principle was achieved as single doses of NOX-A12 reached the expected plasma exposure which translated into an effective and prolonged mobilization of CLL cells into the peripheral blood. In addition, the 100% ORR and 22% CR as well as the virtual absence of additional toxicity on top of BR observed in this pilot group compares very favorably with historical controls. Provided that this promising clinical picture will be maintained in the total sample of 33 patients, further development of this novel anti-CXCL12/SDF-1 Spiegelmer(®) seems warranted. Disclosures: Montillo: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dümmler:NOXXON Pharma AG: Employment. Zöllner:NOXXON Pharma AG: Employment. Zeitler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Kruschinski:NOXXON Pharma AG: Employment.

scholarly journals Preliminary Results of a Phase 1b Study (GO28440) Combining GDC-0199 (ABT-199) with Bendamustine/Rituximab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3337-3337 ◽  
Author(s):  
Gilles Andre Salles ◽  
Thomas E Boyd ◽  
Franck Morschhauser ◽  
Clemens-Martin Wendtner ◽  
James Lymp ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Previous Treatment ◽  
Lymphocytic Leukemia ◽  
Dose Finding ◽  
Previous Exposure ◽  
Phase 1B

Abstract Introduction New therapies are needed for patients (pts) with chronic lymphocytic leukemia (CLL). BCL2 is an anti-apoptotic protein that is overexpressed in CLL and may be associated with resistance to available therapies; GDC-0199 is an orally available, selective BCL2 inhibitor. The combination of bendamustine (B) and rituximab (R) has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated pts with CLL and is often used in these pts. Preclinical data suggest that GDC-0199 combined with BR may show synergistic activity in CLL. Moreover, clinical data from single-agent studies of GDC-0199, and in combination with rituximab in pts with CLL, support combining GDC-0199 with BR in this population. Data presented here are from an ongoing phase 1b study that is evaluating the maximum tolerated dose of GDC-0199 when given in combination with BR, as well as the safety, tolerability, and order of administration of this combination in R/R or previously untreated pts with CLL. Methods Pts with an ECOG PS ≤1, adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts ranging from 100 to 600 mg/day of GDC-0199 using a 3+3 dose escalation design. Pts are assigned to one of two dosing schedules (Figure 1) with GDC-0199 (Schedule A) or BR (Schedule B) introduced first, both incorporating a gradual dose ramp-up of GDC-0199 to reduce the risk of tumor lysis syndrome (TLS). Prophylaxis measures to mitigate TLS include IV hydration, treatment to prevent hyperuricemia and hospitalization. After completing combination therapy, R/R pts will continue single-agent GDC-0199 until disease progression. Previously untreated pts will continue single-agent GDC-0199 for up to 18 months. Dose-limiting toxicity (DLT) data are identified after all pts in a cohort have completed ³21 days of combination treatment at the target dose of GDC-0199 and focus on treatment emergent TLS and cytopenias. Figure 1 Figure 1. Results As of May 2014, 6 pts with R/R CLL have been enrolled in the dose finding stage of the study with a median time on study of 67 (range 43-113) days. All 6 pts were enrolled on Schedule A; 3 pts were enrolled in the 100 mg GDC-0199 cohort and 3 pts were enrolled in the 200 mg cohort. Baseline characteristics of the 6 pts are as follows: median age 67 (range 52-71) years, 3 male pts, median of 2 prior CLL therapies (range 1-3, including 4 pts with previous exposure to fludarabine, cyclophosphamide and rituximab [FCR] and 1 with previous exposure to FCR and B), beta-2 microglobulin ≥3.5 mg/L in 2 pts, and unmutated IGHV in 5 pts. Prior to starting therapy, the median lymphocyte count was 40.85 x 109 cells/L (range 2.11-169 x 109 cells/L), hemoglobin level was 101.5 g/L (range 99-134 g/L), neutrophil count was 2.54 cells/μL (range 1.81-3.8 cells/μL), and platelet count was 83.5 x 109/L (range 49-250 x 109/L). Pts were assigned to 1 of 3 TLS risk groups based on screening ALC and tumor bulk: low risk 1 pt, medium risk 4 pts, and high risk 1 pt. Cytogenetic data are available for 3 pts: 1 pt had del17p, 2 pts had del 11q, and 3 pts had del 13q. No DLTs were observed. All 6 pts have experienced adverse events (AEs, Figure 2). The most common AE was anemia with most Grade ³3 AEs being hematological toxicities (Figure 2). One serious AE of bronchitis was observed in a pt enrolled in the 100 mg GDC-0199 cohort and resolved after treatment. Two pts in the 100 mg GDC-0199 cohort discontinued BR after the 21-day DLT window secondary to treatment emergent cytopenia: 1 with neutropenia after completing 1 cycle of BR (previous treatment FCR without baseline cytopenia) and the second with thrombocytopenia after completing 3 cycles of BR (previous treatment FCR and chlorambucil with thrombocytopenia at screening). Both pts remain on single-agent GDC-0199. No TLS events (laboratory or clinical) were observed and no deaths reported. Figure 2 Figure 2. Conclusion This is the first study to evaluate the combination of GDC-0199 and BR in pts with CLL. Despite 5 pts being identified as medium or high risk for TLS, no pts developed TLS as a result of the ramp-up dosing of GDC-199 and prophylactic measures. The most frequent AEs were hematological toxicities and generally manageable; however, 2 pts had to discontinue BR (after 1 and 3 cycles) but were able to remain on GDC-0199. Dose escalation in R/R pts is continuing in order to evaluate the optimal dose/schedule with a plan to enroll previously untreated pts in the near future. Disclosures Boyd: Genentech: Research Funding; US Oncology/McKesson: Research Funding; Celgene: Consultancy. Morschhauser:Genentech: Travel grant Other; Gilead, Mundipharma, Bayer, Spectrum, Celgene: Honoraria. Wendtner:AbbVie, Genentech, Hoffman-La Roche, Mundipharma: Consultancy, Research Funding. Lymp:Genentech: Employment. Hilger:Genentech: Employment. Vosganian:Genentech: Employment. Huang:Genentech: Employment. Stilgenbauer:Genentech, Hoffman La Roche: Honoraria, Research Funding.

scholarly journals Genomic Mechanisms of 17p / TP53 Loss in Primary “ultra High-risk” and Refractory Chronic Lymphocytic Leukemia: Results from the CLL2O Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2184-2184
Author(s):  
Veronica Teleanu ◽  
Jennifer Edelmann ◽  
Claudia Haferlach ◽  
Stefan Ibach ◽  
Eugen Tausch ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Chromosome 17 ◽  
Tp53 Mutations ◽  
Ultra High Risk ◽  
Treatment Naïve ◽  
Donor Chromosome

Abstract Background: Unraveling the cytogenetic background helped to decipher the molecular basis of many hematologic cancers and to develop specific therapies. Recently, using chromosome banding analysis (CBA), jumping translocations were identified as a cause of 17p loss in multiple myeloma, providing new insights into the origin of clonal evolution and copy number alterations (CNA) (Sawyer et al, Blood 2014). In chronic lymphocytic leukemia (CLL) the genomic mechanisms leading to 17p loss are not fully understood. Aims: Characterization of underlying mechanisms of 17p loss using CBA and correlation with other clinicobiological features in “ultra high-risk” CLL. Methods: Samples from 112 patients (pts.) with refractory and/or 17p- CLL enrolled in the multicenter CLL2O trial were screened for CNAs by Affymetrix 6.0 SNP array analysis of CD19 sorted CLL cells and for chromosomal abnormalities by CBA using CpG oligonucleotide and interleukin-2 stimulation. Results: Considering both CBA and SNP data, 728 aberrations resulted in a mean of 6.5/case. 89 (79%) pts. had 17p deletion and 83 (74%) TP53 mutation. Regarding the origin of 17p/TP53 loss, 6 distinct types of rearrangements could be delineated: 1) whole arm translocations (WAT) 2) jumping translocations (JT) 3) dicentric chromosomes (DC) 4) cytogenetically balanced translocations (CBT) 5) other unbalanced translocations and 6) interstitial 17p deletions. WAT were identified in 33/112 (30%) cases and 30/33 (91%) involved chromosome 17 leading to 17p loss. Chromosomes involved ≥ 2 times in an unbalanced WAT were der(17;18)(q10;q10) (8, 24%), der(8;17)(q10;q10) (5, 15%), der(15;17)(q10;q10) (4, 12%), i(17)(q10) (4, 12 %), der(17;22)(q10;q10) (2, 6%). JT were identified in 11 (10 %) cases, 6 showing jumping WAT with 17q as donor chromosome, 1 case with breakpoints located in the pericentromeric regions of chromosome 17p11 (donor chromosome) and the receptor chromosomes 4p14 and 16p11. In 4 cases, initially a WAT involving 17q occurred and subsequently the partner chromosome “jumped off” leaving a 17p deletion behind. DC were detected in 19 pts., 8 with breakpoint in 17p11, 7/8 with TP53 mutation. Of note, all cases had the breakpoint on chromosome 17 in 17p11 indicating a fragile site affecting the pericentromeric region. Interestingly, of a total of 382 translocations observed by CBA, only 32 were CBT and except for those involving the IGH and IGK/L loci (n=6) all were random. 17p involvement in CBT was detected in 4 cases, 3 had TP53 deletion and all were TP53 mutated. Of the unbalanced translocations, der(17)t(8;17) was identified in 5 pts. simultaneously generating 8q gain. Nevertheless, breakpoints on chromosome 17p covered cytobands 17p11-13 and on chromosome 8, 8q11-22, one case having the breakpoint telomeric to the TP53 locus and no TP53 mutation, pointing to other putative candidate genes on 17p. In 36/112 (32%) cases, 17p deletion was induced by random rearrangements. Interstitial 17p deletions were identified in only 9/112 (8 %) cases. According to the inclusion criteria of the trial, 36/112 (32%) pts. had 17p deletion and were treatment-naïve while 76/112 (68%) were relapsed or refractory to fludarabine or bendamustine based therapy, 53/76 (70%) having a 17p deletion. Treatment naïve pts. had a mean of 7.36 aberrations/case and pretreated pts. 6.09/case. Focusing on WAT and JT, 18/33 (54%) pts. with WAT and 7/11 (63%) pts. with JT were pretreated whereas 57/78 (73%) pts. in the other cytogenetic subgroups had prior therapy exposure. Considering other genomic features, WAT and JT occurred almost exclusively within complex karyotypes (≥3 chromosomal aberrations), 31/33 WAT and 10/11 JT, were IGHV unmutated, 30/33 WAT and 11/11 JT and harbored TP53mutations, 29/33 WAT and 10/11 JT. Conclusions: “Ultra high-risk” CLL pts. are characterized by a high genomic complexity as compared to standard risk treatment-naïve CLL pts. (CLL8 trial with 1.8 CNAs/case). Previous genotoxic therapy had no influence on the total number of aberrations or the underlying mechanism, suggesting an intrinsic genomic instability of the tumor cells with TP53 alterations. WAT and JT emerged as nonrandom aberrations involved in 17p loss. Given the strong association of TP53 deletion with TP53 mutations of the remaining allele, one may speculate that TP53 mutations precedes TP53 deletion by disrupting the normal DNA repair mechanisms permitting incorrect recombinations. Disclosures Stilgenbauer: Amgen: Honoraria, Research Funding; Genzyme: Honoraria, Research Funding.

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