ALBERT

Beschreibung: Human pentraxins are a family of proteins with a unique pentameric structure. Unlike C-reactive protein (CRP), serum amyloid P (SAP) and pentraxin-3 (PTX3) play an opposite role in tissue remodeling. PTX3 induces whereas SAP inhibits the differentiation of CD14+ monocytes into fiborcytes. While in patients with CLL CRP levels are high and were found to be associated with poor overall survival (OS) (Herishanu et al. Ann Med 2017), little is known about the plasma levels or clinical significance of other pentraxins in CLL. Therefore, we obtained plasma sample from 36 randomly chosen treatment-naïve CLL patients and 12 age-matched healthy individuals and, using an enzyme linked immuno-sorbent assay, found that PTX3, CRP and SAP plasma levels were significantly higher in CLL patients than in healthy individuals (P

Beschreibung: Introduction. In the context of chemoimmunotherapy, complete remission (CR) is more common and is associated with improved survival in patients with chronic lymphocytic leukemia (CLL). CR is less frequent in CLL patients treated with ibrutinib, and the prognostic significance of achieving CR with ibrutinib is indeterminate. Methods. We prospectively analyzed 208 CLL patients treated on a phase 2 study (NCT02007044) of first-line (deletion 17p only; n=27) or salvage ibrutinib (n=181), with or without rituximab, between 12/2013 and 01/2018. Response was assessed by international workshop on CLL 2018 guidelines. Categorical variables were compared using the χ2 or Fisher exact tests. Progression-free survival (PFS) was defined as time from treatment initiation to disease progression and/or death, and Kaplan-Meier curves compared using the log-rank test. A landmark analysis at median time of CR achievement (best response) was performed for PFS. Results. After a median follow-up of 34 months (range, 3-48 months), response was evaluable in 194 patients, overall response rate (ORR) was 99%, and CR rate was 24%, with negative minimal residual disease (MRD) in 3% of patients; median time to response was 10 months (range, 3-45 months) and median time to CR was 21 months (5-45 months). None of the patients' baseline characteristics associated with achievement of CR (Table). Among the 47 patients in CR, 7 (15%) discontinued treatment, after a median time from treatment initiation of 19 months (range, 10-39); the main cause of discontinuation was toxicity (5 patients), with second cancer (metastatic melanoma) and disease progression prompting treatment discontinuation only in 2 patients. Among the 145 patients in PR, 50 (34%) discontinued treatment, after a median time from treatment initiation of 14 months (range, 4-45 months); while the main cause of discontinuation was again toxicity (26 patients), 2nd cancers and progressive disease prompted treatment discontinuation in 5 and 14 patients, respectively. Remaining causes of treatment discontinuation among patients in PR were loss to follow-up (3 patients) and consolidation therapy (2 patients). Median PFS was not reached and 28 patients (13%) progressed and/or died. Achievement of CR significantly associated with prolonged PFS (4-year PFS 98% vs 78%, p=0.03)(Figure). The association between CR and prolonged PFS was also confirmed on a landmark analysis (21 months)(p=0.05). Among baseline characteristics shown in the Table, the only factor associated with prolonged PFS was absence of complex karyotype (4-year PFS 80% vs 40%, p=0.05). Median OS has not been reached and 16 (8%) patients have died; of these, only 1 patient was in CR (and cause of death was metastatic melanoma), whereas the remaining 15 were in PR. Among patients in PR, causes of death were: infections in 7 patients, 2nd cancers in 2 patients, Richter transformation in 2 patients and other in 4 patients (small bowel obstruction, colon perforation, intracranial hemorrhage, bradyarrhythmia). Conclusions. This is the first study showing that achievement of CR is a desirable endpoint for patients with CLL treated with ibrutinib, associating with prolonged PFS. Our results support the development of future combination studies, aimed at achieving higher rates of CR in patients treated with ibrutinib. Figure. Figure. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Jain:Infinity: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Cellectis: Research Funding; Verastem: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; ADC Therapeutics: Research Funding; BMS: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Adaptive Biotechnologioes: Research Funding; Celgene: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Adaptive Biotechnologies: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Beschreibung: Background: Outcomes of patients (pts) with Richter transformation (RT) remain dismal with a median survival of less than 1 year with chemoimmunotherapy (CIT). Dysfunction of T cells, NK cells and other immune subsets is common in pts with CLL. Checkpoint blockade is an emerging treatment approach for pts with RT (Ding et al. Blood 2017; Younes et al. ASH 2017). Methods: We designed an investigator-initiated phase II clinical trial combining nivolumab (anti-PD1 monoclonal antibody) with ibrutinib in pts with R/R CLL or RT (NCT02420912). We report data on the RT cohort. Nivolumab was given 3 mg/kg IV every 2 weeks, starting cycle 1 day 1 for a total of 24 cycles. Ibrutinib was given 420 mg once daily starting cycle 2 day 1 (Ibrutinib could be added during cycle 1, in case of worsening disease) and continued until disease progression or unacceptable toxicities. Each cycle was 4 weeks. Eligibility criteria included age ≥18 years, adequate organ function (total bilirubin ≤1.5 x ULN, ALT and AST ≤3 x ULN, creatinine ≤1.5 x ULN). Pts were included if they had received at least one therapy for CLL or RT (pts with del(17p) could be treatment-naïve). Response assessments were done by PET scan and bone marrow after cycle 1, cycle 3, cycle 6, cycle 9, and cycle 12, cycle 18, and cycle 24. Results: A total of 23 pts with RT have been enrolled. The median age was 65 years (range, 49-88); 10 women, 13 men. The median number of prior therapies for CLL/RT was 3 (range, 0-10); one pt with previously untreated CLL who developed RT with del(17p) was enrolled. Prior therapies included CIT (n=18), ibrutinib (n=11), acalabrutinib (n=1), P13K inhibitor (n=4), venetoclax (n=3), allo-SCT (n=2). A total of 10 pts (43%) responded (complete metabolic response, n=8; partial metabolic response, n=2). The median duration of response (censored for allo-SCT) for the responding pts (n=10) is 9.3 months (Figure 1). Two pts previously treated with ibrutinib responded. A total of 4 pts underwent a subsequent allo-SCT after achieving a response to therapy. Four additional pts underwent allo-SCT after receiving a subsequent salvage therapy. The median overall survival for the entire group (n=23) is 13.8 months (Figure 1). One pt had G3 transaminitis and one pt had grade 4 lipase/amylase elevation. One pt developed grade 2 pneumonitis, and one pt had grade 2 uveitis. Correlative studies, including flow-cytometry and immunohistochemistry for PD1 and PDL1 are ongoing. Conclusions: The combination of nivolumab and ibrutinib has clinical activity in pts with RT with a 43% response rate. Disclosures Jain: Pfizer: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BMS: Research Funding; Astra Zeneca: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Servier: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Abbvie: Research Funding; Adaptive Biotechnologioes: Research Funding; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Adaptive Biotechnologioes: Research Funding; Cellectis: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kadia:Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; BMS: Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy. Pemmaraju:novartis: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding. Khoury:Stemline Therapeutics: Research Funding. O'Brien:Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Pfizer: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Research Funding; Alexion: Consultancy; Gilead: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Kite Pharma: Research Funding; Abbvie: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Pharmacyclics: Consultancy, Research Funding; Acerta: Research Funding; Amgen: Consultancy; Janssen: Consultancy; Sunesis: Consultancy, Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding.

Beschreibung: Alterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.

Beschreibung: Thompson and colleagues report that detection of minimal residual disease using next-generation sequencing, which is 2 orders of magnitude more sensitive than flow cytometry, is a much better predictor of progression-free survival.

Beschreibung: BACKGROUND Combined fludarabine, cyclophosphamide, and rituximab (FCR) was the preferred regimen for young fit patients (pts) with CLL. The CLL10 trial established FCR as the preferred first-line chemoimmunotherapy (CIT). Recently, the E1912 trial compared first-line FCR vs. ibrutinib + rituximab for young fit pts with CLL. The ibrutinib arm showed an improved PFS and OS vs. the FCR arm; however, there was no difference in PFS for mutated IGHV (M-IGHV) group. With the FCR studies, it is already known that the long-term benefit is seen in pts with M-IGHV. In the MD Anderson Cancer Center (MDACC) FCR trial, long-term follow up demonstrated that the PFS at 10 yrs was approximately 55% for M-IGHV pts with a plateau after 8 yrs, suggesting that these pts may be cured of their CLL. Hence, CIT remains an appropriate first-line option for pts with M-IGHV with fixed duration treatment and expectation for long treatment-free interval. We hypothesized that 1) achieving higher U-MRD would improve PFS and OS and 2) reducing the amount of chemotherapy might lower the risk of t-MDS/AML. We thus developed a CIT regimen called iFCG which consists of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) for young fit CLL patients with mutated IGHV and without del(17p)/mutated TP53. To decrease chemotherapy exposure, we administered only 3 cycles of chemotherapy in the iFCG regimen. METHODS We designed a phase II study for previously untreated pts with CLL with M-IGHV and absence of del(17p)/mutated TP53 (NCT02629809). All pts had a 2008 IWCLL indication for treatment. Pts received ibrutinib, fludarabine, cyclophosphamide, obinutuzumab for the first 3 cycles. Pts who achieved CR/CRi with bone marrow (BM) undetectable minimal residual disease (U-MRD) after the first 3 cycles received 9 additional cycles of ibrutinib with 3 additional cycles of obinutuzumab; all other pts received 9 additional cycles of ibrutinib and obinutuzumab. Pts with U-MRD (CR/CRi or PR) at 12 cycles stop all therapy, including ibrutinib. Responses were assessed by 2008 IWCLL criteria with BM and CT scans every 3 cycles during the first yr. BM MRD was assessed by flow cytometry (sensitivity 10-4). Post-cycle 12, pts have MRD assessed in blood every 6 months. In pts with available BM samples, MRD was also assessed by an NGS assay (sensitivity up to 10-6). RESULTS 45 pts were treated. Pretreatment characteristics are in Table 1. The median follow-up is 30.2 months. After 3 cycles of iFCG, 39% achieved CR/CRi and 89% achieved BM U-MRD. Responses improved with continued therapy with ibrutinib and obinutuzumab (Figure 1); 73% achieved CR/CRi and 100% achieved BM U-MRD after cycle 12. 41/45 pts completed all planned 12 cycles (4 pts came off study, details below). Per trial design, all 41 pts completing 12 cycles of treatment discontinued ibrutinib since all achieved U-MRD. PFS and OS are shown in Figure 2. No pt had MRD recurrence, CLL progression or Richter transformation, with a median follow-up of 18.7 months (range, 0.2-28.8) post discontinuing ibrutinib. In pts with available BM samples, we also assessed MRD by NGS assay. After 3 cycles of iFCG, 68% (n=28) achieved U-MRD at 10-5 sensitivity and 50% (n=22) achieved U-MRD at 10-6 sensitivity. After cycle 6, the corresponding numbers were 83% (n=30) and 58% (n=24), respectively. After cycle 12, the corresponding numbers were 91% (n=22) and 63% (n=16), respectively. Reasons for study discontinuation included 1) death due to CHF (see below), 2) pulmonary MAC infection, 3) infusion reaction to obinutuzumab, and 4) pt decision. One pt died; 26-yr-old man who developed CHF in cycle 9 (receiving ibrutinib and obinutuzumab). He had no known cardiac comorbidities; he started a weight loss supplement (sympathomimetic agent) few days prior to symptom onset. The pt died from worsening heart failure. One pt developed t-MDS. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% pts, respectively. Neutropenic fever occurred in 6 pts (culture negative 4 pts, PJP pneumonia 1 pt, staphylococcus skin infection 1 pt). Additional infectious complications without neutropenia leading to hospitalization included pneumonia (culture negative) (n=2), cellulitis (n=1), pulmonary MAC infection (n=1), fever (n=1), acute cholecystitis (n=1), and colitis (n=1). CONCLUSIONS The iFCG regimen with only 3 cycles of chemotherapy is an effective time-limited regimen for young pts with M-IGHV and without del(17p)/ mutated TP53. Disclosures Jain: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Thompson:Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; BeiGene: Research Funding; Gilead Sciences: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:AstraZeneca: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Strategia Therapeutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; Cantargia AB: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly and Co.: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Polaris: Research Funding. Bose:Pfizer: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; NS Pharma: Research Funding; Astellas: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:mustangbio: Consultancy, Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria. Wierda:Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding. OffLabel Disclosure: Combination of ibrutinib with chemotherapy is not FDA approved

Beschreibung: Introduction Achieving MRD-negative remission after FCR therapy is an important predictor of longer progression-free (PFS) and overall survival (OS); however, with long-term follow-up, many MRD-negative patients subsequently relapse. The time course and predictive factors for relapse in initially MRD-negative patients have not been extensively characterized. Methods We prospectively analyzed 289 patients treated first-line with FCR for CLL at M.D. Anderson Cancer Center from 2008-15, to determine pre-treatment characteristics associated with post-treatment MRD negativity and the time course of relapse in MRD-negative patients. MRD analysis was performed in BM after course 3 (n=239) and at end of therapy (EOT) (n=231) using standardized 4-color flow cytometry (FLC). Ninety-five MRD-negative patients had 12-monthly serial MRD monitoring on blood. Results Pretreatment characteristics are shown below (N=289). For the total cohort, the only pre-treatment characteristic significantly associated with PFS was IGHV-unmutated (IGHV-UM) (HR 3.0 [1.6-5.5], p

Beschreibung: Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. We recently reported results of the first-line cohort (n=80) of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019) (NCT02756897). Here we report updated data for these 80 pts with focus on MRD results. Methods: Pts with previously untreated CLL meeting 2008 IWCLL treatment criteria were enrolled. All pts had at least one of the following features: del(17p), mutated TP53, del(11q), unmutated IGHV, or an age of 65 years or older. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (assessed by multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy will stop both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of the combination therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death. Results: A total of 80 pts were enrolled. The median age was 65 years (26-83). The baseline characteristics are shown in Table 1. A total of 30% of the pts were 70 years of age or older. Overall, 92% of the pts had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. The median follow-up for all pts is 22.8 months. Five pts came off study during IBR monotherapy (reasons listed below). 75 pts initiated VEN. Serial BM MRD responses are shown in Figure 1. After 3 cycles of IBR monotherapy, none of the 75 pts had achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 12/74 (16%) achieved BM U-MRD remission. After 6 cycles of the combination, 30/72 (42%) achieved BM U-MRD remission. After 12 cycles of the combination, 45/69 (65%) achieved BM U-MRD remission. After 24 cycles of the combination, 23/29 (79%) achieved BM U-MRD remission. PFS and OS are shown in Figure 2. No pt has had CLL progression. Richter's transformation developed in one pt; this was a 63-year-old man with CLL with high-risk genomics (unmutated IGHV and mutated NOTCH1) in whom back pain developed during dose escalation of venetoclax and who was noted to have DLBCL transformation. Two pts died. One pt was a 60-year-old man who was having headache and numbness on the right side for 1 week before starting ibrutinib. The pt received 1 day of ibrutinib monotherapy, had progressive neurologic symptoms, and was found to have CNS cryptococcal infection. Ibrutinib was discontinued and the pt died 6 months later from complications of disseminated cryptococcal infection. This was deemed unrelated to ibrutinib as the pt had symptoms prior to starting ibrutinib. A second pt received only 2 weeks of ibrutinib and was taken off trial due to development of fungal pneumonia. The pt continued ibrutinib (off trial) and died 2 years later from infectious complications. A total of 12 (15%) pts have come off trial. Five pts came off trial during IBR monotherapy [skin rash, n=1; hypertension, n=1; prohibited medication, n=1; unrelated infection (cryptococcus), n=1; withdrew consent, n=1]. Seven pts came off study during the combination phase [recurrent neutropenia, n=2; DLBCL transformation, n=1; pneumonia, n=1; fallopian tube cancer, n=1; allogeneic SCT, n=1; hemolytic anemia/MDS, n=1]. 54% pts had dose reduction of IBR; 29% had dose reduction of VEN. Conclusions: Combined IBR and VEN is an effective chemotherapy-free oral regimen for pts with high-risk previously untreated CLL. Ongoing randomized studies will further help define the role of this combination approach in CLL. Disclosures Jain: BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding. Thompson:AbbVie: Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria. Borthakur:Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; NKarta: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Oncoceutics: Research Funding; Agensys: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Fowler:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Bioline RX: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Konopleva:Agios: Research Funding; Astra Zeneca: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding. Alvarado:Abbott: Honoraria; Jazz Pharmaceuticals: Research Funding. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; medimmune: Honoraria. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Wierda:Janssen: Research Funding; Xencor: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

Beschreibung: Patients with CLL experience generalized immune suppression, susceptibility to infections and secondary malignancies that likely involve complex bi-directional interactions between leukemic cells, components of the tumor microenvironment and immune effectors. CLL cells are capable of secreting IL-10 and exhibit regulatory functions comparable to that of normal B10 cells, a regulatory B cell subset that suppresses effector T-cell function through STAT3-mediated production of IL-10. However, the underlying mechanisms governing IL-10 production by CLL cells are not fully understood. The chemokine CXCL12 is constitutively secreted by bone marrow stroma in CLL, and binds CXCR4 to direct chemotaxis, support tumor survival and activate various signaling pathways, including STAT3. Thus, we investigated if CXCL12 can enhance IL-10 production by activating the STAT3 pathway in CLL. Using peripheral blood mononuclear cells (PBMC) from 24 CLL patients who had not received therapy for ≥2 years, we showed that CXCL12 can enhance IL-10 production by CLL cells by activating S727-STAT3. This effect was CXCR4-mediated since blocking the CXCR4-CXCL12 interaction with a blocking antibody abolished CXCL12-induced IL-10 production. Addition of the STAT3 inhibitor curcubitacin to the culture also abrogated CXCL12-induced IL-10 production, confirming an important role for S727-STAT3 as a mediator of CXCL12-CXCR4-induced IL-10 production by CLL cells. We next determined if activation of the CXCR4-CXCL12-STAT3-IL10 pathway in CLL is important in mediating their immunoregulatory function. Culture of primary CLL withCXCL12 induced significantly more suppression of CD3+ T cell function, including TNF-α, IFN-γ and IL-2 production, and CD107a degranulation, compared to CD3+ T cells cultured with untreated CLL cells or with CXCL12 alone. The addition of IL-10 blocking antibody to the co-culture completely reversed T cell dysfunction, supporting an important for IL-10 in CLL-mediated T-cell suppression. IL-10 has been reported to induce T cell suppression through phosphorylation of Y705-STAT3.. Blocking IL-10 also prevented CLL-induced phosphorylation of Y705-STAT3 in T cells, confirming an important role for CLL-derived IL-10 in activation of Y705-STAT3 and induction of T cell dysfunction. Lenalidomide is an immune-modulatory drug with clinical efficacy in CLL and was recently reported to inhibit STAT3 phosphorylation. To investigate if lenalidomide can inhibit CXCL12-induced STAT3 phosphorylation, we treated CLL cells with lenalidomide and measured p-S727-STAT3 levels. Exposure of CLL cells to 10µM/ml lenalidomide prevented CXCL12-induced increase in p-S727-STAT3 and resulted in significant reduction in the IL-10 response by CLL cells. Lenalidomide also suppressed IL-10-induced Y705-STAT3 phosphorylation in healthy T cells, thus reversing CLL-induced T cell dysfunction. We next confirmed the in vivo relevance of our findings using PBMC cryopreserved from patients treated with lenalidomide monotherapy (NCT00535873). When compared to pretreatment samples, CLL cells from on-treatment samples produced less IL-10 and showed significantly improved T cell function. We thus conclude that the capacity of CLL to produce IL-10 is mediated by the CXCL12-CXCR4-STAT3 pathway and may contribute to immunodeficiency in patients. Lenalidomide can reverse CLL-induced immunosuppression through multiple mechanisms that involve abrogation of the CXCL12-CXCR4-S727STAT3-mediated IL-10 response by CLL B cells and prevention of IL-10-induced phosphorylation of Y705-STAT3 in T cells. Disclosures Estrov: incyte: Consultancy, Research Funding. Wierda:Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy. Rezvani:Pharmacyclics: Research Funding.