ABSTRACT
Background: ACC is a heterogeneous neoplasm and there is no standard treatment for patients (pts) with recurrent/metastatic (R/M) disease. Vascular endothelial growth factor receptor inhibitors (VEGFRi) are frequently used to treat R/M ACC rendering mostly disease stabilization. ACC is resistant to PD-1/PD-L1 inhibitors (PD-L1i), consistent with its low mutational burden and uninflamed immune microenvironment. We hypothesized that the immunomodulatory role of VEGFRi (axitinib) would enhance PD-L1i (Avelumab) activity and be a more effective therapy for R/M ACC. Methods: Eligible pts had R/M ACC with radiological or clinical progression within 6 months (mos) of enrollment. Treatment consisted of axitinib 5 mg PO bid and avelumab 10 mg/Kg IV every 2 weeks. Primary endpoint was objective response rate (ORR) per RECIST 1.1;secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. Simon 2-stage design was applied to test the null hypothesis of ORR ≤ 5% versus the alternative ORR ≥ 20%;≥ 4 responses out of 29 pts was required to reject the null hypothesis. Results: 41 pts enrolled from 07/24/19 to 06/29/ 21;28 were evaluable for the primary endpoint (7 screen failures, 6 evaluable for safety only due to loss of insurance/logistics issues related to COVID-19 pandemic);16 pts were treated in first-line. Mutation data was available for 23 of 28 evaluable pts;7 had NOTCH1 activating mutations. The ORR was 17.9% (5/28, 95%CI: 6.1-36.9%). One response was unconfirmed (pt progressed in non-target lesions 2 mos after achieving a PR), for a confirmed ORR of 14.3% (95%CI: 4-32.7%). The median follow-up time for the 15 alive pts was 11.6 mos (min-max: 7.7-29.2 mos). Median PFS was 7.2 mos (95%CI: 3.7-11.7 mos) with a 6-mos PFS rate of 57% (95%CI: 41-79%). Median OS was 17.4 mos (95%CI: 13-NA). 5 pts remain on therapy, 2/5 with a PR. The median DOR for the 5 responders was 5.2 mos (95% CI: 3.7-NA mos). The most common treatment-related adverse events (TRAEs) were fatigue (62%), hypertension (32%), diarrhea (29%), and stomatitis (29%). Serious TRAEs occurred in 8 (24%) pts, all grade 3 and manageable. 4 (15%) pts discontinued avelumab and 9 (32%) underwent axitinib dose reduction due to toxicity. Conclusions: The study reached its primary endpoint with ≥ 4 responses out of 28 evaluable pts (ORR of 17.8%;confirmed ORR of 14.3%). The ORR and 6- mos PFS rate of 57% with axitinib and avelumab compares favorably with single agent axitinib and warrants further study of the combination.
ABSTRACT
Cancer immunotherapy has shaped the way in which we design cancer treatments, introducing the paradigm of taking advantage of our immune system to fight cancer. We propose that the same concept could be applied to infectious diseases and, especially, to those that hamper the immune system like COVID-19. It is well known that an adaptive immune response is able to eradicate viral infections and CD8+ T-cells are key in such anti-viral response. Furthermore, several studies reported that the number of CD8+ T-cells is reduced in COVID-19 patients since the beginning of SARS-CoV-2 infection and further decreased in severe cases. CD8+ T-cells often show signs of exhaustion, loss of T-cell functions and suppression in COVID-19 patients, suggesting that hampering CD8+ T-cells could be a way by which SARS-CoV-2 infection progresses. Importantly, the number of CD8+ T cells appears to re-increase in patients that are recovering from COVID-19, suggesting that CD8+ T-cells could be a key factor that determines whether our body can recover from the disease. We propose that therapies that boost CD8+ T cells could be effective in clearing SARS-CoV-2 infection in COVID-19. To test this, we will take advantage of the adenosine-mediated immunomodulation. Adenosine, an ATP metabolite that is produced during inflammation, hypoxia and in the tumor microenvironment, was found to suppress the immune response through activation of adenosine receptors present on immune cells. Small molecules antagonists that block one of these receptors, adenosine A2A receptor (A2AR) antagonists, are currently being studied to boost anti-cancer T-cell mediated immune responses. Our data show that treatment with an A2AR antagonist restores and stabilizes Notch1, a key pathway for T-cell functions, along with production of INF-gamma and Granzyme B and proliferation in CD8+ T-cells. As a proof of concept, our data indicates that treatment with an A2AR antagonist increases CD8+ T-cells anti-cancer response in tumor-derived organoids, suggesting that the treatment boosts CD8+ T-cells-mediated immune response. Ongoing work aims to test whether the A2AR antagonist treatment restores several parameters of T-cell function that are specifically modified in COVID-19. This analysis will help to predict the action of the A2AR antagonist on T-cells in vivo and we ultimately aim to test this treatment in a mouse model for COVID-19. Overall, our work could introduce a new paradigm and new therapies for COVID-19 and other infectious diseases.
ABSTRACT
The BCL2-specific inhibitor, venetoclax, has demonstrated remarkable clinical activity in the treatment of chronic lymphocytic leukemia (CLL), either alone or in combination with CD20 antibodies. Nevertheless, patients who fail to attain a complete remission relapse, and require further therapy. Data on retreatment with venetoclax at disease progression are currently limited. Here, we report patterns of clonal evolution in an R/R CLL patient that has demonstrated successful retreatment. A 57 year-old lady with chemotherapy- refractory (FCR, RCHOP, high dose methyl prednisolone) TP53 mutant CLL was treated for 21 months with single-agent venetoclax in 2014 (NCT01889186). She attained an MRD positive CR with the resolution of massive lymphadenopathy and with only low-level (0.01%) disease in the bone marrow. However, she subsequently progressed rapidly with a lymphocyte doubling time of only 4 weeks and was treated with tirabrutinib and idelalisib in combination (NCT02968563) from December 2015 for 37 months before progressing December 2019. She was retreated with venetoclax and rituximab but died of COVID-19-induced respiratory failure in March 2020. To study the clonal evolution underlying these events, in vitro drug sensitivity assays and whole exome sequencing (WES) were used to study peripheral blood mononuclear (PBMC) and bone marrow samples. WES of sample 1 showed multiple mutations in CLL driver genes: SF3B1 R625C, KMT2C R4434Q, and TP53 R110L at VAFs of 37, 17, 35%, respectively. Mutations in other genes associated with CLL included FANCA L217F (47%) and SPEN P3402S (46%). At disease progression (sample 2), following venetoclax, there was the loss of detectable (WES at 100× coverage) TP53 R110L (with loss of 17p deletion on interphase FISH and analysis of copy number) but maintenance of SF3B1 R625C (44%), KMT2C R4434Q 30%), FANCA L217F (47%), and SPEN P3402S (55%). These data, therefore, suggest the TP53 mutant subclone was largely lost during therapy. No other mutations were identified as possible resistance mediators. There were no detectable BCL2 mutations. In vitro drug sensitivity testing to venetoclax showed an EC50 of 228nM (CLL EC50 usually 3-5 nM). The patient was then treated with the BTK inhibitor tirabrutinib in combination with idelalisib, with an excellent clinical response. After 10 months (sample 3, during the lymphocytosis induced by BTKi/PI3Kdi) SF3B1, KMT2C, FANCA, and SPEN mutations were detected at VAFs of 26, 30, 54, and 56%, respectively. At this point the TP53 R110L mutation was detected again at a VAF of 4%, indicating that stopping venetoclax allowed the clone to re-emerge. At this time, there were no detectable BTK or PLCG2 mutations. The patient then responded for a further 37 months before disease progression. At progression (sample 4), SF3B1, KMT2C, FANCA, and SPEN mutations were still detected in the peripheral blood at VAFs of 43, 31, 48, and 50%, respectively. The VAF of the TP53 R110L mutation had increased to 33%. Additionally, a BTK mutation (T474I) was identified with a VAF of 16%. Identical results were obtained using a bone marrow sample. Now, however, in vitro analysis demonstrated a high degree of sensitivity to venetoclax (EC50 0.72 nM). The patient was, therefore, retreated with venetoclax and rituximab. At the point of re-treatment, VAFs were maintained, with the emergence of a new subclonal NOTCH1 G1001D mutation at a VAF of 3%. The patient, unfortunately, died 4 months after commencing therapy due to COVID-19 associated pneumonitis. A full disease reassessment was not made but the patient's blood count had normalized, with rapid clearance of CLL cells from the peripheral blood, recovery of normal hematological indices, resolution of splenomegaly, and partial resolution of lymphadenopathy on CT scan. These data, therefore, suggest that re-treatment with venetoclax in CLL can be successful. Regaining sensitivity to venetoclax may largely depend on shifting clonal dynamics. The molecular basis of venetoclax resistance in this case is currently being investigated. A so in this particular case, it appears that the TP53 mutant subclone was more sensitive to BCL2 inhibition than TP53 wild-type subclone(s), and was largely eliminated by initial venetoclax treatment, contrasting with recently published data suggesting resistance of TP53 mutant hematological malignancies to BCL2 inhibition due to increased thresholds for BAX/BAK activation (Thijssen et al., 2021).
ABSTRACT
Background: Continuous Bruton's tyrosine kinase (BTK) inhibition represents an effective and easily administered oral therapy for patients with CLL;however, it is not curative, can have serious side effects, and is expensive. Novel combinations may provide deep remissions allowing fixed duration therapy. The second generation BTK inhibitor acalabrutinib (ACALA) has demonstrated an improved safety profile compared to ibrutinib. Importantly, unlike ibrutinib, ACALA does not inhibit anti-CD20 monoclonal antibody dependent cellular phagocytosis (VanDerMeid et al, Cancer Immuno Res 2018). Using standard doses, rituximab (RTX) rapidly exhausts the finite innate immune system cytotoxic capacity (Pinney, et al Blood 2020) and also causes loss of cell membrane CD20 from CLL cells by trogocytosis. Previous studies have shown that high frequency low dose (HFLD) IV RTX (20mg/m 2 three times per week) was effective and limited loss of CD20 (Zent, et al Am J Hematol, 2014). Subcutaneous (SQ) RTX is FDA approved in CLL, has similar efficacy and pharmacokinetics, and can be self-administered. This phase II study tested the efficacy and tolerability of the combination of ACALA and HFLD RTX as initial treatment for patients with treatment-naïve CLL. Methods: Eligible patients were treated with 50mg RTX on day 1 and 3 of each week for six 28-day cycles. The first dose was administered IV over 2 hours. If tolerated, subsequent doses were SQ and could be self-administered at home by trained patients. ACALA 100mg BID therapy was initiated on cycle 1 day 8 for a minimum of 12 cycles. Treatment response was assessed during cycles 12 and 24. Patients achieving an iwCLL complete response (CR) with undetectable minimal residual disease (uMRD) by 6-color flow cytometry (£ 1:10 -4)at either time point could stop therapy. The primary objective was to determine the rate of iwCLL CR with a secondary endpoint of rate of uMRD. Results: 37 patients have been treated with a median follow-up of 14 months. Baseline demographics were male/female (22/15) and median age 67 years (range 40-78). High-risk genetic features included TP53 mutation (21.6%), del17p (13.5%), del 11q (16.2%), unmutated IGHV (62.2%), NOTCH1 mutation (21.6%) and SF3B1 mutation (10.8%). Grade 3/4 AEs occurring in ≥5% of patients were infections (13.5%), neutropenia (8.1%) and anemia (8.1%). No patients discontinued therapy due to AEs and there were no deaths on treatment. The most common (≥20%) AEs (all grades and all causality) were infusion-related reactions (62.1%), infections (56.8%) (upper respiratory infections in 29.7% of patients, urinary tract infections in 18.9%, COVID-19 pneumonia in 8.1%), fatigue (51.3%), anemia (51.3%), headache (43.2%), rash or other skin changes (32.4%), thrombocytopenia (29.7%), bruising (27.0%), and diarrhea (21.6%). Injection site reactions (8.1%) from SQ RTX were grade 1. Three patients contracted COVID-19 while on study during times of high community transmission prior to the availability of vaccines. Two required hospitalization, one contracted the virus following cycle 1 requiring a delay in RTX, and all patients remained on ACALA while COVID-19 positive. 27 patients have completed 12 cycles and been evaluated for response. All patients responded with 1 MRD+ CR, 20 partial responses (PR), and 6 PR with sustained lymphocytosis. 10 of these patients have completed 24 cycles and had a sustained PR. One patient with del17p and TP53 mutation had progressive disease after 25 cycles of therapy. All other patients remain on treatment per protocol. Conclusion: HFLD RTX and ACALA is a tolerable, effective and convenient therapy that could be the basis for regimens incorporating other novel agents. It is notable that three patients have contracted COVID-19 during the trial;however, none required intubation, and all remained on ACALA during their infection. This at-home combination markedly decreased patient infection risk during the COVID-19 pandemic. This regimen has the potential to enable RTX to be administered at facilities with limited medica IV infusion capacity which could be very useful in rural and economically disadvantaged areas. While all patients have responded to therapy, no patients to date have achieved an uMRD CR, suggesting that additional agents are required to allow for time-limited treatment. Disclosures: Baran: AstraZeneca/Acerta: Research Funding. Friedberg: Novartis: Other: DSMC;Acerta: Other: DSMC;Bayer: Other: DSMC. Reagan: Kite, a Gilead Company: Consultancy;Genentech: Research Funding;Seagen: Research Funding;Curis: Consultancy. Casulo: Verastem: Research Funding;Genentech: Research Funding;BMS: Research Funding;Gilead: Research Funding. Zent: TG Therapeutics: Research Funding;Acerta/AstraZeneca: Research Funding. Barr: Morphosys: Consultancy;Janssen: Consultancy;Bristol Meyers Squibb: Consultancy;AstraZeneca: Consultancy;Genentech: Consultancy;TG Therapeutics: Consultancy;Beigene: Consultancy;Seattle Genetics: Consultancy;Abbvie/Pharmacyclics: Consultancy;Gilead: Consultancy.
ABSTRACT
Background: Ibrutinib (IBR) and venetoclax (VEN) combination is a highly effective therapy for patients (pts) with CLL (Jain, NEJM 2019;Wierda, ASH 2020;Kater, EHA 2021). We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019;Jain, JAMA Oncology 2021). Here we report updated data for these pts with focus on MRD. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years (yrs). Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry;sensitivity 10 -4) at 24 cycles of combined therapy discontinued both VEN and IBR;MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and ibrutinib for pts who remained BM MRD+ after Cycle 24. Response assessments were performed using BM and CT imaging studies (2008 IWCLL criteria). U-MRD was defined as <0.01%;low MRD+ 0.01% to <1%;high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months in pts off treatment or on ibrutinib monotherapy beyond 24 cycles of combined treatment. Results: A total of 80 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up was 44.1 months. Five pts came off study during 1 st 3 cycles of IBR monotherapy;75 pts initiated VEN. We previously reported that after 12 cycles of the combination, 45/80 (56%) achieved BM U-MRD remission;24/80 (30%) were BM MRD-positive (low MRD+, n=19;high MRD+, n=5). After 24 cycles of the combination, 53/80 (66%) achieved BM U-MRD remission;14/80 (17%) were BM MRD+ (low MRD+, n=13;high MRD+, n=1). Overall, 60/80 (75%) achieved BM U-MRD as the best response. Updated PFS is provided in Figure 1. Of the 53 pts who were BM U-MRD at the end of cycle 24 of the combination, 52 pts had a subsequent blood MRD assessment done in follow-up (1 missed due to COVID-19);51/53 discontinued all therapy, 2 pts continued IBR per treatment physician discretion. With a median time of 18.4 months post Cycle 24, 8 pts had recurrence of blood MRD (defined as MRD ≥ 0.01% in 2 consecutive visits) in follow-up with 1 pt with CLL progression. The sole pt with CLL progression had mutated IGHV with del(11q) and NOTCH1 mutation. The pt had delayed achievement of BM U-MRD with the pt achieving U-MRD for the first time at the end of Cycle 24 of combined therapy. She was noted to have disease progression 22 months off therapy;BTK or PLCG2 mutation were not detected and the patient is currently in clinical remission on acalabrutinib. The time to MRD conversion for these 53 pts is shown in Figure 2. There were 14 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=13;high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 13 pts (all low MRD+ in BM, range 0.01-0.56%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of venetoclax;9/13 pts have resumed VEN. 6/9 pts have achieved U-MRD remission. 2 pts had Richter transformation and 3 pts have died (Jain, JAMA Oncology 2021). Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL. Remissions were durable with some pts having recurrence of blood MRD in follow-up, which may be an early indicator of relapse. In a small subset of the pts with BM MRD+ disease at 24 cycles of combined therapy, additional VEN appears to lead to U-MRD remission in majority of the pts. Whether this will lead to improved long-term PFS remains to be determined. [Formula presented] Disclosures: Jain: TG Therapeutics: Honoraria;Beigene: Honoraria;Janssen: Honoraria;Fate Therapeutics: Research Funding;Aprea Therapeutics: Research Funding;Precision Biosciences: Honoraria, Research Funding;Incyte: Research Funding;Adaptive Biotechnologies: Honoraria, Research Funding;Cellectis: Honoraria, Research Funding;ADC Therapeutics: Honoraria, Research Funding;Servier: Honoraria, Research Funding;Pfizer: Research Funding;Bristol Myers Squibb: Honoraria, Research Funding;AstraZeneca: Honoraria, Research Funding;Genentech: Honoraria, Research Funding;AbbVie: Honoraria, Research Funding;Pharmacyclics: Research Funding. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Amgen: Other: Institution: Honoraria, Research Grant/Funding;Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony;Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding;Janssen: Consultancy, Honoraria;Gilead: Other: Institution: Advisory/Consultancy, Honoraria. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding;Janssen: Other: Advisory Board;AstraZeneca: Other: Advisory Board, Research Funding. Burger: Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau;TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau;Beigene: Research Funding, Speakers Bureau;Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau;AstraZeneca: Consultancy. Borthakur: GSK: Consultancy;ArgenX: Membership on an entity's Board of Directors or advisory committees;University of Texas MD Anderson Cancer Center: Current Employment;Protagonist: Consultancy;Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees;Astex: Research Funding;Ryvu: Research Funding;Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi: Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy;Celgene/BMS: Consultancy;GSK: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Novartis: Consultancy, Research Funding. Kadia: Cellonkos: Other;Aglos: Consultancy;Dalichi Sankyo: Consultancy;AbbVie: Consultancy, Other: Grant/research support;BMS: Other: Grant/research support;Amgen: Other: Grant/research support;Cure: Speakers Bureau;Jazz: Consultancy;Genentech: Consultancy, Other: Grant/research support;Liberum: Consultancy;Novartis: Consultancy;Pfizer: Consultancy, Other;Pulmotech: Other;Sanofi-Aventis: Consultancy;AstraZeneca: Other;Astellas: Other;Genfleet: Other;Ascentage: Other. Konopleva: Sanofi: Other: grant support, Research Funding;Cellectis: Other: grant support;Calithera: Other: grant support, Research Funding;KisoJi: Research Funding;Agios: Other: grant support, Research Funding;Ascentage: Other: grant support, Research Funding;AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding;Ablynx: Other: grant support, Research Funding;Stemline Therapeutics: Research Funding;Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding;AstraZeneca: Other: grant support, Research Funding;Rafael Pharmaceuticals: Other: grant support, Research Funding;Genentech: Consultancy, Honoraria, Other: grant support, Research Funding;F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support;Forty Seven: Other: grant support, Research Funding;Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights;Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Alvarado: BerGenBio: Research Funding;Jazz Pharmaceuticals: Research Funding;Astex Pharmaceuticals: Research Funding;Sun Pharma: Consultancy, Research Funding;MEI Pharma: Research Funding;FibroGen: Research Funding;Daiichi-Sankyo: Research Funding;CytomX Therapeutics: Consultancy. Yilmaz: Pfizer: Research Funding;Daiichi-Sankyo: Research Funding. DiNardo: Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria;Takeda: Honoraria;Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding;Forma: Honoraria, Research Funding;AbbVie: Consultancy, Research Funding;GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Honoraria, Research Funding;ImmuneOnc: Honoraria, Research Funding;Agios/Servier: Consultancy, Honoraria, Research Funding;Foghorn: Honoraria, Research Funding. Bose: Kartos Therapeutics: Honoraria, Research Funding;Sierra Oncology: Honoraria;Novartis: Honoraria;Constellation Pharmaceuticals: Research Funding;NS Pharma: Research Funding;Celgene Corporation: Honoraria, Research Funding;Blueprint Medicines: Honoraria, Research Funding;Pfizer: Research Funding;Promedior: Research Funding;Astellas: Research Funding;Incyte Corporation: Honoraria, Research Funding;BMS: Honoraria, Research Funding;CTI BioPharma: Honoraria, Research Funding. Pemmaraju: Blueprint Medicines: Consultancy;LFB Biotechnologies: Consultancy;Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding;ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees;Dan's House of Hope: Membership on an entity's Board of Directors or advisorycommittees;Roche Diagnostics: Consultancy;MustangBio: Consultancy, Other;Affymetrix: Consultancy, Research Funding;Samus: Other, Research Funding;ImmunoGen, Inc: Consultancy;ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees;Aptitude Health: Consultancy;Plexxicon: Other, Research Funding;Springer Science + Business Media: Other;Protagonist Therapeutics, Inc.: Consultancy;HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees;Clearview Healthcare Partners: Consultancy;Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding;CareDx, Inc.: Consultancy;Sager Strong Foundation: Other;Daiichi Sankyo, Inc.: Other, Research Funding;Incyte: Consultancy;Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding;Bristol-Myers Squibb Co.: Consultancy;DAVA Oncology: Consultancy;Pacylex Pharmaceuticals: Consultancy;Celgene Corporation: Consultancy;Cellectis S.A. ADR: Other, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Wang: Stemline Therapeutics: Honoraria. Kantarjian: Taiho Pharmaceutical Canada: Honoraria;Precision Biosciences: Honoraria;Immunogen: Research Funding;Daiichi-Sankyo: Research Funding;Jazz: Research Funding;BMS: Research Funding;AbbVie: Honoraria, Research Funding;Pfizer: Honoraria, Research Funding;Novartis: Honoraria, Research Funding;NOVA Research: Honoraria;KAHR Medical Ltd: Honoraria;Ipsen Pharmaceuticals: Honoraria;Astra Zeneca: Honoraria;Astellas Health: Honoraria;Aptitude Health: Honoraria;Amgen: Honoraria, Research Funding;Ascentage: Research Funding. Wierda: Juno Therapeutics: Research Funding;AstraZeneca: Research Funding;Xencor: Research Funding;Janssen: Research Funding;Loxo Oncology, Inc.: Research Funding;Cyclacel: Research Funding;Oncternal Therapeutics, Inc.: Research Funding;Miragen: Research Funding;KITE Pharma: Research Funding;Sunesis: Research Funding;Gilead Sciences: Research Funding;Acerta Pharma Inc.: Rese rch Funding;Pharmacyclics LLC, an AbbVie Company: Research Funding;Karyopharm: Research Funding;Genentech: Research Funding;GSK/Novartis: Research Funding;Genzyme Corporation: Consultancy;AbbVie: Research Funding. OffLabel Disclosure: The combination of ibrutinib and venetoclax is not FDA approved