Venetoclax as a single agent and in combination with PI3K‐MTOR1/2 kinase inhibitors against ibrutinib sensitive and resistant mantle cell lymphoma

The increasing number of approved therapies for relapsed mantle cell lymphoma (MCL) provides patients effective treatment options, with increasing complexity in prioritization and sequencing of these therapies. Chemo-immunotherapy remains widely used as frontline MCL treatment with multiple targeted therapies available for relapsed disease. The Bruton’s tyrosine kinase inhibitors (BTKi) ibrutinib, acalabrutinib, and zanubrutinib achieve objective responses in the majority of patients as single agent therapy for relapsed MCL, but differ with regard to toxicity profile and dosing schedule. Lenalidomide and bortezomib are likewise approved for relapsed MCL and are active as monotherapy or in combination with other agents. Venetoclax has been used off-label for the treatment of relapsed and refractory MCL, however data are lacking regarding the efficacy of this approach particularly following BTKi treatment. Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies have emerged as highly effective therapy for relapsed MCL, with the CAR-T treatment brexucabtagene autoleucel now approved for relapsed MCL. In this review the authors summarize evidence to date for currently approved MCL treatments for relapsed disease including sequencing of therapies, and discuss future directions including combination treatment strategies and new therapies under investigation.

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BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽

10.1136/esmoopen-2018-000387 ◽

2018 ◽

Vol 3 (6) ◽

pp. e000387 ◽

Cited By ~ 10

Author(s):

Chiara Tarantelli ◽

Elena Bernasconi ◽

Eugenio Gaudio ◽

Luciano Cascione ◽

Valentina Restelli ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Antitumour Activity ◽

Single Agent ◽

Treatment Strategies ◽

Bet Inhibitor ◽

Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

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Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin’s Lymphomas

Advances in Hematology ◽

10.1155/2012/523842 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Marco Gunnellini ◽

Lorenzo Falchi

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Single Agent ◽

Response Rates ◽

Prognostic Scores ◽

Cell Transplant ◽

Survival Times ◽

Phase Ii Studies ◽

Mantle Cell ◽

Hodgkin's Lymphomas

Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.

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New and emerging Bruton tyrosine kinase inhibitors for treating mantle cell lymphoma – where do they fit in?

Expert Review of Hematology ◽

10.1080/17474086.2018.1506327 ◽

2018 ◽

Vol 11 (9) ◽

pp. 749-756 ◽

Cited By ~ 3

Author(s):

Simon Rule ◽

Robert W. Chen

Keyword(s):

Tyrosine Kinase ◽

Mantle Cell Lymphoma ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Cell Lymphoma ◽

Mantle Cell ◽

Bruton Tyrosine Kinase

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Anti-Tumor Activity of Single-Agent CCI-779 for Relapsed Mantle Cell Lymphoma: A Phase II Trial in the North Central Cancer Treatment Group.

Blood ◽

10.1182/blood.v104.11.129.129 ◽

2004 ◽

Vol 104 (11) ◽

pp. 129-129 ◽

Cited By ~ 3

Author(s):

Thomas Witzig ◽

Susan Geyer ◽

Irene Ghobrial ◽

David Inwards ◽

Rafael Fonseca ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Median Time ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

Pi3k Pathway ◽

Mantle Cell ◽

Grade 3 ◽

Anti Tumor Activity

Abstract Purpose: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1, a member of the phosphatidylinosital 3 kinase (PI3K) pathway. This study tested whether CCI-779, which inhibits the PI3K pathway at the level of the mammalian target of rapamycin (mTOR) could produce tumor responses in patients (pts) with MCL. Patients and Methods: Eligible pts had biopsy-proven, cyclin D1 positive MCL and had relapsed or were refractory to therapy. Pts received CCI-779 250 mg IV every week as a single agent. Pts were re-staged after 1 cycle (4 doses) and every 3 cycles thereafter. Pts with a tumor response after 6 cycles were eligible to continue drug for a total of 12 cycles or 2 cycles after complete remission (CR) and then were observed. Results: Thirty-five pts were enrolled and evaluable for toxicity; 1 patient had MCL by histology but was cyclin D1 negative and ineligible for efficacy evaluation. The median age was 70 years (range, 38–89), 91% were stage 4, and 69% had ≥ 2 extranodal sites. Pts had received a median of 3 prior therapies (range, 1–11) and 54% were refractory to their last treatment. The overall response rate was 38% (13/34) with 1 CR (3%) and 12 PRs (35%), surpassing the pre-defined criteria for a promising agent. Responses tended to occur rapidly with median time to response of 1 month (range, 1–8). To date, 26 patients have progressed, with a median time-to-progression of 6.8 months (95% CI: 3.8 – 9.7). Median duration of response for the 13 responders was 5.7 months (95% CI: 5.2 – 13.2). Overall, 32 out of 35 patients who received treatment had grade 3 or 4 toxicity. The most common toxicities were hematologic with grade 3 (n=24) or grade 4 (n=4). Thrombocytopenia was the most frequent grade 3/4 toxicity (n=25) and the largest cause of dose-reductions, although counts typically recovered within one week. Only 4 patients could tolerate sustained 250 mg per week throughout their treatment (including one who went on to alternate treatment after 1 cycle) and the median dose/month was 175 mg. Conclusions: Single-agent CCI-779 has substantial anti-tumor activity in relapsed MCL. This study demonstrates that agents, which selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. The high response rate warrants further studies of this agent in MCL, but the high incidence of hematologic toxicity suggests that a lower dose should be explored. CCI-779 at 25mg is currently being evaluated in MCL through an NCCTG trial

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Herpes Zoster (HZ) Complicating Bortezomib Therapy of Relapsed/Refractory Indolent B-Cell and Mantle Cell Lymphoma: An Analysis of Two Phase II Trials.

Blood ◽

10.1182/blood.v116.21.2818.2818 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2818-2818

Author(s):

Vicki A. Morrison ◽

Richard I Fisher ◽

Andre Goy ◽

Sven de Vos ◽

Steven H. Bernstein ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Cell Lymphoma ◽

Single Agent ◽

Phase Ii Trials ◽

Two Phase ◽

Advisory Committees ◽

Mantle Cell ◽

Purine Analog

Abstract Abstract 2818 Background: The use of bortezomib-based therapy is known to be associated with an increased risk of HZ in patients (pts) with multiple myeloma, who have disease-related inherent immune defects. A 13% incidence of HZ occurrence in pts with relapsed/refractory MM who received single agent bortezomib has been previously reported (J Clin Oncol 2008; 26:4784-4790). However, the occurrence of HZ in bortezomib-treated pts with non-Hodgkin lymphoma (NHL) has not been previously examined. Methods: We reviewed clinical data from two phase II trials in which bortezomib therapy was administered to pts with relapsed/refractory mantle cell NHL or indolent B-cell NHL. The occurrence of HZ complicating their treatment course was delineated, and an analysis for potential predisposing risk factors was undertaken. Results: A total of 236 relapsed/refractory pts, median age 65 years (yrs), enrolled on these trials was examined. Mantle cell NHL pts (n=155) received single-agent bortezomib, 1.3 mg/m2, days (D) 1, 4, 8, 11, 21-D cycles; those with indolent B-cell NHL (n=81) received either bortezomib, 1.3 mg/m2, D 1, 4, 8, 11, 21-D cycles, plus rituximab, 375 mg/m2, D 1, 8, 15 (cycle 1) and D 1 (cycle 2) (n=41), or bortezomib, 1.6 mg/m2, D 1, 8, 15, 22, 35-D cycles, and rituximab, 375 mg/m2, D 1, 8, 15, 22 (cycle 1) (n=40). HZ occurred in 24 pts (10.2%) overall, with a comparable incidence in both disease subgroups. Median time to HZ occurrence was 39 (range, 11–206) days (< 2 cycles). Overall, 11% of pts had had a prior episode of HZ. Baseline demographic and clinical variables were examined, including age, gender, disease stage, baseline absolute neutrophil and lymphocyte counts, hemoglobin, lactate dehydrogenase, prior HZ, and number and types of prior therapies, to determine if any may predict for subsequent development of HZ. With regard to age, 71% of pts with HZ were age ≥65 yrs, compared to 48% without HZ (p=0.03). 63% of pts with HZ had received ≥2 lines of prior therapy, compared to 47% in those without HZ (p=0.15). 4% of pts with HZ had undergone prior stem cell transplantation, compared to 13% of pts without HZ. Of the pts with HZ, 25% had received prior purine analog therapy, compared to 9% of pts without HZ. The other baseline variables had no impact on the occurrence of HZ. In the 77 pts who responded to bortezomib protocol therapy (complete/partial responses), the incidence of HZ was 14%, compared to an 8% incidence of HZ in the 159 non-responders (p=0.15). Conclusions: HZ may complicate the course of relapsed/refractory indolent or mantle cell NHL pts receiving bortezomib-based therapies, with an incidence similar to the myeloma population. Pts who are elderly, more heavily-pretreated, or have received prior purine analog therapy may be at greater risk of this complication, and should be strongly considered for antiviral prophylaxis during such therapy. Disclosures: Morrison: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Pfizer: Speakers Bureau. Off Label Use: Discussion of Velcade in NHL subtypes other than mantle cell lymphoma is included. Fisher:Allos Therapeutics: Consultancy; CytoKinetics: Consultancy; GSK: Consultancy; MundiPharma: Consultancy; Seattle Genetics: Consultancy; Millennium Pharmaceuticals, Inc,: Consultancy. Goy:Millennium, Celgene, GSK and Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bernstein:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Speakers Bureau. Boral:Millennium Pharmaceuticals, Inc.: Employment; Takeda Pharmaceuticals: Equity Ownership. Neuwirth:Millennium Pharmaceuticals, Inc.: Employment.

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Combination Of Ibrutinib With ABT-199, a BCL-2 Pathway Inhibitor: Effective Therapeutic Strategy In a Novel Mantle Cell Lymphoma Cell Line Model

Blood ◽

10.1182/blood.v122.21.645.645 ◽

2013 ◽

Vol 122 (21) ◽

pp. 645-645 ◽

Cited By ~ 2

Author(s):

Xiaoxian Zhao ◽

Juraj Bodo ◽

Danyu Sun ◽

Jeffrey J. Lin ◽

Lisa Durkin ◽

...

Keyword(s):

Mouse Model ◽

Mantle Cell Lymphoma ◽

Cell Line ◽

Therapeutic Strategy ◽

Cell Lymphoma ◽

Single Agent ◽

Down Regulation ◽

Mantle Cell ◽

Bcr Signaling ◽

Nsg Mouse

Abstract Background Mantle cell lymphoma (MCL) is an aggressive subtype of Non-Hodgkin Lymphoma associated with poor prognosis. Constitutive activation of B-cell receptor (BCR) signaling plays an essential role for the survival and proliferation of malignant B-cells. Targeting Bruton’s tyrosine kinase (BTK), a component of BCR signaling pathway, with ibrutinib is a promising strategy. As a single agent, complete and partial response rates of 21% and 47%, respectively, were observed in a phase 2 study for relapsed or refractory MCL. Simultaneous inhibition of multiple biologic pathways has the potential to result in a synergism. We combined ibrutinib with ABT-199, a BH3 mimetic that selectively targets the BCL-2 pathway, and tested their in vitroefficacy against MCL. Experimental design A novel MCL cell line, CCMCL1, and four other MCL cell lines (Jeko-1, Mino, JVM2, Rec-1) were used for flow cytometry-based apoptosis and cell cycle analyses to evaluate the combinational effect of ibrutinib with ABT-199 (ChemieTek. Indianpolis. IN). The interaction between drugs was examined with Calcusyn software and combination index values served to determine the combined effect as synergistic (<1), additive (=1), or antagonistic (>1). Immunoblotting was performed to investigate signaling pathways of MCL cells exposed to these agents. Results CCMCL1 was derived from primary leukemic MCL cells. Cells were initially directly injected via tail vein into an NSG mouse. Engrafted cells were then isolated at 10 weeks from spleen and placed into routine cell culture. Immunophenotyping showed CCMCL1 cells have similar characteristics as the primary patient MCL cells, which expressed CD5, CD19, CD20, FMC7 and monotypic kappa light chain. Immunohistochemical staining of engrafted mouse spleen tissue showed expression of cyclin D1 and SOX11. The karyotype is highly complex with an IGH@/CCND1 fusion by metaphase FISH. In addition to spleen, MCL cell infiltration was observed in mouse liver, bone marrow, blood, brain, lung, kidney and intestine. In vitro cultured CCMCL1 cells underwent apoptosis upon expose to ibrutinib and ABT-199 as single agents. Combination of these two drugs resulted in synergistic induction of apoptosis (Table 1). Synergism was also observed with Jeko-1, Mino, JVM-2 and Rec-1 cells. Immunoblotting showed CCMCL1 cells have constitutive expression of cyclin D1, SOX11, PAX5 and MCL1. Ibrutinib as a single agent induced a rapid down-regulation of SOX11 and MCL1, while combination of ibrutinib with ABT-199 further enhanced down regulation of SOX11, followed by down-regulation of PAX5 at a later time point. We are currently testing the in vivo efficacy of combining these two drugs in a CCMCL1 NSG mouse model. Conclusion Our CCMCL1/NSG mouse model is a new model for pre-clinical assessment of MCL treatment approaches. Combination of ibrutinib with ABT-199 has synergistic effect of apoptotic induction in CCMCL1 as well as four other MCL cell lines tested. Ibrutinib or ibruitnib/ABT-199 combination induced apoptosis of MCL is associated with down-regulation of SOX11 and PAX5. Simultaneous down regulation of MCL1 via ibrutinib and targeting of BCL2 may contribute to the in vitrosynergism observed. These data support further investigation of this novel therapeutic strategy. Disclosures: No relevant conflicts of interest to declare.

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STAT3 Activation Is Preceded By Two Independent Pathways (BCR-BTK and IL6-JAK) in Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.3028.3028 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3028-3028 ◽

Cited By ~ 1

Author(s):

Hyebin Park ◽

Donglu Zhao ◽

George Tsourdinis ◽

Zhishuo Ou ◽

Archito T. Tamayo ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Signaling Pathways ◽

Cross Talk ◽

Therapeutic Potential ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Prior Therapy ◽

Stat3 Phosphorylation ◽

Mantle Cell

Abstract Introduction Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor outcome and therapeutic challenge. Oral single-agent ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, elicited a response rate of 68% in phase II clinical trial and has been approved by FDA for the treatment of MCL patients who received at least one prior therapy. To increase the possibility of therapeutic potential, the investigation of BTK-dependent/independent signaling pathways is needed. Methods and Results Using both established MCL cell lines and primary MCL cells as a model system, our data demonstrated that ibrutinib effectively inhibited BTK phosphorylation along with quick STAT3 inactivation within 30 minutes of ibrutinib incubation at a dose lower than 100nM. Since the results clearly indicated that ibrutinib inhibited both BTK and STAT3 activation in MCL cells, we next elucidated the function and action between BTK and STAT3. Using a validated BTK-specific siRNA, we knocked down BTK to test the legitimacy of the relationship between BTK and STAT3. The results showed that transient knockdown of BTK significantly inhibited STAT3 phosphorylation in MCL cells. Next, the results from both immunoprecipitation and confocal microscopy showed that STAT3 was BTK-associated transcription protein indicating that BTK could function as a kinase upstream of STAT3, in a similar manner to the JAK/STAT pathway. Since STAT3 is predominately known as the downstream protein of the IL-6/JAK pathway, we examined whether there is a cross-talk between the BTK-STAT3 and the JAK-STAT3 pathways in MCL cells. After stimulation of MCL cells with IgM or IL-6, ibrutinib only inhibited IgM-induced STAT3 activation but not IL-6-induced STAT3 activation. Even with an increased dose of ibrutinib, the basal level of STAT3 phosphorylation remains detectable in MCL cells due to IL-6 autocrine. However, ibrutinib plus JAK inhibitor completely inactivated STAT3 and synergistically inhibited the growth of MCL cells. These data indicate that there are two independent pathways, BCR-BTK and IL6-JAK, which lead to STAT3 activation without cross-talk in MCL cells. Conclusions Our results may lead to the development of more effective combination therapy to block both BCR-BTK and IL-6-JAK signaling pathways for relapsed or refractory MCL. Disclosures Wang: Pharmacyclics: Honoraria, Research Funding.

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Lenalidomide in relapsed/refractory mantle cell lymphoma post-bortezomib: Subgroup analysis of the MCL-001 study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8534 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8534-8534 ◽

Cited By ~ 1

Author(s):

Michael E. Williams ◽

Andre Goy ◽

Rajni Sinha ◽

Sevgi Kalayoglu Besisik ◽

Johannes W. Drach ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Single Agent ◽

Multivariate Logistic Regression Analysis ◽

Disease Status ◽

Prior Therapy ◽

Primary Endpoints ◽

Mantle Cell ◽

Duration Of Response ◽

Patient Subgroups

8534 Background: Lenalidomide, an immunomodulatory agent with antitumor and antiproliferative effects, demonstrated rapid and durable efficacy in patients with relapsed/refractory mantle cell lymphoma (MCL) post-bortezomib in the phase II multicenter MCL-001 study. The objective of this analysis was to explore the efficacy of lenalidomide across patient subgroups. Methods: Single-agent lenalidomide was administered at 25 mg/d PO on days 1-21 of a 28-day cycle until disease progression or intolerability; primary endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent central review committee per modified IWG criteria. Exploratory analyses of ORR and DOR for subgroups were predefined and prospectively conducted. Results: Patients with relapsed/refractory MCL (N=134) had a median age of 67 y, with a median of 4 prior therapies (range, 2-10). The ORR was 28% (7.5% CR/CRu) and DOR was 16.6 months (95% CI, 7.7-26.7). Lenalidomide treatment provided consistent ORR and DOR across all subgroups analyzed by demographics, baseline disease status and prior therapy (Table). High vs normal baseline LDH was the only significant factor by univariate and multivariate logistic regression analysis of ORR (odds ratio=0.193; p=0.002). Conclusions: Single-agent lenalidomide provided consistent clinical benefit in patients with relapsed/refractory MCL post-bortezomib irrespective of patient subgroups at baseline with the exception of LDH. Clinical trial information: NCT00737529. [Table: see text]

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A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.150.150 ◽

2016 ◽

Vol 128 (22) ◽

pp. 150-150 ◽

Cited By ~ 7

Author(s):

Peter Martin ◽

Kristie Blum ◽

Nancy L. Bartlett ◽

Steven I. Park ◽

Kami J. Maddocks ◽

...

Keyword(s):

Phase I ◽

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Hematological Toxicity ◽

Mantle Cell ◽

Previously Treated ◽

Grade 3 ◽

Dose Levels

Abstract Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

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