A Phase II, Open-Label, Single Arm Trial to Assess the Efficacy and Safety of the Combination of Tisagenlecleucel and Ibrutinib in Mantle Cell Lymphoma (TARMAC)

Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.

Download Full-text

T-Cell Clonal Expansion and Activation Associated with Durable Clinical Response to Dual BTK and CDK4/6 Inhibitor Therapy in Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2019-122322 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3973-3973

Author(s):

Christina Y. Lee ◽

Maurizio Di Liberto ◽

Yang Hu ◽

Xiangao Huang ◽

Nancy L Bartlett ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

T Cell ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Committees ◽

Mantle Cell ◽

Progression Of Disease

Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma characterized by the chromosomal translocation (11;14)(q13;q32), resulting in aberrant expression of cyclin D1 and dysregulated cell cycle progression. In a phase I clinical trial in patients with previously treated MCL, the combination of the cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor palbociclib and the Bruton tyrosine kinase inhibitor ibrutinib was safe and active. We hypothesized that clinical responses are in part attributed to dynamic changes in the immune landscape and tumor-immune interaction, given accumulating evidence that inhibition of CDK4/6 augments anti-tumor immunity. In a patient (Pt 17) treated with palbociclib and ibrutinib for over 3 years and experiencing a complete response (CR), there was an over 4-fold increase in circulating CD3+ T cells over time. For the first 19 treatment cycles, the absolute CD3+ T cell count was 862 ± 322 compared to 4,027 ± 253 between cycles 31 and 40, with no clinical suspicion of infection for at least 3 months prior. To investigate the T-cell receptor (TCR) repertoire over the course of treatment, high-throughput sequencing of the TCRB CDR3 region was performed, revealing a more oligoclonal repertoire in the peripheral blood over time. The cumulative frequency of the top 10 TCR clones during cycles 3, 7, and 31 were 3.9%, 6.5%, and 25.8%, respectively. These clones were mapped to single-cell RNA sequencing (scRNA-seq) data and determined to be CD8+ effector and central memory T cells. Furthermore, there appears to not only be increased numbers of CD4+ and CD8+ T cells but also enhanced activation as evidenced by scRNA-seq expression of CD69. These findings suggest a predominant cytotoxic T-cell response, which is consistent with recent preclinical studies using CDK4/6 inhibitors. A similar, less dramatic, pattern of T cell expansion was observed in three additional responding patients, including one with non-leukemic MCL (Pt 25) who achieved a CR with subsequent progression of disease at cycle 25. This patient had a 2-fold increase in the absolute number of circulating CD3+ T cells with a baseline count of 442 ± 168 during cycles 1 to 2 compared to 915 ± 104 between cycles 4 and 23, prior to a substantial decrease to 452 during cycle 24 and further to 114 during cycle 25. There was no evidence of clonal T cell expansion in the peripheral blood samples from cycles 4, 20, and 24. Whether this is related to a lack of circulating tumor cells remains to be determined. Interestingly, scRNA-seq analysis revealed a remarkable increase in PDCD1 (encoding PD-1) expression upon disease progression (abstract by Di Liberto et al.). Our findings offer potential new insights into the tumor-immune interaction associated with a durable treatment responses and drug resistance in targeting CDK4/6 and BTK in MCL. In preclinical models, CDK4/6 inhibition has been linked to changes in the tumor microenvironment to enhance the immune response, and here we present the first longitudinal data obtained from patients within the context of a clinical trial. Expansion of the cohort from the ongoing phase II trial, cytokine profiling, and functional assays are underway to further characterize the oligoclonal CD8+ T cell and other immune populations as well as to explore the potential therapeutic role of combinations with immune checkpoint blockade in lymphoma. Figure 1. Differential T-cell responses in relapsed/refractory MCL patients on palbociclib and ibrutinib combination therapy, including a leukemic MCL patient with a CR (Pt 17) and a non-leukemic MCL patient with a CR and subsequent progression of disease (Pt 25). A, Absolute B-cell and T-cell counts during various treatment cycles for Pt 17 (top) and Pt 25 (bottom). B, Cumulative productive frequency of the top 10 clonal TCR rearrangements in a given treatment cycle. C, Change in abundance of the top 10 TCR clones across a given treatment cycle. D, Differential abundance of productive TCR clones that have significantly increased or decreased in frequency between treatment cycles. Abbreviations: CR, complete response. MCL, mantle cell lymphoma. PD, progression of disease. Pt, patient. TCR, T-cell receptor. Figure 1 Disclosures Bartlett: Pharmacyclics: Research Funding; Pfizer: Research Funding; Millennium: Research Funding; Merck: Research Funding; Kite Pharma: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Genentech, Inc.: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding. Maddocks:Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Research Funding. Leonard:MorphoSys: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Merck: Consultancy; Miltenyi: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; Sandoz: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Celgene: Consultancy; Merck: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; Karyopharm Therapeutics: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Gilead: Consultancy. Galluzzi:Luke Heller TECPR2 Foundation: Consultancy; Astra Zeneca: Consultancy; Inzen: Consultancy; OmniSEQ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:I-MAB: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy; Sandoz: Consultancy. OffLabel Disclosure: Palbociclib, a CDK4/6 inhibitor, was used off-label in combination with ibrutinib in a phase I clinical trial in patients with relapsed/refractory mantle cell lymphoma.

Download Full-text

Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽

10.1182/blood-2019-124192 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5263-5263

Author(s):

Karin Hohloch ◽

Christine Windemuth-Kieselbach ◽

Pier Luigi Zinzani ◽

Roberto E. Cacchione ◽

Wojciech Jurczak ◽

...

Keyword(s):

Follicular Lymphoma ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Therapy ◽

First Line ◽

Advisory Committees ◽

Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

Download Full-text

Alternating Courses of 3x CHOP and 3x DHAP Plus Rituximab Followed by a High Dose ARA-C Containing Myeloablative Regimen and Autologous Stem Cell Transplantation (ASCT) Is Superior to 6 Courses CHOP Plus Rituximab Followed by Myeloablative Radiochemotherapy and ASCT In Mantle Cell Lymphoma: Results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network (MCL net)

Blood ◽

10.1182/blood.v116.21.110.110 ◽

2010 ◽

Vol 116 (21) ◽

pp. 110-110 ◽

Cited By ~ 20

Author(s):

Olivier Hermine ◽

Eva Hoster ◽

Jan Walewski ◽

Vincent Ribrag ◽

Nicole Brousse ◽

...

Keyword(s):

Treatment Failure ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

High Dose ◽

Advisory Committees ◽

Overall Response ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 110 Background: Mantle Cell Lymphoma (MCL) has been characterized by poor long term prognosis with a median survival of only 3 to 4 years. However, outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggested that the addition of rituximab to CHOP like chemotherapy and/or high dose ARA-C may significantly improve remission rates and PFS. A French phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an overall response rate of 95% with a CR rate of 61% translating into a median EFS of 83 months and a 75% survival rate at 5 years (Delarue et al ASH 2008). Methods: To evaluate the potential superiority of a high dose ARA-C containing regimen, the MCL net initiated a randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B). Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point time to treatment failure (TTF) was monitored continuously by a sequential procedure based on a one sided triangular test. Stable disease after induction, progression or death from any causes, were considered as treatment failure. Sample size was calculated to detect a hazard ratio of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results: From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 391 patients evaluable for the primary analysis (19 no MCL, 87 not yet documented) displayed similar characteristics in both treatment arms: median age 55 vs 56 years, male 78% vs 79%, stage IV 85% vs 79%, B symptoms 43% vs 33%, ECOG >2 5% vs 5%, elevated LDH 37% vs 38%, and MIPI low/int/high risk 61%/25%/14% vs 62%/23%/15%, respectively. After induction overall response was similarly high in both arms (A: 90% vs B: 94%; p=0.19) and CR rate and combined CR/CRu rate were significantly higher in arm B (26% vs 39%; p=0.012 and 41% vs 60%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%) and after transplantation overall response and CR rates were comparable in both arms (97% vs 97% and 63% vs 65%, respectively). After a median follow up of 27 months, patients in arm B experienced a significantly longer TTF (49 months vs NR; p=0.0384, hazard ratio 0.68) mainly due to a lower number of relapses after CR/CRu/PR (20% vs 10%), whereas the rate of ASCT-related deaths in remission was similar in both arms (3% vs 4%). Although CR rate after ASCT was comparable in both arms, remission duration (RD) after ASCT was superior in Arm B (48m vs NR; p=0.047). Interestingly, for patients in CR after ASCT, RD after ASCT was also presumably superior in arm B (51 months vs NR; p=0.077). At the time of analysis overall survival was similar in both arms with medians not reached and 79% vs. 80% survival rates at 3 years (p=0.74). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 8% vs 28%, WBC 48% vs 75%, platelets 9% vs 74%, respectively), an excess of renal toxicity (creatinine grade 1/2: 8% vs 38%, grade 3/4: none vs 2%), and more frequent grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar, except for higher grade 3/4 mucositis (43% vs. 61%) in Arm B, and higher grade 1/2 liver toxicity and constipation in Arm A. Conclusions: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years. Disclosures: Walewski: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Feugier:roche: Consultancy, Honoraria. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Gisselbrecht:Roche: Research Funding.

Download Full-text

Pharmacogenomics Drives Lenalidomide Efficacy and MRD Kinetics in Mantle Cell Lymphoma after Autologous Transplantation: Results from the MCL0208 Multicenter, Phase III, Randomized Clinical Trial from the Fondazione Italiana Linfomi (FIL)

Blood ◽

10.1182/blood-2020-134875 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 16-17

Author(s):

Simone Ferrero ◽

Daniele Grimaldi ◽

Elena Arrigoni ◽

Gian Maria Zaccaria ◽

Beatrice Alessandria ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Treatment Efficacy ◽

Research Funding ◽

Cell Lymphoma ◽

Autologous Transplantation ◽

Phase Iii ◽

Strong Linkage Disequilibrium ◽

Advisory Committees ◽

Mantle Cell

Background and Aims. Prediction of treatment efficacy is an active and growing field of pharmacology. In the Fondazione Italiana Linfomi (FIL) MCL0208 phase III trial (NCT02354313), a 24 months lenalidomide maintenance (LM, 15 mg days 1-21 every 28 days) after high-dose immuno-chemotherapy followed by autologous transplantation (ASCT) in 300 frontline mantle cell lymphoma (MCL) patients showed substantial clinical activity in terms of Progression-Free Survival (PFS) vs observation (OBS). However, this benefit seemed not uniform across patient series. To deeper investigate the differential pattern of response to lenalidomide, a wide analysis of the host pharmacogenomics (PG) background was planned, in order to dissect whether specific germline polymorphisms of transmembrane transporters, metabolic enzymes or cell surface receptors (ABCB1, ABCG2, VEGFA, FCGR2A, NCF4, GSTP1, CRBN) might predict the drug efficacy. Actually, several single nucleotide polymorphisms (SNPs) of ABCB1 exert an effect on substrate affinity of lenalidomide for the transmembrane transporter. Moreover, VEGFA is involved in the anti-angiogenic activity of lenalidomide and might eventually upregulate ABCB1 expression, too. Patients and methods. Genotypes for SNPs were obtained through allele-specific (ASO) probes on germline DNA from peripheral blood. Minor allele frequencies (MAFs) were obtained and the Hardy-Weinberg equilibrium (HWE) was checked. Genotypes were used to infer individual haplotypes by Arlequin and Haploview softwares. Minimal residual disease (MRD) was assessed with ASO primers on either IGH or BCL-1/IGH rearrangements by RQ-PCR in bone marrow samples. TP53 disruption was identified by NGS targeting resequencing and copy number variation analysis. Clinical-biological correlations were screened by automated machine learning methods and validated by both Kaplan-Meier at univariate level and Cox models for multivariate analysis (MV). A logistic regression was implemented to investigate correlations between polymorphisms and MRD kinetics. Results. 278 out of 300 patients (93%) were fully genotyped. The MAF values of the SNPs were very similar to published data and the HWE was confirmed. Most notably, ABCB1 c.2677G>T/A(W) and VEGFA c.2055A>C were significantly associated to outcome and are thus described in this abstract. In the case of ABCB1, the three loci were in strong linkage disequilibrium (p<0.001). 31% of patients were homozygous for ABCB1 wild type alleles (GG, "WT"), 53% heterozygous (GW, "HET") and 16% polymorphic on both chromosomes (WW, "POL"). 20% were VEGFA WT (AA), 47% HET (AC) and 33% POL (CC). PG did not impact on induction therapy and randomization rates of this trial, as superimposable polymorphism frequencies were described between the enrolled and randomized population. Conversely, both ABCB1 HET and POL and VEGFA HET/POL associated with higher MRD clearance rates vs WT after 6 months of LM (93% vs 71% and 91% vs 67%, respectively). Interestingly, the risk of MRD reappearance during LM was 86% lower for patients harboring either polymorphism vs WT (odds ratio 0.14, 95% CI 0.02-0.99; p<0.05). Actually, ABCB1 HET/POL predicted for a more favorable PFS vs WT in LM (3yPFS 85% vs 69% p<0.05, Fig.1A), as well as VEGFA HET/POL (3yPFS 85% vs 59% p<0.01, Fig.1B). The two polymorphisms co-occurred in 57% of patients, being 12% ABCB1 HET/POL only, 23% VEGFA HET/POL and 8% ABCB1/VEGFA WT. Interestingly, patients with either polymorphism had superimposable outcome to patients in whom both co-occurred (Fig.1C). Finally, MV showed that either polymorphism was protective for PFS among randomized patients (HR=0.42; 95% CI 0.20-0.85; p<0.05). According to this hypothesis, among the 17 ABCB1/VEGFA WT patients LM did not improved PFS vs OBS (Fig.1D), independently from TP53 disruption. Conclusions. The first PG data on LM after ASCT in MCL suggested that: 1) ABCB1 and VEGFA polymorphisms did not impact on the chemotherapeutic efficacy of FIL-MCL0208 trial; 2) both polymorphisms favored sustained MRD clearance during LM; 3) either polymorphism conferred a survival advantage during LM. Taken together, these observations hint that a variable excretion of lenalidomide through ABCB1 (heralded by SNPs), as well as an altered VEGFA pathway, could predict treatment efficacy. This observation might be very useful in the future to tailor lenalidomide therapy to MCL patients. Disclosures Ferrero: Servier: Speakers Bureau; Gilead: Research Funding, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boccomini:SC Ematologia, ASOU Città della Salute e della Scienza di Torino, Turin, Italy: Current Employment. Maria:Roche: Consultancy, Other: travel, accomodations, expenses; Abbvie: Consultancy, Other: travel, accomodations, expenses; BMS: Consultancy; MSD: Consultancy; Janssen: Consultancy, Other: travel, accomodations, expenses; Gilead: Consultancy, Other: travel, accomodations, expenses, Research Funding. Ferreri:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Hutchinson: Research Funding; BMS: Research Funding. Palumbo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. OffLabel Disclosure: Lenalidomide maintenance in mantle cell lymphoma

Download Full-text

Clinical, Metabolic and Molecular Responses After 4 Courses of R-DHAP and After Autologous Stem Cell Transplantation for Untreated Mantle Cell Lymphoma Patients Included in the LyMa Trial, a Lysa Study

Blood ◽

10.1182/blood.v120.21.152.152 ◽

2012 ◽

Vol 120 (21) ◽

pp. 152-152 ◽

Cited By ~ 8

Author(s):

Steven Le Gouill ◽

Mary Callanan ◽

Elizabeth Macintyre ◽

marie-Hélène delfau-Larue ◽

Caroline bodet-Milin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Response Rates ◽

High Dose ◽

Molecular Response ◽

Advisory Committees ◽

Mantle Cell

Abstract Abstract 152 Mantle cell lymphoma (MCL) is a rare B-cell malignancy characterized by the t(11;14) translocation. The European MCL network has demonstrated that a sequential R-CHOP/R-DHAP chemotherapy regimen prior to autologous stem cell transplantation (ASCT) provides better disease control than R-CHOP (Hermine et al, ASH 2010, abstract 110) and that molecular minimal residual disease (MRD) measured by IGH real-time quantitative polymerase chain reaction (PCR) before and after ASCT is an important prognostic factor to predict progression-free survival (PFS) (Pott et al. Blood. 2010;115(16):3215–23). Indeed, the use of high-dose aracytine upfront before ASCT is now recommended and molecular remission appears to be a major objective for future clinical trials in MCL. It therefore appeared interesting to appreciate response rates combining standard evaluation (Cheson 1999), FDG-PET imaging (Cheson 2007) and PCR techniques after rituximab plus upfront high-dose aracytine (R-DHAP) followed by ASCT. Response rates after 4 courses of R-DHAP were one of the objectives of the LyMa trial (NCT00921414). This trial is a randomized, open-label, phase III study that evaluates the efficacy of rituximab maintenance therapy in MCL patients aged between 18 and 66 years old, undergoing first-line treatment with 4xR-DHAP and exhibiting a response after ASCT (R-BEAM). Patients who do not reach a sufficient partial remission after R-DHAP are planned to receive 4 additional courses of R-CHOP before ASCT. The LyMa trial started in September 2008 and was designed to enroll 299 patients over a 4 years period. To date (August 2012), 295 patients have been included. Herein, we report response rates according to the combination of Cheson 1999 and 2007 criteria plus molecular response rates after 4xR-DHAP and after ASCT for the first 200 enrolled patients (last inclusion in August 2011). Results: One patient withdrew consent and the analysis is therefore on 199 patients. The cohort's median age is 57.2 years (range 29.7–65.7) and 41 patients are female (20%). At diagnosis, simplified MIPI was low in 104 cases (52%), intermediate in 55 (28%) and high in 40 (20%).Twenty-five patients (12.5%) presented with a blastoid variant. The panel of pathologist experts confirmed the diagnosis in all reviewed cases. Among the 199 evaluable patients, 182 (91%) received 4 courses of R-DHAP and 12 patients (all in PR according to Cheson 99 criteria) received 4 additional courses of R-CHOP because of insufficient clinical response after R-DHAP. Among these 12 patients, 5 reached CR/CRu after R-CHOP. Ultimately, 164 patients (82%) proceeded to ASCT (158 after R-DHAP and 6 after RDHAP/R-CHOP) and 154 (77.4%) have been randomized between rituximab maintenance or no maintenance. In an intention-to-treat (ITT) analysis and according to Cheson 1999 criteria, 152 patients (76.3%) reached CR (n=74) or CRu (n=78) after 4 courses of R-DHAP while 25 patients reached PR and 8 presented with SD/Prog. According to Cheson 2007 criteria (n= 170; PET not done in 17 cases and data missing in 12 cases), 129 patients reached CR while 41 patients remained FDG-TEP positive. Response rates according to Cheson 1999 and 2007 criteria for transplanted patients (n=164) were CR (n=109)/CRu (n=45) in 94% and CR in 84.5% (129 patients underwent FDG-PET after ASCT), respectively. Regarding MRD, diagnosis samples were available for 186/199 patients. Forty-one diagnosis samples have not yet been analyzed and 14 proved to be not informative. To date, the molecular response on peripheral blood (PB) after 4 courses of R-DHAP has been assessed in 103 cases and found negative in 80 cases and positive in 22 cases (not evaluable in one case). MRD on bone marrow (BM) after 4 courses of R-DHAP has been measured in 97 cases and found negative in 59 and positive in 36 (not evaluable in one case). After ASCT, PB and BM MRD were found negative in 91 patients (95 samples have been analyzed to date) and 67 (87 samples analyzed), respectively. Thus, in the LyMa trial,CR/CRu rates after only 4 courses of RDHAP, according to Cheson 1999 and 2007 criteria, are very high confirming the major anti-tumoral impact of high-dose aracytine upfront in MCL. In addition, these encouraging results seem to be confirmed at the molecular level strengthening the interest of an MRD-guided management of MCL patients. Results will be updated at the time of the meeting and patients' outcome according to disease status will be presented. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Temsirolimus in Combination with Bendamustine and Rituximab for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Report on An Ongoing Phase I/II Trial

Blood ◽

10.1182/blood.v118.21.2697.2697 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2697-2697 ◽

Cited By ~ 5

Author(s):

Georg Hess ◽

Ulrich Keller ◽

Johannes Atta ◽

Christian Buske ◽

Peter Borchmann ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Response Rates ◽

Advisory Committees ◽

Mantle Cell ◽

Grade 3 ◽

Entire Treatment ◽

Ongoing Phase

Abstract Abstract 2697 Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. Based on a phase III trial in relapsed MCL which proved superiority of temsirolimus to standard options, the drug is approved for this indication in the EU. Additionally, promising response rates could be observed in patients with follicular and diffuse large B-cell lymphoma (Smith et al, JCO 2010). Whereas combination to single agent rituximab seems feasible and with improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information on the feasibility and efficacy in combination with chemotherapy. Bendamustine has been shown to be effective in indolent lymphoma and has a beneficial side effect profile (Rummel et al, JCO, 2005). To evaluate the potential of the combination of temsirolimus with bendamustine and rituximab an ongoing phase I/II trial was initiated. Methods: This is a multicenter, national, prospective trial, approved by the centralized EC. Patients were eligible if they had histologically proven follicular (FL) or mantle cell lymphoma (MCL), the latter with Cyclin D1 positivity or detectable t(11;14), 1–3 prior treatment lines, no curative option available, no refractoriness to bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of bendamustine 90mg/m2 day 1–2, rituximab 375mg/m2 day 1 and temsirolimus day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. In the ongoing phase I part (3+3 design) the following dose cohorts for temsirolimus were planed: A 25mg, B 50mg, C 75mg. Currently cohort C is ongoing. Toxicity was evaluated throughout the treatment and analysis for DLT was performed after 2 cycles. An independent data safety monitoring board decided on the escalation to the next dose level. Results: Overall 9 patients have been included until now (6 pts cohort A, 3 patients cohort B) and 4 patients are in the prescreening period (cohort C). Median age 64; Histology: 8MCL/1FL; sex 2F/7M, median number of pretreatments 2 (1–3). Adverse events: overall the treatment was well tolerated. Toxicity was predominant hematologic with mostly leukopenia and thrombocytopenia. In 29 evaluable cycles of chemotherapy the following grade 3/4 toxicities were noted: Thrombocytopenia in 3 (all grade 3); leukopenia in 11 (9 grade 3; 2 grade 4), and increase in triglycerides, hyperglycemia and hypertension in one patient each (all grade 3). Importantly, one case of pneumonitis occurred, which resolved after steroid treatment and study treatment could be resumed w/o further problems. In addition, one reaction to contrast agent, an allergic reaction to berries and a transient parasthesia during the study phase were noted, leading to hospitalization. All of these events occurred several days after the last application of study drug and were considered not to be associated to the study treatment. As the episode of hypertension led to hospital admission, it was considered to be potentially a DLT, and cohort A was escalated to 6 patients w/o further DLT. In cohort B no DLT were observed in 3 patients and cohort C has been opened for inclusion. 5 patients have completed the entire treatment, in one patient treatment was stopped after cycle 3 due to delayed recovery of platelets, and treatment is ongoing in 3 patients. At interim staging all 9 patients evaluable achieved a partial remission (ORR 100%). After completion of the entire treatment ORR was 100% with 1 CR and 5 PR in 6 evaluable patients. Summary: In this ongoing phase I/II trial the combination of temsirolimus with bendamustine and Rituximab was feasible applying 3 weekly doses of up to 50mg temsirolimus in a 4 week cycle. Until now promising response rates have been noticed. Cohort C is currently recruiting patients (Temsirolimus 75mg), updated results of the phase I part of the trial will be presented at the meeting. If no dose limiting toxicities are observed, the extended phase II part of the trial will be initiated with patients stratified according to lymphoma subtype (30 patients each with FL and MCL). Disclosures: Hess: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Keller:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Dreyling:Pfizer: Research Funding, Speakers Bureau, scientific advisory.

Download Full-text

Patterns of Treatment for Newly Diagnosed and Relapsed/Refractory Peripheral T-Cell Lymphoma in the Community Setting

Blood ◽

10.1182/blood.v126.23.3952.3952 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3952-3952

Author(s):

Tatyana Feldman ◽

Michael McGuire ◽

Claudio Faria ◽

Andre Goy ◽

Charles M. Farber ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Retrospective Review ◽

Research Funding ◽

Cell Lymphoma ◽

Response Rates ◽

Initial Therapy ◽

T Cell Lymphoma ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Background: Peripheral T-Cell lymphomas (PTCL) are an uncommon, heterogeneous group of disorders that are difficult to treat due a lack of a consensus standard of care algorithms. Conventional B-cell lymphoma chemotherapy regimens have been adapted for use in PTCL but have shown low response rates, short durations of response and generally poor outcomes. Mature T/NK cell lymphoma-specific therapies are now available, however their sequencing into treatment algorithms is not defined. The objective of this study was to determine which regimens are currently being used and the associated outcomes for PTCL patients (pts) in community settings. Patients & methods: A retrospective review was performed of newly diagnosed and relapsed/refractory pts with PTCL, including anaplastic large cell lymphoma (ALCL), PTCL not otherwise specified (NOS), and angioimmunoblastic T-cell lymphoma (AITL) treated by Regional Cancer Care Associates between January 1, 2010 and April 30, 2015. Pts were identified using the COTA software platform, which extracts data from electronic health records and permits real-time observational database analysis. Results: 93 pts with ALCL (n=30), PTCL-NOS (n=44), or AITL (n=19) treated by 30 physicians throughout New Jersey were identified. Median age at diagnosis was 61 (range: 19-91), with ALCL pts younger than other subtypes (53 years, 65 years, 62 years, respectively). Pts were predominantly male (63%). 55 pts (81% of assessed pts) had an Ann Arbor stage of III/IV and 34 pts (41% of assessed pts) had an international prognostic index (IPI) score >3. ALK positivity was identified in 40% of assessed ALCL pts. Median time to the 1st oncology visit from pathologic diagnosis was 29 days; time to treatment initiation was 15 days later. The analysis demonstrated significant variation in the treatment of newly diagnosed pts. As initial 1st line therapy, there were 13 different regimens used among 21 pts with ALCL, 18 different regimens among 29 pts with PTCL-NOS, and 7 regimens used in the 16 pts with AITL. CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) was the most frequently prescribed 1st line chemotherapy regimen, used by 37 pts (56%) and an additional 12 pts (18%) were prescribed a CHOP-like regimen. The complete response rates and duration of response for first line CHOP plus CHOP-like regimens (excluding pts consolidated by transplant n=38) was 39% / 33.7 months for all PTCL subtypes (75% CR/37.8 months for ALCL, 24% CR/26.5 months for PTCL-NOS, and 22%CR/36.9 months for AITL). The 4-year PFS and OS for these 1st line CHOP/CHOP-like pts was 50% and 50% respectively. Transplants were performed as part of initial therapy in 12 pts (2 allo; 10 auto) with a 4-year PFS 57% and 4-year OS 55% (p=0.29 and p=0.63; log-rank, compared to CHOP without BMT). Relapsed/refractory PTCL show similar variability in treatment regimens. There were 7 different salvage regimens for the 7 ALCL pts, 15 different regimens for the 15 PTCL-NOS pts, and 5 different regimens for the 5 AITL pts. Across all patient types there were 29 unique regimens used to treat relapsed/refractory PTCL pts. Romidepsin monotherapy (n=6) and brentuximab monotherapy (n=6) were the most common regimens. Salvage transplants were performed in 6 pts (3 allo & 3 auto). From date of diagnosis ALCL (ALK positive) pts had a 4-year PFS 68% and an OS at 4-years 100%. ALCL (ALK negative) pts had a 4-year PFS of 73% and an OS 80%. PTCL-NOS pts had a 4-year PFS of 32% and OS 42% (median PFS 13 months and a median OS 30 months). AITL pts had a 4-year PFS 48% and OS 42% (median PFS 12 months and a median OS 25 months). Conclusion: This retrospective review demonstrated significant variability in the regimens used to treat PTCL pts outside of protocol settings. Although CHOP / CHOP-like therapy was the most common initial therapy (used in 74% of pts) with transplant up-front consolidation in 12 pts (26%), there appears to be no consensus on the optimal management approach for the PTCL subtypes and in each line of therapy. No benefit was noted in our series for upfront transplant. The survival outcomes in this community based cohort are comparable with recent multi-center institutional studies (COMPLETE and Abramson et al) and demonstrate improving survival for AITL pts versus historical control. There is a need to assess the comparative effectiveness of available treatment options in these diseases to better inform future treatment decisions. Disclosures Feldman: Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. McGuire:Celgene: Employment. Faria:Celgene: Employment. Goy:Pharmacyclics/JNJ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Membership on an entity's Board of Directors or advisory committees. Farber:Jansen Pharmacyclics: Honoraria, Speakers Bureau; Gilead Sciences: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Choi:COTA: Employment. Connors:COTA: Employment. Paramanathan:COTA: Employment. Schultz:COTA: Employment. Goldberg:Ariad: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Novartis: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Pfizer: Research Funding.

Download Full-text

End of Phase 1 Results from Zuma-6: Axicabtagene Ciloleucel (Axi-Cel) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-111523 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4192-4192 ◽

Cited By ~ 16

Author(s):

Caron A. Jacobson ◽

Frederick L. Locke ◽

David B. Miklos ◽

Alex F. Herrera ◽

Jason R. Westin ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Car T Cell ◽

Large B Cell Lymphoma ◽

Car T ◽

Grade 3

Abstract Background: Axi-cel is a US FDA-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for treatment of adult patients (pts) with relapsed or refractory large B cell lymphoma after ≥ 2 prior lines of therapy. In ZUMA-1, the pivotal study of pts with refractory large B cell lymphoma, the objective response rate (ORR) was 82%, including a 58% complete response (CR) rate (Neepalu and Locke, et al. N Engl J Med. 2017). Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events were observed in 12% and 31% of pts, respectively, and were generally reversible. Checkpoint proteins, such as PD-1 and PD-L1, have been shown to be expressed on both CAR T cells and in the tumor microenvironment and subsequently upregulated after CAR T cell infusion (Vranic, et al. PLoS One. 2017; Cherkassky, et al. J Clin Invest. 2016; Galon, et al. ASCO 2017. #3025). This suggests that axi-cel activity could be augmented by incorporating PD-L1 blockade. This end of Phase 1 analysis of ZUMA-6 examines the safety and preliminary efficacy of axi-cel in combination with the anti-PD-L1 antibody atezolizumab (atezo) in pts with refractory diffuse large B cell lymphoma (DLBCL; NCT02926833). Methods: Eligible pts (≥ 18 years) with refractory DLBCL, defined as stable or progressive disease to last line of therapy or relapse within 12 months after autologous stem cell transplant, must have recieved prior CD20-targeting and anthracycline-containing regimen and had ECOG ≤ 1 and adequate bone marrow and organ function. Pts received low-dose conditioning with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day × 3 days followed by axi-cel infusion at a target dose of 2 × 106 cells/kg. Atezo was administered at 1200 mg every 21 days for 4 doses starting on Day 21, 14, and 1 post-axi-cel infusion for Cohorts 1, 2, and 3, respectively. This report describes Phase 1 results from all 3 cohorts. Incidence of dose-limiting toxicities (DLTs) was the primary endpoint. Secondary endpoints included the frequency of adverse events (AEs), disease response, pharmacokinetics, and biomarkers. Results: As of January 19, 2018, 12 pts have received axi-cel and at least 1 dose of atezo (3 in Cohort 1; 3 in Cohort 2, 6 in Cohort 3). Median age was 55 years (range, 30 - 66). Most pts (9/12, 75%) had received ≥ 3 prior therapies, and 4 pts (33%) had an International Prognostic Index score of 3 or 4. The median follow-up from axi-cel infusion was 4.4 months (range, 0.8 - 12.6), with 50% of pts having ≥ 6 months of follow-up. Eight pts (67%) have received all 4 doses of atezo, and 11/12 pts have received all scheduled doses of atezo. One pt in Cohort 3 experienced a DLT of Grade 4 thrombocytopenia and neutropenia lasting longer than 30 days. All pts experienced at least 1 AE (92% Grade ≥ 3), with no apparent exacerbation or recurrence of axi-cel-related toxicity following atezo infusion. Only 1 Grade ≥ 3 AE was attributed solely to atezo. Overall, the most common grade ≥ 3 AEs were anemia (9/12, 75%), encephalopathy (5/12, 42%), and neutropenia (5/12, 42%). Grade ≥ 3 CRS and neurologic events occurred in 3 (25%) and 6 (50%) pts, respectively. The ORR in evaluable pts was 9/10 (90%), with 6 pts (60%) in CR and 3 (30%) in partial response (PR); 2/6 pts (33%) had converted to CR at month 6 and month 9 after initially achieving a PR. CAR T cell expansion as measured by area under the curve in the first 28 days (AUC0-28) was over 2-fold higher in ZUMA-6 than the median observed in pts with DLBCL in ZUMA-1 (ZUMA-6: median, 823 cells/µL × days, range, 99 - 2301; ZUMA-1: median, 357 cells/µL × days, range, 5 - 11,507; Figure). Median CAR T cell levels remained higher than ZUMA-1 beyond 28 days. However, initial peak CAR T cell levels were similar (ZUMA-6: median, 68 cells/µL, range, 9 - 274; ZUMA-1: median, 32 cells/µL, range, 1 - 1513). Interferon-γ (IFNγ) levels peaked within the first week after axi-cel infusion and reached a median of 730.5 pg/mL (range, 212 - 1876). The median peak IFNγ level in pts from ZUMA-6 was 1.5-fold higher than that from pts enrolled in Cohort 1 of ZUMA-1 (493.8 pg/mL, range, 32.4 - 1876). Conclusions: PD-L1 blockade with atezo following axi-cel infusion has a manageable safety profile, with a low incidence of DLTs and no clinically significant evidence of increased incidence of AEs. Encouraging efficacy results support the opening of Phase 2 of ZUMA-6 in which 22 pts will be treated according to the Cohort 3 schedule. Pharmacokinetic data suggest the potential for enhanced CAR T cell expansion. Figure. Figure. Disclosures Locke: Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Miklos:Kite - Gilead: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Janssen: Consultancy, Research Funding. Herrera:Merck, Inc.: Consultancy, Research Funding; Immune Design: Research Funding; Pharmacyclics: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Seattle Genetics: Research Funding; Gilead Sciences: Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Westin:Apotex: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Lee:Kite Pharma, Caladrius Biosciences: Employment; Kite Pharma, Caladrius Biosciences: Equity Ownership; Kite Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Rossi:KITE: Employment. Zheng:Kite Pharma: Employment. Avanzi:Kite Pharma: Employment. Roberts:KITE: Employment. Sun:Kite, a Gilead Company: Employment.

Download Full-text

Initial Report of a Multi-Institution Phase I/Ib Study of Ibrutinib with Venetoclax in Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.2958.2958 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2958-2958 ◽

Cited By ~ 4

Author(s):

Craig A. Portell ◽

Robert W Chen ◽

Nolan Wages ◽

Jonathon B. Cohen ◽

Michael J. Weber ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Complete Response ◽

Targeted Agents ◽

Advisory Committees ◽

Second Stage ◽

Optimal Dosing ◽

Mantle Cell

Abstract Introduction Mantle cell lymphoma (MCL) which relapses or becomes refractory to frontline chemotherapy can be a clinical challenge. There have been several targeted agents approved in relapsed MCL including bortezomib, lenalidomide and ibrutinib (IBR) with the best single-agent responses seen with IBR. IBR is an oral, Bruton tyrosine kinase (BTK) inhibitor which has an overall response rate (ORR) of 67% with a median duration of response of 17.5 months in relapsed MCL (Wang, Blood 2015). While these responses are impressive in this population, only 1/3 of patients will have a complete response and only 1/3 of responding patients will have a 24 month PFS. Thus, improvements are needed. Venetoclax (VEN) is an oral selective BCL2 inhibitor which is currently FDA approved in relapsed 17p-deleted chronic lymphocytic leukemia. We and others have shown synergistic cytotoxicity with VEN and IBR (Axelrod Leukemia 2014) which prompted us to explore the combination in a Phase I/Ib clinical trial (clinicaltrials.gov ID: NCT02419560). This study was supported by a grant from AbbVie Inc. Methods Given overlapping toxicities with VEN and IBR, namely neutropenia and GI toxicities, potential for drug-drug interactions given both are metabolized by CYP3A, and a wide range of therapeutic dosing for the two drugs, a dose finding study is appropriate. A continual-reassessment model was designed to test six dosing strategies (table 1). Subjects start treatment with single agent VEN at 100mg PO daily and increase to the allocated dose per table 1. After 1 week of VEN, subjects start the allocated dose of IBR. Subjects are monitored closely for tumor lysis syndrome (TLS) and hospitalized for TLS monitoring when starting IBR. Subjects are treated with the combination for 6 months and are encouraged to continue IBR after that time. The study enrolls in 2 stages. In the first stage, subjects are enrolled one at a time to sequential arms. Up to 2 subjects are allowed on each arm in a zone before enrollment in the zone is paused. Subsequent zones are enrolled once at least one subject in every arm of the zone does not have a DLT during the DLT window. The second stage begins when a subject has a DLT or all arms have enrolled at least 1 subject. In the second stage, subsequent subjects are allocated to an arm based on DLT's and ORR at 2 months occurring in prior patients on the study, thus the study aims to find the optimal dosing combination of IBR and VEN for both toxicity and response. Enrollment will continue until 10 subjects are allocated to an arm or 28 total subjects are enrolled. Eligible patients must have documented relapsed MCL after at least 1 line of chemotherapy. Subjects must not have bulky disease, no evidence of TLS, and must not have been previously treated with IBR. Results Enrollment began 10/2015 and at the time of submission, we have treated 8 subjects and have finished stage I of the study. Subjects were enrolled on arms A to E. Mean age is 63 years (range 49-81). 7 of the 8 subjects are male. 5 subjects were refractory to their prior treatment and 3 subjects have progressed after an autologous bone marrow transplant. Seven of the 8 subjects are evaluable for adverse events. 5 subjects have completed the 6-week DLT window. There have been 15 related adverse events reported with 14 of these being grade 1 or 2. No TLS has been reported. One DLT at arm E was identified (grade 4 neutropenia) which prompted us to move to stage II of the study. Three subjects (arm A, B, and C) are evaluable for response with all achieving at least a partial response. One subject on arm C, had a complete response at 4 months of the combination. Conclusion: Early results suggest tolerability for the combination of IBR and VEN in Relapsed MCL. There have been no signs of TLS, though subjects with high risk for TLS are excluded. One DLT (neutropenia) has been reported in Arm E and thus modeling will start to find the optimal combination using both toxicity and response. Responses have been seen across the various treatment arms. Continual re-assessment modeling is an adequate study design for combination studies with targeted agents to identify optimal dosing, accounting for both toxicity and response. Disclosures Portell: Infinity: Research Funding; Roche/Genentech: Research Funding; Acerta: Research Funding; AbbVie: Research Funding. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Cohen:Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kahl:Seattle Genetics: Consultancy; Celgene: Consultancy; Infinity: Consultancy; Gilead: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy. Williams:Jansen: Research Funding; Pharmacyclics: Research Funding.

Download Full-text

Mutations Affecting RNA Binding Proteins Are a Novel Feature of Mantle Cell Lymphoma

Blood ◽

10.1182/blood-2019-129136 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1478-1478

Author(s):

Krysta M Coyle ◽

Prasath Pararajalingam ◽

Sarah E Arthur ◽

Nicole Thomas ◽

Miguel Alcaide ◽

...

Keyword(s):

Alternative Splicing ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Board Of Directors ◽

Research Funding ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cell Lymphoma ◽

Advisory Committees ◽

Mantle Cell

Objectives Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. We sought to extend our understanding of the molecular etiology of this malignancy using an integrative genomic analysis of diagnostic biopsies. Methods We performed exome sequencing on 51 frozen MCL tumors and analyzed these alongside previously published exome cohorts. We sequenced tumour genomes and matched constitutional DNA from 34 frozen MCLs, along with matched constitutional DNA, to more broadly identify the pattern of non-coding mutations. Based on mutations identified in this discovery cohort, we re-sequenced 18 recurrently-mutated genes in 212 archival MCLs, each having clinical follow-up data. We also performed RNA-seq on 110 of these cases and analyzed these data for alternative splicing and differential expression, including the differential splicing of HNRNPH1 in the context of recurrent intronic mutations. We investigated the functional and phenotypic effect of mutations and deregulated HNRNPH1 protein through ectopic expression of full-length HNRNPH1 and a mini-gene containing the exons and introns affected by mutations. Using custom droplet digital PCR (ddPCR) assays, we validated alternative splicing patterns in HNRNPH1 itself and other targets identified through re-analysis of available CLIP-seq data. Results In addition to confirming the prognostic association of TP53 and NOTCH1 mutations in MCL, we identified two additional genes associated with outcome: EWSR1 with poor outcome (HR = 5.6) and MEF2B with good outcome (HR = 0.2). By comparing mutation patterns to diffuse large B-cell lymphoma (DLBCL), we identified an MCL-specific missense hot spot in MEF2B, non-specific truncating mutations in EWSR1, and truncating mutations affecting the DAZAP1 C-terminus in both MCL and DLBCL. The DAZAP1 mutations are predicted to alter protein sub-cellular localization and disrupt protein-protein interactions. We also identified the focal recurrence of non-coding mutations surrounding a single exon of the HNRNPH1 gene that were largely restricted to MCL. These mutations affected a region bound by HNRNPH1 protein and disrupted the preferred binding motif of this protein. Intronic mutations were significantly associated with alternative splicing of the HNRNPH1 mRNA and appear to disrupt a negative regulatory loop that normally limits the level of HNRNPH1. Using cell-based assays, we have evaluated the role of HNRNPH1 in cell survival and proliferation. Our interrogation of alternative splicing events in downstream targets implicate HNRNPH1 as a master splicing regulator which may broadly perturb the transcriptome and proteome to favor lymphomagenesis in MCL. Conclusions We discovered three novel MCL-related genes with roles in RNA trafficking or splicing, namely EWSR1, DAZAP1, and HNRNPH1. Mutations in these RNA-binding proteins were identified in 49 of 291 (17%) samples analyzed. Our results improve the current understanding of the MCL mutational landscape, highlight the similarities and differences between MCL and DLBCL, and strongly implicate a role for aberrant regulation of RNA metabolism in MCL pathobiology. We elucidated a functional role for recurrent non-coding HNRNPH1 mutations specific to MCL and identified multiple downstream targets. We continue to explore putative trans targets of HNRNPH1, a novel oncoprotein in MCL. Disclosures Steidl: Seattle Genetics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Bayer: Consultancy; Nanostring: Patents & Royalties: Filed patent on behalf of BC Cancer; Juno Therapeutics: Consultancy; Tioma: Research Funding. Connors:Bristol-Myers Squibb: Consultancy; Seattle Genetics: Honoraria, Research Funding; Takeda Pharmaceuticals: Honoraria. Villa:Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Johnson:Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding. Scott:Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Celgene: Consultancy; Roche/Genentech: Research Funding.

Download Full-text