Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Imatinib +/- Brentuximab Vedotin Induces Sustained Complete Remission in Chemotherapy-Resistant Anaplastic Large Cell Lymphoma Expressing PDGFR

Blood ◽

10.1182/blood-2019-129955 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4037-4037

Author(s):

Philipp Bernhard Staber ◽

Christoph Kornauth ◽

Ines Garces de los Fayos Alonso ◽

Wilhelm Woessmann ◽

Wolfram Klapper ◽

...

Keyword(s):

Stem Cell ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Large Cell Lymphoma ◽

Pdgfr Alpha

Background. Anaplastic lymphoma kinase positive systemic anaplastic large cell lymphoma (ALK+ ALCL) represents an aggressive T-cell malignancy that primarily affects children and younger adults. Upon treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens its prognosis is relatively favourable compared to other aggressive T-cell lymphomas, however, the rare event of disease reoccurrence remains particularly challenging. ALCL is CD30 positive, and mono treatment with brentuximab vedotin (BrV) can achieve long term remissions in only few relapsed patients not receiving consolidating stem cell transplantation (Pro B. et al. Blood 2017). A subset of ALCL patients express platelet derived growth factor receptor (PDGFR) alpha or beta in their tumour cells which is induced by ALK via AP-1 transcription factor activation. We previously demonstrated that PDGFR blockade by the Abl/c-Kit/PDGFR kinase inhibitor imatinib is an effective treatment concept for ALK+ ALCL in experimental mouse models (Laimer D. et al. Nature Med. 2012). Here we aimed to assess the prognostic value of PDGFR expression and to probe the clinical value of its targeting by imatinib in ALK+ ALCL patients. Methods. The impact of PDGFR expression to predict clinical outcome was analyzed in samples of 98 ALK+ ALCL patients included in the studies NHL-BFM 90, 95 and ALCL99 between 1992 and 2006. Six patients (age 18-45) with chemo-refractory ALK+ ALCL were prospectively treated with imatinib plus (4) or minus (2) BrV. 33% (2/6) had previously received salvage treatment with stem cell transplantation (SCT). Three of the patients had been enrolled in a prospective single-arm study combining imatinib and BrV, a trial that was terminated due to poor patient recruitment (AGMT ALCL1 trial, EudraCT No.: 2013-003505-26, supported by Takeda®). PDGFR alpha and beta expression analyses were performed on tumour samples of treated patients. Results. ALK+ ALCL patients with high PDGFR expression on tumor cells (n=11) had a significantly lower event-free survival rate (EFS) at 5 years compared to patients with no or low expression (n=87) (27±13% versus 70±5%, respectively, p<0.001, figure 1a). Four of the six patients with relapsed/ refractory ALK+ ALCL responded to imatinib +/- BrV with a rapid metabolic complete remission (CR). At a median clinical follow-up of 52 months (range 20 to108) all responding patients demonstrated an ongoing CR without SCT even after imatinib was discontinued with an average time on imatinib of 49 weeks (range 32 to 130; figure 1b). Half (2/4) of responding patients received no or only 1 infusion of BrV; both non-responding patients had received BrV. Importantly, despite the few patients that could be prospectively treated, PDGFR expression status had a significant impact on clinical course. All patients (4/4) who expressed either PDGFR alpha or beta in tumour cells and in the lymph node microenvironment responded with an ongoing metabolic CR, whereas the two patients whose lymphoma cells had negative PDGFR expression failed to respond (EFS: 4 versus 210 weeks, p = 0.018; figure 1c). Conclusions. 1) PDGFR expression is a poor risk factor in ALK+ ALCL. 2) Imatinib alone or in combination with BrV overcomes chemo-resistance conferred by PDGFR expression. 3) Imatinib treatment can be discontinued with ongoing CR. 4) These observations suggest that PDGFR expressing ALK+ ALCL patients might benefit from early treatment with imatinib. Disclosures Staber: Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Gilead: 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. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Mayerhoefer:Siemens: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Greil:Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ratiopharm: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; GSK: Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Boehringer Ingelheim: Honoraria; Mundipharma: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Imatinib - bcr-abl Inhibitor

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The Survival Outcome of the Patients with Relapsed/Refractory Anaplastic Large-Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2738.2738 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2738-2738 ◽

Cited By ~ 1

Author(s):

Dai Chihara ◽

Michelle A. Fanale ◽

Mansoor Noorani ◽

Jason R Westin ◽

Loretta Nastoupil ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Survival Outcome ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Large Cell Lymphoma

Abstract Purpose: We assessed the survival outcome of patients with anaplastic large cell lymphoma (ALCL) who experienced disease progression or relapse after first line and subsequent therapy. We sought to evaluate the impact of brentuximab vedotin (BV), and survival outcome of patients with ALCL who experienced progression after BV. Patients and Methods: A total of 176 patients (74 ALK+, 102 ALK-) initially diagnosed between 1999 and 2014 were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) after the progression/relapse following first-line chemotherapy (PFS1 and OS1), after first salvage therapy (PFS2 and OS2) and after second salvage therapy (PFS3 and OS3) were calculated. Outcome was separately analyzed according to the ALK status focusing on the use of BV. Results: The median age of the patients was 50 (range: 18-89). With a median follow up of 64 months, 111 patients (38 ALK+, 73 ALK-) experienced progression/relapse after the first-line therapy, of which 4 ALK- patients were post upfront stem cell transplant (SCT). Thirty and 15 patients eventually underwent autologous and allogeneic SCT after salvage chemotherapy, respectively. The median PFS1 and OS1 in patients with ALK+ALCL and ALK-ALCL were 8.4 and 28.5 months, and 13.1 and 47.7 months, respectively. In patients with ALK+ALCL, the median PFS1, PFS2 and PFS3 were 53.6, 5.2 and 2.3 months, respectively. The median OS1, OS2 and OS3 were not reached, 47.3 and 6.1 months, respectively. In patients with ALK-ALCL, the median PFS1, PFS2 and PFS3 were 12.9, 3.0 and 2.0 months, respectively. The median OS1, OS2 and OS3 were 54.3, 10.8 and 5.8 months, respectively. Interestingly, there were no significant difference in PFS2 between ALK+ALCL and ALK-ALCL. However, OS2 was significantly longer in patients with ALK+ALCL, suggesting possibly continued chemosensitivity of recurrent ALK+ALCL. A total of 30 patients received BV in 1st salvage (15 patients) and after 2nd salvage (15 patients).The use of BV at 1st salvage was associated with significantly longer PFS2 and OS2 both in patients with ALK-ALCL but not with ALK+ALCL likely due to small number of cases. Mutivariate analysis adjusting baseline PIT risk factors and the duration of the response to first line therapy revealed that use of BV (at any point in the salvage setting) is significantly associated with longer OS2 (HR: 0.43, 95%CI: 0.23-0.80). Overall, 12 patients experienced relapse/progression after BV treatment. The median OS after BV failure was 1.4 months (95%CI: 0.5-9.5 months) (Figure). Summary: Survival outcome for relapsed/refractory patients with ALK+ and ALK- patients is improved with BV. However, survival outcome after BV failure is very poor. A new treatment strategies to consolidate or maintain the response after BV and to develop more safe and better therapeutic options are needed. Figure 1. Figure 1. Disclosures Fanale: Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Research Funding; Infinity: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Research Funding; Genentech: Research Funding; Medimmune: Research Funding; Novartis: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Molecular Templates: Research Funding; ADC Therapeutics: Research Funding; Onyx: Research Funding; Gilead: Research Funding. Westin:Spectrum: Research Funding. Nastoupil:Celgene: Honoraria; Genentech: Honoraria; AbbVie: Research Funding; Janssen: Research Funding; TG Therapeutics: Research Funding. Wang:Celgene: Research Funding.

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Ibrutinib for Transformed Lymphoma; A Report of 4 Patients

Blood ◽

10.1182/blood.v126.23.5115.5115 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5115-5115

Author(s):

Amy Sharma ◽

Sadia Riaz ◽

Jonathan E. Kolitz ◽

Jacqueline C. Barrientos ◽

Steven L Allen

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large Cell ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Large Cell Lymphoma ◽

Large B Cell

Abstract Introduction Large cell lymphoma transformed from an indolent lymphoproliferative disorder typically carries a worse prognosis than de novo diffuse large B cell lymphoma. When transformation to large cell lymphoma occurs in CLL (Richter's syndrome), traditional anthracycline or platinum based therapy is associated with a median survival of <12 months. Better, more targeted therapies are needed. We describe 4 patients with transformation to large cell lymphoma who responded to ibrutinib. Cases: Patient A, age 68 at transformation, was a 64 year old male at diagnosis with CLL Rai stage 1. He was initially asymptomatic with a performance status of 0. 4 years later he developed dyspnea on exertion after one block and was found to have a left pleural effusion with diffuse lymphadenopathy with increased PET avidity. Biopsy of a supraclavicular node was positive for extracavitary primary effusion lymphoma, HHV8+, CD5-, CD10-. Patient was given R-CHOP x 6 cycles; he relapsed after 18 months and was given ibrutinib 560mg daily with monthly rituximab x 6 and achieved a PR with reversion to CLL. He is currently continuing ibrutinib in this remission for 10+ months. Patient B, age 90 at transformation, was a 68 year old female at diagnosis of CLL, Rai stage 0. She developed stage III CLL 18 years after diagnosis, was treated with BR x 6 cycles. 2 years later she developed Richter's transformation which was CD10+. Although she achieved a PR after 4 months of ibrutinib 560mg with monthly rituximab, her PS was 4 and she was transferred to hospice and expired 4.5 months after initiating ibrutinib/rituximab. Patient C, age 87 at relapse, was a 73 year old male at diagnosis when he originally presented with stage 1 DLBCL transformed from marginal zone lymphoma. He had 3 cycles of R-CHOP and RT to involved area and was disease free for 14 years until he had worsening thrombocytopenia. This was monitored for 3 years until age 87 when CT/PET showed increasing SUV in multiple lymph nodes and the spleen. Biopsy showed diffuse large B cell lymphoma, CD10-. He was started on ibrutinib 560mg with monthly rituximab x 6. He achieved a CR by CT/PET except for persistent splenic disease. He underwent splenectomy and continues in CR on ibrutinib at 9+ months. Patient D is an 83 year old female with large cell transformation from marginal zone lymphoma at diagnosis. She had stage IV disease with large cells involving pleural fluid and bone marrow. She was CD10-. She received R-CHOP x 3 with progressive disease. At that time ibrutinib 560mg alone was initiated. She has a CR based on recent CT/PET findings and is continuing ibrutinib at 18+ months. Conclusion: All of the above patients responded to ibrutinib given with or without rituximab with symptomatic and objective remissions; all of the CD10 negative cases are alive and still responding 9-18 months after initiating therapy. Studies examining the efficacy of ibrutinib in diffuse large B cell lymphoma are underway. This report supports the need for further study of ibrutinib in the transformed setting, particularly in the elderly where patients may not be appropriate for aggressive therapies. Disclosures Off Label Use: Ibrutinib was used to treat transformed large cell lymphoma.. Kolitz:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Barrientos:Gilead: Research Funding; NIH/NCATS: Research Funding; ASH-AMFDP: Research Funding. Allen:Millennium: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Equity Ownership; Onconova: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees.

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Long-Term Responders after Brentuximab Vedotin: Experience on 57 Patients with Relapsed and Refractory Hodgkin and Anaplastic Large Cell Lymphoma

Blood ◽

10.1182/blood.v126.23.2725.2725 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2725-2725 ◽

Cited By ~ 1

Author(s):

Pier Luigi Zinzani ◽

Letizia Gandolfi ◽

Beatrice Casadei ◽

Cinzia Pellegrini ◽

Alessandro Broccoli ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cell Lymphoma ◽

Large Cell ◽

Median Number ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Large Cell Lymphoma

Abstract Brentuximab vedotin (BV) is an antibody drug-conjugate targeting CD30 linked to monomethyl auristatin E. Several studies have shown the efficacy of BV in patients with refractory or relapsed Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). We reviewed our clinical database to evaluate the long-term efficacy of this treatment. From July 2009 to February 2015, 57 patients were treated with BV in our Institute: 43 with a diagnosis of HL and 14 with sALCL. Thirty-six were males and 21 were females, with a median age of 33 years (range 16-77). All of them had been heavily pretreated before BV with a median number of previous therapies of 3 (range 2-10). Thirty-nine had refractory disease and 18 were relapsed. Autologous stem cells transplantation had failed in 30 patients. BV was administered at a dosage of 1.8 mg/mq, every 21 days, for a maximum of 16 cycles. The median number of cycles was 8 (range 2-16); 13 patients completed the entire schedule. The best overall response rate was globally 57,8% (33 of 57 patients), including 25 (43.8%) complete responses (CR): 18 with HL and 7 with sALCL. At present, 20/25 (80%) patients are still in continuous CR (CCR) with a median follow up of 9 months (range 3-41): 10 of them have consolidated the response with a stem cell transplantation (SCT) (4 auto-SCT and 6 allo-SCT) and 10 patients have remained in CR without any other therapy after BV. Among these long-term responders without any consolidation (7 patients with HL and 3 with sALCL), the median follow-up is 12 months (range 3-37); in particular there are 3 patients in CCR after at least 24 months. The global overall survival rate at 68 months is 71% (no patients with sALCL dead) and the median overall survival has not been reached yet. The global progression-free survival rate at 48 months is 30%, the median is achieved at 11,7 months. Toxicity was primarily neurological with peripheral sensory symptoms (30%) and motor neuropathy (5%); the majority was grade 3 in severity (8 patients). This study confirms the safety and the high efficacy of BV that can be considered an effective treatment in patients with relapsed or refractory HL or sALCL. This drug can induce a durable complete response representing a "bridge" to auto-SCT or allo-SCT. However our data show a subset of patients that can be considered "long-term responders", who have remained in CCR without any consolidation after BV. Disclosures Zinzani: Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cavo:Janssen: Honoraria; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria.

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Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2020-136614 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Yuliya Linhares ◽

Mitul D Gandhi ◽

Michael Chung ◽

Jennifer Adeleye ◽

David Ungar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Advisory Board ◽

Publicly Traded ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Large B Cell

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

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Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study

Blood ◽

10.1182/blood-2018-99-116277 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2937-2937

Author(s):

Thomas E. Witzig ◽

Lubomir Sokol ◽

Eric D Jacobsen ◽

Won-Seog Kim ◽

Francine M. Foss ◽

...

Keyword(s):

Medical Education ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Advisory Board ◽

T Cell Lymphoma ◽

Advisory Committees ◽

Cxcl12 Expression ◽

Phase 2 Study

Abstract Background Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post-translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T-cell lymphoma (AITL) and CXCL12+ peripheral T-cell lymphoma (PTCL) patients (pts). Methods This Phase 2 study is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) cohort to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL, age >/=18 years and a performance status of 0-2. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1-21 of 28-day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in patients who received standard of care treatment. Results As of 25 July 2018, 34 PTCL pts (13 AITL, 1 ALK- ALCL, 20 PTCL-NOS) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 15 pts in the ongoing AITL histology and CXCL12 cohorts. Median number of prior treatment regimens was 3. The most common treatment-related adverse events (AE) (grade ≥ 3) are hematological, including neutropenia (50%), thrombocytopenia (43%), leukopenia (33%), febrile neutropenia (27%), and anemia (20%). Skin and subcutaneous tissue disorders were reported in 9 pts, 6 of them with AITL histology. One pt with AITL experienced an episode of possible Stevens Johnson Syndrome that resolved with dose discontinuation and did not recur upon re-challenge at one dose level reduction. Of 18 evaluable patients enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. Pre-treatment tumor tissue CXCL12 expression correlated with favorable pt outcomes. In the AITL cohort (10 evaluable pts), 1 PR and 1 SD have been observed so far, with 5 pts pending cycle 2 response evaluation. In the CXCL12+ cohort (n=3 evaluable pts), 1 SD has been observed, with 2 pts pending cycle 2 response evaluation. Plasma levels of CXCL12 decreased over time with tipifarnib treatment. Expression of CXCL12 mRNA and other biomarkers in pre-treatment biopsies of pts in the AITL and CXCL12+ cohorts are being evaluated using RT-PCR assays. In addition, the prognostic value of CXCL12 is being investigated in approximately 100 diagnostic specimens of PTCL pts who received standard therapy. Preliminary data suggest that CXCL12 overexpression is observed in approximately 25% of PTCL and negatively affects pt survival. Conclusion Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment continues. Disclosures Witzig: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sokol:Mallinckrodt Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Spectrum Pharmaceuticals: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Kim:Takeda: Research Funding; J&J: Research Funding; Mundipharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Celltrion: Research Funding. Foss:Miragen: Consultancy, Speakers Bureau; Spectrum: Consultancy; Seattle genetics: Consultancy; Mallinkrodt: Consultancy. Advani:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Janssen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Agensys: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Infinity: Research Funding. Marin Niebla:Amgen: Other: Medical education of Staff, Speakers Bureau; Roche: Consultancy, Other: Medical education of Staff, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Other: Medical education of Staff, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Medical education of Staff, Speakers Bureau. Piris:Kura: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Curry:Kura Oncology: Employment, Equity Ownership. Gualberto:Kura Oncology: Employment, Equity Ownership.

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Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-126242 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4082-4082

Author(s):

Beth A. Christian ◽

Ying Huang ◽

Sabarish Ayyappan ◽

Robert A Baiocchi ◽

Jonathan E Brammer ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Board ◽

Advisory Committees ◽

Oral Agents ◽

Grade 3 ◽

Aggressive B Cell Lymphoma

Introduction: Venetoclax, a BCL2 inhibitor, has demonstrated efficacy both as a single agent and in combination with rituximabin several subtypes of B-cell non-Hodgkin lymphoma (NHL). The combination of obinutuzumab and lenalidomide has demonstrated safety and preliminary efficacy in follicular lymphoma (Fowler et al., JCO 2015; 35: 7531). We conducted a phase I study of obinutuzumab, venetoclax, and lenalidomide to determine the safety, maximum tolerated dose, and preliminary efficacy of the combination. Methods: Patients with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell (HGBCL), marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous (ASCT) but not allogeneic stem cell transplant were permitted. Prior lenalidomide or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required. Treatment consisted of obinutuzumab 1000 mg on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6 with escalating doses of lenalidomide days 1-21 and venetoclax days 1-28 of a 28 day cycle (Table 1). A 3+3 dose escalation schema was followed. The DLT period was 1 cycle and patients had to receive 80% of the doses of the oral agents and all doses of obinutuzumab to be considered evaluable for DLT. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection; grade 3 infection that fails to resolve within 7 days; and grade 3 or 4 non-hematologic toxicity. Patients without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed by CT or PET/CT every 3 months for 12 months and then every 6 months until disease progression. Results: 22 patients were treated. Median age was 61 years (range 31-78 years) with 16 males. Median prior therapies was 2 (range 1-10) and included 5 patients who had relapsed after chimeric antigen receptor T-cell therapy and 2 patients relapsed after ASCT. Median baseline lactate dehydrogenase was 259.5 U/L (range 147-5133, ULN 190 U/L). 16 patients had aggressive B-cell lymphoma including DLBCL, HGBCL, primary mediastinal and transformed FL, 5 patients had FL and 1 patient had marginal zone lymphoma. At dose level (DL) 1, one patient experienced a DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. No further DLTs occurred at DL 2-4. DL 4 was expanded and was determined to be the MTD. Four patients, 1 in each dose level, were not evaluable for DLT and were replaced including 3 who did not receiving 80% of the oral agents due to required dose reductions and 1 patient for disease progression. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n=20, 90.9%), thrombocytopenia (n=5, 22.7%), and anemia (n=3, 13.6%). Grade 3-4 infections (n=6, 27%) included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. Other grade 3-4 AEs occurring once each included dysgeusia, dyspnea, nausea, vomiting, and hyperhidrosis. No clinically significant tumor lysis has occurred. Patients have received a median of 3 cycles (range 1-12) of treatment. Three patients remain on therapy and 5 patients are on follow up. Dose reductions of lenalidomide occurred for 17 patients (77%) and of venetoclax for 11 patients (50%). Nine patients have achieved a response (41%), including 8 complete (CR) and 1 partial responses (PR). Responses have occurred at each DL and include 4 patients with FL (2 CR, 2 PR), 4 patients with aggressive lymphoma (4 CR) and 1 patient with MZL (CR). 14 patients are off of the study, 9 with progression, 2 for alternative therapy, and 1 each for DLT, physician preference, and a diagnosis of MDS in a patient with 3 prior lines of chemotherapy. Conclusions: Combined treatment with obinutuzumab, venetoclax, and lenalidomide administered up to 12 cycles is feasible with activity in multiple subtypes of relapsed NHL. Enrollment in expansion cohorts of FL and aggressive B-cell lymphoma is ongoing. Disclosures Christian: Celgene: Research Funding; Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding. Baiocchi:Prelude: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy. Awan:Gilead: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Sunesis: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Obinutuzumab - off label use in relapsed aggressive B-cell lymphoma and indolent B-cell lymphoma Venetoclax - off label use in relapsed B-cell lymphoma

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Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update

Blood ◽

10.1182/blood.v118.21.443.443 ◽

2011 ◽

Vol 118 (21) ◽

pp. 443-443 ◽

Cited By ~ 9

Author(s):

Ranjana H. Advani ◽

Andrei R. Shustov ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership

Abstract Abstract 443 Background: Systemic anaplastic large cell lymphoma (sALCL) is a T-cell non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30. sALCL accounts for 2–5% of all cases of NHL; approximately 40–65% of patients experience recurrent disease after frontline treatment with few effective treatment options. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); updated results of this trial are presented. Methods: Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of efficacy was based on objective response assessments per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patients were enrolled between June 2009 and May 2010 at 22 clinical sites in the US, Canada, and Europe. Results: 58 patients with a median of 2 prior therapies (range 1–6) were treated; 57% were male and the median age was 52 years (range 14–76). Seventy-two percent of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission (CR) or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the objective response rate (ORR) was 86%, the CR rate was 57%, and 97% of patients had a reduction in tumor volume postbaseline. At the time of this updated analysis (data cut May 2011), all but 2 patients had discontinued treatment with brentuximab vedotin; the median number of treatment cycles was 7 (range 1–16). The median duration of objective response was 13.0 months (range 0.1–19.1+) and the median duration of response for patients achieving a CR was 17.1 months (range 0.7–19.1+). Median progression-free survival (PFS) was 14.6 months and median overall survival was not yet reached. Per investigator assessment, the median PFS with brentuximab vedotin was significantly longer than the median PFS achieved with the most recent prior therapy (20.0 months vs. 5.9 months; P value <0.001). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity, regardless of baseline disease characteristics, tumor burden, or prior treatment history. Responses were particularly noteworthy in patients who had never responded to any previous therapy (n=13); in this subgroup of patients, 10 achieved an objective response (77%) and 4 a CR (31%). After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The most common adverse events observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Most AEs in the study were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined in a Standardised MedDRA Query; no Grade 4 events were observed. In patients with neuropathy, 79% (26 of 33) have experienced resolution or some improvement and the median time to resolution or improvement was 13.3 weeks (range 0.3–48.7). Conclusions: Durable complete remissions were achieved with brentuximab vedotin, and treatment was associated with manageable toxicity, in patients with relapsed or refractory sALCL. Approximately half of the responding patients (24 of 50) continued in remission at the time of this analysis; updated results of efficacy and long term safety will be presented at the meeting. Based on the results from this study, a trial evaluating the safety of brentuximab vedotin administered in sequence and in combination with multiagent chemotherapy was initiated and is currently ongoing in frontline sALCL. Disclosures: Advani: Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Shustov:Millennium: Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Brice:Roche: Honoraria; Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Cephalon: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Blood ◽

10.1182/blood.v120.21.2745.2745 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2745-2745 ◽

Cited By ~ 3

Author(s):

Barbara Pro ◽

Ranjana H. Advani ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Frontline Treatment ◽

Long Term Follow Up ◽

Alk Positive

Abstract Abstract 2745 Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive malignancy that accounts for 2–5% of all non-Hodgkin lymphoma (NHL) cases. Approximately 40–65% of patients with sALCL develop recurrent disease after frontline treatment and few effective treatment options exist for this population. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin selectively induces apoptotic death of CD30-positive cells by binding, internalizing, and releasing MMAE. A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); long-term follow-up data from this ongoing trial are presented. Methods: Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 58 patients were enrolled at 22 clinical sites in the US, Canada, and Europe. The median age was 52 years (range 14–76) and 57% were male. 72% of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission [CR] or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the ORR was 86% (50 of 58 patients) and the CR rate was 59% (34 of 58 patients). At the time of this analysis (datacut April 2012), all patients had discontinued treatment and the median observation time from first dose was 22.8 months (range, 0.8–32.2). The median duration of objective response for all patients was 13.2 months (range, 0.1–27.7+) and the median duration of response for patients who obtained a CR has not yet been met (range, 0.7–27.7+). Of the patients who achieved a CR, over half (18 of 34; 53%) were in continued remission at the time of this analysis. The median progression-free survival (PFS) for all patients was 14.6 months and the median overall survival has not yet been reached. After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The median PFS has not yet been met for the group of patients who achieved a CR and received a subsequent SCT (range, 8.1–29+), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 months (range, 2.6–26+). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity regardless of baseline disease characteristics, tumor burden, or prior treatment history. Median PFS did not appear to be influenced by ALK status; in the subgroup of ALK-positive patients (n=16) PFS was 14.6 months versus 14.3 months for ALK-negative patients (n=42). The median overall survival has not yet been met for either ALK-positive or ALK-negative patients. The most common (reported in ≥20% of patients) adverse events (AEs) observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined by a Standardised MedDRA Query; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in peripheral neuropathy has occurred in 79% of patients with neuropathy events (26 of 33 patients) and the median time to resolution or improvement was 13.4 weeks (range, 0.3–48.7). Conclusions: 34 of 58 patients (59%) with relapsed or refractory sALCL obtained a durable CR with brentuximab vedotin and treatment was associated with manageable toxicity. PFS did not appear to be influenced by ALK status. These long-term follow-up results underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is planned to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas. Disclosures: Pro: Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Non-Bcl2 Mutations Are Predominant in Patients (pts) with Venetoclax Resistant Mantle Cell Lymphoma (MCL) - Response and Clinical Outcomes in Ultra-Refractory MCL

Blood ◽

10.1182/blood-2019-126175 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2815-2815 ◽

Cited By ~ 1

Author(s):

Preetesh Jain ◽

Shuangtao Zhao ◽

Rashmi Kanagal-Shamanna ◽

Lucy Navsaria ◽

Holly Hill ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Advisory Board ◽

Advisory Committees ◽

Ki 67 ◽

Mantle Cell ◽

Btk Inhibitors

Introduction: Mantle cell lymphoma (MCL) patients (pts) who progress after ibrutinib and other lines of treatment "ultra-refractory MCL" have poor outcomes and exhibit BTK mutations infrequently (Jain P et al BJH 2018, Martin P et al Blood 2016). Venetoclax has shown promising efficacy in Phase I trial in NHL (Davids M et al JCO 2017) and is now under trials in MCL. Venetoclax response in pts with MCL after progression on ibrutinib was reported (Eyre T et al Haematologica 2018), however, genomic alterations associated with venetoclax resistance are not described. We present our experience in 24 pts with MCL treated with venetoclax and report their mutation profiles associated with progression on venetoclax. Methods: We collected data from 24 pts with MCL who were treated with venetoclax (off clinical trial) as a salvage measure after failing multiple lines of prior therapies. Pt characteristics were collected from the time of initiating venetoclax. Progression free survival (PFS) was calculated from the time of initiating venetoclax to the date of progression or to last follow up date/date of death while overall survival (OS) was calculated from the time of initiating venetoclax to the date of last follow up date/date of death. Post venetoclax survival was calculated from the date of discontinuing venetoclax to the date of last follow up/death. Whole-exome sequencing (WES) with SureSelect Human All Exon V6 was performed from evaluable biopsy samples from 7 pts (5 pts at/before starting venetoclax and 6 pts after progression of venetoclax), this included 5 pts who have pairs available for analysis (pre and post venetoclax). Results: Twenty four pts were treated with venetoclax (12 started as single agent and 8 started with combination with obinutuzumab and 3 with BTK inhibitors with/without obinutuzumab). Four pts had initial single agent venetoclax and later were rechallenged with combinations. Initial dose of venetoclax was dose escalation from 20 mg, then 50 mg then 100 mg PO daily up to 400 mg daily in 18/24 pts while in 3 pts it was 100 mg daily and in another 3 it was 400 mg daily. Median age at venetoclax start was 69 years (58-82). Median number of prior lines of therapy was 5 (range 1-11; including 17 pts who progressed on ibrutinib or other BTK inhibitors, 5 had exposure to ibrutinib and discontinued for intolerance, 4 had prior SCT and 2 had prior anti CD19 cellular therapy). At the baseline (pre/at-venetoclax start), 13 pts (54%) had blastoid/pleomorphic histology and 11 (46%) had classic variant morphology, the median Ki-67% was 60% (5-90%) and pts with Ki-67% ≥ 50 were 11 (55%), 4 pts did not have available Ki-67% values. Overall response rate (ORR) was 65% (13/20) - complete remission 25% (5/20) and partial remission 40% (8/20). Stable disease was observed in 10% (2/10), primary refractory were 25% (5/20). Four pts were not evaluable for response assessment. The median follow up after starting venetoclax was 17.5 months (1-27). The median PFS was 7.7 months (2 year 20%) and the median OS was 13.5 months (2 year 30%) Figure-1A-B. Pts in CR had a PFS of 15 months vs no CR 10 months (p=0.29). At the last follow up, 11 pts remained on venetoclax therapy (4 alive and 7 dead). Overall, 15 pts progressed and 14 pts were alive. The median post venetoclax survival was 6 months. Among 20 pts who discontinued venetoclax, 1 achieved CR and 3 PR on subsequent therapies. Among the 20 pts who discontinued venetoclax, 6 discontinued due to intolerance. In addition, we evaluated the somatic mutation profile in pts who progressed on venetoclax using WES. Figure-1C shows mutation spectrum. In our cohort, pts with MCL who progressed on venetoclax exhibited infrequent Bcl2 mutations (one pt at progression; 14 %; p.H3D) while the mutation frequency of other genes such as TP53 (71% vs. 40%), ATM (43% vs. 20%), KMT2D (57% vs. 20%), CELSR3 (57% vs. 20%), and KMT2C (43% vs. 20%) increased by > 2-fold at progression (compared to pretreatment samples, p=N.S due to small cohort size). The mutation of CARD11 (14%) and SMARCA4 (14%) was only observed at progression. Further details on copy number abnormalities will be presented. Conclusions: Venetoclax has promising results in refractory pts with MCL. Combination clinical trials with obinutuzumab, acalabrutinib are ongoing in MCL. We have characterized mutations and aneuploidy abnormalities in venetoclax resistant MCL pts and shown that unlike CLL, Bcl2 mutations are infrequent in venetoclax resistant MCL. Disclosures Nastoupil: Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Curis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Fowler:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Aviara: Research Funding; Dava Oncology: Honoraria; Juno Therapeutics: Research Funding; Celgene: Honoraria, Research Funding; BioInvent: Consultancy, Research Funding; Guidepoint Global: Consultancy; Kite Pharma: Consultancy, Research Funding; Acerta Pharma: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Loxo Oncology: Research Funding; VelosBio: Research Funding.

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