Ixazomib in Previously Untreated Indolent B-Cell Non-Hodgkin Lymphoma

Abstract Background: Frontline treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) typically involves intravenously administered anti-CD20 monoclonal antibodies with or without cytotoxic chemotherapy. Effective and low-toxicity therapies with improved convenience of administration are sought. We hypothesized that ixazomib (Ix) could safely and conveniently induce remissions in patients with untreated iB-NHL. Here we present the first data on frontline use of Ix in untreated iB-NHL. Methods: This single-arm, open-label phase II "window" trial for patients with untreated iB-NHL (NCT02339922) opened to enrollment in May 2016. Eligibility included histopathologically confirmed iB-NHL, measurable disease, a clinical indication for treatment based on NCCN guidelines, and no prior systemic treatment. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity and four doses of weekly rituximab (R) were added during the 7th cycle, after the initial window period. The primary endpoint was investigator-assessed response rate after independent radiology review. Response assessment occurred at every 2 cycles and using standard (Lugano) criteria. Tumor tissue was collected for gene expression profiling and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. Results: As of July 1, 2018, 15 patients were treated. The median age was 64 years (range, 47 to 81) and 53% were men. Disease histologies included follicular lymphoma (FL, n = 10), mantle cell lymphoma (MCL, n = 2), marginal zone lymphoma (MZL, n = 2), and small lymphocytic lymphoma (SLL, n = 1). At the start of therapy, all had stage III/IV disease and B-symptoms were present in 40%. For patients with FL, 80% had poor risk by FLIPI. Overall, the indication for treatment included symptoms due to disease (40%), steady progression of disease (33%), and cytopenia due to disease (27%). To date, 14 patients were evaluable for response and 13 experienced tumor burden reduction during the Ix-only window (Figure 1). Of patients with FL, 6 completed the Ix-only window phase and, of these, 5 achieved PR. An additional 4 patients with FL have not completed all 6 cycles of Ix monotherapy. Of these, 1 patient achieved a PR after 4 cycles and continues on treatment, 1 patient came off study with stable disease after 4 cycles, and 2 patients have experienced tumor reduction without meeting formal response criteria and continue on treatment (after 2 and 4 cycles, respectively). Of those patients with FL that received R, all achieved formal remission (3 CR, 3 PR). Median progression free survival has not been reached with a median follow up of 7.4 months. No patient with non-FL histology had yet achieved a PR during the Ix-only window or had undergone response assessment after receiving R at the time of the data cut. The most common adverse events (AEs) for all pts were grade 1-2 and included nausea (53%), diarrhea (53%), rash (40%), and fatigue (33%). Peripheral neuropathy occurred in 20% patients (grade 2 in 7%). A single grade ≥ 3 AE occurred (syncope, grade 3). Conclusions: Data from this interim analysis suggest that Ix monotherapy is well tolerated and highly active in the frontline treatment of FL with all patients demonstrating tumor reduction to date and augmented responses following the addition of R. Non-FL histologies of B-NHL appear less responsive to Ix, but numbers are small. Accrual on study continues. Correlative analyses are underway to determine if Ix or Ix-R may represent a viable frontline option for some patients with iB-NHL. Figure 1. Waterfall plot of response. Number of cycles of treatment received to date indicated for each subject. Four weekly doses of rituximab are added, per protocol, with the 7th cycle of ixazomib. Asterisk indicates treatment on study ongoing. Disclosures Graf: Acerta: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding. Lynch:T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:Genentech: Consultancy; Genentech: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Gilead Sciences: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Gopal:Pfizer: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Brim: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Incyte: Consultancy; Teva: Research Funding.

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

Blood ◽

10.1182/blood-2018-99-117172 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4185-4185 ◽

Cited By ~ 1

Author(s):

Kami J. Maddocks ◽

Farrukh T. Awan ◽

Ying Huang ◽

Sabarish Ayyappan ◽

Robert A Baiocchi ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Phase I Study ◽

Hematologic Toxicity ◽

Tumor Lysis ◽

Genetics Research ◽

Non Hodgkin Lymphoma ◽

Grade 3

Abstract Introduction: Combined obinutuzumab (O) and lenalidomide (L) has demonstrated safety and preliminary efficacy in follicular lymphoma1. Venetoclax (V), a BCL2 inhibitor, as a single agent2 and in combination with rituximab3 is under development in several subtypes of B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of O, V, and L to determine the maximum tolerated dose, dose-limiting toxicities (DLT), and preliminary efficacy. Methods: Pts with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell, Burkitt, marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant were permitted. Prior L 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 at study entry. Treatment consisted of escalating doses of L days 1-21 and V days 1-28 of a 28 day cycle (Table 1). O 1000 mg was administered on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6. A 3+3 dose escalation schema was followed. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection or grade 3 that fails to resolve within 7 days; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, tumor flare reaction controllable with steroids, tumor lysis syndrome that does not require dialysis, diarrhea, nausea, or vomiting responsive to medical treatment, transient electrolyte abnormalities or elevations of ALT / AST that resolve ≤ grade 1 within 48 hours, grade 3 infusion reactions responsive to medical therapy. Pts without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: 14 pts have been treated. Median age is 61 years (range 35-78 years) with 10 males. Median prior therapies is 2 (range 1-10). 5 pts had bulky disease (≥ 7.5 cm) and median baseline lactate dehydrogenase was 274 U/L (range 151-894, 12/14 above ULN 190 U/L). 10 pts were refractory to their last therapy. Histologies include DLBCL/transformed lymphoma (n=11) and FL (n=3). 3 pts were treated at dose level (DL) 1 (V 400 mg / L 15 mg). One pt experienced DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. One pt with DLBCL was replaced for disease progression. 4 pts were then treated at DL 2 (V 600 mg / L 15 mg), and no DLTs were encountered. One pt was replaced due to missed doses of the oral agents. A total of 3 pts have been treated at DL 3 (V 800 mg / L 15 mg) and no DLTs have occurred at the time of data cutoff. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n= 11, 78.6%), anemia (n=1, 7%), and thrombocytopenia (n=2, 14.3%). Grade 3-4 infections included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. No clinically significant tumor lysis has occurred. Pts have received a median of 3 cycles (range 1-12) and 4 remain on therapy. Five pts have achieved a response. At DL 1, a pt with DLBCL, GC type, achieved a complete response (CR) and 2 pts with transformed FL achieved a partial response (PR). At DL 2, 1 pt with FL achieved a CR. At DL 3, 1 pt with transformed FL/double hit achieved a PR. Ten pts have discontinued, 6 with progression and 1 for DLT, alternative treatment, physician preference, and diagnosis of MDS in a patient with 3 prior lines of chemotherapy, respectively. Conclusions: Combined treatment with O, V, and L administered up to 12 cycles has been feasible with hematologic toxicity being the most common adverse event. Enrollment is ongoing and will include expansion cohorts in FL and DLBCL.Fowler et al. Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study. JCO 2015; 35: 7531.Gerecitano et al. A Phase 1 Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma. Blood 2015; 126: 254.Zinzani et al. Phase 2 Study of Venetoclax Plus Rituximab or Randomized Ven Plus Bendamustine+Rituximab (BR) Versus BR in Patients with Relapsed/Refractory Follicular Lymphoma: Interim Data. Blood 2016; 128:617. Disclosures Maddocks: Merck: Research Funding; Pharmacyclics/Janssen: Honoraria; BMS: Research Funding; Pharmacyclics: Research Funding; Teva: Honoraria; Novartis: Research Funding; AstraZeneca: Honoraria. Jaglowski:Juno: Consultancy; Kite Pharma: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding; Morphosys: Research Funding; Seattle Genetics: Research Funding. Christian:Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Immunomedics: Research Funding.

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Results of a Phase 3 Randomised Multicenter Study Comparing Pixantrone + Rituximab with Gemcitabine + Rituximab in Patients with Relapsed Aggressive B-Cell Non-Hodgkin Lymphoma Not Eligible for Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-112455 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4189-4189

Author(s):

Gilles Andre Salles ◽

Wojciech Jurczak ◽

David J. Andorsky ◽

Donald P. Quick ◽

Jack W. Singer ◽

...

Keyword(s):

Stem Cell ◽

B Cell ◽

Hodgkin Lymphoma ◽

Stock Options ◽

Research Funding ◽

De Novo ◽

Phase 3 ◽

Non Hodgkin Lymphoma ◽

Grade 3 ◽

To Receive

Abstract Introduction: There are limited treatment options for patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who are not candidates for high-dose therapy and stem-cell transplant (SCT). Reasons for ineligibility for intensive treatment include advanced age and overall condition, comorbidities, failure to respond to standard salvage treatment regimens, progressive disease following previous SCT, and presence of other adverse risk factors. The PIX306 study evaluated the efficacy of pixantrone + rituximab (PIX+R) compared with gemcitabine + rituximab (GEM+R) in patients with relapsed aggressive B-cell NHL in this particular clinical setting. We present the primary results of the core analysis of the PIX306 trial. Methods: PIX306 was a phase 3, multicentre, open-label, randomized trial in patients aged ≥18 years diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from indolent lymphoma, or grade 3 follicular lymphoma (FL) who relapsed after at least one standard rituximab-containing multi-agent regimen. Primary refractory de novo DLBCL and grade 3 FL, defined as progression within 12 weeks of the last cycle of the first-line treatment regimen, was an exclusion criterion. Patients were randomly allocated 1:1 to receive PIX 50 mg/m2 or GEM 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, each in combination with R 375 mg/m2 on day 1, for up to 6 cycles, with follow-up for progression up to 96 weeks. The primary endpoint was progression-free survival (PFS) as determined by the Independent Radiology Committee (IRC). Disease response was assessed according to the Modified IWG 2007 Revised Response Criteria. The current analysis is based on 197 PFS events (IRC). Overall survival (OS), complete response (CR), overall response rate (ORR), and safety were secondary endpoints. Results: The ITT population included 312 patients; 155 and 157 patients were randomly allocated to receive PIX+R and GEM+R, respectively. Groups were well balanced; no statistically significant differences in baseline demographics were shown (Table). Median age was 73 years (range: 26-91 years). Overall, 193 (61.9%) patients had received only one line of prior chemotherapy. Most patients (n=242; 77.6%) had de novo DLBCL, 43 (13.8%) had DLBCL transformed from indolent NHL and 27 (8.7%) had grade 3 FL. The majority of patients had Ann Arbor stage III/IV (n=230; 73.7%) disease, 166 (53.2%) patients had an IPI score of ≥3, and in 195 (62.5%) patients extranodal disease was diagnosed at baseline. In total, 116 (37.2%) patients had their first disease relapse within 1 year following the initiation of the front-line therapy for DLBCL or FL. Thirty-three (10.6%) patients had undergone a previous SCT. The study did not meet its primary objective of efficacy, as measured by PFS, of PIX+R vs GEM+R [P= 0.28; HR=0.85 (95% CI: 0.64, 1.14)]. The median PFS (95% CI) in the PIX+R and the GEM+R groups were 7.3 months (5.2; 8.4) and 6.3 months (4.4; 8.1), respectively. Median OS was 13.3 vs 19.6 months [HR=1.13 (95% CI: 0.83, 1.53), P=0.43], CR was observed in 35.5% vs 21.7% of patients, and ORR was 61.9% vs 43.9% in the PIX-R and GEM-R groups, respectively. Both regimens were reasonably tolerated and no new safety signals were reported. Cardiac failure was reported as a serious adverse event in 3 and 2 patients (2.0% and 1.3%) receiving PIX-R and GEM-R, respectively. Conclusions: This is the first study to investigate the efficacy of PIX+R vs GEM+R as second-line or later therapy in patients with relapsed aggressive B-cell NHL who are not eligible for SCT and who have few therapeutic options. Even though the present study did not meet its primary endpoint, the PFS observed in both the PIX+R and GEM+R groups were longer than the study outcomes previously reported in similar patient populations. Disclosures Salles: Merck: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Acerta: Honoraria; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Morphosys: Honoraria. Jurczak:Epizyme: Research Funding; Celgene: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Afimed: Research Funding; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Acerta: Consultancy, Research Funding; AstraZeneca: Consultancy; European Medicines Agency: Consultancy; Servier: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; TG therapeutics: Research Funding. Andorsky:AstraZeneca: Consultancy; CTI BioPharma: Consultancy, Research Funding; Celgene: Research Funding; Genentech: Consultancy. Quick:CTI BioPharma: Research Funding. Singer:CTI BioPharma: Employment, Other: Stock options. Bedi Singh:CTI BioPharma: Employment, Other: Stock options. Wang:CTI BioPharma: Employment, Equity Ownership. Egorov:Servier: Employment. Gabarroca:Servier: Employment. Pettengell:CTI: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Servier: Honoraria; Takeda: Honoraria.

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Phase II Window Study of Pembrolizumab in Untreated B-Cell Non-Hodgkin Lymphoproliferative Diseases

Blood ◽

10.1182/blood-2019-124984 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5258-5258

Author(s):

Ajay K. Gopal ◽

Adam Greenbaum ◽

Ryan C. Lynch ◽

Edus H. Warren ◽

Chaitra S. Ujjani ◽

...

Keyword(s):

T Cell ◽

Partial Response ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Response Rate ◽

Progression Free Survival ◽

Response Assessment ◽

Complete Response ◽

Non Hodgkin Lymphoma

INTRODUCTION While chemoimmunotherapy is effective in indolent B-cell non-Hodgkin lymphoma (iBCL), most patients are older and may benefit from a chemotherapy-free approach. Pembrolizumab is an immune checkpoint inhibitor which blocks the PD-1 receptor. Upon chronic antigen stimulation, T-cells can lose their anti-tumor activity due to PD-1 signaling. Multiple in vitro and in vivo studies have demonstrated that blockade of PD-1 can reverse the T-cell dysfunction induced by the tumor microenvironment. Pembrolizumab has shown an excellent safety and toxicity profile. Pembrolizumab as a single agent is FDA approved for numerous solid tumors and some lymphoma subtypes including Hodgkin lymphoma and primary mediastinal B-cell lymphoma. PD-1 inhibitors have also shown activity in the relapsed/refractory iBCL with overall responses reported to range from 10 to 60% (Ding et al., 2017; Lesokhin et al., 2016; Nastoupil et al., 2017a). However, the overwhelming majority of the patients in these studies had received prior chemotherapy. Patients with untreated iBCL have a relatively intact immune system and may have a greater capacity to mount an effective anti-tumor immune response upon reversal of T-cell dysfunction. OBJECTIVES The primary objective is evaluate the efficacy of pembrolizumab as monotherapy for patients with untreated iBCL based on ORR measured at the end of a 6-cycle treatment period. Secondary objective include: Safety and toxicity.Efficacy including complete response, clinical benefit rate (complete response + partial response + stable disease) ≥6 months, time to next therapy, progression-free survival, and duration of response. SUBJECTS AND METHODS Patients ≥ 18 years of age with previously untreated radiographically measurable follicular or marginal zone lymphoma with an indication for treatment are included. These indications include significant symptoms, end organ damage, cytopenias, or steady progression. Major exclusions include known autoimmune disease, major organ dysfunction, or ECOG ≥ 2. Treatment consists of 200 mg pembrolizumab IV on day 1 of each 21-day cycle. Initial response assessment occurs after 6 cycles. Patients with a complete or partial response can remain on the trial. Patients who have stable disease or progressive disease and are asymptomatic (excluding hyperprogression) will receive 3 additional cycles and then will be restaged to account for a delayed response. Those patients with a complete or partial response after those additional cycles can remain on the trial. Subsequently, response assessment occurs every 3 cycles. Patients without progressive disease or unacceptable toxicity are able to continue up to 18 cycles. Up to 33 patients will be enrolled, and follow-up may continue for an additional 2 years. STATISTICAL METHODS The primary efficacy endpoint is the overall response rate (CR + PR). Secondary endpoints include duration of response, progression free survival, and time to next therapy (see treatment schema). A sample size of 33 participants is planned to provide 80% power at the 5% significance level to distinguish the observed overall response rate from a true rate of ≥ 40% versus ≤ 20%) using a Simon 2-stage minimax design. The trial will be terminated early if fewer than 5 of the first 18 patients have a response. The thresholds used in this design are based on what is considered to be a clinically meaningful response rate with a novel agent with very low rates of adverse events and toxicity compared to standard regimens. This response rate threshold is also higher than what has been observed using anti-PD-1 therapy in the relapsed/refractory setting. RECRUITMENT Three patients have been accrued to the study. To date, all patients have remained on study with no grade 3-5 adverse events. CORRELATIVE STUDIES Given that pembrolizumab is known to modulate the tumor immune microenvironment, we are also performing clinical correlates on a companion protocol. Using several 22 color flow cytometry panels and 6-color multiplex immunohistochemistry, we will analyze pre- and post-treatment lymph nodes and peripheral blood. These studies will examine over 50 populations of immune cells in addition to T-cell activation/exhaustion markers such as PD-1, TIM-3, LAG-3, CTLA-4, and PD-L1. TRIAL REGISTRATION Clinicaltrials.gov (NCT03498612). Funding for both the trial and correlative studies has been provided by Merck. Figure Disclosures Gopal: Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding. Lynch:Rhizen Pharmaceuticals S.A: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy; T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Juno Therapeutics: Research Funding. Ujjani:Pharmacyclics: Honoraria; PCYC: Research Funding; Astrazeneca: Consultancy; Atara: Consultancy; Gilead: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding. Shadman:ADC Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Sound Biologics: Consultancy; Mustang Bio: Research Funding; TG Therapeutic: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; Gilead: Consultancy, Research Funding; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Acerta Pharma: Research Funding; BeiGene: Research Funding; Sunesis: Research Funding; Astra Zeneca: Consultancy; Atara Biotherapeutics: Consultancy. Smith:Denovo Biopharma: Research Funding; Incyte Corporation: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma BV: Research Funding; Ayala (spouse): Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Seattle Genetics: Research Funding; Portola Pharmaceuticals: Research Funding. Till:Mustang Bio: Patents & Royalties, Research Funding. Fromm:Merck, Inc.: Research Funding. Shustov:Seattle Genetics, Inc.: Research Funding. OffLabel Disclosure: Pembrolizumab for the treatment of indolent non-Hodgkin lymphoma

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Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial

Blood ◽

10.1182/blood-2018-11-880526 ◽

2019 ◽

Vol 133 (18) ◽

pp. 1964-1976 ◽

Cited By ~ 38

Author(s):

Andrew D. Zelenetz ◽

Gilles Salles ◽

Kylie D. Mason ◽

Carla Casulo ◽

Steven Le Gouill ◽

...

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Phase 2 ◽

Non Hodgkin Lymphoma ◽

Phase 1B ◽

Grade 3

Abstract Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2+ and MYC+) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.

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Outcomes in patients with aggressive B‐cell non‐Hodgkin lymphoma after intensive frontline treatment failure

Cancer ◽

10.1002/cncr.32526 ◽

2019 ◽

Vol 126 (2) ◽

pp. 293-303 ◽

Cited By ~ 2

Author(s):

Emily C. Ayers ◽

Shaoying Li ◽

L. Jeffrey Medeiros ◽

David A. Bond ◽

Kami J. Maddocks ◽

...

Keyword(s):

Treatment Failure ◽

B Cell ◽

Hodgkin Lymphoma ◽

Non Hodgkin Lymphoma ◽

Frontline Treatment

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Phase I/II Trial of Ofatumumab/Lenalidamide for Patients with Relasped/Refractory B-Cell Non-Hodgkin Lymphoma: High Response Rate in Indolent Lymphoma

Blood ◽

10.1182/blood.v120.21.3692.3692 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3692-3692

Author(s):

Julie M Vose ◽

Fausto R. Loberiza ◽

R. Gregory Bociek ◽

Philip Bierman ◽

James O. Armitage

Keyword(s):

Phase I ◽

B Cell ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

High Response Rate ◽

Indolent Lymphoma ◽

Non Hodgkin Lymphoma

Abstract Abstract 3692 Introduction: Lenalidomide and ofatumumab have demonstrated clinical activity as single agents in a variety of types of non-Hodgkin lymphoma (NHL). This trial is a phase I/II trial combining these two agents for treatment of patients with relapsed and refractory B-cell NHL. Methods: Patients with relapsed and refractory B-cell NHL of any histology were enrolled on a phase I/II trial combining lenalidomide and ofatumumab. Nine patients were on the phase I part of the trial and received a fixed dose of ofatumumab 1000 mg weekly × 8 doses along with lenalidomide 15 mg (N=3), or10 mg (N=6) for 21/28 days until the time of progression. The phase II portion of the study has 28 patients on the study with adequate follow-up at the time of analysis. The phase II doses were ofatumumab 1000 mg weekly × 8 along with lenalidomide 10 mg on 21/28 days. The lenalidomide was dose adjusted according to standard dose reduction criteria. All patients were on either a daily aspirin or other anticoagulation for thrombosis (DVT) prophylaxis. Results: Thirty seven evaluable patients had adequate follow-up at the time of the analysis. The patients had a median age of 65 years (range 36–81), 76% were male, and 89% have an ECOG performance status of 0–1. The majority of patients had a relapsed indolent lymphoma with 12/37 (32%) follicular lymphoma (FL), 6/37 (16%) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), 7/37 (19%) mantle cell lymphoma (MCL), one unclassifiable indolent lymphoma (3%), and 11/37 (30%) diffuse large B-cell lymphoma (DLBLC). The median duration of follow-up of surviving patients was 13 months (range 4–24). The complete response (CR) rate was 2/37 (5%) (one each FL and DLBCL) and the partial response (PR) rate was 13/37 (35%) for an overall response rate (ORR) of 15/37 (40%). The 1 year progression-free survival (PFS) was 41% (95% CI; 23–58) and the 1-year overall survival (OS) was 68% (95% CI; 49–82). In an analysis of response by patient variables, those significant included the patients with an FL histology (ORR 83%) vs. DLBCL (ORR 18%) or other(SLL, MCL, unclassifiable) (ORR 21%) (p= 0.001) and lactic dehydrogenase (LDH) normal (ORR 56%) vs. elevated (ORR 14%) (p= 0.01). In an analysis of variables for PFS, the variables with significance include diagnosis of FL (1-year PFS 67%) vs. DLBCL (9%) and SLL, MCL, unclassifiable (45%) (p=0.002), LDH normal (1-year PFS 55%) vs. elevated LDH (1-year PFS 19%), and number of prior chemotherapies 1–2 (1-year PFS 58%) vs. > 3 (1-year PFS 19%). Higher grade toxicities included grade 4 neutropenia in 9/37 (24%), one each of grade 4 bacteremia, one grade 4 DVT, stroke, and acute renal failure. Conclusions: The combination of lenalidomide and ofatumumab was well tolerated by most patients. The patients with indolent NHL had a high response rate of 83% and a 1-year PFS of 67%. Disclosures: Vose: Glaxo Smith Kline: Research Funding; Celgene: Research Funding. Off Label Use: Lenalidamide and Ofatumumab will be discussed for use in indolent and aggressive non-Hodgkin lymphoma.

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Idelalisib Treatment Is Associated with Improved Cytopenias in Patients with Relapsed/Refractory iNHL and CLL

Blood ◽

10.1182/blood.v126.23.1747.1747 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1747-1747

Author(s):

Susan O'Brien ◽

Andrew John Davies ◽

Ian W. Flinn ◽

Ajay K Gopal ◽

Thomas J. Kipps ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Lymphocytic Leukemia ◽

B Cell Malignancies ◽

Advisory Committees ◽

Time To Peak ◽

Non Hodgkin Lymphoma ◽

Pharmaceutical Industries ◽

Grade 3 ◽

Over Time

Abstract BACKGROUND Chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) are B-cell malignancies associated with neutropenia, anemia and thrombocytopenia.The etiology of impaired hematopoiesis is not well understood, however the bone marrow leukemia/lymphoma cell infiltrates that often occur with these diseases is thought to contribute. In studies evaluating the selective PI3Kd inhibitor idelalisib (IDL) in B-cell malignancies, hematologic responses across all 3 lineages were observed in a majority of patients (pts) with baseline (BL) cytopenias. This post hoc analysis reports hemogram changes in pts with relapsed or refractory (R/R) CLL/iNHL treated with IDL in two pivotal studies and describes trends in hematologic parameters over time during IDL treatment in pts with or without BL cytopenias. METHODS In phase 3 study 312-0116 (NCT01539512), frail pts with R/R CLL were randomized to receive a combination of 8 doses of rituximab (R) with IDL 150 mg BID or placebo (P). In phase 2 study 101-09 (NCT01282424), pts with refractory iNHL received IDL 150 mg BID. In both studies, IDL was continued until disease progression (PD) or unacceptable toxicity. Trial inclusion criteria allowed enrollment of pts with BL cytopenias of any grade (CLL) or grade ˂3 (iNHL). Hematologic profiles for pts in each study were categorized as normal or abnormal (any grade of cytopenia) at BL. In the iNHL study, pts with PD at the first assessment were excluded from this analysis to avoid confounding by underlying uncontrolled disease. RESULTS A total of 345 pts participated in the 2 trials. The overall response rates of IDL-treated patients in the CLL and iNHL studies were 81% and 57%, respectively. For pts with CLL on IDL+R (n=110), BL cytopenias (grade ≥1) included anemia (76%), thrombocytopenia (62%), and neutropenia (34%). For pts with iNHL on IDL-mono (n=115), BL cytopenias included anemia (50.4%), thrombocytopenia (64.3%), and neutropenia (75.7%). We present changes in hemoglobin (Hgb), platelet (PLT), or neutrophil (ANC) counts over time (BL, peak, and time to peak) in pts with an abnormal BL hemogram in Table 1. Median hematologic lab values over time were unchanged in pts with normal hemograms at BL. Among patients with BL cytopenia, anemia and thrombocytopenia improved over time in pts with CLL and iNHL while on treatment with IDL. For pts with CLL, the magnitude of improvement was larger for pts in the IDL+R arm compared to those in the P+R arm. For pts in the IDL+R arm, median peak values of Hgb and PLT were observed within 6 months of IDL initiation. For pts with iNHL, median peak values for Hgb and PLT were observed within 3 months. ANC remained stable over time in CLL, and increased in iNHL. CONCLUSIONS Idelalisib treatment was associated with improvement in Hgb and PLT counts in this population of pts with R/R CLL or iNHL. In those pts with BL anemia or thrombocytopenia, peak improvement in Hgb or PLT values occurred early in treatment (≤3 months for iNHL and ≤6 months for CLL). Disclosures O'Brien: Gilead: Research Funding. Davies:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Gopal:Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding; Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria. Kipps:Pharmacyclics Abbvie Celgene Genentech Astra Zeneca Gilead Sciences: Other: Advisor. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche: Speakers Bureau. Newcomb:Gilead: Employment. Waldapfel:Gilead: Employment. Zhang:Gilead: Employment. Stilgenbauer:Gilead: Honoraria, Research Funding.

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Extended Use of Rituximab in Older Adults with Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v124.21.1279.1279 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1279-1279

Author(s):

Matthew J. Matasar ◽

Coral L. Atoria ◽

Elena B. Elkin ◽

Chadi Nabhan

Keyword(s):

B Cell ◽

Hodgkin Lymphoma ◽

Rural Areas ◽

Research Funding ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

The United States ◽

Non Hodgkin Lymphoma ◽

To Receive

Abstract Background: The introduction of rituximab has improved outcomes in B-cell non-Hodgkin lymphoma (BCL) across all histologies. Extended use of rituximab, or maintenance rituximab, improves progression-free survival in follicular lymphoma (FL) patients who achieve a response to induction rituximab with or without chemotherapy, but there is no evidence of an overall survival benefit. There is currently little evidence to support extended use of rituximab in other histologic subgroups, and older patients in particular may be at risk of adverse events. Our objective was to characterize patterns and predictors of extended rituximab therapy in a population-based cohort of older BCL patients in the United States. Methods: In the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset,we identified patients 66 years and older diagnosed with BCL in 2000-2010. Histology was classified as diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), FL, mantle cell lymphoma (MCL), other indolent BCL, and BCL not otherwise specified (NOS). We identified Medicare claims for rituximab starting at any point following diagnosis. Extended rituximab therapy was defined as a duration of greater than 7 months with no gap in rituximab claims greater than 6 months. Demographic and clinical characteristics associated with extended rituximab were evaluated in multivariable logistic regression. Results: There were 24,232 BCL patients who received rituximab during the study period. The cohort was predominantly white (91%), half were men, 15% had a Charlson comorbidity score ≥2, and 12% were 85 years or older. DLBCL was the most common histology (44%), followed by FL (21%), other indolent BCL (17%), BCL-NOS (13%), MCL (6%), and BL (1%). Overall, most patients (85%) received rituximab for ≤7 months, but duration varied by histology (Table 1). More than a quarter of FL patients had extended therapy, including 7% who had rituximab for more than 24 months. Among patients with other histologies, receipt of extended therapy varied from 20% (other indolent BCL) to 8% (BL). Compared with FL patients and controlling for demographic and disease characteristics, patients with other histologies were less likely to receive extended rituximab therapy (p<0.0001). Adjusted odds ratios were 0.91 (95% CI 0.78-1.05) for MCL, 0.83 (0.75-0.91) for other indolent BCL, 0.67 (0.60-0.75) for BCL-NOS, 0.32 (0.29-0.36) for DLBCL, and 0.28 (0.15-0.53) for BL. However, 75% of patients who had extended rituximab, and 63% of those who had rituximab >24 months, were of non-FL histology. Controlling for histology and other characteristics, extended rituximab therapy was more likely among women (adjusted OR 1.09, 95% CI 1.01-1.18), and less likely among unmarried patients (0.92, 0.85-0.99) and those in rural areas (0.84, 0.75-0.94). There was significant regional variation (p<0.0001), with patients in the West (adjusted OR 0.86, 95% CI 0.79-0.95), and Midwest (0.75, 0.66-0.86) less likely to receive extended rituximab than those in the Northeast. There was no significant relationship between extended therapy and age, race, or comorbidity. Conclusions: While FL patients were more likely than others to receive extended rituximab, the majority of patients receiving extended rituximab had other diagnoses across the entire spectrum of B-cell lymphoma, for which extended rituximab is neither indicated nor supported by guidelines or prospective data. After controlling for histology, several demographic characteristics significantly influenced the duration of therapy. Extended use of rituximab – particularly in patients for whom it is not clearly indicated – may have important implications for clinical outcomes, toxicity, and costs. Table 1 Duration of rituximab use across B-cell lymphoma histologic subgroups Histology Duration of Rituximab N ≤7 mos >7-24 mos >24 mos DLBCL 10,567 91% 7% 2% FL 5,001 76% 17% 7% BL 127 92% 6% 2% MCL 1,339 79% 16% 5% Other indolent 4,095 80% 15% 5% BCL NOS 3,103 83% 13% 4% Total 24,232 80% 15% 5% Disclosures Matasar: Merck: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Honoraria; Spectrum: Honoraria. Nabhan:Celgene: Honoraria, Research Funding.

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Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL)

Blood ◽

10.1182/blood.v124.21.1708.1708 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1708-1708 ◽

Cited By ~ 8

Author(s):

Ajay K. Gopal ◽

Brad S. Kahl ◽

Sven de Vos ◽

Nina D. Wagner-Johnston ◽

Stephen J. Schuster ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Employment Equity ◽

Non Hodgkin Lymphoma ◽

Duration Of Response ◽

Equity Ownership ◽

Grade 3 ◽

Systemic Therapies

Abstract Introduction: Rituximab-alkylator combinations are the standard therapies for patients (pts) with iNHL, however, refractory disease nearly uniformly develops. Once iNHL becomes double-refractory to both rituximab + alkylating agents, there are limited options to induce durable remissions. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable clinical activity in double-refractory iNHL (Gopal NEJM 2014). FDA granted accelerated approval for Idelalisib (Zydelig®) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. Based on these encouraging initial results, we now describe long-term follow up, safety, and remission durations of this double-refractory iNHL population treated with idelalisib. Methods: Eligible iNHL pts included those with measurable disease refractory to both rituximab and an alkylating agent. Refractory was defined as lack of response to, or progression of lymphoma within 6 months of completion of index therapy, confirmed by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007, and Owen 2013). The new data cutoff date for this analysis was June 2014, 20 months after the last patient enrolled. Results: Enrolled pts (N = 125) had a median age of 64 years and included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], including bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and autologous transplant (n=14). 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. 38 pts (30%) had elevated LDH, and 33 pts (26%) had bulky disease >7 cm. The median time to progression from last prior therapy was 3.9 months. With a median exposure of 11.1 months (range 0.7 to 35.4), the overall response rate (ORR) is 56% (95% CI = 46.8-64.9) with 70 responders, comprising 12 CRs (9.6%), 58 PRs (46.4%). The median time to response was 1.9 months (time of first evaluation) and time to CR was 4.5 months. There were 43 pts with stable disease (SD) (34.4%). 90% of pts experienced some decrease in tumor burden. ORR for iNHL subtypes is: FL (54%), SLL (61%), MZL (47%), and LPL/WM (70%). CR rate for iNHL subtypes is: FL (14%), SLL (4%), MZL (7%), and LPL/WM (0%). Among responders, median DOR is 13.9 (0.03-31.3) months. DOR for iNHL subtypes in months (Figure 1) is: FL 11.8, SLL 13.9, MZL 18.4, and LPL/WM (not yet reached). Median PFS for all pts is 11.0 months, in comparison to a median PFS of the last prior regimen of 3.9 months (p<.0001). The median PFS for individual subtypes in months was: FL 11.0, SLL11.1, MZL 6.6, and LPL/WM 22.2. The median overall survival of all patients was 30.8 months. The adverse events include (total%/≥ grade 3%) diarrhea/colitis (50/18), fatigue (30/2), nausea (31/2), cough (32/0), pyrexia (30/2), dyspnea (18/5), rash (14/2), pneumonia (14/11), and pneumonitis (4/3). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 18 pts (14%). Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated without recurrence of ALT/AST elevation. Overall, 30 pts (24%) have discontinued therapy due to adverse events. Conclusions: The prolonged administration of idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in inducing and maintaining remissions in double-refractory iNHL population with an ORR of 56%, PFS of 11 months, and DOR of 13.9 months. The response rate and long term duration of responses in the small number of subjects with LPL/WM is very promising, and will be evaluated in larger trials of this disease. The observed disease control compared to prior regimens suggests the potential for prolonged clinical benefit in this challenging patient population with unmet medical need. Figure 1: Duration of Response by Disease Group. Figure 1:. Duration of Response by Disease Group. Disclosures Gopal: Gilead Sciences: Research Funding. Off Label Use: Zydelig is a kinase inhibitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities; 2) Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Kahl:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Schuster:Gilead Sciences: Research Funding. Jurczak:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Flowers:Gilead Sciences: Research Funding. Martin:Gilead Sciences: Research Funding. Viardot:Gilead Sciences: Research Funding. Blum:Gilead Sciences: Research Funding. Goy:Gilead Sciences: Research Funding. Davies:Gilead Sciences: Research Funding. Zinzani:Gilead Sciences: Research Funding. Dreyling:Gilead Sciences: Research Funding. Holes:Gilead Sciences: Employment, Equity Ownership. Sorensen:Gilead Sciences: Employment, Equity Ownership. Godfrey:Gilead Sciences: Employment, Equity Ownership. Salles:Gilead Sciences: Research Funding.

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Interim Analysis of a Phase 1 Study of the Antibody-Drug Conjugate SGN-CD19A in Relapsed or Refractory B-Lineage Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v124.21.1741.1741 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1741-1741 ◽

Cited By ~ 11

Author(s):

Craig H. Moskowitz ◽

Andres Forero-Torres ◽

Bijal D. Shah ◽

Ranjana Advani ◽

Paul Hamlin ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Phase 1 ◽

Objective Response ◽

Antibody Drug Conjugate ◽

Employment Equity ◽

Non Hodgkin Lymphoma ◽

Equity Ownership ◽

Grade 3

Abstract Background CD19, a B-cell specific marker, is expressed in the majority of patients with B-cell non-Hodgkin lymphoma (NHL). SGN-CD19A is a novel antibody-drug conjugate (ADC) composed of a humanized anti-CD19 monoclonal antibody conjugated to the microtubule-disrupting agent monomethyl auristatin F (MMAF) via a maleimidocaproyl linker. Methods This ongoing phase 1, open-label, dose-escalation study investigates the safety, tolerability, pharmacokinetics, and antitumor activity of SGN-CD19A in patients with relapsed or refractory B-cell NHL (NCT 01786135). Eligible patients are ≥12 years of age and must have a confirmed diagnosis of diffuse large B-cell lymphoma (DLBCL), including transformed follicular histology; mantle cell lymphoma (MCL); follicular lymphoma grade 3 (FL3); Burkitt lymphoma; or B-cell lymphoblastic lymphoma. Patients must be relapsed or refractory to at least 1 prior systemic regimen. Patients with DLBCL or FL3 must have also received intensive salvage therapy with or without autologous stem cell transplant (SCT), unless they refused or were deemed ineligible. A modified continual reassessment method is used for dose allocation and maximum tolerated dose (MTD) estimation. SGN-CD19A is administered IV on Day 1 of 21-day cycles (0.5–6 mg/kg). Response is assessed with CT and PET scans according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results To date, 44 patients have been treated: 39 patients (89%) with DLBCL (including 10 with transformed DLBCL), 4 (9%) with MCL, and 1 (2%) with FL3. Median age was 65 years (range, 33–81). Patients had a median of 2 prior systemic therapies (range, 1–7), and 10 patients (23%) had autologous SCT. Twenty-six patients (59%) were refractory to their most recent prior therapy, and 18 (41%) were relapsed. Patients received a median of 3 cycles of treatment (range, 1–12) at doses from 0.5–6 mg/kg. Eleven patients (25%) remain on treatment, and 33 have discontinued treatment (18 due to progressive disease [PD], 5 for investigator decision, 5 for adverse events [AE], 4 because of patient decision/non-AE, and 1 for SCT). No dose-limiting toxicity (DLT) in Cycle 1 has been reported. Treatment-emergent AEs reported in ≥20% of patients were blurred vision (59%), dry eye (39%), fatigue (39%), constipation (32%), keratopathy (23%), and pyrexia (20%). Corneal exam findings consistent with superficial microcystic keratopathy were observed in 25 patients (57%) and were mostly Grade 1/2. Grade 3/4 corneal AEs were observed in 4 patients at the higher doses; the majority resolved or improved to Grade 1/2 at last follow-up. Corneal AEs were treated with ophthalmic steroids, and during the trial steroid eye drop prophylaxis was instituted with each dose of study drug. SGN-CD19A ADC plasma exposures were approximately dose-proportional. Accumulation was observed following multiple dose administrations, consistent with a mean terminal half-life of about 2 weeks, suggesting less frequent dosing might be possible. In the 43 efficacy-evaluable patients, the objective response rate (ORR) is 30% (95% CI [17, 46]), including 7 complete responses (CRs; 16%) and 6 partial responses (PRs; 14%). Of the 13 patients with an objective response, 8 are still on study with follow-up times of 0.1–31 weeks; 2 are no longer on study; and 3 had subsequent PD or death with response durations of 14, 19, and 31 weeks. Table Best Clinical Response by Disease Status Relative to Most Recent Therapy, n (%) Relapsed N=17 Refractory N=26 Total N=43 CR 5 (29) 2 (8) 7 (16) PR 4 (24) 2 (8) 6(14) SD 4 (24) 9 (35) 13 (30) PD 4 (24) 13 (50) 17 (40) ORR (CR + PR), (95% CI) 53 (28, 77) 15 (4, 35) 30 (17, 46) Conclusions To date, SGN-CD19A has shown evidence of clinical activity with an ORR of 30% and CR rate of 16%. Enrollment in the trial is ongoing to further refine optimal dose and schedule. SGN-CD19A is generally well-tolerated. No DLTs have been observed in tested dose levels. Observed ocular AEs are manageable with steroid eye drops and dose modifications. The high response rate (53%) in relapsed patients and low rate of bone marrow suppression or neuropathy suggest that SGN-CD19A could be incorporated into novel combination regimens in earlier lines of therapy. Disclosures Moskowitz: Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Off Label Use: SGN-CD19A is an investigational agent being studied in patients with B-cell malignancies. SGN-CD19A is not approved for use. . Forero-Torres:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Shah:Pharmacyclics: Speakers Bureau; SWOG: Consultancy; Celgene: Consultancy, Speakers Bureau; NCCN: Consultancy; Seattle Genetics, Inc.: Research Funding; Janssen: Speakers Bureau. Advani:Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding. Kim:Bayer: Consultancy; Eli Lily: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Kostic:Seattle Genetics, Inc.: Employment, Equity Ownership. Sandalic:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Research Funding, Travel expenses Other.

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