Treatment Outcomes of Consolidative Radiation in Extranodal Early-Stage Diffuse Large B-Cell Lymphoma

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin Lymphoma, with approximately 25-30% of patients presenting as early or limited-stage (stage I and II). Though treatment with chemoimmunotherapy is standard of care, the role of consolidative radiotherapy (RT) in limited-stage (LS) patients is not well defined. Recent studies have attempted to shorten chemotherapy courses and eliminate RT for LS patients. Additionally, recent single institutional data has suggested LS patients with extranodal (EN) disease may have better outcomes if treated with RT. We aimed to investigate whether the addition of RT provided a survival benefit in early-stage DLBCL patients based on primary site at presentation comparing nodal to EN disease. Methods The National Cancer Database was utilized to identify patients diagnosed with LS-DLBCL from 2004 to 2015. Only patients treated with multiagent chemotherapy were included. Patients with international prognostic index (IPI) score available were separated into low (0-1 factors) or high-risk (2-4) groups. Landmark analysis was performed to exclude patients with last contact, including death, within 12 months of diagnosis. Kaplan-Meier survival analysis was used to compare overall survival (OS). Cox regression analysis was used to identify hazard ratios for survival using RT between subgroups. Results Of the 39,745 LS patients identified, 62.9% had nodal disease and 37.1% had EN disease with stage I disease accounting for 51.5% of patients. Only 6,628 patients had reported IPI scores with the majority having low-risk IPI (69.2%). Compared to patients with only nodal disease, patients with EN involvement were more likely to receive consolidative RT (42.9% vs 37.2%; p<0.05). EN patients were most likely to receive RT with primary bone (67.7% of 1526 patients), skin/soft tissue (60.3% of 1353), breast (58.6% of 652), testes (58.4% of 950) and thyroid (56.6% of 1059) involvement (all p<0.05). GI (18.1% of 4652) and lung (23.3% of 614) primaries were least likely to receive RT (p<0.05). With a median follow up of 58.8 months, the addition of RT was associated with improved 5-year OS for all LS patients as compared to those treated with chemotherapy alone (68 vs. 62%, p<0.001). While RT was associated with improved 5-year OS in both the nodal and EN disease patients, nodal patients had a greater benefit of receiving RT as compared to EN patients (nodal: 71% vs. 63%, p<0.001; EN: 64% vs. 62%; p<0.001). Specifically, in EN patients, the addition of RT significantly increased 5-year OS for skin/soft tissue (60% vs. 57%, p<.001), head and neck (63% vs. 60%, p<0.02), testicular (63% vs. 45%, p<.001), and thyroid sites (73% vs. 67%, p <0.02). Furthermore, RT slightly improved 5-year OS outcomes for patients with both low-risk (75% vs. 73%; p<0.01) and high-risk IPI (52% vs. 50%; p<0.04). On multivariate analysis, adjusting for age, stage, and Charlson-Deyo comorbidity score, the addition of RT was an independent factor for improved survival for all LS patients (Hazard Ratio [HR] 0.84, 95% Confidence Interval [CI] 0.81-0.88; p<0.001) along with EN sites of skin/soft tissue (HR 0.72, 95% CI 0.58-0.88; p<0.01), testicle (HR 0.70, 95% CI 0.54-0.90, p<0.01) and thyroid (HR 0.68, 95% CI 0.51-0.90; p<0.01). No significant survival differences were observed in patients with EN involvement of the lung, bone, breast, or GI tract when RT was added to their treatment. Conclusions We report the largest retrospective study on EN outcomes utilizing consolidative RT in early-stage DLBCL. Though there is no consensus on optimal treatment indications for RT in LS-DLBCL, this data shows improved OS in both nodal only disease and within specific EN disease subgroups when RT is added to front-line chemotherapy. As recent studies have attempted to shorten chemotherapy cycles and limit the use of RT, these results suggest caution against omission of RT in select patients. Figure 1 Figure 1. Disclosures Shah: AstraZeneca: Research Funding; Seattle Genetics: Research Funding; Epizyme: Research Funding. Stephens: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Abbvie: Consultancy; JUNO: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽

10.1182/blood.v122.21.4395.4395 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4395-4395 ◽

Cited By ~ 8

Author(s):

Bertrand Coiffier ◽

Catherine Thieblemont ◽

Sophie de Guibert ◽

Jehan Dupuis ◽

Vincent Ribrag ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Clinical Activity ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Duration Of Response ◽

Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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An International Collaborative Study of Outcome and Prognostic Factors in Patients with Secondary CNS Involvement By Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.1874.1874 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1874-1874 ◽

Cited By ~ 1

Author(s):

Tarec Christoffer El-Galaly ◽

Chan Yoon Cheah ◽

Mette Dahl Bendtsen ◽

Gita Thanarasjasingam ◽

Roopesh Kansara ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Systemic Disease ◽

Performance Status ◽

B Cell Lymphoma ◽

Cns Involvement ◽

First Line ◽

Advisory Committees ◽

Large B Cell Lymphoma

Abstract Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically <6 months. However, data in patients that develop SCNS following primary therapy that contains a rituximab-based-regimen as well as the impact of more intensified treatment for SCNS are limited. Aims: The aims of this study were to i) describe the natural history of SCNS in a large cohort of patients treated with immunochemotherapy, and ii) determine prognostic factors after SCNS. Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye) in patients without known CNS involvement at the time of first pathologic diagnosis of DLBCL. Patients were identified from local databases and/or regional/national registries in Denmark, Canada (British Columbia), Australia, Israel, US (University of Iowa/Mayo Clinic SPORE), and England (Guy's and St. Thomas' Hospital, London). Clinico-pathologic and treatment characteristics at the time of SCNS were collected from medical records. Results: In total, 281 patients with SCNS diagnosed between 2001 and 2016 were included. Median age at SCNS was 64 (range 20-93) years and male:female ratio was 1.3. SCNS occurred as part of first relapse in 244 (87%) patients and 112 (40%) had documented concurrent systemic disease at the time of SCNS. The median time from initial DLBCL diagnosis to SCNS was 9 months, which was similar for patients treated with (N=76, 27%) or without upfront CNS prophylaxis (N=205, 73%) (10 vs 9 Mo; P=0.3). The median post-SCNS OS was 4 months (interquartile range 2-13) and the 2yr survival rate was 20% (95% CI 15-25) for the entire cohort. Associations between clinicopathologic features, management strategy, and post-SCNS survival are shown in Table 1, which excludes patients who did not receive any treatment against SCNS, patients treated with steroids alone, and a patient with unavailable treatment information (n=43, 15%). In multivariable analysis, performance status >1, concurrent leptomeningeal and parenchymal involvement, SCNS developing before completion of 1st line treatment, and combined systemic and CNS involvement by DLBCL were associated with inferior outcomes. Upfront CNS prophylaxis did not influence post-SCNS OS. High-dose methotrexate (HDMTX) and/or platinum based treatment regimens (i.e. ICE, DHAP, or GDP [+/- IT treatment and/or radiotherapy], N=163) for SCNS were associated with reduced risk of death (HR 0.45 [0.32-0.62, P<0.01]). The 2yr post-SCNS survival for patients treated with HDMTX and/or platinum-based regimens (N=163) was 29% (95% CI 22-37). For patients with isolated parenchymal SCNS, single modality treatment with radiotherapy resulted in 2-yr OS of 19% (95% CI 8-35). For the subgroup of 49 patients treated with HDMTX- and/or platinum-based regimens for isolated SCNS after 1st line DLBCL treatment and with performance status 0 or 1, the 2yr post-SCNS survival was 46% (95% CI 31-59). Overall, 9% of the patients received HDT with ASCT as part of salvage therapy at the time of SCNS. Amongst 36 SCNS patients without systemic involvement and in CR following intensive treatment (HDMTX and/or platinum-based treatments), 11 patients consolidated with HDT had similar outcomes to 25 patients treated without consolidating HDT (P=0.9, Fig 1) Conclusions: Outcomes for patients with SCNS remain poor in this large international cohort of patients from the immunochemotherapy era. Combined parenchymal and leptomeningeal disease, presence of systemic disease concurrent with SCNS, performance status >1, and SCNS developing during first line treatment were independently associated with inferior OS. However, a significant fraction of patients with isolated SCNS after first line DLBCL treatment and with good performance status may achieve long-term remissions after intensive regimens for SCNS. Disclosures El-Galaly: Roche: Consultancy, Other: travel funding. Cheah:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Speaker's Bureau. Kansara:Celgene: Honoraria. Connors:Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Villa:Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding.

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Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-120013 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 96-96 ◽

Cited By ~ 12

Author(s):

Dahlia Sano ◽

Loretta J. Nastoupil ◽

Nathan H. Fowler ◽

Luis Fayad ◽

F. B. Hagemeister ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Age Groups ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Car T ◽

Large B Cell

Abstract Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients <65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were <65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger (<65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

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The Analysis of HIV-Associated Lymphoma in Japan

Blood ◽

10.1182/blood-2018-99-114060 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5315-5315

Author(s):

Shotaro Hagiwara ◽

Kentaro Yoshinaga ◽

Masayuki Shiseki ◽

Junji Tanaka ◽

Seiji Okada

Keyword(s):

Board Of Directors ◽

Burkitt Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Primary Cns Lymphoma ◽

B Cell Lymphoma ◽

Cns Lymphoma ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background. The recent advance of antiretroviral therapy decreased the morbidity of opportunistic infections. However, the incidence of HIV-associated lymphoma remains high. Also, the outcome of the HIV-associated lymphoma is unclear in the era of rituximab. In order to address these clinical questions, we performed a nation-wide epidemiological study. Methods. Patients with HIV-associated lymphoma were extracted from the database of Japanese society of hematology blood disease registry from January 2012 to December 2015. We analyzed the patient's age, sex, subtypes of lymphoma, the international prognostic index (IPI) for diffuse large B cell lymphoma, and overall survival. Results. Eighty-one patients were extracted from the database. Eighty patients were available for the survival analysis. Seventy-six (93.8%) patients of them were male. The median age was 52.5(25-88) year-old. However, there were two peaks of age; the first peak was 38-40-year-old and the second was 59-62-year-old. Sub-types of lymphomas were diffuse large B cell lymphoma (DLBCL)(48.1%), Burkitt lymphoma(19.8%), primary CNS lymphoma(8.6%), plasmablastic lymphoma(7.4%), peripheral T cell lymphoma(3.7%), Hodgkin's lymphoma(3.7%), primary effusion lymphoma(2.5%), MALT lymphoma(1.2%), Follicular lymphoma(1.2%) and Adult T cell lymphoma/leukemia(1.2%). Extra-nodal involvement at the diagnosis was observed in 61.7%. The involved sites were the brain, stomach, small bowel, colon, thyroid and the others. In DLBCL, the patients with IPI high and high-intermediate risk was 51.3%. The median observation period was 26 months. Estimated 3 years overall survival (OS) in all cases was 68.8+/-0.63%. Although there was no statistical significance, however, the 3 years, OS of Burkitt lymphoma tended to be better than that of DLBCL (84.6%+/-10.0 versus 67.7+/-8.8%). Log-rank analysis showed the OS in DLBCL patients with IPI high-intermediate and high risk was significantly worse than the patients with low, and low-intermediate risk (p<0.001). Estimated 3 years OS was 90+/-9.5% vs. 38.0+/-13.0%, respectively. The outcome of patients with primary CNS lymphoma remains poor, estimated 3 years OS was 45.7+/-22.4%. Conclusion. Our study showed diversity in the pathological subtype of HIV lymphoma. In the era of rituximab, the outcome seemed to be improved in patients with DLBCL and Burkitt lymphoma. However, the survival remains short in patients with poor prognostic factors and primary CNS lymphoma. Figure. Figure. Disclosures Hagiwara: Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Shiseki:NOVARTIS Pharma: Honoraria, Research Funding; Bristol-Myers Sqibb: Honoraria; Otsuka: Speakers Bureau. Tanaka:Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Otsuka: Honoraria; Pfizer: 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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Phase 1b/2a Open-Label, Multiple-Dose, Dose-Escalation Study To Evaluate The Safety and Tolerability Of Intravenous Infusion Of SNS01-T In Patients With Relapsed Or Refractory Multiple Myeloma, Mantle Cell Lymphoma, Or Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v122.21.1950.1950 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1950-1950 ◽

Cited By ~ 1

Author(s):

John A Lust ◽

Charles Barranco ◽

Saad Z Usmani ◽

Frits van Rhee ◽

Mehdi Hamadani ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Equity Ownership ◽

Pro Inflammatory Cytokines

Abstract Eukaryotic translation initiation factor 5A (eIF5A) has been implicated in the regulation of cell proliferation, apoptosis, and inflammation, and is the only known protein to be modified by hypusination. Hypusinated eIF5A, the predominant form of eIF5A in cancer cells, is involved in cell survival and activation of inflammatory pathways. In contrast, accumulation of the unhypusinated form of eIF5A is associated with apoptosis and mutants of eIF5A that cannot be hypusinated (e.g. eIF5AK50R) are pro-apoptotic. SNS01-T was designed to treat B-cell cancers and consists of two active components: a plasmid DNA expressing the pro-apoptotic eIF5AK50R under the control of a B cell-specific promoter, and an siRNA against an untranslated region of native eIF5A mRNA. When these two components are combined with linear polyethyleneimine (PEI), the nucleic acids are condensed into nanoparticles for protection from degradation in the blood and enhanced cellular delivery. The mode of action of SNS01-T is siRNA-mediated inhibition of hypusinated eIF5A and simultaneous over-expression of pro-apoptotic eIF5AK50R to induce cell death. In vitro cell studies and in vivo xenograft studies have demonstrated the efficacy of this approach. The safety and tolerability of intravenous administration of SNS01-T is being investigated in a first-in-human Phase1b/2a study in patients with relapsed or refractory multiple myeloma (MM), mantle cell lymphoma (MCL) or diffuse large B cell lymphoma (DLBCL). Eligible patients are being enrolled sequentially into four cohorts at increasing doses. Each patient receives an intravenous infusion of SNS01-T twice weekly for 6 consecutive weeks. Eligible patients must have been diagnosed with MM according to IMWG criteria, or with MCL or DLBCL with histologic confirmation. Patients also must have measurable disease, have relapsed or refractory disease after two or more prior treatment regimens, have a life expectancy of at least 3 months, and not be eligible to receive any other standard therapy known to extend life expectancy. The primary objective is to evaluate the safety and tolerability of multiple escalating doses of SNS01-T. Secondary objectives include analysis of pharmacokinetics, immunogenicity, pro-inflammatory cytokines, and therapeutic efficacy. The required 3 patients per cohort have completed the dosing schedule in cohorts 1 and 2 from a total of 10 patients enrolled (9 patients with MM and 1 with DLBCL). Of the ten patients enrolled, four completed the full treatment period, two did not complete dosing but were evaluable for safety, and four (three in cohort 1 and one in cohort 2) discontinued treatment after fewer than 8 doses and were not evaluable. There were no drug-related serious adverse events or dose limiting toxicities in either cohort 1 or 2. In cohort 1 (0.0125 mg/kg SNS01-T), two of three evaluable patients did not progress on treatment and were considered stable at week 3 and week 6, the end of the dosing regimen. The third patient progressed after receiving 10 of the 12 doses and was evaluable for safety. In cohort 2 (0.05 mg/kg), 3 patients (2 with MM and 1 with DLBCL) were evaluable for safety. Stabilization of serum monoclonal protein levels was observed in one MM patient of cohort 2. Two patients (1 with MM and 1 with DLBCL) progressed after receiving 8 of the 12 doses and were evaluable for safety. Results from ongoing pharmacokinetic studies, immunogenicity studies, and quantification of pro-inflammatory cytokines will be discussed. The planned dose levels for the third and fourth groups are 0.2 and 0.375 mg/kg, respectively. The results to date of this first-in-human clinical trial indicate that SNS01-T can be administered safely and the MTD has not yet been reached (Clinical Trials.gov Identifier: NCT01435720). Disclosures: Barranco: Senesco Technologies: Consultancy. Usmani:Celgene, Onyx, Millenium: Consultancy, Research Funding, Speakers Bureau. van Rhee:Jansen&Jansen: Research Funding. Thompson:Senesco Technologies: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Taylor:Senesco Technologies: stock options Other. Dondero:Senesco Technologies: Employment. Browne:Senesco Technologies Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Siegel:Celgene, Millenium, Onyx (same for all): Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

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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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PD-1 Blockade for Diffuse Large B-Cell Lymphoma after Autologous Stem Cell Transplantation

Blood ◽

10.1182/blood-2018-99-114914 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 706-706 ◽

Cited By ~ 1

Author(s):

Yi-Bin Chen ◽

Philippe Armand ◽

Robert A. Redd ◽

Jad Bsat ◽

Reid W Merryman ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Disease Relapse ◽

Advisory Committees ◽

Prior Therapy ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background: The leading cause of death after high-dose chemotherapy and autologous stem cell transplantation (ASCT) for relapsed / refractory (R/R) diffuse large B-cell lymphoma (DLBCL) remains disease relapse. Except for specific subsets, DLBCL appears to have relatively low susceptibility to single-agent PD-1 blockade. However, administering PD-1 blockade early after ASCT could leverage the remodeling immune landscape and minimal residual disease state to increase the therapeutic effect of PD-1 blockade and decrease the relapse rate after ASCT. A prior study with pidilizumab showed encouraging results in this setting (Armand et al. JCO 2013;31:4199-206), but the specificity of that antibody is still under investigation. We therefore conducted a phase 2 multi-center single-arm study of the anti-PD-1 monoclonal antibody pembrolizumab (pembro) in patients with chemosensitive DLBCL after ASCT. Another arm of this study enrolled pts with R/R classical Hodgkin lymphoma and will be presented separately. Methods: Patients ≥ 18y with R/R DLBCL who had received no more than 3 lines of prior therapy and had undergone ASCT with chemosensitive disease were enrolled on this study. In addition to meeting standard eligibility criteria for pembro treatment, pts had to have recovered from ASCT toxicities and had to begin study treatment within 60 days of stem cell infusion, with a goal of starting treatment within 21 days of hospital discharge. All patients received pembro 200mg IV every 3 weeks for 8 cycles. PET-CT scans were obtained at post-ASCT baseline, after 3 and 7 cycles, then at 12 and 18 months post-ASCT. The primary endpoint was the progression-free survival rate (PFS) at 18 months after ASCT, assessed using the International Harmonization Project 2007 criteria, with the approach considered promising if 22 patients were alive and in remission at 18 months. Results: 31 pts were enrolled and 2 withdrew consent before starting treatment. Among the 29 eligible pts, median age was 57 (22-76). Prior to ASCT, 18 (62%) were in CR and 11 (38%) were in PR. At study baseline (post-ASCT), 25 (86%) were in CR. 18 pts (62%) completed all 8 cycles of pembro per protocol. 11 pts (38%) stopped pembro early for pt choice (n=1, after febrile neutropenia), toxicity (n=6, including 3 pts with gr3 pneumonitis, 1 with g3 hepatitis, 1 with gr4 aplastic anemia) or progressive disease (n=4). 23 pts (79%) experienced a total of 57 gr3 or higher adverse events (AEs). The most common gr4 AE was neutropenia (n=6, 21%). Concerning related AEs, 9 pts (31%) experienced 14 gr3-4 AEs at least probably related to pembro including neutropenia (4 gr3, 1 gr 4) and pneumonitis (2 gr3). 10 pts (34%) experienced at least one immune-related AE of gr2 or higher severity including pneumonitis (n=1 gr2, n=2 gr3), transaminitis (n=1 gr2, n=1 gr3) and rash (n=1 gr2, n=1 gr3). There were no treatment-related deaths. Among the 29 eligible pts, 1 patient withdrew consent after cycle 1 and 1 pt was lost to follow-up after the 12m assessment (in CR). 27 pts (93%) were evaluable for the primary endpoint. 10 patients (34%, 95% CI: 18-54%) experienced disease relapse at a median of 5 months (3-18) after ASCT, and all other evaluable patients (n=17, 59%, 95% CI: 39-76%) were in CR at the 18m timepoint. 2 pts have died, both of whom had relapse at 3m after ASCT. Correlative studies including immune reconstitution and MRD analyses are ongoing. Conclusions: Pembrolizumab administered after ASCT in patients with R/R DLBCL is feasible with toxicity similar to its use in the R/R setting for other hematological malignancies. The high rate of neutropenia on this study, which is not a common AE of pembro in other settings, may be related to the burden of prior therapy or possibly to an accentuated toxicity of pembro in this specific patient population. The 18-month progression-free rate did not meet the protocol-specified primary objective, and therefore does not support a larger confirmatory study. Future studies in this setting should likely focus on specific subsets of DLBCL, e.g. primary mediastinal BCL, EBV+ DLBCL, T cell histiocyte rich LCL, which may be especially sensitive to PD1 blockade. Disclosures Chen: REGiMMUNE: Consultancy; Magenta Therapeutics: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Armand:Pfizer: Consultancy; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Infinity: Consultancy; Affimed: Consultancy, Research Funding; Otsuka: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Herrera:Seattle Genetics: Research Funding; KiTE Pharma: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding. LaCasce:Humanigen: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Data safety and monitoring board; Research to Practice: Speakers Bureau; Seattle Genetics: Consultancy, Honoraria. Jacobson:Pfizer: Consultancy; Precision Bioscience: Consultancy; Kite: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Humanigen: Consultancy. Jacobsen:Merck: Consultancy; Seattle Genetics: Consultancy. Rodig:Merck & Co., Inc.: Research Funding; Affimed Inc.: Research Funding; KITE Pharma: Research Funding; Bristol-Meyers-Squibb: Research Funding. Shipp:AstraZeneca: Honoraria; Merck: Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phase I/II Study of MAK683 in Patients with Advanced Malignancies, Including Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-147904 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1422-1422

Author(s):

Vincent Ribrag ◽

Jean-Marie Michot ◽

Lara Igleias ◽

Daniel Tan ◽

Brigette Ma ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Biomedical Research ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Advanced Malignancies ◽

Large B Cell

Abstract Introduction: Polycomb repressive complex 2 (PRC2) regulates transcription via trimethylation of histone H3 at lysine 27 (H3K27me3). Enhancer of zeste homolog 2 (EZH2) in conjunction with embryonic ectoderm development (EED) is a catalytic subunit of PRC2 and functions as a histone methyltransferase for H3K27. H3K27me3 appears to be a unifying component in many malignancies, inducing transcriptional repression. EED is a core component of PRC2 that modifies the epigenetic status of target genes, including cell cycle control genes. Dysregulation of this pathway leads to tumorigenesis in several diseases. MAK683 is a specific oral inhibitor that impairs EED binding to H3K27me3. This is a Phase I/II study of MAK683 in adult patients with advanced malignancies for whom no effective standard treatment is available. Here, we present data from a subset of patients with diffuse large B-cell lymphoma (DLBCL). Methods: Patients with DLBCL received escalating doses of MAK683 in fasted conditions. Patients were administered MAK683 10, 20, 40, 80, 120, 240, 300, 500, and 800 mg once daily (QD) or 60, 80, 120, 150, and 300 mg twice daily (BID) orally in 28-day cycles until unacceptable or dose-limiting toxicities (DLTs) had developed, disease progression, or death. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended Phase II dose (RP2D). Results: As of March 5, 2021, 31 patients with an Eastern Cooperative Oncology Group Performance Status of 0-2 were treated. Median age was 70 years (range: 33-84) and patients were heavily pre-treated, with a median of 4 (range: 1-16) prior lines of therapy. Overall, 30 patients (97%) discontinued treatment due to progressive disease (26 patients, 84%), adverse events (3 patients, 10%), and physician's decision (1 patient, 3%). In total, 21 (68%) patients experienced ≥1 treatment-related adverse event (TRAE) of any grade, and the most common (≥20%) TRAEs were thrombocytopenia (29%) and anemia (23%). Grade 3/4 TRAEs were reported in 14 (45%) patients, with ≥15% of patients reporting thrombocytopenia (19%), neutropenia, and decreased neutrophil count (16% each). DLTs were reported in 7 patients, all of which were hematological and therefore may be related to the underlying disease in this subset of patients. Patients in both the QD dosing group (120 mg, 240 mg, and 800 mg; n=1 each) and BID dosing group (60 mg, n=1; 80 mg, n=2; 150 mg, n=1) reported DLTs. There were no treatment-related deaths in this study. Overall response rate was 16% (95% CI: 5─34) and the disease control rate was 29% (95% CI: 14─48). Two patients (6%) achieved a complete response (CR) and 3 patients (10%) achieved a partial response. Four patients (13%) reported stable disease. Pharmacokinetic data showed rapid absorption of MAK683 across all dosing regimens tested and drug exposure increased with dose. Conclusions: MAK683 was generally well tolerated and there were preliminary signs of activity in patients with treatment-resistant DLBCL. The use of MAK683 as a novel strategy for the inhibition of EED may have potential in relapsed/refractory DLBCL. Disclosures Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Michot: GSK: Honoraria; MSD: Consultancy, Honoraria; Celgene: Honoraria; Innate Pharma: Research Funding; Incyte: Research Funding; H3 biomedecine: Research Funding; GSK: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Gamamabs: Research Funding; Forma: Research Funding; Exelixis: Research Funding; Eos: Research Funding; Eisai: Research Funding; Debiopharm: Research Funding; Daiichi Sankyo,: Research Funding; Clovis: Research Funding; Chugai: Research Funding; Boeringer Ingelheim: Research Funding; Celgene: Research Funding; Blueprint: Research Funding; Beigene: Research Funding; Bayer: Research Funding; Argen-x: Research Funding; Amgen: Research Funding; Agios: Research Funding; Aduro: Research Funding; Abbvie: Research Funding; ASTEX: Research Funding, Speakers Bureau; Astra Zeneca: Honoraria, Research Funding; Roche: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Igleias: Merck Serono, MSD, BMS, Lilly, Roche, Bayer, Sanofi: Consultancy. Tan: Novartis, Bayer, Boehringer Ingelheim, MSD, Astra Zeneca, Eli-Lilly, Loxo: Consultancy; Astra Zeneca, Pfizer, Novartis: Research Funding; Merck, Pfizer, Novartis, Takeda, Bayer, Boehringer Ingelheim, Roche: Honoraria. Ma: Novartis, Merck, Y-Biologies, Taiho, Daiichi: Honoraria, Speakers Bureau; Novartis, Inglheim: Research Funding. Wainberg: Plexxikon, BMS, EMD Serono: Research Funding; Roche, Novartis, BMS, Merck, Pfizer, Lilly, Bayer, Astra Zeneca, Daiichi, Astellas, Amgen: Consultancy. Fan: Novartis Institutes for Biomedical Research: Current Employment. Suenaga: Novartis Pharma K.K.: Current Employment. Cheng: Novartis: Current Employment. Lai: Novartis: Current equity holder in publicly-traded company; Novartis Institutes for Biomedical Research: Current Employment. Yokota: AstraZeneca, Chugai Pharma, MSD, Syneos Health, Lilly, Incyte, Novartis, GlaxoSmithKline, Ascent: Research Funding; Abbott Japan, Ono Pharmaceutical, Chugai Pharma, Bristol-Myers Squibb, Merck Biopharma, MSD, Rakuten Medical, Eisai: Honoraria; Merck Biopharma, MSD, Rakuten Medical: Membership on an entity's Board of Directors or advisory committees.

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Healthcare Resource Utilization and Costs in Patients with Relapsed and Refractory Diffuse Large B-Cell Lymphoma: A U.S. Real-World Observational Study

Blood ◽

10.1182/blood-2019-128368 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2133-2133

Author(s):

Xiaoqin Yang ◽

François Laliberté ◽

Guillaume Germain ◽

Monika Raut ◽

Mei Sheng Duh ◽

...

Keyword(s):

Board Of Directors ◽

Healthcare Costs ◽

Research Funding ◽

Index Date ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Icd 10 ◽

Large B Cell

Background: Around a third of patients with diffuse large B-cell lymphoma (DLBCL) either relapse following first-line (1L) chemoimmunotherapy (CIT) or are refractory to 1L CIT. Among patients with relapsed or refractory (R/R) disease eligible for second-line (2L) therapy, fewer than half survive beyond 5 years. Refractory DLBCL entails a poorer prognosis than relapsed DLBCL; however, literature on healthcare resource use (HRU) for these two populations is sparse. This study sought to describe HRU and healthcare costs in U.S. patients with relapsed and refractory DLBCL. Methods: A retrospective claims analysis was conducted using the Optum® ClinformaticsTM DataMartTM database (01/2013-03/2018). Adult patients with ≥1 hospitalizations or ≥2 outpatient (OP) visits with an ICD-10-CM diagnosis code for DLBCL after 10/01/2015 were included. Patients were defined as (1) incident if they had no prior ICD-9-CM diagnosis code for unspecified DLBCL or primary mediastinal large B-cell lymphoma (PMBCL), or as (2) prevalent if they had a prior ICD-9-CM code for unspecified DLBCL or PMBCL. For incident cases, the index date was defined as the date of the first ICD-10 code for DLBCL or other lymphoma (after 10/01/2015); for prevalent cases, the index date was the date of the first unspecified ICD-9 code for DLBCL or PMBCL. Patients with an ICD-10 code for PMBCL at any time, or an ICD-9/ICD-10 code for Hodgkin lymphoma, multiple myeloma, and other selected lymphomas during the 12 months before the index date were excluded. Patients with DLBCL were classified as relapsed if they initiated 2L ≥90 days after the last dose of the 1L therapy and as refractory if they initiated 2L <90 days after the last dose of 1L therapy. The 12-month period prior to the index date was defined as the baseline period. HRU (including hospitalizations, OP, ER, and other visits) and associated costs, including pharmacy costs, were evaluated per patient per year (PPPY) from the initiation of 1L up until end of data availability or end of continuous health plan enrollment. Results: A total of 139 and 68 incident DLBCL patients were identified as relapsed and refractory, respectively, with median (interquartile range [IQR]) age of 74 (68-81) and 72 (67-78), and mean Quan-Charlson comorbidity index score of 3.1 in both cohorts. The mean (SD) number of baseline all-cause hospitalizations was 0.35 (0.67) for relapsed and 0.40 (0.98) for refractory patients. Mean total baseline healthcare costs were $21,195 for relapse and $29,754 for refractory patients. R/R patients with prevalent DLBCL (153 relapsed; 21 refractory) had similar baseline characteristics. In incident DLBCL patients, those with relapsed and refractory DLBCL were observed for 495 and 346 days, respectively. On average, 1.7 and 2.4 hospitalizations PPPY occurred in relapsed and refractory patients, respectively. The table shows the breakdown of HRU by type of visits. Although hospitalizations were qualitatively higher in refractory patient, mean ± SD total healthcare costs were in similar range (relapsed= $164,631 ± 115,503; refractory= $159,729 ± 102,442). Corresponding OP costs (relapsed= $99,748 ± 85,350; refractory= $86,505 ± 59,081) were mainly driven by DLBCL anti-cancer therapy costs and were qualitatively higher among relapse compared to refractory patients ($41,768 ± 46,135 and $29,454 ± 32,242, respectively). In prevalent DLBCL, evaluation periods of relapsed and refractory patients lasted 964 and 786 days, respectively. Patients with relapsed DLBCL had 1.1 hospitalizations PPPY, and those with refractory DLBCL had 1.9 hospitalizations PPPY. Corresponding mean ± SD total healthcare costs were $112,653 ± 79,617 and $95,465 ± 50,167 PPPY, respectively. More pronounced results (i.e., higher rates of hospitalizations and corresponding healthcare costs for refractory compared to relapse patients) were observed in a sensitivity analysis when HRU and costs were assessed up to 6 months post-index date, which suggests that refractory patients are more likely to be hospitalized early on. Conclusions: In this U.S. real-world study, patients with R/R DLBCL incurred substantial HRU and costs, thereby imposing a considerable burden on the healthcare system. There was a trend towards higher hospitalizations for refractory patients, suggesting a worse prognosis; however total healthcare costs were similar, offset by higher anti-cancer therapy costs among relapsed patients. Disclosures Yang: Merck & Co.: Employment. Laliberté:Janssen Scientific Affairs, LLC: Research Funding; Merck & Co., Inc.: Research Funding. Germain:Janssen Scientific Affairs, LLC: Research Funding; Merck & Co., Inc.: Research Funding. Raut:Merck & Co., Inc.: Employment. Duh:Analysis Group, Inc., a consulting firm that has received research funding from Shire, a Takeda company, to conduct this study: Employment; Shire: Research Funding; Merck: Research Funding. Sen:Merck & Co., Inc.: Employment. Lejeune:Merck & Co., Inc.: Research Funding. Desai:Merck & Co., Inc.: Employment. Armand:Merck & Co.: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Pfizer Inc: Research Funding; Otsuka: Research Funding; Bristol Myers Squibb Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; Roche: Research Funding; Dana-Farber Cancer Institute: Employment; Sigma-Tau: Research Funding; Affimed: Research Funding; Serventa: Research Funding; Infinity Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.

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