Refractory Aggressive non-Hodgkin Lymphoma Research Articles

Abstract CT164: Phase 1a/1b clinical trial of LP-284, a highly potent TP53 mutation agnostic DNA damaging agent, in patients with refractory or relapsed lymphomas and solid tumors (NCT06132503)

Abstract Background: Patients (pts) with relapsed or refractory (R/R) aggressive non-Hodgkin lymphoma (NHL) typically experience poor prognosis. In addition, despite advances in NHL therapies, TP53 mutations and double rearrangements of MYC and BCL2 have been associated with adverse clinical outcomes. LP-284, a DNA damaging agent with nanomolar potency in NHL cells, is agnostic of TP53 mutation status. In a TP53-mutated mantle cell lymphoma (MCL) xenograft model, LP-284 inhibited tumor growth at least 3-fold more than ibrutinib and bortezomib. Furthermore, LP-284 resulted in near complete tumor regression in a MCL model that is refractory to ibrutinib and bortezomib. In a high-grade B-cell lymphoma with MYC and BCL2 rearrangement xenograft model, LP-284 led to 99% tumor growth inhibition when used as a single agent and showed synergistic effect with rituximab. The above data strongly suggests that LP-284 is a promising therapy for aggressive R/R NHL, especially subgroups with TP53 mutation and/or MYC/BCL2 rearrangements. LP-284 also showed promise in the setting of solid tumors, as evidenced by strong anti-tumor potency in a spectrum of solid tumor cell lines and sarcoma xenograft models. Methods: This Phase 1, first-in-human, open-label, dose escalation study assesses the safety, tolerability, pharmacokinetics (PK) and clinical activity of LP-284 in adult pts with R/R lymphomas and solid tumors. Up to 30 adult pts will be enrolled in the Phase 1a dose escalation study. After completion of Phase 1a, up to 40 pts with R/R diffuse large B-cell lymphoma (DLBCL) and MCL, each, will be enrolled for a dose expansion Phase 1b study. The primary objectives of the Phase 1a study are to evaluate the safety and tolerability of escalating doses of LP-284 and to determine the MTD and RP2D. Participants will receive LP-284 via i.v. infusion on days 1, 8, and 15 of 28-day cycles. A Bayesian Optimal Interval (BOIN) design is being used to determine the MTD. Dose escalation involves single patient cohorts for the first 2 dose levels and at least 3 pts/cohort for subsequent dose levels. The secondary objectives are to characterize the PK and to assess the clinical activity of LP-284. The exploratory objectives are to evaluate the association between tumor response and changes in ctDNA and importantly to identify potential genomic features associated with LP-284 response, particularly those related to DNA damage response pathways. The primary objectives of Phase 1b are to obtain preliminary estimates of clinical activity in adult patients with R/R DLBCL and MCL, and to determine the dose of LP-284 for further development based on exposure-response/safety relationships derived from the totality of the data obtained from both Phase 1a and 1b. Trial (NCT06132503) is open to accrual. Citation Format: Jianli Zhou, Reginald Ewesuedo, Giulia Agnello, Aditya Kulkarni, Kishor Bhatia. Phase 1a/1b clinical trial of LP-284, a highly potent TP53 mutation agnostic DNA damaging agent, in patients with refractory or relapsed lymphomas and solid tumors (NCT06132503) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT164.

Mitoxantrone Hydrochloride Liposome, Gemcitabine, Vinorelbine with or without Rituximab (GVM±R) in Patients with Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

Background: In patients with relapsed/refractory (r/r) aggressive non-Hodgkin lymphoma (aNHL), achieving a response to salvage therapy is a crucial predictor for long-term survival, as only chemosensitive patients have the opportunity to undergo autologous stem cell transplantation. Mitoxantrone hydrochloride liposome (PLM60) has shown good efficacy and safety in r/r peripheral T-cell lymphoma (PTCL) based on a prior study, with an objective response rate (ORR) of 40.7% and a complete response rate (CRR) of 20.4% (2020 ASH abstract 42). To determine the appropriate dosage of PLM60 in a multi-drug combination chemotherapy, we conducted a phase I clinical study aiming to explore the maximum tolerated dose (MTD) of PLM60 when combined with gemcitabine, vinorelbine, with or without rituximab (GVM±R). This trial was registered at www.clinicaltrials.gov as NCT05299164. Methods: The study was a prospective, single-center, single-arm, 3+3 dose-escalation study involving patients aged 18-70 years with r/r aNHL. PLM60 was administered on day 1 at four different dose levels (DL) (DL1: 16 mg/m 2, DL2: 18 mg/m 2, DL3: 20 mg/m 2, DL4: 22 mg/m 2), gemcitabine on day 1 and 8 at 800 mg/m 2, vinorelbine on day 1 and 8 at 20 mg/m 2, and rituximab on day 0 at 375 mg/m 2 (only administered in CD20+ lymphoma based on the investigator's judgment). The treatment was repeated every 21 days. Up to 6 cycles of therapy were planned. After the first cycle, dose-limiting toxicity (DLT) was assessed to determine the MTD of PLM60 in the GVM±R regimen. Results: As of July 15, 2023, the study had enrolled 12 eligible patients (DL1: n=6, DL2: n=6), with different aNHL subtypes, including 6 with diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), 3 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL, NOS, and 1 with sezary syndrome (SS). The median age of the patients was 49 years (range, 23 to 69), with 41.7% being male. All patients had advanced-stage disease, with 33.3% in stage III and 66.7% in stage IV. They had received a median of 2.5 lines of therapy (range, 2 to 7), and 91.7% (11/12) of patients had received anthracycline-containing chemotherapy in their prior treatment. All patients with DLBCL, NOS had received rituximab during their prior therapy. 66.7% (8/12) of the patients were refractory to their last line therapy, and 2 out of the 6 patients with DLBCL, NOS experienced relapse after anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy. During the study, two patients experienced DLTs of grade 4 neutropenia lasting for more than 7 days, with one occurring in the DL1 group and the other in the DL2 group. In response to these observations, an additional three patients were enrolled in each of the groups. The most common grade 3/4 TRAEs with an incidence ≥10% were leucopenia (91.7%), neutropenia (83.3%), thrombocytopenia (66.7%), anemia (41.7%), febrile neutropenia (25.0%), pneumonia (25.0%), and hypokalemia (25.0%). With a median follow-up of 2.5 months, 11 patients were evaluated for efficacy, showing an ORR of 72.7% (95% CI 39.0% to 94.0%) and a CRR of 45.5% (95% CI 16.8% to 76.6%). In the DL1 group (16 mg/m 2), the CRR was 50.0% (3/6), and the ORR was 66.7% (4/6), while the DL2 group (18 mg/m 2) had a CRR of 40.0% (2/5) and an ORR of 80.0% (4/5) (Table 1). Among the DLBCL patients, the CRR was 60.0% (3/5), and among AITL patients, the CRR was 66.7% (2/3). Patients with PTCL NOS and SS achieved partial responses (PR). Two DLBCL patients who had previously received multiple lines of therapy, including anti-CD19 CAR T-cell therapy, achieved CR after GVM±R treatment. Conclusions: The GVM±R regimen exhibited manageable safety and encouraging efficacy in patients with r/r aNHL, despite the fact that the majority of these patients had received anthracycline-containing chemotherapy in their previous treatment. The trial is still ongoing to determine the recommended phase 2 dose for the subsequent phase 2 clinical study.

Abstract CT130: An open label, dose escalation, phase 1 study of AT101, a novel CD19-directed CAR-T cell therapy targeting a membrane-proximal epitope of CD19, in patients with relapsed or refractory B cell non-Hodgkin lymphoma

Abstract Background and Preliminary Data: All the FDA-approved CD19 CAR-T cell therapies are based on an antigen-binding domain (scFv) based on the FMC63 antibody which binds to the membrane-distal region of CD19 to an epitope encoded by exons 3 and 4 (Klesmith JR, Biochemistry, 2019; Zhang Z, JITC, 2020). While these CART19 products are very effective in the clinic, the majority of patients still do not respond or eventually relapse due to several mechanisms of resistance, including T cell dysfunction and epitope CD19-negative escape. Novel strategies to enhance the activity of CART cells and reduce escape are critically needed. We recently demonstrated that modifications of the binding region of the CAR (scFv) (Singh N., Nat Med, 2021) can drastically change the interaction between the CAR T cell and the cancer cells, potentially improving the anti-tumor effect. To this goal, we developed a novel anti-CD19 antibody clone (1218) that binds to a membrane-proximal epitope of CD19 (exon 2 region K59-K63) thereby not competing with FMC63. We developed a novel CART19, called AT101, using a humanized 1218 scFv along with 4-1BB costimulatory and CD3zeta domain in a lentiviral backbone. In preclinical models, AT101 showed more potent in vitro cytotoxicity against CD19-positive B lymphoma cells in a long-term killing assay and in a B-ALL (NALM6) in vivo model as compared to the control of FMC63 based CAR-T cells. In addition, differently than FMC63-based CART, AT101 could target tumor cells expressing point mutations of CD19 that are associated with relapse post-CART19 (FMC63) (Zhang Z, JITC, 2020) and leukemic blasts aberrantly expressing FMC63 CAR19 on their surface (Ruella M, Nat Med, 2018). Based on the preclinical efficacy and safety, a phase 1 clinical trial testing autologous AT101 was started for patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Trial Design and Methods: This open-label, multi-center, first-in-human Phase 1 study will assess the safety and feasibility of AT101 in patients with relapsed or refractory B cell non-Hodgkin lymphoma. Key eligibility criteria include patients aged ≥19 years of age with histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. In this phase 1 trial, patients (n=3 per dose level; up to n=18 in total) are treated with AT101 in 3 dose-escalation cohorts based on a standard 3 + 3 design. CART doses are 2.0 × 105, 1.0 × 106, or 5.0 × 106 CAR+T cells/kg. The primary objective is to determine the safety, the maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of AT101 in participants following lymphodepletion with cyclophosphamide and fludarabine (250 mg/m2 and 25 mg/m2). The secondary objective is to evaluate the preliminary efficacy assessments (overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), event-free survival (EFS), and pharmacokinetics of AT101. Exploratory objectives include assessment of CD19 expression and cytokines in the blood. Patients will be followed for safety for at least 60 months post AT101 infusion. Clinical trial registry number: NCT05338931. As of January 11, 2023, AT101 has been infused to six patients in cohort 1 and three patients in cohort 2. Detailed results will be presented at the meeting. Citation Format: Yunlin Zhang, Ki Hyun Kim, Dok Hyun Yoon, Ruchi P. Patel, Jae-Cheol Jo, Hyungwoo Cho, Jong-Ho Lee, Hyun-Jong Lee, Lei-Guang Cui, In-Sik Hwang, Young Ha Lee, Jong-Hoon Kim, Yong Gu Lee, Puneeth Guruprasad, Jong-Seo Lee, Junho Chung, Marco Ruella. An open label, dose escalation, phase 1 study of AT101, a novel CD19-directed CAR-T cell therapy targeting a membrane-proximal epitope of CD19, in patients with relapsed or refractory B cell non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT130.

SUNMO: A Phase III Trial Evaluating the Efficacy and Safety of Mosunetuzumab in Combination with Polatuzumab Vedotin Versus Rituximab in Combination with Gemcitabine Plus Oxaliplatin in Patients with Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

SUNMO: A Phase III Trial Evaluating the Efficacy and Safety of Mosunetuzumab in Combination with Polatuzumab Vedotin Versus Rituximab in Combination with Gemcitabine Plus Oxaliplatin in Patients with Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Impact of CD19 CAR T-cell product type on outcomes in relapsed or refractory aggressive B-NHL

AbstractCD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). After adjustment for age, hematopoietic cell transplantation-specific comorbidity index, lactate dehydrogenase (LDH), largest lesion diameter, and absolute lymphocyte count (ALC), CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower cytokine release syndrome (CRS) severity compared with axicel (adjusted odds ratio [aOR], 0.19; 95% confidence interval [CI]; 0.08-0.46), with a trend toward lower CRS severity with tisacel compared with axicel (aOR, 0.47; 95% CI, 0.21-1.06; P = .07). Tisacel (aOR, 0.17; 95% CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95% CI, 0.06-0.47) were both associated with lower immune effector cell-associated neurotoxicity syndrome severity compared with axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared with axicel. Although sensitivity analyses using either positron emission tomography- or computed tomography-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients.

CAR T-cell Therapy in Indolent Lymphoma

Introduction CD19 directed chimeric antigen receptor (CAR) T-cell therapy has had a transformative impact on the natural history of chemotherapy refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL), inducing long-term remissions in 40–50% of patients.1–5 It does this, however, at the expense of both financial and clinical toxicity. But the cost and risk of care in the absence of CAR T-cells in these instances outweighs the risk of the therapy itself, and so it has broadly been accepted as a standard of care for these patients. Moving CD19 directed CAR T-cell therapy into the slower growing, but historically incurable, indolent B-NHLs has the potential to challenge this balance between risks and benefits. Will CAR T-cells offer definitive therapy for these otherwise incurable diseases? If not, will CAR T-cells positively affect long-term survival over alternative therapies? The answer to these questions will determine how oncologists weigh the financial and clinical costs against the therapeutic benefits.

Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Phase 1 Results from ZUMA-6: Axicabtagene Ciloleucel (axi-cel; KTE-C19) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma (DLBCL)

▪Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, has shown promising efficacy in refractory aggressive non-Hodgkin lymphoma in the ZUMA-1 trial with an objective response rate (ORR) of 82%, including 54% complete responses (CRs; Locke et al. AACR 2017. #9986). Checkpoint expression within the tumor environment, at baseline and post-CAR T cell infusion, suggests that checkpoint blockade could augment axi-cel activity (Galon et al. ASCO 2017. #3025; Vranic et al. PLOS One. 2016). ZUMA-6 is a phase 1/2 study evaluating the safety and efficacy of combination treatment with axi-cel and the anti-PD-L1 antibody, atezolizumab (atezo), in patients with refractory DLBCL (NCT02926833).Methods: Eligible patients (≥ 18 years) had received ≥ 1 prior CD20-targeting and anthracycline-containing regimen with stable or progressive disease to last line of therapy or early relapse after autologous stem cell transplant, had an ECOG ≤ 1, and had adequate bone marrow and organ function. Patients received low-dose conditioning with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day × 3 days, followed by axi-cel infusion at a target dose of 2 × 106 cells/kg. In the phase 1 portion of the study, in cohorts 1, 2, and 3, atezo 1200 mg was administered every 21 days for 4 doses starting on day 21, 14, and 1 post-axi-cel infusion, respectively. This report describes phase 1 results from the first 2 dosing cohorts. The primary endpoint of phase 1 was incidence of dose-limiting toxicities (DLTs) within 21 days from the first atezo dose. Secondary endpoints included frequency of adverse events (AEs), ORR, and biomarkers.Results: As of the June 23, 2017 data cut-off, there were 6 patients dosed with axi-cel and atezo (3 in cohort 1; 3 in cohort 2). Median age was 52 years (range, 29-66). Patients had a median of 3 prior therapies (range, 2-4), 4 had disease progression as best response to last prior treatment before study entry, and 3 had an International Prognostic Index score of 3 or 4. No DLTs were observed in either cohort and there was no evidence of worsening or recurrent AEs consistent with cytokine release syndrome (CRS), neurologic events (NE), or other CAR T cell-related toxicities following atezo administration in either dosing schedule. All patients experienced at least 1 AE, the majority of which were cytopenias attributed to conditioning chemotherapy. The most common grade ≥ 3 AEs were anemia (67%), encephalopathy (67%), and hyponatremia (50%). Incidences of grade ≥ 3 CRS and NE were 33% and 67%, respectively. Five patients were evaluable for response; ORR was 100% (5/5) with 1 CR observed. One CR and 2 partial responses are ongoing. All 6 ZUMA-6 patients demonstrated a CAR T cell area under the curve in the first 28 days (AUC28) that was over 2-fold higher than the median observed in patients with DLBCL enrolled in ZUMA-1 (ZUMA-6 range, 816-2301 days × cells/uL; ZUMA-1 median, 374 days × cells/uL). A second peak of > 2-fold over the pre-atezo level in serum concentrations of the immune-modulating cytokine interferon gamma was also observed 1 week after the first atezo infusion in 4/5 evaluable patients. Cohort 3 is currently enrolling and updated results, including those from cohort 3, will be presented.Conclusions: In this ongoing phase 1 study, PD-L1 blockade with atezo following axi-cel infusion appeared to have a manageable safety profile, and translational evidence suggested an enhancing pharmacodynamic action on CAR T cells. Results collected thus far support further evaluation of the combination in the phase 2 portion of the study. DisclosuresLocke:Kite Pharma: Consultancy; Cellular Biomedicine Group Inc: Consultancy. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Miklos:Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses; Pharmacyclics, LLC: Consultancy, Other: Travel expenses, Patents & Royalties, Research Funding; Kite Pharma: Consultancy, Other: Travel expenses, Research Funding; Adaptive Biotechnologies: Consultancy, Other: Travel expenses; Roche: Research Funding; Genentech: Research Funding; Novartis: Research Funding. Herrara:BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Immune Design: Research Funding. Jacobson:Kite Pharma: Consultancy; Pharmacyclics, LLC: Consultancy. Lee:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Bot:Kite Pharma: Employment, Equity Ownership. Xue:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Roberts:Kite Pharma: Employment, Equity Ownership.

Evaluating the Indirect Costs of Care Associated with Salvage Chemotherapy for Relapsed and Refractory Aggressive-Histology Lymphoma: A Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial

Background: The randomized CCTG LY.12 trial demonstrated that gemcitabine, cisplatin and dexamethasone (GDP) was non-inferior to dexamethasone, cytarabine, cisplatin (DHAP), with or without rituximab, in patients with relapsed or refractory (R/R) aggressive non-Hodgkin lymphoma (NHL) prior to autologous stem cell transplantation (ASCT) [ Crump JCO 2014 ]. A cost-utility analysis also proved GDP to be associated with both lower direct costs and similar quality-adjusted outcomes, and as such, is the preferred salvage regimen in this patient population [ Cheung JNCI 2015 ]. We conducted an analysis of such costs (lost productivity, paid and unpaid caregiver time) based on the trial data.Methods: Resource utilization data were collected for all Canadian patients in the trial. Lost productivity data for both patients and caregivers were collected at baseline and with each chemotherapy cycle pre-ASCT, from a proportion of the Canadian patients, using an adapted Lost Productivity questionnaire. The human capital approach was utilized to calculate lost productivity costs using published Canadian salary standards according to field of employment [ http://www.statcan.gc.ca ]. Costs were presented in 2012 Canadian dollars from a societal perspective, and disaggregated to highlight the costs of patient lost productivity, paid caregiving hours and lost productivity from family members providing unpaid caregiving, and these were compared between the two treatment strategies. All statistical tests were two-sided, using the Wilcox rank sum test.Results: Of the 519 Canadian pts in the trial, 374 completed at least 2 lost productivity instruments (72%) and are included in this analysis. In this subset, 62% of patients were male, the mean age was 53 years (range: 23-70 years), with 27% of patients being older than 60 years of age. There were no significant differences between the two arms with respect to demographics and lymphoma disease characteristics. As well, the lost productivity subset of patients was representative of the whole Canadian cohort, with no significant or meaningful differences in baseline characteristics.Average per patient indirect costs over the period of 2-3 cycles of chemotherapy were $2655 (95% CI $2253 to $3058) for patients in the GDP arm, an outpatient chemotherapy regimen, and $3010 (95% CI $2334 to $3686) for patients in the DHAP arm, a 3-day inpatient chemotherapy regimen (Table 1). There was no statistically significant difference in costs detected (difference $354; p=0.38). At salvage chemotherapy start, 69% of pts in the GDP arm and 73% in the DHAP arm were non-workers (on disability or sick leave). Of those still working full time at baseline, 3.5% reported decreasing their workload (part-time or stopped working) in the GDP arm, compared with 7.4% in the DHAP arm. Patients in both treatment arms reported substantial limitations in their usual activities, with approximately 50% impairment due to their health status.The different cost components were disaggregated. Lost productivity of patients accounts for 65% of total indirect costs. Average patient lost productivity costs were $1908 with GDP and $1782 with DHAP (p = NS). Average care costs, including both paid and unpaid assistance, were $757 (95% CI $476 to $1037) with GDP vs. $1238 (95% CI $626 to 1850) with DHAP (difference $481; p=0.07). Over the period of 2-3 cycles of salvage chemotherapy, patients in the GDP arm paid for an average of 14.9 hours of care compared with 21.3 hours in the DHAP arm (p = NS) .Thirty-nine pts (10.4%) did not have any unpaid caregivers, while the rest were cared for by a combination of: a spouse (68.5%), child/parent (34.8%), other relative (19.5%), friend (16.3%) or neighbor (2.9%). The average number of unpaid caregiver hours appeared lower with GDP (24.9 hrs; 95% CI 14.2 to 35.5) compared to DHAP (42.7 hrs; 95% CI 15.1 to 70.3).Conclusions: Salvage chemotherapy for R/R aggressive NHL is associated with significant indirect costs to the patients and their caregivers, with a significant majority (approximately 70% of patients) not working or having to reduce their workload during this treatment time. Although there were no significant differences in all indirect costs between the two treatment arms, the paid and unpaid caregiving costs did appear higher with the DHAP arm. These data potentially provide further support for GDP being the preferred treatment approach in this patient population. [Display omitted] DisclosuresPrica:Celgene: Honoraria; Janssen: Honoraria. Hay:Janssen: Research Funding; Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Kite: Research Funding; Amgen: Research Funding. Crump:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Ortho: Consultancy, Membership on an entity's Board of Directors or advisory committees.

CD19 CAR T-cell product type independently impacts CRS and ICANS severity in patients with aggressive NHL.

7532 Background: CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells achieve high response rates in patients (pts) with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (NHL), but are limited by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Pivotal trial data suggested distinct toxicity risks across CD19 CAR T-cell products, but differences in pt and disease characteristics may have confounded these observations. Thus, we assessed the independent impact of 3 CD19 CAR T-cell products (axicabtagene ciloleucel[axicel], tisagenlecleucel [tisacel], and JCAR014) on CRS and ICANS severity in 136 pts with R/R aggressive NHL. Methods: We retrospectively analyzed aggressive NHL pts treated at our institutions with cyclophosphamide and fludarabine lymphodepletion (LD) followed by CD19 CAR T-cell therapy. Axicel and tisacel pts were treated off trial using commercial products. JCAR014 (defined-composition 4-1BB-costimulated CD19 CAR T cells) was administered in all pts at the dose of 2x106/kg on a phase I/II clinical trial (NCT01865617). CRS and ICANS were graded according to the ASTCT criteria and CTCAE 4.03, respectively. We used multivariable proportional odds logistic regression to model CRS and ICANS grade. Results: The CAR T-cell product was axicel, tisacel, or JCAR014 in 50%, 28%, and 22% of pts, respectively. Compared to axicel pts, we observed higher preLD LDH levels in tisacel and JCAR014 pts, and lower preLD albumin with tisacel (p < 0.001) with comparable age and hematopoietic cell transplantation comorbidity (HCT-CI) indexes across CAR T-cell products. Higher day-28 overall response rate by Lugano criteria was observed after axicel (71%) compared to tisacel (56%) and JCAR014 (53%). Adjusting for age, HCT-CI, preLD LDH, preLD albumin, CAR T-cell product type was associated with CRS severity (tisacel versus [vs] axicel, OR = 0.45, p = 0.05; JCAR014 vs axicel, OR = 0.29, p = 0.005;). Age had limited or no impact on CRS severity (OR 95%CI, 0.97-1.02), while the effect of HCT-CI was undetermined (OR 95%CI, 0.85-1.27). In a multivariable model including the same covariates as above, CAR T-cell product type (tisacel vs axicel, OR =.14, p <.001; JCAR014 vs axicel, OR = 0.31, p = 0.009), preLD LDH (OR, 3.96 per log10 increase; p = 0.04) and age (OR per 10-year increase, 1.32; p =.06) were associated with ICANS severity. Interaction effect testing suggested effect modification of age by the CAR T-cell product type (tisacel/JCAR014 versus axicel, p = 0.06); using a multivariable model including this interaction term, the predicted probabilities of grade ≥3 ICANS in a 70 year-old after axicel, tisacel, and JCAR014 were 40%, 6%, and 8%, respectively. Conclusions: CAR T-cell product type independently impacts CRS and ICANS severity in NHL pts. Our findings provide key insights to guide patient and CAR T-cell product selection.

Evaluating the Indirect Costs of Care Associated with Salvage Chemotherapy for Relapsed and Refractory Aggressive-Histology Lymphoma: A Subset Analysis of the Canadian Cancer Trials Group (CCTG) LY.12 Clinical Trial.

We conducted an analysis of indirect costs alongside the LY.12 randomized trial in patients with relapsed or refractory (R/R) aggressive non-Hodgkin lymphoma (NHL). Lost productivity data for Canadian patients and caregivers in the trial were collected at baseline and with each chemotherapy cycle pre-transplant, using an adapted Lost Productivity questionnaire. Mean per patient indirect costs were CAD 2999 for patients in the GDP arm and CAD 3400 in the DHAP arm. A substantial majority was not working or had to reduce their workload during this treatment time. Salvage chemotherapy for R/R aggressive NHL is associated with significant indirect costs to patients and their caregivers.

Management of Patients with Aggressive B Cell Non-Hodgkin Lymphoma after Relapse from Axicabtagene Ciloleucel: Single Center Real-World Experience

Background: Chimeric Antigen Receptor (CAR) T-cell therapy has changed the treatment landscape for patients with Non-Hodgkin Lymphoma (NHL). Despite the excellent responses in relapsed or refractory (R/R) aggressive NHL (aNHL), the outcome of patients (pts) that fail CAR T-cell therapy remains poor, and there is not a clear path for management of their disease. Methods: We conducted a retrospective analysis of aNHL pts treated with axicabtagene ciloleucel (axi-cel) at the Mayo Clinic campuses in Arizona and Florida between June 2018 and August 2020. We evaluated the predisposing factors, management, toxicities, and response after CAR T-cell therapy failure. Statistical calculations using parametric tests were performed, and survival curves were estimated using the Kaplan-Meier method and compared statistically using the log-rank test and Pearson's correlation. Results: Thirty-four pts with aNHL received axi-cel. The median age was 53 years [IQR 42-63], and 62% were male. All pts received inpatient axi-cel infusions and the median length of hospital stay was 14 days (IQR: 11-17). Cytokine Release Syndrome (CRS) was observed in 91% of pts (3% grade ≥3), while Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) was observed in 41% (24% grade ≥3). At day 30 response assessment, 16 pts (47%) had complete responses (CR), 9 (26%) had a partial response (PR), 4 (12%) had stable disease (SD), 4 (12%) showed progression with primary refractory disease (PD) and 1 (3%) died before assessment due to grade 5 ICANS (Table 1). After a median follow-up of 178 days, we observed PD in 12 (35%) pts. The median time-to-progression was 72 days (IQR 58-93) and most of the pts (83%) progressed during the first 3 months. None of the patients with more than 5 months of sustained response developed progression of disease. The likelihood of progression during the first 6 months after axi-cel infusion was 19%, 57%, 50% for pts that initially achieved a CR, PR, SD, respectively. Expression of CD19 was observed in 66% (4/6) of pts with available biopsies after axi-cel suggesting a failure mechanism other than antigen escape. The mortality rate of the R/R aNHL group was 58% with a median survival time of 83 days (IQR: 50-109). There was no association between age, stage, number of previous therapies, time from previous therapy to axi-cel infusion, time from apheresis to infusion, use of tocilizumab, or steroids with progression of disease. Of note, no correlation between CRS or ICANS with progression of disease was found (2-way ANOVA test F (1, 4) = 3.802, p=0.1230). Maintaining a response to axi-cel treatment (CR, PR, or SD) for ≥ 3 months was a strong predictor of durable response with an HR of 0.05 (p= <0.0001). Eleven R/R pts received subsequent therapies with a median time to retreatment of 76 days. Those treatments included: Radiotherapy (n=7), pembrolizumab (n=3), polatuzumab-rituximab with (n=3) and without (n=1) bendamustine, obinutuzumab with (n=1) or without (n=1) lenalidomide, Hyper-CVAD (n=2), R-GemOx (n=1), rituximab with lenalidomide (n=1) and intrathecal methotrexate (n=1). Only 2 (17%) patients have responded to salvage therapy achieving PR (one patient treated with radiotherapy and the other with rituximab-lenalidomide after two other salvage therapies). Conclusion: Our experience demonstrates the majority of aNHL patients respond to axi-cel. If patients maintain their response for more than 3 months, the likelihood of progression is very low - 15%. Similar to what has been previously reported in the literature, our series showed that 35% of patients progressed after axi-cel, and subsequently have a poor prognosis with median survival after a relapse of only 83 days (IQR: 50-109). Therapy options following axi-cel were limited due to severe cytopenias, only 2 of 11 patients have responded to salvage therapy, suggesting that conventional treatments are probably not effective/safe in this high-risk group of patients. Interestingly, the majority of R/R pts with available biopsies showed persistent CD19 expression suggesting that CAR T-cell exhaustion, poor in vivo expansion, and inhibitory signals of the tumor microenvironment may contribute to resistance. Additional strategies for monitoring of axi-cel persistence and its immunophenotypic profile could be helpful for prognosis and management of CAR T-cell pts receiving axi-cel. Disclosures Kharfan-Dabaja: Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Castro:Fate Therapeutics: Research Funding; Kite Pharma: Research Funding; Pharmacyclics: Research Funding.

Phase I/II study of bendamustine in combination with ofatumumab, carboplatin, etoposide (BOCE) for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma

We developed an outpatient salvage chemotherapy regimen using bendamustine, ofatumumab, carboplatin and etoposide (BOCE) to treat relapsed/refractory non-Hodgkin lymphoma (RR NHL) in a single-center phase I/II study. Primary objectives were safety, tolerability and overall response rate (ORR). Thirty-five RR NHL patients (57% de novo large cell [DLBCL] or grade 3B follicular [FL], 26% transformed DLBCL, 9% grade 3A FL, 3% mantle cell; median age = 62, median prior therapies = 1) were treated. Median follow-up was 24.1 months. ORR was 69% (CR = 49%, PR = 20% [ORR = 70%, CR = 50%, PR = 20% in the de novo DLBCL/grade 3B FL subgroup]). Median progression-free survival was 5.1 months and overall-survival 26.2 months. Twelve patients subsequently underwent stem cell transplantation. The most common non-hematologic grade 3–4 toxicities were neutropenic fever and hypophosphatemia. There were no treatment-related deaths. In conclusion, BOCE is a safe and effective outpatient salvage regimen for patients with RR NHL and serves as an effective bridge to stem cell transplantation.

Open-Label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma

The phase 2 portion of this open-label phase 2/3 study assessed the efficacy and safety of blinatumomab as second salvage for aggressive relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) following platinum-based first salvage chemotherapy. Forty-one patients with aggressive disease (32% relapsed; 68% refractory) enrolled and received stepwise blinatumomab (9–28–112 μg/day) in a 70-day cycle 1 and an optional 28-day cycle 2; 19 (46%) completed cycle 1 and 3 (7%) completed cycle 2. The overall response rate after 12 weeks was 37%, including 9 (22%) complete metabolic responses. Eight (20%) patients (all responders) subsequently received stem cell transplants. Grade ≥3 adverse events were reported in 29 (71%) patients. Grade 3 cytokine release syndrome occurred in one patient. Grade 3 neurologic events occurred in 10 (24%) patients; all resolved. Blinatumomab monotherapy appears effective as second salvage therapy in patients with r/r aggressive B-NHL. Trial registration: NCT02910063.

Efficacy and safety of pixantrone for the treatment of multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphomas.

Few treatment options exist for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who fail first- and second-line therapies. Pixantrone is a novel aza-anthracenedione agent with reduced potential for cardiotoxicity but maintained anti-tumour activity relative to anthracyclines. The current retrospective, observational, real-life study was undertaken in 79 patients who received pixantrone monotherapy for multiply R/R aggressive B-cell NHL in Spain and Italy. Before pixantrone, patients had received a median of 3 prior therapies and 84.6% of them were refractory to the last regimen. Median progression-free survival (mPFS) was 2.8months (95% confidence interval [CI] 2.1-3.6) and median overall survival (mOS) was 4.0months (95%CI 5.6-7.9), with an objective response rate (ORR) of 29% (complete remission [CR]: 13.2%, partial remission [PR]: 15.2%). Patients receiving ≥2 cycles of pixantrone showed mPFS and mOS of 3.1 and 6.0months, respectively, and an ORR of 36.8% (CR: 17.5%, PR: 19.3%). Overall, 63.3% of patients reported ≥1 adverse event (AE), most commonly haematological AEs. One patient developed grade 2 sinus tachycardia. Pixantrone was effective and well tolerated in a real-world population of multiply R/R patients with aggressive B-cell NHL, many of whom had very poor prognostic factors.

Results of a Phase I/II Study of Bendamustine in Combination with Ofatumumab, Carboplatin and Etoposide (BOCE) for Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphomas

Background Currently available salvage chemotherapy regimens for patients (pts) with relapsed or refractory (RR) aggressive B-cell non-Hodgkin lymphoma (NHL) are mostly inpatient regimens and offer comparable response rates. Bendamustine has single agent activity in RR NHL. In vitro studies with Ofatumumab in NHL show more complement-dependent cytotoxicity than rituximab. We developed an outpatient salvage chemotherapy and replaced ifosfamide and rituximab in the R-ICE regimen with Bendamustine and Ofatumumab, respectively, in combination with Carboplatin and Etoposide (BOCE) in a phase I/II study. We previously reported the phase I study outcomes (Gaballa et al, ASCO 2014). Here, we report the final results of the BOCE phase I/II trial. Methods Patients were eligible if they had RR B-cell NHL. The phase I design was a standard 3+3 design using escalating doses of bendamustine (70, 90, 120 mg/m2 Days 1-2) combined with ofatumumab (cycle 1: 300mg Day 1, 1000mg Day 3; cycle 2 and 3: 1000mg Day 1), carboplatin (AUC 5 Day 2) and etoposide (100mg/m2 Days 1-3). No dose limiting toxicity (DLT) was observed in the phase I study and the recommended phase II dose (RP2D) of bendamustine was 120 mg/m2 Days 1-2. Results Thirty-six pts were enrolled (phase I, n=11; phase II, n=25; males, n=21; females, n=15). One patient withdrew consent prior to starting treatment and was not included in the analysis. Median age was 62 (range 41-78). Patients had relapsed (n=17, 49%) or refractory (n=18; 51%) NHL (table 1). Among DLBCL pts who had documented FISH (n=14), 4 were double hit (positive rearrangement for Myc and BCL-2), 1 was triple hit (positive rearrangement for Myc, BCL-2 and BCL-6). Of those pts with fully documented IHC (n=8), 2 patients were were double expressor. The number of median prior treatments was 1 (Range 1-5). There were no DLTs or treatment-related deaths. Grade III-IV toxicities included: neutropenia (71%), thrombocytopenia (66%), leukopenia (40%), neutropenic fever (31%), anemia (26%), lymphopenia (26%), hypophosphatemia (17%) and hyponatremia (11%). Eighteen serious adverse events occurred in 14 pts which included: infection (11%), neutropenic fever (9%), thrombocytopenia (6%), thromboembolic event (6%), dehydration (3%), hypercalcemia (3%), tumor lysis (3%), pre-syncope (3%) and GI bleeding (3%). Infusion-related reactions occurred in 40% of pts (all grade I-II). Efficacy analysis was conducted on all phase II patients in addition to phase I patients who received the RP2D of bendamustine (n=27). The median-follow up was 23.9 months. The overall response rate was 70% (48% CR, 22% PR). Eight pts (30%) were refractory to treatment. The median progression-free survival (PFS) was 5.1 months and median overall-survival (OS) was 18.1 months. Fifteen pts died, all from disease progression. Of the 19 pts who responded, the median duration of response was 10.1 months. One patient failed stem-cell collection. Among all phase I and II patients, 12 patients subsequently underwent stem cell transplantation (SCT) (Autologous SCT, n=5; Allogeneic SCT, n=7). Autologous SCT was performed in RR DLBCL patients while allogeneic SCT was performed in: RR FL (n=4), transformed DLBCL (n=2), and Richter's transformation (n=1). In pts undergoing SCT, median PFS was not reached and median OS was 27.3 months. Conclusions BOCE is a safe and effective outpatient salvage chemotherapy regimen for pts with RR NHL. It yields favorable response rates compared to currently available salvage chemotherapy regimens and is an effective bridge to SCT. High grade toxicities were mostly hematologic. Patients who were successfully bridged to SCT had significantly better outcomes. Disclosures Pro: Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria. Porcu:Innate Pharma: Honoraria, Other: Scientific Board, Research Funding; BeiGene: Other: Scientific Board, Research Funding; Incyte: Research Funding; Daiichi: Research Funding; Kyowa: Honoraria, Other: Scientific Board, Research Funding; ADCT: Research Funding; Spectrum: Consultancy; Viracta: Honoraria, Other: Scientific Board, Research Funding. OffLabel Disclosure: Bendamustine - alkylating agent with off-label use in relapse or refractory aggressive lymphomas Ofatumumab - monoclonal antibody which binds to CD20 resulting in complement-dependent cytotoxicity

Retrospective Analysis of Gemcitabine and Oxaliplatin (GemOx)-Based Treatment in Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Retrospective Analysis of Gemcitabine and Oxaliplatin (GemOx)-Based Treatment in Patients with Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Another disappointment in treating relapsed, refractory high-risk aggressive B-cell lymphomas.

Clinical Outcomes of Fludarabine and Melphalan With an 800 cGy Total Body Irradiation Conditioning Regimen in Patients With Refractory or Relapsed Aggressive Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

IntroductionAllogeneic hematopoietic stem cell transplant with reduced-intensity conditioning is an effective therapeutic option for patients with refractory or relapsed aggressive non-Hodgkin lymphoma (NHL). Patients and MethodsWe retrospectively evaluated survival outcomes and the efficacy of our fludarabine/melphalan/total body irradiation (TBI) (FMT) regimen. A total of 89 patients had received the FMT regimen from 2007 to 2017. ResultsThe majority of patients (n = 81; 91%) belonged to the histologic subtype of aggressive NHL. The estimated 3-year overall survival and disease-free survival for the entire cohort during a median follow-up of 31 months were 47.1% (95% confidence interval, 36%-57%) and 45.4% (95% confidence interval, 35%-56%), respectively. The cumulative incidence rates of relapse and non-relapse mortality at 3 years were 33.1% and 13.8%, respectively. In analyses of risk factors affecting survival outcomes, chemosensitive disease status at transplant (hazard ratio [HR], 2.45; P = .010), delayed relapse after first-line chemotherapy (HR, 2.101; P = .009), no grade III to IV acute graft-versus-host disease (HR, 11.212; P < .001), and mild chronic graft-versus-host disease (HR, 0.448; P = .016) were independent significant predictors of favorable overall survival. Also, similar parameters were related to favorable disease-free survival. All non-hematologic toxicities occurred within 50 days after allogeneic hematopoietic stem cell transplant, and most of the adverse events were tolerable and manageable with a < 30% incidence. ConclusionOur FMT regimen shows favorable transplant outcomes with relatively low-risk toxicities, so it may be a promising strategy for patients with relapsed or refractory aggressive NHL.

Long-term Survival and Cost-effectiveness Associated With Axicabtagene Ciloleucel vs Chemotherapy for Treatment of B-Cell Lymphoma

Axicabtagene ciloleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option for B-cell lymphoma. It is expected to have long-term survival benefits; however, long-term survival data are limited. To estimate the long-term survival and cost-effectiveness of axicabtagene ciloleucel for treatment of relapsed or refractory B-cell lymphoma. Economic evaluation study using a survival analysis that digitized and extrapolated survival curves published in the ZUMA-1 trial (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma), which enrolled patients between November 2015 and September 2016 and had a maximum follow-up of 24 months. Five different survival models (standard parametric, flexible parametric, 2 mixture cure models, and a flexible parametric mixture model) were used to extrapolate the survival curves to a lifetime horizon from January through June 2018. A cost-effectiveness analysis, from both a trial-based and lifetime horizon, was also conducted to inform the value of this novel therapy. The model was based on data from 111 patients with B-cell lymphoma who were enrolled in the ZUMA-1 trial. One-time administration of axicabtagene ciloleucel compared with chemotherapy. Undiscounted and discounted life-years (LYs) and quality-adjusted life-years (QALYs), total costs, and incremental costs per LY and QALY gained. The modeled cohort of 111 patients started at 58 years of age. At the end of the trial, treatment with axicabtagene ciloleucel resulted in 0.48 more LYs and 0.34 more QALYs than chemotherapy, producing a cost-effectiveness estimate of $896 600 per QALY for public payers and $1 615 000 per QALY for commercial payers. Extrapolated long-term survival for patients treated with axicabtagene ciloleucel ranged from 2.83 to 9.19 discounted LYs and from 2.07 to 7.62 discounted QALYs. Incrementally, treatment with axicabtagene ciloleucel was associated with 1.89 to 5.82 discounted LYs and 1.52 to 4.90 discounted QALYs vs chemotherapy. With the use of these incremental estimates of survival, cost-effectiveness estimates ranged from $82 400 to $230 900 per QALY gained for public payers and from $100 400 to $289 000 per QALY gained for commercial payers. Treatment with axicabtagene ciloleucel appears to be associated with incremental gains in survival over chemotherapy. The range in projected long-term survival was wide and reflected uncertainty owing to limited follow-up data. Cost-effectiveness is associated with long-term survival, with further evidence needed to reduce uncertainty.