Summary
Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2·5 μmol/l concentrations of vorinostat synergize with both etoposide and platinums, we ...hypothesized that pulse high‐dose vorinostat could safely augment the anti‐tumour activity of (R)ICE (rituximab), ifosphamide, carboplatin, etoposide chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 d in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty‐nine patients median age 56 years, median 2 prior therapies, 14 chemoresistant (of 27 evaluable), 2 prior transplants were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 d. Common dose limiting toxicities included infection (n = 2), hypokalaemia (n = 2), and transaminitis (n = 2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4·5 μmol/l (range 4·2–6·0 μmol/l) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High‐dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted.
Human CD8
+
effector T cells derived from CD45RO
+
CD62L
+
precursors enriched for central memory (T
CM
) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive ...transfer, whereas effectors derived from CD45RO
+
CD62L
−
precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8
+
effector T cells derived from CD45RA
+
CD62L
+
precursors enriched for naïve and stem cell memory precursors (T
N/SCM
) with that of T
CM
. We found that cytotoxic T cells (CTLs) derived from T
CM
transcribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from T
N/SCM
. Higher frequencies of CTLs derived from T
CM
retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/Scid IL-2RγC
null
mice, CD8
+
T
CM
derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8
+
T
CM
derived CD19CAR
+
CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8
+
T
N/SCM
derived counterparts. These studies support the use of T
CM
enriched cell products for adoptive therapy of cancer.
Abstract
Introduction: Anti-CD19 CAR T cells with CD3 zeta and CD28 signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies at the NCI ...(Kochenderfer, JCO 2014). KTE-C19 utilizes the same CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better, ASCO 2014). Updated results from the phase 1 portion of ZUMA-1 are presented here.
Methods: Subjects received KTE-C19 at a target dose of 2 × 10⁁6 anti-CD19 CAR T cells/kg after a fixed dose conditioning chemo regimen of cyclophosphamide and fludarabine. The primary objective of phase 1 was to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Key secondary objectives were ORR, duration of response, and biomarkers. Key inclusion criteria were ? 18 years old, ECOG 0-1, and chemo-refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ? 12 months after ASCT.
Results: As of 20 Nov 2015, 7 subjects were dosed. All subjects were evaluable for safety and 6 were evaluable for efficacy with a median follow up time of 13 weeks post KTE-C19 infusion. 1 subject experienced a DLT of grade (gr) 4 encephalopathy and gr 4 cytokine release syndrome (CRS) and died due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. CRS and neurotoxicity were managed with supportive care, α-IL6R and steroids. 5 of 7 (71%) subjects responded including 4 CRs (57%). CAR T cells peaked within 2 weeks and were detectable 1-3+ months post infusion.
Conclusions: The KTE-C19 regimen evaluated was safe for further study. The predominant toxicities include CRS and neurotoxicity which are generally reversible. CRs and PRs have been observed in subjects with refractory disease. The potentially pivotal phase 2 portion of the study is ongoing (NCT02348216). SubjectSex/Age/ECOGDisease TypeTreatment HistoryGr 3 or Higher KTE-C19-Related Adverse EventsBest Response1M/59/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 encephalopathy (resolved)Partial Response (PR)3M/69/1DLBCLRefractory to 2nd line chemotherapyGr 3 tremor (resolved)Complete Remission* (CR)Gr 3 delirium (resolved)Gr 3 agitation (resolved)Gr 3 restlessness (resolved)Gr 3 somnolence (resolved)4M/69/0DLBCLRefractory to 4th line chemotherapyGr 3 encephalopathy (resolved)Stable DiseaseGr 3 hypophosphataemia (resolved)5M/67/1DLBCLRelapse ≤ 12 mo after ASCTNoneComplete RemissionOngoing 3 mo+6F/34/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 hypoxia (resolved)Complete RemissionOngoing 3 mo+7M/40/0DLBCLRelapse ≤ 12 mo after ASCTNoneComplete RemissionOngoing 3 mo+8F/29/1DLBCLRefractory to 1st, 2nd, 3rd line chemotherapyGr 4 CRSNEGr 4 encephalopathy
This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program®
Citation Format: Armin Ghobadi, Frederick L. Locke, Sattva S. Neelapu, Tanya Siddiqi, Julio C. Chavez, Chitra M. Hosing, Nancy L. Bartlett, Lihua E. Budde, Adrian Bot, John M. Rossi, Marika Sherman, Lynn Navale, Meg Elias, Jeff Wiezorek, William Y. Go. Updated phase I results from ZUMA-1: a phase I-II multicenter study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in subjects with refractory aggressive non-Hodgkin lymphoma (NHL). abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT135.
Introduction:
CAR T-cell therapy has revolutionized the treatment of relapsed/refractory B cell lymphomas, providing hope to patients who previously faced dismal outcomes. Despite unprecedented ...efficacy including high response rates and a significant proportion of durable responses, significant toxicities are still prevalent. Toxicities related to immune therapy including cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) along with infections and hematologic toxicity, complicate the post CAR T-cell infusion course. Innate patient-related factors including presence of comorbidities, advanced physiologic age, and poor fitness, likely contribute to poor short-term outcomes, however no validated risk scores incorporating these factors have been validated in patients receiving CAR T-cell therapy for lymphoma. In the present study we identified the ability of a patient to walk 500 feet (ft) or more during the 6 Minute Walk Test (6MWT) at baseline as a predictive marker for poor short-term outcomes after CAR T-cell infusion.
Methods:
We retrospectively analyzed charts of 78 patients who received commercially available CAR T-cell products for the treatment of lymphoma between May, 2019 and March, 2021 who had baseline assessment by physical therapy at the time of admission for CAR T-cell therapy. CRS and ICANS were scored by ASTCT guidelines. Demographics were analyzed with descriptive statistics. Univariate analysis was performed by Chi Squared.
Results:
The analysis included 78 patients with a median age of 63 (range, 21-82), 37% (n=29) were female. Patients were treated for DLBCL (64%, n=50), transformed follicular lymphoma (tFL; 29%, n=23), primary mediastinal B cell lymphoma (PMBCL; 4%, n=3), and mantle cell lymphoma (MCL; 3%, n=2). Patients received axicabtagene ciloleucel (94%, n=73), tisagenlecleucel (4%, n=3), or brexucabtagene autoleucel (3%, n=2). Patients had a median of 3 prior lines of therapy (range 2-7) and 53% (n=42) received bridging chemotherapy.
Among the 70 patients who completed the 6MWT, the mean distance was 909 ft (range, 20-2045), 8 patients were unable to compete the assessment due to debility and were included in the analysis as a 0 distance. Patients who were unable to complete 500 feet (n=17) were deemed to have poor endurance (PE). The PE group of patients were 3.6 times more likely to have a prolonged length of stay (p=0.02), while they were 1.5 times less likely to be alive at 100 days post CAR T infusion (p = 0.002). Patients also tended to have higher rates of ICANS (76% vs 41%), lower overall response rates (ORR) (78% vs 98%), and higher 30 day mortality (18% vs 2%), although these did not reach statistical significance, p=0.08, 0.06, and 0.07, respectively. CRS did not appear to be related to PE status, neither did age, or prior lines of therapy.
Conclusions:
Within the limitations of a retrospective study, we demonstrate that the baseline physical therapy-assessed measure of function and endurance, namely the 6MWT, correlates with several critical short-term outcomes in CAR T patients with lymphoma. These include prolonged length of stay, survival at day 100, and there is suggested correlation with ORR, ICANS, and 30-day survival as well. These findings illustrate the potential for early recognition of deconditioned patients that may do poorly after CAR T-cell therapy. Identification of these patients could allow for therapeutic interventions prior to CAR T infusion or during their post-infusion hospital stay, designed to enhance their strength and endurance, and potentially improve these short-term outcomes. Prospective intervention studies are planned based on these findings.
Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria. Budde: Kite Pharma: Consultancy; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding.
Bendamustine is a chemotherapeutic agent that has shown broad activity in patients with lymphoid malignancies. It contains both alkylating and nucleoside analog moieties, and thus, is not commonly ...used for stem cell mobilization due to concerns that it may adversely affect stem cell collection. Here we describe the lymphoma subset of a prospective, non-randomized phase II study of bendamustine, etoposide, and dexamethasone (BED) as a mobilization agent for lymphoid malignancies.
This subset analysis includes diffuse large B-cell lymphoma (N=3), follicular lymphoma (N=1), primary mediastinal B-cell lymphoma (N=1), and NK/T-cell lymphoma (N=1). Patients received bendamustine (120 mg/m
IV d 1, 2), etoposide (200 mg/m
IV d 1-3), and dexamethasone (40 mg PO d 1-4) followed by filgrastim (10 mcg/kg/d sc. through collection).
We successfully collected stem cells from all patients, with a median of 7.9×10
/kg of body weight (range, 4.4 to 17.3×10
/kg) over a median of 1.5 days (range, 1 to 3) of apheresis. All patients who received transplants were engrafted using kinetics that were comparable to those of other mobilization regimens. Three non-hematologic significant adverse events were observed in one patient, and included bacterial sepsis (grade 3), tumor lysis syndrome (grade 3), and disease progression (grade 5).
For non-Hodgkin lymphoma, mobilization with bendamustine is safe and effective.
Introduction
Chimeric Antigen Receptor (CAR) T cell therapy has improved outcomes for relapsed and/or refractory (r/r) B cell lymphomas. Bridging therapy might be needed in some patients for disease ...control while CAR T product is being produced. Radiation therapy is known to control the growth of lymphoma and modulate tumor microenvironment, however use of this therapy in the setting of CAR T cell therapy has not been well described. In the present study, we report the efficacy and toxicities of patients treated with a dose of radiation that is lower than previously described for bridging in lymphoma and compare efficacy and toxicities to patients treated with chemotherapy bridging or without bridging therapy.
Methods
We retrospectively compared rates of toxicities and outcomes of 82 patients treated with FDA approved CD19-directed CAR T cells at our institution between November 1, 2018 and April 1, 2020. This study was conducted with approval from the City of Hope National Medical Center Institutional Review Board.
All patients received standard lymphodepleting chemotherapy (LDP) regimen with cyclophosphamide and fludarabine followed by infusion of CAR T cells at day 0. Clinical response was determined 28-35 days following cell administration. Median dose of radiation treatment was 24 Gy (range 4 - 44) in 1.8 - 2.25 Gy fractions. Chemotherapy regimens were at provider discretion.
Results
From our institutional database of 82 patients, a total of 7 patients received radiation as bridging therapy. All received the predefined radiation doses with no significant immediate complications. Target organs included the head and neck (4), limbs (2), and chest wall. Structures threatened by the progressing disease included neurovascular (4), limb threatening (2), and major organ threatening (5). All threatened sites were preserved with the use of radiation therapy. 72% of patients receiving RAD had disease that was primary refractory to chemotherapy. The characteristics of patients treated with radiation bridging (RAD) were similar to those treated with chemotherapy bridging (CB) or without bridging (NB), except that patients treated with RAD tended to have less extensive disease (table 1). The adverse rates of CAR T treatment emergent toxicity (CRS, neurotoxicity, hematologic toxicity, or infectious rates) in the RAD group were 83%, 50%, 83%, and 33% respectively. These are comparable to the CB or NB groups (table 2).
Response rates were similar among the three groups with ORR 86% for RAD, 88% for CB, and 93% for the NB group (p = 0.98). Rates of progressive disease were the lowest in the RAD group (14%), followed by NB (21%) and CB (42%) after a median follow up of 241 days (range 43 - 785), however this did not reach statistical significance (p = 0.44).
Discussion
In the present study we demonstrate real world rates of toxicities in patients receiving bridging chemo or bridging radiation. The rates of toxicities were similar regardless of the type of bridging that was utilized. In addition, there was no statistically significant difference in response or relapse rates among the different groups. There was a trend toward lower relapse rates among those treated with radiation. Importantly, this trend was seen even though the majority of radiation doses given were lower than previously described for this indication. Importantly, the vital structures that were threatened by lymphoma were effectively preserved with the utilization of radiation therapy in this setting even with the majority of cases having primary chemo-refractory disease. Additional studies using higher patient number will be needed to strengthen this observation. Our study also sets the stage for future prospective studies optimizing the role of radiation in CAR T cell therapy.
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Shouse:Kite Pharma: Honoraria, Speakers Bureau. Budde:Mustang Therapeutics: Research Funding; Merck: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy; Roche: Consultancy; AstraZeneca: Research Funding.
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