Advances in Cellular Therapy and Transplantation

Educational Objectives

The goal of this program is to improve hematologic malignancies. After hearing and assimilating this program, the clinician will be better able to:

1. Prevent graft-vs-host disease in patients receiving allogeneic chimeric antigen receptor T-cell therapy.
2. Determine whether a patient is a candidate for allogeneic or autologous transplantation.
3. Relate the diversity of a patient’s microbiome to the success of allogeneic hematopoietic-cell transplantation.

Summary

The ZUMA trials: a series of studies of the autologous chimeric antigen receptor T-cell (CAR-T) products axicabtagene ciloleucel (axi-cel;(Yescarta) and brexucabtagene autoleucel (brexu-cel;(Tecartus)

The ZUMA-12 trial: evaluated CAR-T therapy (CARTT) as the front-line therapy for patients with high-risk large B-cell lymphoma (LBCL); high risk was defined as double-hit or triple-hit disease or an International Prognostic Index [IPI] score of ≥3; all patients persistent or progressive disease after receiving 2 cycles of chemoimmunotherapy; the best overall response rate was ≈90%, and ≈80% had complete response; at a median follow-up of ≈16 mo, ≈75% of patients had an ongoing response; median overall survival was ≈25 mo, and complete responses (CR) were consistent among key subgroups; no new safety signals were observed, compared with axi-cel treatment in later lines of therapy; CAR-T expansion was higher in participants in ZUMA-12 compared with those in ZUMA-1; ZUMA-12 is the first study of front-line CARTT in LBCL; outcomes with CARTT vs the current standard of care are yet to be evaluated in a randomized study

Allogeneic CARTT: off the shelf products with CAR-T containing cells that are derived not from patients themselves but from, eg, healthy donors, cord blood, renewable stem cells; the advantages are, eg, ready availability, rapid administration, rare production failures, derivation from healthier cell sources; graft-vs-host disease (GVHD) may be circumvented by gene-editing that deletes the native T-cell receptor (TCR) or by using natural killer cells, which do not have TCRs; the risk for rejection may be minimized with the use of enhanced lymphodepletion; administration of fludarabine and cyclophosphamide aids in CAR-T expansion and persistence; in allogeneic CARTT, lymphodepletion may be intensified by increasing the dose of chemotherapy or by using the monoclonal antibody alemtuzumab (eg, Campath, Lemtrada, Mabcampath) against CD52; gene-editing may be used to selectively disrupt CD52 expression and effect targeted lymphodepletion of the host and sparing of CAR-T cells

Production of CAR-T products: healthy donors undergo leukapheresis; a viral vector is used to transduce the CAR into T-cells; gene-editing is used to modify TCRs and CD52 expression

Aggregate study results of allogenic CARTT: no patients dropped out between enrollment and infusion (in contrast to studies with autologous therapy); GVHD was minimal; cytokine release syndrome (CRS) and neurotoxicity were mainly grades 1 and 2; in one study, 27% of patients had a grade ≥3 infection; initial efficacy data was good; the CR rate was 40% to 50% in the relapsed/refractory setting across all trials; durable CR rates are similar to those seen in autologous CAR-T products (ie, ≈35%); the possibility of mutagenesis with gene-editing remains a concern

Toxicity: CRS is the most common type of toxicity caused by CAR-T cells with varied symptoms (eg, fever, hypotension, shortness of breath); caused by the release of inflammatory cytokines from infused T-cells during expansion; neurologic toxicity (NT) (ie, immune effector cell-associated neurotoxicity syndrome [ICANS]) may occur concurrently with or without CRS; multiple organ systems may be impacted

Prophylactic corticosteroid use: used in the ZUMA-1 study to improve the safety profile of axi-cel; patients in cohort 6 received 10 mg of dexamethasone once daily for 3 days prior to axi-cel infusion; corticosteroids and tocilizumab were administered earlier in patients with low grade CRS and NT; updated data show no patients had grade ≥3 CRS; ≈13% of patients had grade ≥3 NT vs≈31% in other cohorts; the median cumulative corticosteroid dose used in cohort 6 was 4-fold lower; clinical efficacy of CARTT was comparable to that observed in other cohorts; prophylactic use of corticosteroids is recommended for axi-cel therapy

Axi-cel vs tisagenlecleucel (tisa-cel): studies show similar overall survival rates; one found better overall response rate with axi-cel; rates of CRS, ICANS, and intensive care unit admission were higher with axi-cel; tisa-cel may be preferable for patients who are older and more frail

Representation of Black patients: enrollment of Black patients was assessed in CAR-T studies; marked under-representation of Black individuals was observed across cancer studies, in particular studies of hematologic malignancies; participation to prevalence ratio (PPR) in studies for multiple myeloma (MM) was 0.04; Al Hadidi et al (2022) analyzed 7 CAR-T registration trials for therapies approved by the US Food and Drug Administration (FDA) and found black participants constituted ≈3.6% of treated patients, and the PPR was 0.17 for MM and 0.6 for LBCL; registration trials should mandate specific enrollment thresholds as part of the approval process to reduce disparities in representation

Role of allogeneic transplantation (AT): offers the highest chance for cure in patients with adverse risk acute myeloid leukemia (AML); patients with favorable risk AML do not benefit from AT, because of the risk inherent in the procedure; a study evaluated patients with intermediate risk AML (independent of molecular features) in first remission with matched donors; patients were randomized after induction to be consolidated with chemotherapy or AT; the trial was stopped because of poor accrual, but overall survival was not significantly different between the groups; the relapse risk was higher in the chemotherapy group, but all patients who relapsed were salvaged with AT; delayed AT in intermediate risk AML may be an option

Upfront autologous transplantation (AuT) in myeloma: data from the MASTER trial were analyzed to determine whether AuT had any added benefit in patients on quadruplet therapy; 40% of patients were minimal residual disease (MRD)-negative after 4 cycles of quadruplet therapy vs 70% after AuT; patients with a high-risk cytogenetic abnormality (HRCA) derived the greatest benefit in MRD reduction with AuT; upfront AuT may be considered as part of front-line therapy, especially for patients with HRCA or who are MRD-positive after induction; extended therapy may produce similar benefits

Microbiome in transplantation: Peled et al (2020) studied microbiome composition in patients undergoing AT; the diversity of the microbiome decreases over the course of AT; patients with lower microbiome diversity had higher rates of overall and GVHD-related mortality; the microbiome plays an important role in modulating alloreactivity and GVHD; a follow-up study found consumption of sugars, sweets, and fruits was associated with lower fecal α-diversity in AT recipients; evidence-based nutritional recommendations for AT recipients are in development

Fecal microbiome therapy (FMT): an early phase study found administering donor FMT to AT recipients was safe in steroid-refractory gastrointestinal GVHD; outcomes were promising

Microbiota and CARTT: Smith et al (2022) found CAR-T recipients had lower microbiome diversity compared with healthy controls; patients who received anaerobic-targeting antibiotics (eg, piperacillin-tazobactam, imipenem, meropenem [PIM]) 4 wk prior to CARTT had significantly worse survival rates vs patients who did not receive PIM; exposure to PIM was associated with increased ICANS; bacterial species associated with day 100 CR and CAR-mediated toxicity were identified

Questions and Answers

Neurotoxicity of different CAR-T products: in axi-cel vs tisa-cel studies, axi-cel had a worse safety profile regarding NT; comparison between trials is difficult because different grading systems were used; allogeneic CAR-T products have grade ≤2 CRS and NT and may be safer than autologous CAR-T products

Approach to intermediate risk cytogenetics AML: molecular genetics and cytogenetics should be considered in tandem; patients with NPM1 mutations without any poor risk comutations may be downgraded from intermediate risk; the previously discussed study found that patients who relapse after consolidation with chemotherapy may be salvaged; however, AT may be considered earlier for older patients

Readings

Al Hadidi S, Schinke C, Thanendrarajan S, et al. Enrollment of black participants in pivotal clinical trials supporting us food and drug administration approval of chimeric antigen receptor-T cell therapy for hematological malignant neoplasms. JAMA Netw Open. 2022; 5(4):e228161. Published 2022 Apr 1. doi:10.1001/jamanetworkopen.2022.8161; Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: Mechanisms, manifestations and management. Blood Rev. 2019; 34:45-55. doi:10.1016/j.blre.2018.11.002; Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma [published online ahead of print, 2021 Dec 13]. J Clin Oncol. 2021;JCO2101935. doi:10.1200/JCO.21.01935; Depil S, Duchateau P, Grupp SA, et al. 'Off-the-shelf' allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020; 19(3):185-199. doi:10.1038/s41573-019-0051-2; Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nat Med. 2022; 28(4):735-742. doi:10.1038/s41591-022-01731-4; Oluwole OO, Forcade E, Muñoz J, et al. Prophylactic corticosteroid use with axicabtagene ciloleucel (axi-cel) in patients (Pts) with relapsed/refractory large B-Cell lymphoma (R/R LBCL): one-year follow-up of ZUMA-1 cohort 6 (C6). Blood. 2021; 138(Supplement 1):2832. doi:10.1182/blood-2021-147403; Peled JU, Gomes ALC, Devlin SM, et al. Microbiota as predictor of mortality in allogeneic hematopoietic-cell transplantation. N Engl J Med. 2020; 382(9):822-834. doi:10.1056/NEJMoa1900623; Smith M, Dai A, Ghilardi G, et al. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat Med. 2022; 28(4):713-723. doi:10.1038/s41591-022-01702-9.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Nawas’s lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Nawas was recorded at the 7th Annual Updates from ASH 2021: Practice Changing Abstracts, held virtually on February 18, 2022, and presented by Pritzker School of Medicine, University of Chicago. For more information about upcoming CME activities from this presenter, please visit cme.uchicago.edu. Audio Digest thanks the speakers and Pritzker School of Medicine, University of Chicago for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

ON131302

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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