Syed Ali Abutalib, MD
Paolo Strati, MD
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel gene therapies for resistant non-Hodgkin lymphomas (NHL), including axicabtagene ciloleucel and lisocabtagene maraleucel. For full details of these study abstracts, visit ashpublications.org.
Further Insight Into Resistance Mechanisms of Axicabtagene Ciloleucel
ABSTRACT 556: Tumor CD58 aberrations limit durable responses in relapsed and refractory large B cell lymphoma (LBCL) patients treated with axicabtagene ciloleucel.1
Background: On October 18, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to axicabtagene ciloleucel (anti-CD19 chimeric antigen receptor [CAR] T-cell therapy) for the treatment of adults with relapsed and refractory LBCL after at least two lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Decrease or loss of CD19 expression is a well-described resistance mechanism after axicabtagene ciloleucel therapy in resistant LBCL and suggests that co-targeting or sequential targeting of alternate B-cell antigens might be required to improve the efficacy of anti-CD19 CAR T-cell products. Moreover, mutations in and loss of expression of CD58 (LFA-3) have been described in approximately 20% of cases of LBCL. As the ligand for CD2 on T cells, CD58 provides co-stimulation to T cells, and CD58 loss or mutation has been linked to immune resistance in LBCL.
Methods: CD58 status in 51 patients with resistant LBCL treated at Stanford with commercial axicabtagene ciloleucel. Immuno-histochemistry (IHC) on tumor biopsy samples and/or deep sequencing of circulating tumor DNA by CAPP-Sequencing was performed.
Results: The investigators identified 12 of 51 patients (24%) with a CD58 aberration (lack of expression by IHC or mutation by CAPP-Sequencing).
Progression-free survival was significantly decreased in patients with a CD58 aberration (median progression-free survival of 3 months vs not reached for those with intact CD58, P < .0001). Just 1 of 12 patients with a CD58 alteration achieved a durable, complete response to treatment, whereas the remaining 11 patients experienced disease progression, most commonly after a period of initial response.
“CD58 aberrations may be an important biomarker to forecast inferior outcomes in patients treated with axicabtagene ciloleucel.”— Syed Ali Abutalib, MD, and Paolo Strati, MD
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Complete responses were less common in patients with CD58 aberrations (25% vs 82% for those with intact CD58, P < .0001).
Further, biology of CAR T-cell responses toward tumors lacking functional CD58 demonstrated significantly reduced cytokine production and cytolytic activity in response to CD58 knockout vs wildtype tumor cells. To overcome CD58 loss in LBCL, the investigators generated second- and third-generation CAR T-cell constructs integrating CD2 co-stimulatory domains within the CAR molecule and were able to overcome CD58 knockout in tumor cells
Clinical Implications: The study showed that CD58 aberrations may be an important biomarker to forecast inferior outcomes in patients treated with axicabtagene ciloleucel. They modeled the biologic basis for this finding and generated CAR T cells capable of overcoming CD58 loss in B-cell malignancies. These data provide rationale for investigating CD58 status for patients receiving CAR-based therapeutics and devising next-generation CARs capable of overcoming this newly discovered mechanism of resistance.
Moving Axicabtagene Ciloleucel Earlier in High-Risk LBCLs
ABSTRACT 405: Interim analysis of ZUMA-12: A phase II multicenter, open-label, single-arm study of axicabtagene ciloleucel in adults with high-risk LBCL (ClinicalTrials.gov identifier NCT03761056).2
Background: About 50% of patients with high-risk diffuse LBCL will not achieve long-term remission with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, highlighting an unmet need for new therapies earlier in the course of therapy.
Methods: Eligible adults met two criteria for high-risk LBCL: (1) double- or triple-hit lymphoma by fluorescent in situ hybridization per investigator or LBCL with International Prognostic Index (IPI) score ≥ 3; and (2) positive interim PET per Lugano classification (Deauville score [DS] of 4 or 5) after two cycles of an anti-CD20 monoclonal antibody and anthracycline–containing regimen. Of note, patients with primary mediastinal and primary CNS LBCL were not eligible.
Patients underwent leukapheresis at least 2 weeks after prior systemic therapy and optional nonchemotherapy bridging at investigator discretion, followed by conditioning chemotherapy (cyclophosphamide at 500 mg/m2/d and fludarabine at 30 mg/m2/d for 3 days) and a single axicabtagene ciloleucel infusion (target dose = 2 × 106 CAR T cells/kg).
Investigators presented interim efficacy, safety, and pharmacokinetics results. As of July 15, 2020, 31 patients have been enrolled and treated; as of January 24, 2020, in a planned interim analysis, 15 patients were treated with axicabtagene ciloleucel with at least 3 months of follow-up.
Results:
Of 12 response-evaluable patients, the investigator-assessed objective response rate was 92% (95% confidence interval [CI] = 62%–100%), with a complete response rate (primary endpoint) of 75% (95% CI = 43%–95%); 75% of patients had ongoing responses at data cutoff.
Of 15 safety-evaluable patients, 80% experienced grade ≥ 3 adverse events. The most common grade ≥ 3 adverse events (≥ 25%) were white blood cell count decreased (40%), anemia (27%), and encephalopathy (27%).
Grade ≥ 3 cytokine-release syndrome and neurologic events occurred in 20% and 27% of patients, respectively.
All cases of cytokine-release syndrome and 10 of 11 neurologic events of any grade resolved (causally unrelated grade 1 tremor was ongoing in a patient at data cutoff).
Median time to the onset of cytokine-release syndrome was 4 days (range, 1–8 days), with median duration of 5 days (range, 2–12 days).
Median time to onset of neurologic events was 9 days (range, 2–44 days), with median duration of 10 days (range, 1–40 days).
Grade ≥ 3 infection was reported in 27%, and a grade ≥ 3 neutrophil count decrease was reported in 20%. No grade 5 adverse events occurred.
Higher frequency of CCR7+CD45RA+ T cells in the preinfusion product was associated with greater expansion of CAR T cells, as compared in ZUMA-1 study, suggestive of improved T-cell fitness in earlier treatment.
Clinical Implications: ZUMA-12 evaluated CAR T-cell therapy in earlier line of therapy in high-risk LBCL, which notably was defined by both histology and/or IPI and abnormal (DS 4 or 5) interim PET scan after two cycles of chemoimmunotherapy. Axicabtagene ciloleucel demonstrated significant clinical benefit, with high objective response and complete response rates and a manageable safety profile. The study is active but not recruiting with 40 actual participants.
In this study, leukapheresis was performed at the time of study entry; as such, T-cell fitness could have been affected by the two previous cycles of chemotherapy. Of note, first-line (“chemotherapy-naive”) CAR T-cell therapy trials with leukapheresis performed before initiation of any treatment may portend better results.
Anti-CD22 CAR T Cells in Resistant Large B-Cell Lymphoma and
B-Cell Acute Lymphoblastic Leukemia
ABSTRACT 736: Phase I CD22-directed CAR T-cell therapy—Durable complete responses in adults with resistant LBCL after failure of CD19-directed CAR T-cell therapy and high response rates in adults with resistant B-cell acute lymphoblastic leukemia (ALL; NCT04088890).3
Background: Autologous CAR T cells targeting CD22 have yielded objective response rates of 70% to 90% in pediatric patients with resistant B-cell ALL, including those who had previously failed to respond to CD19-directed CAR T-cell therapy.4,5
Methods: The current cohort includes patients treated at dose level 1, which was 1 x 106 CAR+ cells/kg. Primary objectives assessed the ability to successfully manufacture the CAR T cells and safety. Overall response rate at 28 days postinfusion was a secondary objective.
Results: All patients (LBCL: n = 3, B-cell ALL: n = 6) reached day 28 and were included in the safety and response analysis.
Eight patients (88.9%) experienced cytokine-release syndrome; all were grade 1 or 2.
There were no cases of immune effector cell–associated neurotoxicity syndrome.
No differences in toxicities were seen across the patient age spectrum, and no grade 5 toxicities occurred; two of three patients with LBCL experienced prolonged grade 3 to 4 cytopenias.
All three patients with LBCL achieved a response at day +28 (overall response rate = 100%; complete response, n = 1, partial response, n = 2). Both patients with a day 28 partial response improved to complete response by days 90 and 180. All patients remain in complete response, with a median follow-up of 8.4 months (range, 6–9.3 days).
“The armamentarium of CAR T-cell therapies available for patients with resistant mantle cell lymphoma may soon grow beyond brexucabtagene autoleucel.”— Syed Ali Abutalib, MD, and Paolo Strati, MD
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All six patients with B-cell ALL achieved a complete response at day +28 (overall response rate = 100%; minimal residual disease [MRD]-negative, n = 5, MRD-positive, n = 1). After a median follow-up of 5.1 months (range, 1–8.2 days), three patients relapsed at 2.5, 4, and 5.5 months after infusion; one patient died while undergoing subsequent therapy 7.3 months postinfusion. CD22 expression by flow cytometry was downregulated or absent in two patients after relapse.
Clinical Implications: Infusion of CD22-targeting CAR T cells in resistant LBCL and B-cell ALL is safe and well tolerated. Manufacturing of CAR T cells was uniformly successful. To date, all three heavily treated adults with LBCL whose disease relapsed after prior CAR19 have achieved complete remission durable to at least 6 months. All adults with B-cell ALL have achieved complete remission following anti-CD22 CAR T-cell therapy, though early relapses have been observed. Accrual is ongoing; a larger cohort sample and longer follow-up will help better assess the safety (particularly cytopenia) and efficacy of this strategy in patients with LBCL and guide future treatment indications and combination strategies.
Lisocabtagene Maraleucel in Resistant Mantle Cell Lymphoma
ABSTRACT 118: Phase I multicenter TRANSCEND NHL 001 study—Safety and preliminary efficacy in patients with resistant mantle cell lymphoma (MCL) receiving lisocabtagene maraleucel (NCT02631044).6
Background: Most patients with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. Lisocabtagene maraleucel, an investigational, CD19-directed, defined composition, 4-1BB CAR T-cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells, has shown clinical activity in adults with resistant LBCL.7
Methods: Patients were eligible after at least one prior line of therapy. After lymphodepleting chemotherapy, patients received lisocabtagene maraleucel infusion at one of two dose levels: dose level 1 (DL1) was 50 × 106 CAR+ T cells, and dose level 2 (DL2) was 100 × 106 CAR+ T cells. Bridging therapy was allowed between leukapheresis and initiation of lymphodepleting chemotherapy. Primary endpoints were safety and objective response rate.
Results: At data cutoff, 41 patients had undergone leukapheresis, and 32 had received lisocabtagene maraleucel (DL1, n = 6; DL2, n = 26). Patients had received a median (range) of three (1–7) prior systemic therapies, and most (72%) were refractory to their last therapy. Of 28 patients (87.5%) who had received a prior Bruton’s tyrosine kinase inhibitor, 11 (34%) were refractory to the therapy. A total of 17 patients (53%) received bridging therapy.
A total of 18 patients (56%) had serious treatment-emergent adverse events, and 27 (84%) had grade ≥ 3 treatment-emergent adverse events, primarily neutropenia (41%), anemia (34%), and thrombocytopenia (31%).
Median (range) follow-up duration was 10.9 months (1.2–24.8 months) for DL1 and 3.1 months (0.4–23.0 months) for DL2.
Grade ≥ 3 thrombocytopenia was more frequent at DL2 (n = 9 of 26 [35%]) than at DL1 (n = 1 of 6 [17%]). Prolonged grade ≥ 3 cytopenias (present at study day +29) occurred in 11 patients (34%).
A total of 16 patients (50%; DL1, n = 2 of 6 [33%]; DL2, n = 14 of 26 [54%]) had cytokine-release syndrome, including 1 grade 4 event at DL2. There were no grade 3 or 5 cytokine-release syndrome events.
Median (range) time to cytokine-release syndrome onset and resolution was 6 days (2–10 days) and 4 days (2–9 days), respectively.
Nine patients (28%) had neurotoxicity, all at DL2, including three grade 3 neurotoxicities. No grade 4 or 5 neurotoxicity was reported.
Median (range) time to neurotoxicity onset and resolution was 8 days (2–25 days) and 3 days (1–51 days), respectively.
Grade 5 treatment-emergent adverse events occurred in two patients (at DL2): one patient with a high tumor burden had tumor-lysis syndrome and one patient had cryptococcal meningoencephalitis.
Of 32 patients, 27 responded to lisocabtagene maraleucel (objective response rate, 84%: DL1, n = 4 of 6 [67%]; DL2, n = 23 of 26 [88%]), and 19 (59%) achieved a complete response (DL1, n = 2 of 6 [33%]; DL2, n = 17 of 26 [65%]).
Overall, the median (range) time to first complete response was 1 month (1–6 months). At data cutoff, 20 of 27 responders (74%) were censored with an ongoing response or had completed the study.
Clinical Implications: In this phase I study of patients with resistant MCL, treatment with lisocabtagene maraleucel was associated with a low incidence of grade ≥ 3 cytokine-release syndrome and neurotoxicity as well as promising clinical activity. Dose confirmation is ongoing at DL2 in the MCL cohort. The armamentarium of CAR T-cell therapies available for patients with resistant MCL may soon grow beyond brexucabtagene autoleucel. Although conclusions regarding comparative efficacy cannot be made based on interstudy comparisons, the different toxicity profile and dynamics will help inform the appropriate infusion setting (inpatient vs outpatient) and monitoring duration.
Axicabtagene Ciloleucel in Resistant Indolent NHL
ABSTRACT 700: Phase II ZUMA-5 study: Primary analysis of axicabtagene ciloleucel in patients with resistant indolent NHL (NCT03105336).8
Background: Patients with advanced-stage indolent NHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), frequently relapse with standard treatment, underscoring a need for novel therapies.
Methods: Adults with FL (grades 1–3a) or MZL (nodal or extranodal) had relapsed or refractory disease after at least two lines of therapy (must include an anti-CD20 monoclonal antibody plus an alkylating agent) and an Eastern Cooperative Oncology Group performance status of 0 or 1. The primary efficacy analysis occurred when at least 80 treated patients with FL had at least 12 months follow-up.
Results: A total of 146 patients with indolent NHL (124 FL; 22 MZL) received axicabtagene ciloleucel. Disease progression up to 2 years after initial chemoimmunotherapy occurred in 55% of patients, and 68% were refractory to the last prior treatment. Axicabtagene ciloleucel was successfully manufactured for all enrolled patients.
With a median follow-up of 17.5 months (range, 1.4–31.6 months), the overall response rate was 92% among efficacy-evaluable patients with indolent NHL (n = 104), with a 76% complete remission rate. In patients with FL (n = 84), the overall response rate was 94% (80% complete response rate); in those with MZL (n = 20), the overall response rate was 85% (60% complete response rate). As of data cutoff, 62% of all treated patients had ongoing responses (64% for FL). The medians for duration of response, progression-free survival, and overall survival were not reached for those with FL, and the median progression-free survival was 11.5 months for those with MZL.
Grade ≥ 3 adverse events occurred in 86% of patients with indolent NHL (85% in those with FL; 95% in those with MZL), most commonly neutropenia (33%), decreased neutrophil count (27%), and anemia (23%). Grade ≥ 3 cytokine-release syndrome occurred in 7% of patients with indolent NHL (6% in those with FL; 9% in those with MZL). Grade ≥ 3 neurologic events occurred in 19% of patients with indolent NHL (15% in those with FL; 41% in those with MZL).
Grade 5 adverse events occurred in three patients.
Clinical Implications: Axicabtagene ciloleucel had considerable and durable clinical benefit in patients with indolent NHL, with high overall response and complete response rates. Axicabtagene ciloleucel had a manageable safety profile, with lower rates of grade ≥ 3 neurotoxicity observed in patients with FL than in those with MZL and those previously reported in aggressive NHL.9 Given the short median progression-free survival observed in patients with MZL, further biologic insight to guide future combination strategies is needed for these patients.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Strati has served as a consultant or advisor to Genentech/Roche and has received research funding from AstraZeneca.
REFERENCES
1. Majzner RG, Frank MJ, Mount C, et al: CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering 2020 ASH Annual Meeting & Exposition. Abstract 556. Presented December 7, 2020.
2. Neelapu SS, Dickinson M, Ulrickson ML, et al: Interim analysis of ZUMA-12: A phase 2 study of axicabtagene ciloleucel as first-line therapy in patients with high-risk large B cell lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 405. Presented December 6, 2020.
3. Baird JH, Frank MJ, Craig J, et al: CD22-directed CAR T-cell therapy mediates durable complete responses in adults with relapsed or refractory large B-cell lymphoma after failure of CD19-directed CAR T-cell therapy and high response rates in adults with relapsed or refractory B-cell acute lymphoblastic leukemia. 2020 ASH Annual Meeting & Exposition. Abstract 736. Presented December 7, 2020.
4. Haso W, Lee DW, Shah NN, et al: Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121:1165-1174, 2013.
5. Pan J, Niu Q, Deng B, et al: CD22 CAR T-cell therapy in refractory or relapsed B acute lymphoblastic leukemia. Leukemia 33:2854-2866, 2019.
6. Palomba ML, Gordon LI, Siddiqi T, et al: Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. 2020 ASH Annual Meeting & Exposition. Abstract 118. Presented December 5, 2020.
7. Abramson JS, Palomba ML, Gordon LI, et al: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet 396:839-852, 2020.
8. Jacobson C, Chavez JC, Sehgal AR, et al: Primary analysis of Zuma-5: A phase 2 study of axicabtagene ciloleucel in patients with relapsed/refractory indolent non-Hodgkin lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 700. Presented December 7, 2020.
9. Locke FL, Ghobadi A, Jacobson CA, et al: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol 20:31-42, 2019.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Strati is Assistant Professor in the Department of Lymphoma and Myeloma and Department of Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center, Houston.
