In this month’s Pharmacy SIG Literature Update: a focus CAR-T therapies and alternatives for toxicity management.

Literature summaries are provided as information only. Please refer to the original published articles for complete details on study methodology, results and discussion.

*** Must read. Landmark publication that affects practice

** Recommend reading. Secondary paper that adds to literature

* Consider reading. Cursory importance to the practice

Large B-cell Lymphoma

***Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicenter seamless design study. Lancet 2020;396(10254):839-852. https://pubmed.ncbi.nlm.nih.gov/32888407

• Multicenter prospective study evaluated activity and safety of lisocabtagene maraleucel (liso-cel) in adult patients (n = 269) with R/R large B-cell lymphomas (DLBCL including high-grade and transformed, PMBCL, and FL grade 3B). Primary endpoints were AEs, dose-limiting toxicities, and the objective response rate (ORR).
• Patients were assigned to 1 of 3 target dose levels (1: 50 x 106 , 2: 100 X 106 , or 3: 150 x 106 CAR T cells) and were administered in sequential infusion of two compartments (CD8+ and CD4+ ) at equal target doses. Lymphodepletion chemotherapy (fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 daily x 3 days) was given 2-7 days prior to the cell infusions. Patients who achieved a CR but then relapsed could receive retreatment. Outpatient administration and monitoring was allowed per investigator’s discretion.
• Baseline characteristics: median prior LOTs was 3 (1-8) with 97% with at least 2 prior LOT; 42% were 65 years or older; 67% had chemotherapy refractory disease; 35% had previous HCT (auto and allo), 3% had secondary CNS involvement, and 59% received bridging therapy
• Overall safety and activity did not differ by dose level. The recommended target dose was 100 x 106 CAR T cells (50 x 106 CD8+ and 50 x 106 CD4+ ). Grade 1-2 CRS was numerically higher at dose level 3, and ORR was numerically higher at dose level 2 and 3.
• 256 patients were included in the efficacy-evaluable set. ORR was 73% (95% CI, 66.8-78.0) with a 53% CR (95% CI, 46.8-59.4) and 20% PR (95% CI, 14.9-24.9). ORR was achieved across all Monthly Literature Update October 2021 2 subgroups, including high-grade B-cell lymphomas. At 12 months: DOR = 54.7%, PFS = 44.1%, and OS = 57.9%.
• Most common grade 3 or worse: neutropenia (60%), anemia (37%) and thrombocytopenia (27%). CRS and neurological events occurred in 42% and 30%, respectively, grade 3 or worse CRS and neurological events occurred in 2% and 10%, respectively. Median onset of CRS was 5 days (1-14), and median onset of neurological events was 9 days (1-66). Nine (6%) patients had a dose-limiting toxicity; 1 patient died from diffuse alveolar damage. Prolonged cytopenias at day 29 was 37%, hypogammaglobulinemia was 14%, and grade 3 or worse infections was 12%.
• The authors concluded that their study showed that liso-cel can lead to rapid and durable remission, with low incidence of all-grade CRS and neurological events among patients with high-risk aggressive R/R large B-cell lymphomas. Clinically meaningful activity was noted in patients with unmet medical need, such as those with characteristics of poor prognosis.

Outpatient administration

*Carlos R. Bachier, John E. Godwin, Charalambos Andreadis, et al; Outpatient treatment with lisocabtagene maraleucel (liso-cel) across a variety of clinical sites from three ongoing clinical studies in relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 8037-8037.

• Study sought to characterize whether patients (pts) could be safely monitored in the outpatient setting after receiving lisocabtagene maraleucel (liso-cel), CD19-directed CAR T cell product was administered at equal target doses of CD8+ and CD4+ CAR+ T cells, across university (TRANSCEND/PILOT) and non-university (OUTREACH) sites in TRANSCEND NHL 001 (NCT02631044), OUTREACH (NCT03744676), and PILOT (NCT03483103).
• Eligible pts had R/R LBCL after systemic chemoimmunotherapy (TRANSCEND and OUTREACH: ≥2 prior lines of therapy and ECOG PS ≤1; PILOT: 1 prior line of therapy and deemed TNE for autologous hematopoietic stem cell transplantation based on ECOG PS, organ function, and/or age). For outpatient infusion of liso-cel, pts were required to receive safety monitoring education, have a caregiver and stay within 1 h travel to site of care for 30 d post-treatment.
• At data cutoff, 53 pts had received liso-cel on Study Day 1 and were monitored as outpatients (university, n = 33; non-university, n = 20), including pts ≥65 y of age (n = 23) and with high tumor burden (SPD ≥50 cm2 ; n = 16).
• Any grade CRS and NEs were reported in 18 (34%) and 14 pts (26%), respectively. Severe CRS and/or NEs occurred in only 2 pts (4%) and were reversible. Median (range) time to onset of CRS and NEs was 5 (2–9) and 8.5 (3–22) d, respectively. Tocilizumab and/or corticosteroids for treatment of CRS and/or NEs were required in 8 pts (15%).
• Overall, 30 pts (57%) required hospitalization post-treatment, with a median (range) time to hospitalization post-treatment of 5.5 (2–22) d; 9 pts (17%) were hospitalized Study Day 4 or earlier. Two pts required ICU-level care. There were no grade 5 treatment-emergent AEs. Safety in pts monitored as outpatients was comparable across types of sites.
• Overall response rate was 81% (95% CI, 68–91). Safety and efficacy were consistent with data from inpatients across the 3 studies (N = 270). 3
• Patients with R/R LBCL were successfully treated with liso-cel and monitored for CAR T cellrelated toxicity in the outpatient setting across different types of sites. Incidences of severe CRS, NEs, and early hospitalization were low; 43% of pts did not require hospitalization.

*John E. Godwin, Bassam Ibrahim Mattar, Michael B. Maris et al, Outreach: Preliminary safety and efficacy results from a phase 2 study of lisocabtagene maraleucel (liso-cel) in the nonuniversity setting. Journal of Clinical Oncology 39, no. 15_suppl.e19513

• OUTREACH (NCT03744676) evaluates safety and efficacy of liso-cel in patients (pts) with R/R large B-cell lymphoma (LBCL) across inpatient and outpatient settings at nonuniversity medical centers (NMCs).
• Eligible pts had R/R PET-positive disease after ≥2 lines of prior systemic therapy, ECOG PS ≤1, and adequate organ function. Prior autologous HSCT was allowed. Pts received sequential infusions of equal target doses of CD8+ and CD4+ cells at a total target dose of 100 × 106 CAR+ T cells. Outpatient AE monitoring/management was managed by a multidisciplinary CAR T cell therapy team following standard operating procedures (SOPs).
• Primary endpoint was incidence of grade (G) ≥3 cytokine release syndrome (CRS) graded per 2014 Lee criteria, neurological events (NEs), prolonged cytopenias (Day 29 G≥3 lab values), and infections. Secondary endpoints were safety and overall response rate (ORR).
• At data cutoff, 46 pts (inpatients n = 16, outpatients n = 30) were treated with liso-cel. Inpatients and outpatients had similar demographics and baseline disease characteristics; median age was 63 y (range, 34–83), 63% had diffuse LBCL not otherwise specified, and 91% were refractory to last therapy.
• Safety data were similar across inpatients and outpatients. Early (study Day ≤4) and overall hospitalization in outpatients was reported in 27% and 63%, respectively; median time to hospitalization was 5 (2–61) days and median length of stay was 6 (1–28) days.
• For efficacy-evaluable pts (n = 44), ORR was 75% for inpatients and 79% for outpatients; CR rates were 50% and 61%, respectively.
• Overall, Liso-cel was successfully administered to pts with R/R LBCL in the outpatient setting. The incidences of severe CRS and NEs and use of tocilizumab and/or corticosteroids were similar in inpatients and outpatients, and consistent with the pivotal study observations.

Mantle Cell Lymphoma

***Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med 2020;382(1331):1331-1342. https://pubmed.ncbi.nlm.nih.gov/32242358

• Multicenter, phase 2 trial that evaluated KTE-X19 in patients with r/r mantle cell lymphoma (MCL) who had received previous BTKi therapy and up to 5 prior therapies. Primary endpoint was the percentage of patients with objective response (CR or PR).
• Patients received conditioning chemotherapy (fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 on days -5, -4, -3) followed by a single infusion of KTE-X19 (2 x 106 CAR T-cells/kg) on day 0. Bridging therapy was optional at the investigator’s discretion. 74 patients were enrolled, KTE-X19 was manufactured for 71 patients and administered to 68. 4
• Baseline characteristics: median age was 65 (38-79), 56% had intermediate or high-risk features, 17% had TP53 mutation, Ki-67 index ≥ 30% was 82%, median prior LOTs was 3 (1-5), 43% had prior auto-HCT, and 62% were primary refractory to BTKi therapy.
• Primary efficacy analysis was conducted after 60 patients had been treated and followed for 7 months. Objective response was 93% (95% CI, 84-98); 67% (95% CI, 53-78) had a CR. Objective response was consistent among key subgroups including high-risk features. At a median of 12.3 months, 57% in the primary efficacy analysis were in remission. Median DOR has not been reached. PFS at 12 months was 61% and OS at 12 months was 83%. Two patients who had an objective response and then progressed received a second infusion approximately 1 year later; analysis in these patients is ongoing.
• Common AEs grade 3 or higher were cytopenias (94%) and infections (32%). CRS occurred in 91% of patients; grade 3 or higher was 15%. Median onset to CRS was 2 days (1-13) with a median duration of 11 days. Neurological events occurred in 63% of patients; grade 3 or higher was 31%. Median onset to neurological events was 7 days (1-32) with a median duration of 12 days with events fully resolving in 86%. 68% of patients had serious AEs. Two grade 5 infections occurred.
• The authors concluded that their study showed that KTE-X19 induced durable remissions in majority of patients with relapsed or refractory MCL after failure of BTKi therapy. The trial led to serious and life-threatening toxic events that are largely consistent with those reported in previous studies of anti-CD19 CAR T-cell therapies in patients with aggressive B-cell lymphomas.

Acute Lymphoblastic Leukemia

***Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapse or refractory adult B-cell acute lymphoblastic leukemia: phase 2 results of the single-arm, open-label, multicenter ZUMA-3 study. Lancet 2021;398(10299):491-502. https://pubmed.ncbi.nlm.nih.gov/34097852

• International, multicenter, phase 2 study evaluating the efficacy and safety of the autologous anti-CD19 CAR-T therapy KTE-X19 in adult patients with R/R B-precursor acute lymphoblastic leukemia. Primary endpoint was the rate of overall CR or CR with incomplete hematological recovery. Secondary endpoints were duration of response (DOR), relapse-free survival (RFS), OS, MRD negativity rate, and allo-SCT rate.
• Patients received lymphodepletion chemotherapy (fludarabine 25mg/m2 on days -4,-3, -2 and cyclophosphamide 900 mg/m2 on day -2) followed by a single KTE-X19 infusion (1 x 106 CAR T cells/kg) on Day 0. 71 patients were enrolled, KTE-X19 was successfully manufactured for 65 patients and administered to 55.
• Baseline characteristics: median age was 40 years with 15% 65 years or older, 47% received 3 or more prior LOTs, 45% previously received blinatumomab, 22% previously received inotuzumab, 42% previously received alloHCT, 33% had primary refractory disease, and 93% received bridging therapy with 62% having > 25% bone marrow blasts after therapy.
• At a median follow-up of 16.4 months, 71% (95% CI, 57-82) had CR or CR with incomplete hematological recovery with 56% reaching CR. Median DOR was 12.8 months (95% CI, 8.7–not 5 estimable), median RFS was 11.6 months (2.7-15.5), and median OS was 18.2 months (15.9–not estimable). Among responders, median OS was not reached, and 97% had MRD negativity. Ten patients received consolidation alloHCT after KTE-X19 infusion; median time to alloHCT was 98 days (IQR 72-134).
• Most common grade 3 or higher AEs were anemia (49%) and pyrexia (36%). 25% of patients had grade 3 or higher infections. CRS occurred in 89% of patients with grade 3 or higher occurring in 24%. Median onset to CRS was 5 days (IQR 3-7), and median duration was 7.5 days (5-18). Neurological events occurred in 60% of patients with grade 3 or higher occurring in 25% of patients. Median onset of neurological events was 9 days (7-11) and median duration was 7 days (4-19). Two grade 5 events occurred (brain herniation and septic shock). 36% of treated patients had died as of data cutoff date, primarily from progressive disease (24%).
• The authors concluded that their study showed that a single infusion of KTE-X19 could induce durable remission with manageable safety in heavily pretreated B-precursor ALL, addressing a substantial unmet need. The rapid manufacturing time supports the feasibility of providing this novel therapy to adult patients with rapidly progressive disease. As such, KTE-X19 has potential for long-term clinical benefit in this patient population.

Multiple Myeloma

***Munshi NC, Anderson LD, Shah N et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384:705-716. https://pubmed.ncbi.nlm.nih.gov/33626253

• Phase 2, single-group study of ide-cel at doses of 150 x 106 , 300 x 106 , or 450 x 106 CAR+ T-cells in MM patients who had received at least 3 previous regimens and disease refractory to last regimen
• 140 patients underwent leukapheresis, of which 128 were infused. Of those infused, median age was 61 years, 51% had high tumor burden (> 50% BM plasma cells), and median number of previous regimens was 6. 94% has undergone an autoHCT, 84% had triple-refractory disease, and 60% had penta-refractory disease.
• 4, 70, and 54 patients were treated at target doses of 150 x 106 , 300 x 106 , or 450 x 106 CAR+ T cells, respectively. ORR was 73% at a median follow-up of 13.3 months, with 33% having a CR or sCR and 52% with VGPR or better. At the target doses, ORR was 50%, 69%, and 81% and CR rate was 25%, 29%, and 39%, respectively. Median time to first response was 1 month, and to CR or better was 2.8 months. Median DOR was 10.7 months overall, and 11.3 months at the 450 x 106 cell dose. Median OS was 19.4 months with an OS of 78% of 12 months.
• 99% of patients experienced grade >3 ADEs, the most common being neutropenia (89%), anemia (60%), and thrombocytopenia (52%). CRS occurred in 84% of patients, with only 4% experiencing grade 3 CRS and < 1% experiencing grade 4 or 5 CRS. Median time to CRS onset was 1 day with a median duration of 5 days. ICANS was reported in 18% of patients, of whom 3% had grade 3. No grade 4 or 5 ICANS was observed. 3% of patients died of ide-cel-related adverse events.
• Authors conclude that ide-cel induces responses in an impressive amount of heavily pretreated relapsed and refractory MM 6

***Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigendirected chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398:314-24. https://pubmed.ncbi.nlm.nih.gov/34175021

• Phase 1b/2, single-arm study of cilta-cel at a target dose of 0.75 x 106 (range 0.5 – 1.0 x 106 ) CAR+ T-cells/kg in MM patients who had received at least 3 previous regimens with disease progression within 12 months of last therapy  113 patients underwent leukapheresis, of which 97 were infused. Of those infused, median age was 61 years, and median number of previous regimens was 6. 94% has undergone an autoHCT, 88% had triple-refractory disease, and 42% had penta-refractory disease.
• ORR was 97% at a median follow-up of 12.4 months, with 67% achieving a sCR. Median time to first response was 1 month, to best response was 2.6 months, and to CR or better was 1.9 months. Median PFS was not reached, and 12-month PFS was 77% overall and 85% in those who achieved a CR or better. 12-month OS was 89%.
• 100% of patients experienced grade >3 ADEs, the most common being neutropenia (95%), anemia (68%), leukopenia (61%) and thrombocytopenia (60%). CRS occurred in 95% of patients, with only 3% experiencing grade 3 CRS and 2% experiencing grade 4 or 5 CRS. Median time to CRS onset was 7 days with a median duration of 4 days. ICANS was reported in 17% of patients, of whom 32% had grade >3. No grade 5 ICANS was observed. 6% of patients died of cila-celrelated adverse events.
• Authors conclude that cilta-cel leads to early, deep, and durable responses in heavily pretreated patients with MM

Toxicity Management

*Strati P, Ahmed S, Kebriaei P, et al. Clinical efficacy of anakinra to mitigate CAR T-cell therapy associated toxicity in large B-cell lymphoma. Blood Adv 2020;4(13):3123-3127

• Single-center review of 8 patients who received anakinra for grade >3 ICANS, >3 CRS, or HLH after axicabtagene ciloleucel for large B-cell lymphoma. Anakinra was initiated in 6 patients for severe ICANS and in 2 patients for HLH management.
• Anakinra was started at a median of 12 days after cell infusion with patients having received a median cumulative dose of dexamethasone 273 mg and median of 2 tocilizumab doses at time of initiation. Anakinra was dosed between 50 and 200 mg (median daily dose 100 mg) subcutaneously for a median of 7 days.
• Four patients had a clinical response to anakinra for high-grade ICANS leading to either resolution or reduction of severity. These patients received anakinra at a dose of 100 mg SC daily for 7 days. Of the non-responders, both ICANS patients continued anakinra until they eventually expired. Two patients receiving a short course of anakinra for severe HLH showed no response.
• The authors conclude that anakinra represents a potential steroid-sparing strategy for CAR T-cell toxicities, mainly ICANS. 7

*Jatiani SS, Aleman A, Madduri D, et al. Myeloma CAR-T CRS management with IL-1R antagonist anakinra. Clin Lymphoma Myeloma Leuk 2020;20(9):632-636

• This report describes the clinical features of 2 patients experiencing CRS after anti-BCMA CAR-T therapy. One of these patients was treated with tocilizumab alone whereas the other was also treated with the addition of anakinra.
• Patient one developed CRS on day 2 with fever, hypotension, and tachycardia requiring ICU care. Tocilizumab 4 mg/kg was given in addition to supportive care. The patient remained febrile but stable until resolution by day 8 and eventual discharge.
• Patient two also developed CRS on day 2 with fever and hypotension requiring treatment with tocilizumab 8 mg/kg. The patient remained febrile on day 3 and received anakinra 200 mg subcutaneously 3 times a day until day 7 when the patient defervesced.
• The authors conclude that there is merit in the use of anakinra for the adjunctive treatment of CRS following CAR-T therapy in myeloma patients.

**Zhang L, Wang S, Xu J, et al. Etanercept as a new therapeutic option for cytokine release syndrome following chimeric antigen receptor T cell therapy. Exp Hematol Oncol 2021;10:16

• This study describes a single center experience with LCAR-B38M, an anti-BCMA CAR T-cell therapy. Fifty-hour cytokines were analyzed in all 8 patients and the authors found a significant increase in IL-6, IL-10, and TGF-alpha, and TNF-alpha.
• Three patients exhibited markedly elevated levels of TNF-alpha, prompting use of etanercept for CRS treatment. One patient received etanercept 25 mg subcutaneously on day 8 after 24 hours of high-grade fevers which subsequently defervesced. Another patient also had resolution of symptoms after receiving the same etanercept dosing after a febrile event with TNF-alpha levels 30 times the baseline value
• A third patient developed fever on day 8 along with neutropenia, transaminitis, hypotension, and arthralgias. The patient went on to receive three doses of tocilizumab 240 mg without resolution of symptoms. On Day 11 etanercept 50 mg was given with subsequent recovery over the course of a few days.
• The authors suggest that etanercept can be used to manage CRS associated with CAR T-cell therapy, especially in patients with rapid elevations of TNF-alpha.

Abbreviations

ADE: adverse drug event

AE: adverse event

autoHCT: autologous hematopoietic cell transplant

BM: bone marrow

BTKi: Bruton tyrosine kinase inhibitor

Cilta-cel: ciltacabtagene autoleucel

CNS: central nervous sytem

CR: complete response

CRS: cytokine release syndrome

DLBCL: diffuse large B-cell lymphoma

DOR: duration of response

FL: follicular lymphoma

ICANS: immune effector cell-associated neurotoxicity syndrome

Ide-cel: idecabtagene ciloleucel

LBCL: large B-cell lymphoma

Liso-cel: lisocabtagene maraleucel

LOT: lines of therapy

MCL: mantle cell lymhpoma

MM: multiple myeloma

NE: neurotoxicity event

ORR: overall response rate

OS: overall survival

PET: positron emission tomography scan

PFS: progression-free survival

PMBCL: primary mediastinal B-cell lymphoma

sCR: stringent complete response

VGPR: very good partial response

ASTCT Pharmacy SIG Research Working Committee:

Jennifer Collins, Kelly Gaffney, Katie Gatwood, Arpita Gandhi, Jitesh Kawedia, Binni Kunvarjee, Andrew Lin, Dennis Marjoncu, Jonathan Ptachcinski, Julianna Roddy, Lily Yan

Tags: Literature, CAR T, Pharmacy, Update, Special interest group, therapies, alternatives