Cilta-cel is a CAR-T cell therapy that expresses 2 BCMA-targeting single-domain antibodies, designed to confer avidity. In the multicohort, phase 2 CARTITUDE-2 study (NCT04133636), the safety and ...efficacy of cilta-cel in various clinical settings and suitability of outpatient administration was explored in patients with multiple myeloma.
Patients enrolled in Cohort A had progressive MM after 1–3 prior lines of therapy (LOT), including a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), were lenalidomide refractory, and were naïve to BCMA-targeting agents. A single cilta-cel infusion (target dose: 0.75 × 106 CAR+ viable T cells/kg) was given 5–7 days after start of lymphodepletion (daily cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 for 3 days). The primary outcome was minimal residual disease (MRD) 10-5 negativity. Secondary outcomes were response rates (per IMWG criteria) and safety (per CTCAE; CRS and ICANS by ASTCT).
As of the February 2021 data cutoff (median follow-up: 5.8 months 2.5–9.8), 20 patients (65% male; median age 60 years 38–75) received cilta-cel; 1 patient was treated in an outpatient setting. Patients (n = 12: <3 prior LOT; n = 8: 3 prior LOT) received a median of 2 (1–3) prior LOT. All patients were exposed to PI, IMiD, and dexamethasone, 95% to alkylating agents, and 65% to daratumumab. The majority (95%) were refractory to the last LOT; 40% were triple-class refractory. Overall response rate was 95% (95% CI: 75–100), 75% (95% CI: 51–91) achieved stringent CR/CR, and 85% (95% CI: 62–97) achieved ≥VGPR. Median time to first response was 1.0 month (0.7–3.3); median time to best response was 1.9 month (0.9–5.1). Median duration of response was not reached. All patients (n = 4) with MRD-evaluable samples at 10-5 at data cutoff were MRD-negative. Hematologic AEs ≥20% were neutropenia (95%; grade 3/4: 90%), thrombocytopenia (80%; grade 3/4: 35%), anemia (65%; grade 3/4: 40%), lymphopenia (60%; grade 3/4: 55%), and leukopenia (55%; all grade 3/4). 85% of patients had CRS; 10% were grade 3/4. Median time to CRS onset was 7 days (5–9), with a median duration of 3.5 days (2–11). CAR-T cell neurotoxicity occurred in 20% of patients (all grade 1/2). Three patients had ICANS (n = 1: grade 1; n = 2: grade 2); median time to onset was 8 days (7–11) and median duration was 2 days (1–2). One patient had grade 2 facial paralysis; time to onset was 29 days with a duration of 51 days. One death occurred due to Covid-19 (assessed as treatment-related by investigator). The safety profile was manageable in the patient who was treated in an outpatient setting.
Updated efficacy and safety findings will inform suitability of outpatient treatment in this and other cohorts of CARTITUDE-2 as well as the CARTITUDE-4 study.
A single cilta-cel infusion at the recommended phase 2 dose led to early and deep responses with a manageable safety profile in patients with MM who had 1–3 prior LOT.
Cilta-cel (JNJ-68284528) is a chimeric antigen receptor T cell (CAR-T) therapy with two B-cell maturation antigen (BCMA)-targeting, single-domain antibodies designed to confer high avidity binding. ...CARTITUDE-2 (NCT04133636) is a phase 2, multicohort, open-label study assessing the efficacy and safety of cilta-cel in patients with multiple myeloma (MM) in various clinical settings. We describe the mitigation and management strategies implemented to identify and reduce the risk for neurologic adverse events in patients enrolled in Cohort A (progressive MM after 1-3 prior lines of therapy).
Eligible patients (≥18 years of age) had MM per International Myeloma Working Group criteria, measurable disease, Eastern Cooperative Oncology Group performance status ≤1, progressive disease after 1-3 prior lines of therapy (including a proteasome inhibitor and an immunomodulatory drug), were lenalidomide refractory, and had not received BCMA-targeting agents. Cilta-cel (0.75 × 106 range 0.5– 1.0 × 106 CAR+ viable T cells/kg) was given as a single infusion 5–7 days after start of lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 daily for 3 days). Monitoring and mitigation strategies for neurologic adverse events include providing more effective bridging therapy to reduce tumor burden prior to lymphodepletion, frequent assessment of CAR-T related immune effector cellassociated neurotoxicity syndrome (ICANS) using the immune effector cellassociated encephalopathy tool, regular handwriting assessments to detect micrographia, and neuroimaging (brain MRI) and electroencephalogram for patients with prior neurologic disease. Management strategies include evaluating infectious and paraneoplastic etiologies upon observation of ICANS ≥grade 1, administration of tocilizumab (if concurrent with cytokine release syndrome CRS, all grade of ICANS) and/or dexamethasone (grade 2/3) or methylprednisolone (grade 4). ICANS and CRS were graded by American Society for Transplantation and Cellular Therapy criteria; neurotoxicities not classified as ICANS were graded per common terminology criteria for adverse events, v5.0.
As of 15 Jan 2021 (median follow-up: 5.8 months range: 2.5–9.8), 20 patients in Cohort A received cilta-cel. Median age was 60 years (range: 38–75) and 65% were male. Neurotoxicities occurred in 4 patients (20%). Three patients had ICANS (grade 1/2); median time to onset of symptoms was 8 days (range: 7–11) and median duration was 2 days (range: 1–2). Two of the 3 patients received supportive measures to treat ICANS, including levetiracetam and steroids; all 3 had concurrent CRS and all recovered. One patient developed isolated facial paralysis (grade 2) on Day 29 after cilta-cel infusion and recovered 51 days after onset following treatment with dexamethasone for 28 days. No movement or neurocognitive disorders were reported.
Early detection and management of neurologic adverse events can lead to better treatment outcomes.
Neurologic adverse events were generally manageable in patients with MM following treatment with cilta-cel. With a median of 5.8 months of follow-up, there were no movement or neurocognitive disorders in patients from Cohort A.
Background:
There are limited treatment options for red blood cell (RBC) transfusion dependent (TD) LR (IPSS Low/Int‐1) MDS patients who are relapsed/refractory to ESAs. Imetelstat is a ...first‐in‐class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in some MDS patients across all disease stages. Preliminary results show that imetelstat is effective treatment in LR‐MDS patients inducing durable TI (Steensma et al ASH 2018 Abstr463).
Aims:
We report updated efficacy data with a median follow‐up of 12.1 months in 38 LR non‐del(5q) MDS patients, R/R to ESA and LEN/HMA naive from the open‐label, single‐arm Part 1 of IMerge, an ongoing phase 2/3 study (NCT02598661).
Methods:
Part 1 of the IMerge study included patients with LR MDS, who were heavily transfused (≥4U/8wks), were R/R to ESA or had sEPO >500 mU/mL. Imetelstat 7.5 mg/kg was administered IV every 4 weeks. The primary endpoint was 8‐week TI rate; key secondary endpoints included 24‐week TI rate, safety, duration of TI, and hematologic improvement (HI) rate. Among the initially enrolled patients, higher 8‐week TI rate was observed in the non‐del5q, LEN/HMA naive patients. Therefore, the study was amended to subsequently enroll only these patients. From a total of 57 patients enrolled in Part 1, 38 were non‐del(5q), LEN/HMA naïve patients (13 in the initial and 25 in the expansion cohort). Here we report long‐term efficacy, safety and biomarker data from these 38 patients.
Results:
Median baseline RBC transfusion burden was 8U/8weeks (range 4–14), 37% of the patients had IPSS Int‐1; 71% had WHO 2001 RARS or RCMD‐RS subtype and 32% with evaluable sEPO levels had baseline level >500 mU/mL.
As of 23 January 2019, median follow‐up was 12.1 months for the 38 patients, representing 30.4 and 11.6 months for the initial 13 and additional 25 patients, respectively. The 8‐week TI rate was 45% (17/38) and median TI duration was 8.5 months (range 1.8–32.4). Of the 17 responding patients, 10 (59%) remained transfusion free for over 24 weeks. The 8‐week TI rate did not differ based on the presence of ring sideroblasts or baseline sEPO levels. The 24‐week TI rate was 26% (10/38). Erythroid HI, defined as transfusion reduction by at least 4 units /8 weeks (IWG2006), was achieved in 68% (26/38) of the patients. The most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. 6/38 patients had IPSS‐R intermediate/poor cytogenetic risk. All 6 patents achieved 8‐week TI; 2/6 patients achieved partial cytogenetic response. Post treatment decrease in telomerase hTERT RNA level was observed in 25/34 (73.5%) patients with available sample. Among 7 patients with pre‐ and post‐treatment mutation analyses, six had SF3B1 mutations at baseline, and a decrease in the mutation VAF was observed in 2 patients that had longest TI duration on study.
Summary/Conclusion:
In high RBC transfusion burden patients with non‐del(5q) LR‐MDS R/R to ESA and naive to LEN/HMA, single‐agent imetelstat yielded 8‐week TI rate of 45%, with a median duration of 8.5 months (range 1.8–32.4). The 24‐week TI rate was 26%. HI‐E rate was 68%. All patients with IPSS‐R intermediate and poor cytogenetic risk responded. Biomarker analyses of telomerase activity and mutation allele burden indicate an effect on the malignant mutant clone. These data support Part 2 of IMerge, Phase 3 placebo‐controlled, randomized portion of the study, expected to open mid‐2019.
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