Background: No FDA approved treatments exist for relapsed/refractory (RR) AL Amyloidosis. Chimeric antigen receptor T-cell (CAR-T) is a novel approach to treating RR AL Amyloidosis. In this study, we report safety and efficacy data from the first 20 patients in NEXICART-2, the first U.S. clinical trial of any CAR-T in RR AL Amyloidosis.

Methods: NEXICART-2 (NCT06097832) is a single-arm, multi-site U.S. Phase 1/2 dose escalation and expansion trial of autologous BCMA-targeted CAR-T NXC-201 in RR AL Amyloidosis. It will enroll approximately 40 patients (pts). Pts must have been exposed to bortezomib and anti-CD-38 antibody with persistent or relapsed disease with measurable disease (dFLC >5mg/dl or dFLC >2mg/dl with abnormal k:l ratio, or serum M-spike >0.5g/dl). Lymphodepletion was with fludarabine and cyclophosphamide. The primary endpoint is complete hematologic response (CR) rate (Palladini 2012, 2020, 2021). Cardiac, renal and hepatic responses were assessed by consensus criteria (Comenzo 2012; Palladini 2014).

Patient Characteristics: Twenty pts (12 F, 8 M), median age 66 years (range: 49 – 82) were included. Median follow-up 128 days (range 26 – 391). Median prior lines 4 (range: 1 - 12); including 10 (50%) with prior autologous stem cell transplant. Median dFLC at enrollment was 4.9 mg/dl (range: 2.0 - 27.4). Median NT-proBNP was 355 ng/L (range: 113 - 2,017). Sixty percent (12/20) had cardiac involvement. Of the 12, while patients had more advanced cardiac staging at diagnosis (Mayo stage II (N = 6), Illa (N = 5), and Illb (N = 1)), cardiac stage was more modest at enrollment (Mayo stage I (N = 5), II (N = 4) and Illa (N = 3)). 7/12 had New York Heart Association (NYHA) class II heart failure, 5/12 class I. Thirty-five percent (7/20) of pts had kidney involvement, with median 3.0g (range 2 – 10.3g) of proteinuria in 24h.

Safety: Three pts received 150 million and 17 received 450 million CAR+T cells. Cytokine release syndrome (CRS) was observed in 15 pts (grade 1 (N = 11), grade 2 (N = 4)) CRS onset was on day 1 (N = 10), 2 (N = 2), or 3 (N = 3), with median duration of 1 day (range: 1-5). No immune effector cell associated neurotoxicity (ICANs) or neurotoxicity of any kind was observed. Adverse events included neutropenia (grade 2 (N = 2), grade 3 (N = 8), grade 4 (N = 9)) One pt with pre-existing stage 4 chronic kidney disease prior to enrollment died 6 months after dosing due to dialysis catheter infection (deemed unrelated to drug). Additionally, 2 pts experienced ≥ grade 3 infections, 1 pt experienced grade 3 febrile neutropenia lasting 4 days and 2 pts with pre-existing atrial fibrillation experienced transient arrythmias responsive to beta-blockers. No other cardiac toxicity or decompensation was seen.

Efficacy: Ninety-five percent of patients (19/20) normalized pathological disease markers (involved FLC or M-spike) after NXC-201, all within 14 days (median 7 days), all with reduction of dFLC to <1 mg/dL. 14/16 tested were MRD negative in bone marrow by flow cytometry (10-6 sensitivity) or clonoSEQ (10-6 sensitivity, 1 pt 10-5) at day 25. MRD status is not yet available for 4 pts. Four patients had a cardiac organ response and one patient improved NYHA classification from II to I. Two patients had a renal organ response. One patient had a liver organ response. Only the one pt with pre-existing stage 4 chronic kidney disease prior to enrollment had renal progression. There were no cardiac progressions. As of the data cutoff, 19/20 pts treated with NXC-201 are in VGPR/CR; and no hematologic progressions have been recorded. Updated results will be communicated at presentation time.

Conclusion: In this first 20-patient reported U.S. CAR-T clinical trial experience in RR AL Amyloidosis, we demonstrate that NXC-201 can be given safely and resulted in rapid and deep hematologic responses in all pts treated. Our data suggests that the novel anti-BCMA CAR-T NXC-201 may become a valuable treatment option for RR AL pts.

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2025
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