Feasibility of a Novel Academic Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) (HBI0101) for the Treatment of Relapsed and Refractory AL Amyloidosis
Authors: Lebel Eyal , Kfir-Erenfeld Shlomit , Asherie Nathalie , Grisariu Sigal , Avni Batia , Elias Shlomo , Assayag Miri , Dubnikov Tatyana , Zalcman Nomi , Pick Marjorie , Zimran Eran , Cohen Yael C. , Avivi Mazza Irit , Cohen Cyrille , Stepensky Polina , Gatt Moshe E 
Published: December 2023

BACKGROUND: While anti-BCMA chimeric antigen receptor T-cell therapy (CART) have proven safe and efficient in multiple myeloma (MM), its application to AL amyloidosis (AL), has been restricted due to the frailty of this population and rarity of disease. HBI0101 therapy is a novel anti-BCMA CART-based therapy developed at Hadassah Medical Center and Bar-Ilan University for MM treatment. In a phase Ia-b/2 study (NCT04720313), HBI0101 has demonstrated manageable safety with therapeutic efficacy in over 70 MM patients. Although BCMA targeting in AL has been questioned because of relatively low expression of this antigen on AL plasma cells (PC), we have previously reported that this level of expression is sufficient to enable PC eradication by HBI0101 CART ex vivo. Based on this observation, we have treated 9 AL patients in our study, which represent the largest cohort of AL treated with anti-BCMA CART reported so far.
METHODS: The patients were treated within the following cohorts: 1 received 150x10^6 CART cells, 2 received 450x10^6 CART cells and 6 received 800x10^6 CART cells. Two of the patients were treated on a compassionate basis due to concomitant myelodysplastic syndrome (MDS) / ECOG 4 performance status. Patients with creatinine clearance ≥30ml/min (n=7) received lymphodepletion with fludarabine 25mg/m 2 and cyclophosphamide 250mg/m 2 on days -5 to -3 before infusion, and patients with creatinine clearance &lt;30ml/min (n=2) received lymphodepletion with bendamustine 90mg/m 2 and on days -4 and -3 before infusion. Two patients with NYHA stage 3 and MAYO stage 3b AL-related heart failure were admitted electively to the intensive care unit before infusion for close monitoring.
RESULTS: Nine AL patients with relapsed/refractory disease were included, with a median of 6 prior lines of therapy (range: 3-10), all refractory to their last line of therapy. All patients were triple refractory to PI, IMiD and anti-CD38 antibody, 6 were penta-refractory and 5 were refractory to the anti-BCMA antibody drug conjugate belantamab mafodotin. Seven had cardiac involvement, including 4 with MAYO-stage 3a/3b at study entry.
Hematologic adverse events included: grade 3-4 neutropenia in 5 patients, Grade 2-3 anemia in 3 patients, and worsening of pre-existing thrombocytopenia to grade 4 in 1 patient. Three patients developed AL-related organ deterioration (kidney- 2, heart- 1), subsequently resolved to baseline function. Cytokine-released syndrome (CRS) was observed in 7/9 (grade 1-2- 5 patients; grade 3- 2 patients). None of the patients developed immune effector cell-associated neurotoxicity syndrome (ICANs). There were no treatment-related deaths.
Eight out of nine patients were evaluable for efficacy (one patient has not yet completed the first post-treatment evaluation). The overall hematological response rate was 100%, including complete responses in 5 patients, very good partial responses in 2, and partial response in 1 patient. Minimal residual disease (MRD) negativity based on flow cytometry 10^-5 was achieved in 5/8. Best hematological response was achieved after 17 to 57 days (median- 28.5 days). The hematologic responses translated into clinical improvement in all patients, whereas 6/8 met the official criteria for organ responses. With a median follow-up of 7.3 months (range: 2.5-16.5), the median duration of response thus far is 5m (range: 2.5-16.5). Updated results will be communicated at the presentation time.
CONCLUSION: In the largest cohort of AL patients treated with CART reported to date, we demonstrated acceptable toxicity in this frail population, with a remarkable hematologic efficacy, leading to organ responses in most participants. Our data suggests that anti-BCMA CART modality may become a powerful clinical tool to improve organ function and survival, even in advanced AL patients.