Varnimcabtagene autoleucel (var-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy with adaptive intra-patient dose escalation and was approved in Spain in 2021 for patients older than 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia. We report activity and safety from var-cel’s pivotal trial in this patient population.

Several academic and commercial chimeric antigen receptor T cell products targeting CD19 (CART19) have achieved complete response (CR) rates of 60%–85% in patients with CD19-positive relapsed/ refractory (R/R) acute lymphoblastic leukemia (ALL).1–12 Patients with isolated extramedullary disease (iEMD) have been systematically excluded from most CART19 clinical trials performed to date, including the pivotal trial for the only commercially available product,2 probably due to the lack of consensus in the evaluation of response to therapy in these patients as well as concerns about poor efficacy and increased risk of neurotoxicity in individuals with central nervous system (CNS) disease. Consequently, data on safety and efficacy of CART19 therapy in patients with R/R ALL and iEMD remain scarce even though iEMD is particularly frequent in patients with relapsed disease after allogeneic hematopoietic cell transplantation (alloHCT)13 or blinatumomab.14

Patients with chronic lymphocytic leukemia (CLL) who do not respond to targeted therapies have an unfavourable prognosis, particularly if tumor cells harbour high-risk genomic aberrations (e.g. TP53 aberrations or complex karyotype) or the disease has transformed into diffuse large B-cell lymphoma (DLBCL), also known as Richter’s transformation (RT) (1). Current guidelines recommend allogeneic hematopoietic cell transplantation (alloHCT) for patients with high-risk CLL or RT (1–3). Chimeric antigen receptor T-cells targeting CD19 (CART19) are also emerging as alternative options for these patients, even though there are currently no approved products for them.

Despite currently available therapies, most patients with relapsed/refractory (R/R) B cell malignancies such as acute lymphoblastic leukemia (ALL) and diffuse large B cell lymphoma (DLBCL) remain incurable. R/R ALL is associated with a complete response rate (CRR) around 30%–45% and a median overall survival (OS) around 4– 8 months, depending on age, type of salvage therapy, and response to it.1–4 The prognosis is particularly poor for patients relapsing after allogeneic hematopoietic cell transplantation (alloHCT).

The prognosis of patients with relapsed/ refractory (R/R) acute lymphoblastic leukemia (ALL) remains poor, particularly for those relapsing after allogeneic hematopoietic cell transplantation (alloHCT).1 Novel agents such as inotuzumab ozogamicin or blinatumomab achieve increased response rates, but these are generally transient unless followed by alloHCT.

Varnimcabtagene autoleucel (IMN-003A, varnim-cel), an autologous CD19-targeted chimeric antigen receptor T cell therapy with 4-1BB co-stimulatory domain and A3B1 murine scFv showed deep, durable responses in patients with relapsed/refractory B cell malignancies (RR BCM) in the phase 2 IMAGINE study in India (Efficacy and Safety of IMN-003A in Patients with RRBCM, CTRI/2022/03/041162). Varnimcel is approved in India for RR B-cell Non-Hodgkin Lymphoma (B-NHL) above age 18 years.

The outcome of patients with chronic lymphocytic leukemia (CLL) has significantly improved with the advent of targeted therapies including rituximab, obinutuzumab, ibrutinib, idelalisib, or venetoclax. Unfortunately, the prognosis of patients who fail these novel agents remains poor.

Genetically modifying autologous T cells to express chimeric antigen receptors (CARs), thus redirecting them to eliminate tumor cells, is a new and revolutionary therapeutic modality for cancer treatment and, in particular, for CD19+ B cell malignancies.

Adoptive T-cell transfer (ACT) immunotherapy is a field in continuous expansion especially during the last three decades. ACT involves ex vivo expansion of tumor-specific cells and reinfusion into the patient. Among these therapies, the use of Chimeric Antigen Receptor (CAR) T-cells for the treatment of several hematologic malignancies has shown unprecedented efficacy rates. Consequently, the development of these therapies from bench to bedside has been done in an impressively short amount of time (1–3).

Varnimcabtagene autoleucel (varnim-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T cell therapy, has demonstrated an antitumor activity and toxicity profile consistent with known CAR T-cell associated adverse effects in patients with relapsed or refractory B-cell malignancies, including B-cell acute lymphoblastic leukemia (B-ALL) and B-cell non-Hodgkin lymphoma (B-NHL). 

Varnimcabtagene autoleucel (varnim-cel), a CD19 antigen-directed chimeric antigen receptor (CAR) T cell therapy with murine A3B1 binder, is currently approved in Spain (Hospital Exemption) for r/r B-ALL (> 25 years) and in India for r/r B-NHL (>18 years) [ASH 2022, 2023].

Varnimcabtagene autoleucel (varnim-cel), an autologous second-generation CAR T-cell product with a 4-1BB costimulatory domain and murine A3B1 binder, was approved in India in February 2024 for relapsed / refractory (r/r) Bcell Non-Hodgkin’s Lymphoma (B-NHL) above 18 years based on safety and efficacy data (ASH 2022, 2023). In this observational study, we present real-world data on the access, safety, and efficacy of the commercial use of this product across multiple clinical centres in India.

Phase-2 first-in-India industry study of varnimcabtagene autoleucel (IMN-003A) in relapsed refractory B cell malignancies: IMAGINE study B-NHL subanalysis

Pharmacokinetic profile of varnimcabtagene autoleucel (IMN-003A), first-in-India industry CD19-directed CAR-T cell therapy for patients with relapsed / refractory B cell malignancies (IMAGINE study)

Phase-2 study of varnimcabtagene autoleucel (IMN-003A) first-in-India industry CD19-directed CAR-T with fractionated infusion for patients with relapsed refractory B cell malignancies: IMAGINE study

The Bengaluru score - a prognostic predictive score for clinical efficacy outcomes based on discovery cohort of patients treated with varnimcabtagene autoleucel (IMN-003A) in the phase-2 (IMAGINE) study

Reinfusion of varnimcabtagene autoleucel (IMN-003A) in patients with relapsed refractory B cell malignancies is feasible with sustained responses

Primary analysis of varnimcabtagene autoleucel (IMN-003A) in phase 2 study (IMAGINE), a
first-in-India industry CD19-directed CAR-T cell therapy for patients with relapsed refractory B
cell malignancies

Varnimcabtagene autoleucel (IMN-003A): Pharmacokinetic profile with predominant naive and central memory phenotype demonstrates sustained in vivo persistence and durable responses in a first-in-India industry phase-2 study (IMAGINE)

Modified Endothelial Activation and Stress Index (mEASIX) Score and Immune Effector Cell Associated Haematotoxicity (ICAHT) following varnimcabtagene autoleucel (IMN-003A), a CD19-directed Chimeric Antigen Receptor T (CAR-T) cell therapy, in the phase-2 study (IMAGINE)

Hypogammaglobulinemia and infection risk in relapsed refractory B cell malignancy patients treated with varnimcabtagene autoleucel (IMN-003A), a CD19-directed Chimeric Antigen Receptor T (CAR-T) cell therapy, in the phase-2 study (IMAGINE)

Factors associated with refractory or relapse after varnimcabtagene autoleucel (IMN-003A) in patients with relapsed refractory B cell malignancies: phase 2 first-in-India industry (IMAGINE) study

Varnimcabtagene autoleucel (IMN-003A): Differences in T cell subset phenotype in B-ALL and B-NHL cohorts did not influence efficacy outcomes in the phase-2 study (IMAGINE)

Cytokine profile following varnimcabtagene autoleucel (IMN-003A) in patients with relapsed refractory B cell malignancies in the first-in-India industry phase-2 study (IMAGINE)

Response, peak and persistence of varnimcabtagene autoleucel (IMN-003A), first-in-India industry CD19-directed CAR-T cell therapy, with fractionated infusions for patients with relapsed and/or refractory B cell malignancies: early results (IMAGINE study)

Early results from a phase-2 study of varnimcabtagene autoleucel (IMN-003A), a first-in-India industry CD19-directed CAR-T cell therapy with fractionated infusions for patients with relapsed and/or refractory B cell malignancies (IMAGINE Study)