Risk factors associated with CD19-targeted CAR T-cell failure

Tumor burden at the time of CAR T-cell infusion.

Tumor burden at the time of CAR T-cell infusion.

A single-center study assessed bone marrow blast percentage immediately before CAR T-cell infusion (after lymphodepleting chemotherapy). High tumor burden (HTB) was defined as 40% blasts or more, and low tumor burden (LTB) was defined as less than 40% blasts.[173]

Tumor burden at the time of CAR T-cell infusion. › A single-center study assessed bone marrow blast percentage immediately before CAR T-cell infusion (after lymphodepleting chemotherapy). High tumor burden (HTB) was defined as 40% blasts or more, and low tumor burden (LTB) was defined as less than 40% blasts.[173]

In the HTB cohort of patients (n = 15), the best ORR was 87%, and the MRD-negative CR rate was 80%.

Tumor burden at the time of CAR T-cell infusion. › A single-center study assessed bone marrow blast percentage immediately before CAR T-cell infusion (after lymphodepleting chemotherapy). High tumor burden (HTB) was defined as 40% blasts or more, and low tumor burden (LTB) was defined as less than 40% blasts.[173]

In the LTB cohort of patients (n = 55), the best ORR was 100%, and all responders were MRD negative.

Tumor burden at the time of CAR T-cell infusion. › A single-center study assessed bone marrow blast percentage immediately before CAR T-cell infusion (after lymphodepleting chemotherapy). High tumor burden (HTB) was defined as 40% blasts or more, and low tumor burden (LTB) was defined as less than 40% blasts.[173]

Among HTB patients, the probability of continued remission was 49% (95% CI, 27%–88%) at 12 months and 39% (95% CI, 19%–82%) at 24 months.

Tumor burden at the time of CAR T-cell infusion. › A single-center study assessed bone marrow blast percentage immediately before CAR T-cell infusion (after lymphodepleting chemotherapy). High tumor burden (HTB) was defined as 40% blasts or more, and low tumor burden (LTB) was defined as less than 40% blasts.[173]

Among LTB patients, the probability of continued remission was 86% (95% CI, 77%–96%) at 12 months and 78% (95% CI, 67%–91%) at 24 months.

Tumor burden at the time of CAR T-cell infusion.

A study of 420 patients assessed the risk factors associated with long-term survival.[189]

Tumor burden at the time of CAR T-cell infusion. › A study of 420 patients assessed the risk factors associated with long-term survival.[189]

On multivariate analysis, a disease burden of 5% or higher, noted by bone marrow flow cytometry before starting lymphodepleting chemotherapy, was associated with a hazard ratio (HR) of 2.52 (95% CI, 1.86–3.41) for inferior EFS, compared with patients who had a lower disease burden.

Tumor burden at the time of CAR T-cell infusion.

In a study of 180 patients who received tisagenlecleucel infusions, univariate and multivariate analyses showed that high-disease burden (>5% bone marrow blasts, CNS3 disease [defined as cerebrospinal fluid specimen with ≥5 white blood cells/μL with lymphoblasts and/or the presence of cranial nerve palsies], or non-CNS extramedullary disease [EMD]) was associated with inferior outcomes.[192]

Tumor burden at the time of CAR T-cell infusion. › In a study of 180 patients who received tisagenlecleucel infusions, univariate and multivariate analyses showed that high-disease burden (>5% bone marrow blasts, CNS3 disease [defined as cerebrospinal fluid specimen with ≥5 white blood cells/μL with lymphoblasts and/or the presence of cranial nerve palsies], or non-CNS extramedullary disease [EMD]) was associated with inferior outcomes.[192]

Patients with a high-disease burden had poorer outcomes (12-month OS rate, 58%; EFS rate, 31%) than patients with a low-disease burden (12-month OS rate, 85%; EFS rate, 70%) and patients with undetectable disease (12-month OS rate, 95%; EFS rate, 72%; P < .0001 for OS and EFS).

Previous failure to respond to blinatumomab.

Previous failure to respond to blinatumomab.

In a study of 420 pediatric and young adult patients with ALL who were treated with CD19-targeted CAR T cells, the following results were reported:[189]

Previous failure to respond to blinatumomab. › In a study of 420 pediatric and young adult patients with ALL who were treated with CD19-targeted CAR T cells, the following results were reported:[189]

Patients who had previously failed to respond to blinatumomab before CAR T-cell therapy had lower CR rates after CAR T-cell therapy (20 of 31, 64.5%) compared with previous responders to blinatumomab (39 of 42, 92.9%) or blinatumomab-naïve patients (317 of 339, 93.5%; P < .0001).

Previous failure to respond to blinatumomab. › In a study of 420 pediatric and young adult patients with ALL who were treated with CD19-targeted CAR T cells, the following results were reported:[189]

Blinatumomab nonresponders had worse 6-month EFS rates (27.3%; 95% CI, 13.6%–43.0%) than blinatumomab responders (66.9%; 95% CI, 50.6%–78.9%; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5%–77%; P < .0001).

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD).

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD).

Early studies recognized that B-cell aplasia was a functional measurement of CD19-targeted CAR T-cell persistence, and that loss of B-cell aplasia within the first few months of treatment resulted in high rates of relapse.[171] However, it is an imperfect measurement because CD19-negative relapse can occur despite persistent B-cell aplasia. NGS-MRD techniques rely on clonal rearrangements in the IgH or TCR sequences in lymphoblasts, which typically persist even when CD19 surface expression is lost.

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD).

To define the risk of relapse, one study assessed B-cell aplasia and NGS-MRD in bone marrow over time in 143 patients who received tisagenlecleucel.[193]

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD). › To define the risk of relapse, one study assessed B-cell aplasia and NGS-MRD in bone marrow over time in 143 patients who received tisagenlecleucel.[193]

Multivariate analysis at day 28 showed independent associations of NGS-MRD greater than 0 (HR, 4.87; 95% CI, 2.18–10.8; P < .001) and loss of B-cell aplasia (HR, 3.33; 95% CI, 1.44–7.69; P = .005) with relapse.

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD). › To define the risk of relapse, one study assessed B-cell aplasia and NGS-MRD in bone marrow over time in 143 patients who received tisagenlecleucel.[193]

By 3 months, the NGS-MRD HR increased to 12 (95% CI, 2.87–50; P < .001), whereas loss of B-cell aplasia was not independently predictive (HR, 1.27; 95% CI, 0.33–4.79; P = .7).

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD). › To define the risk of relapse, one study assessed B-cell aplasia and NGS-MRD in bone marrow over time in 143 patients who received tisagenlecleucel.[193]

Early loss of B-cell aplasia was more predictive of relapse than a later loss of B-cell aplasia.

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD). › To define the risk of relapse, one study assessed B-cell aplasia and NGS-MRD in bone marrow over time in 143 patients who received tisagenlecleucel.[193]

Loss of B-cell aplasia in the first 6 months led to an EFS rate lower than 20%; however, patients who lost B-cell aplasia at 1 year had an EFS rate of 75%.

Persistent B-cell aplasia and next-generation sequencing of MRD (NGS-MRD). › To define the risk of relapse, one study assessed B-cell aplasia and NGS-MRD in bone marrow over time in 143 patients who received tisagenlecleucel.[193]

Notably, NGS-MRD positivity occurring at any time after CAR T-cell therapy led to a very high risk of relapse.

CAR T-cell dose.

CAR T-cell dose.

A retrospective multicenter study reviewed the doses of CD19-targeted CAR T cells (tisagenlecleucel) given per kilogram by quartiles and assessed patient outcomes.[194]

CAR T-cell dose. › A retrospective multicenter study reviewed the doses of CD19-targeted CAR T cells (tisagenlecleucel) given per kilogram by quartiles and assessed patient outcomes.[194]

Patients who received the highest quartile dose had improved OS (HR, 0.22; 95% CI, 0.08–0.61), EFS (HR, 0.24; 95% CI, 0.12–0.49), and RFS (HR, 0.18; 95% CI, 0.07–0.49), compared with those who received the lowest quartile dose.

CAR T-cell dose. › A retrospective multicenter study reviewed the doses of CD19-targeted CAR T cells (tisagenlecleucel) given per kilogram by quartiles and assessed patient outcomes.[194]

Higher doses of CAR T cells were not associated with additional toxicities.

CAR T-cell dose. › A retrospective multicenter study reviewed the doses of CD19-targeted CAR T cells (tisagenlecleucel) given per kilogram by quartiles and assessed patient outcomes.[194]

A potential confounding factor was the significantly higher number of patients with favorable cytogenetics who received the highest quartile dose.

CAR T-cell dose. › A retrospective multicenter study reviewed the doses of CD19-targeted CAR T cells (tisagenlecleucel) given per kilogram by quartiles and assessed patient outcomes.[194]

Further research is warranted to elucidate the relationship between threshold dosing and post-CAR T-cell therapy outcomes for tisagenlecleucel.

Timing of relapse after HSCT before treatment with CD19-targeted CAR T cells.

Timing of relapse after HSCT before treatment with CD19-targeted CAR T cells.

A retrospective study reported the outcomes of 81 patients with multiply relapsed or primary refractory B-ALL who were treated with tisagenlecleucel. Eighty percent of these patients had previously underwent allogeneic HSCT.[195]

Timing of relapse after HSCT before treatment with CD19-targeted CAR T cells. › A retrospective study reported the outcomes of 81 patients with multiply relapsed or primary refractory B-ALL who were treated with tisagenlecleucel. Eighty percent of these patients had previously underwent allogeneic HSCT.[195]

Seventy-one of 81 patients (87.7%) were in remission at day 28 after CAR T-cell therapy.

Timing of relapse after HSCT before treatment with CD19-targeted CAR T cells. › A retrospective study reported the outcomes of 81 patients with multiply relapsed or primary refractory B-ALL who were treated with tisagenlecleucel. Eighty percent of these patients had previously underwent allogeneic HSCT.[195]

At 2 years after CAR T-cell therapy, the EFS rate was 45.3%, and the OS rate was 53.2%.

Timing of relapse after HSCT before treatment with CD19-targeted CAR T cells. › A retrospective study reported the outcomes of 81 patients with multiply relapsed or primary refractory B-ALL who were treated with tisagenlecleucel. Eighty percent of these patients had previously underwent allogeneic HSCT.[195]

Of the patients who previously underwent transplant, time to relapse after HSCT was a significant predictor of outcome when receiving tisagenlecleucel. Patients who had relapsed within 6 months of allogeneic HSCT had an EFS rate of 18.4%, compared with 55.5% for those who relapsed 6 months or more after HSCT.