Considerations for apheresis timing and bridging therapy before CD19 CAR T-cell therapy
| Treatment modality . | Therapies . | Considerations . |
|---|---|---|
| Timing to apheresis | The following factors should be taken into consideration to determine optimal timing for apheresis: Quantity of peripheral T cells: a minimum absolute lymphocyte count of >300 cells per μL or CD3+ cell count of 100 to 200 cells per μL is recommended. Circulating peripheral blasts: it is generally not advisable to collect with a high circulating blast count (WBC > 20-40 000/μL with >50%-80% leukemic blasts) because this can interfere with manufacturing.42 Quantity of prior therapy exposure: we recommend collecting T cells as early as feasible because continued courses of chemotherapy selectively deplete early lineage cells, which are important for T-cell expansion.40,41 Time from prior therapy: a minimum treatment-free period is needed before collection, ranging from 72 h for corticosteroids, to 2 wk for cytotoxic chemotherapy, to longer periods for certain immunotherapies (eg, 6 wk-3 mo for pembrolizumab). Patients with a history of HSCT: we recommend that apheresis occur at least 100 to 120 d after HSCT and immunosuppression be discontinued at least 4 wk before apheresis without signs of graft-versus-host disease to avoid the risk of collecting alloreactive T-cells. | |
| Chemotherapy | Intensive regimens: 4-drug induction (vincristine, corticosteroid, asparaginase and anthracycline); cyclophosphamide with etoposide; high-dose cytarabine. Less-intensive regimens: maintenance-style chemotherapy (oral mercaptopurine, oral methotrexate, ±vincristine, and short course of corticosteroids); abbreviated consolidation cycle with cyclophosphamide and low-dose cytarabine; intermediate-dose VP-16/cytosine arabinoside; intermediate-dose methotrexate; 3-drug induction (vincristine, corticosteroid, and asparaginase) IT chemotherapy should be added to the above regimens | The chemotherapy regimen chosen should attempt to balance the desire for disease reduction/control with the risk of infections or toxicities that could delay or preclude infusion.44,45 When possible, would be ideal to allow for count recovery in between bridging chemotherapy and CD19 CAR T-cell infusion. The addition of IT chemotherapy is crucial for CNS prophylaxis or to treat CNS involvement. |
| Immunotherapy | Blinatumomab; inotuzumab ozogamicin | Blinatumomab: risk for CD19 antigen downregulation or escape, which may lead to worse outcomes after CAR T cells or even preclude the use of CD19 CAR T cells.18,20,26 Thus, we recommend against the immediate use of blinatumomab as a bridge to CD19 CAR T cells. Inotuzumab: Can induce prolonged BCA. We recommend cautious use of inotuzumab immediately before CD19 CAR T cells, given data showing CD19+ antigen load may be associated with CAR T-cell persistence.32 In addition, for patients who are planning to proceed to consolidative HSCT after CD19 CAR T cells, inotuzumab is associated with increased risk of sinusoidal obstructive syndrome.46 |
| Radiotherapy | No standard dosing protocols available | May be considered for patients with bulky EMD not responsive to chemotherapy; minimal data available on its efficacy before CAR T-cell therapy.47,48 |
| Treatment modality . | Therapies . | Considerations . |
|---|---|---|
| Timing to apheresis | The following factors should be taken into consideration to determine optimal timing for apheresis: Quantity of peripheral T cells: a minimum absolute lymphocyte count of >300 cells per μL or CD3+ cell count of 100 to 200 cells per μL is recommended. Circulating peripheral blasts: it is generally not advisable to collect with a high circulating blast count (WBC > 20-40 000/μL with >50%-80% leukemic blasts) because this can interfere with manufacturing.42 Quantity of prior therapy exposure: we recommend collecting T cells as early as feasible because continued courses of chemotherapy selectively deplete early lineage cells, which are important for T-cell expansion.40,41 Time from prior therapy: a minimum treatment-free period is needed before collection, ranging from 72 h for corticosteroids, to 2 wk for cytotoxic chemotherapy, to longer periods for certain immunotherapies (eg, 6 wk-3 mo for pembrolizumab). Patients with a history of HSCT: we recommend that apheresis occur at least 100 to 120 d after HSCT and immunosuppression be discontinued at least 4 wk before apheresis without signs of graft-versus-host disease to avoid the risk of collecting alloreactive T-cells. | |
| Chemotherapy | Intensive regimens: 4-drug induction (vincristine, corticosteroid, asparaginase and anthracycline); cyclophosphamide with etoposide; high-dose cytarabine. Less-intensive regimens: maintenance-style chemotherapy (oral mercaptopurine, oral methotrexate, ±vincristine, and short course of corticosteroids); abbreviated consolidation cycle with cyclophosphamide and low-dose cytarabine; intermediate-dose VP-16/cytosine arabinoside; intermediate-dose methotrexate; 3-drug induction (vincristine, corticosteroid, and asparaginase) IT chemotherapy should be added to the above regimens | The chemotherapy regimen chosen should attempt to balance the desire for disease reduction/control with the risk of infections or toxicities that could delay or preclude infusion.44,45 When possible, would be ideal to allow for count recovery in between bridging chemotherapy and CD19 CAR T-cell infusion. The addition of IT chemotherapy is crucial for CNS prophylaxis or to treat CNS involvement. |
| Immunotherapy | Blinatumomab; inotuzumab ozogamicin | Blinatumomab: risk for CD19 antigen downregulation or escape, which may lead to worse outcomes after CAR T cells or even preclude the use of CD19 CAR T cells.18,20,26 Thus, we recommend against the immediate use of blinatumomab as a bridge to CD19 CAR T cells. Inotuzumab: Can induce prolonged BCA. We recommend cautious use of inotuzumab immediately before CD19 CAR T cells, given data showing CD19+ antigen load may be associated with CAR T-cell persistence.32 In addition, for patients who are planning to proceed to consolidative HSCT after CD19 CAR T cells, inotuzumab is associated with increased risk of sinusoidal obstructive syndrome.46 |
| Radiotherapy | No standard dosing protocols available | May be considered for patients with bulky EMD not responsive to chemotherapy; minimal data available on its efficacy before CAR T-cell therapy.47,48 |
IT, intrathecal; WBC, white blood cell.