Special populations and unique patient scenarios for CD19 CAR T-cell therapy
| Special population or unique scenario . | Summary and recommendations . | Available data . |
|---|---|---|
| Isolated CNS relapse of B-ALL | CAR T cells are effective in eradication of CNS disease in B-ALL. Consider CAR T cells in: Multiply relapsed isolated CNS disease. Early isolated CNS relapse (not currently an approved indication for tisagenlecleucel) Given favorable outcomes with standard of care therapy for late, isolated first relapse,80 CAR T cells would not be considered first line in this setting. | Several retrospective studies described outcomes after CD19 CAR T cells for B-ALL with CNS involvement using aggregate data sets. Importantly, severe neurotoxicity was not found to be increased in patients with CNS involvement.31,53,54, CHOP clinical trials: in a pooled analysis of 5 clinical trials at CHOP, the CR rate for patients treated with murine or humanized CD19 CAR T cells for isolated CNS disease (n = 43) was 98%.53 Of those, 38% experienced a subsequent relapse (7/16 with CNS involvement at post-CAR relapse); 2-y OS was 91%. PRWCC study: the CR rate for patients treated with tisagenlecleucel for isolated CNS disease (n = 23) was 96%.31 Of those, 32% experienced a subsequent relapse (4/7 with CNS involvement at post-CAR relapse); 2-y OS was 81%. International experience: in a multicenter study of 55 patients with CNS-positive disease treated with a variety of CD28 or 4-1BB CD19 CAR T cells, the CR rate was 94%.54 The 2-y EFS and OS were 40% and 75% for the full cohort, and 44% and 93% for those with isolated CNS disease (n = 15). Notably, among 8 patients who received tisagenlecleucel for isolated CNS disease, 6 subsequently relapsed (all in the CNS), but 2-y OS was 100%. |
| Primary refractory disease | High-risk patients with primary refractory disease should be considered for early referral to CAR T cells. The role for consolidative HSCT for patients who receive CAR T cells for primary refractory disease warrants prospective study. | As most clinical trials have enrolled patients with both r/r disease, isolating outcomes for those with primary refractory disease is challenging. Nonetheless, in patients with primary refractory disease across either early phase studies20 or pivotal trials,6 substantial benefit has been seen. An ongoing, multicenter, phase 2 clinical trial through the Children’s Oncology Group (NCT03876769) is evaluating long-term outcomes following CD19 CAR T cells in high-risk patients with detectable MRD by flow cytometry after 2 cycles of frontline chemotherapy. Given excellent outcomes with chemotherapy alone81 patients with NCI standard-risk B-ALL who are MRD+ after 2 cycles of chemotherapy, are presently excluded from the aforementioned study. The role of consolidative HSCT is ill defined; the COG study is testing use of CD19 CAR T cells in an earlier setting when consolidative HSCT may or may not be needed. |
| First relapse of ALL | Clinical trials evaluating the role for CD19 CAR T cells are urgently needed given the limited remission rates and toxicity associated with chemotherapy-based induction regimens for patients with first relapse. | Tisagenlecleucel is not currently approved for patients with first relapse. |
| History of previous HSCT | CAR T cells are an effective salvage treatment for patients with post-HSCT relapse of B-ALL. Given the risks associated with second HSCT,68 CAR T cells with curative potential should be preferentially considered to try to avoid the need for a consolidative second HSCT. | There are limited effective options for patients with post-HSCT relapsed B-ALL. A large proportion of patients treated with CAR T cells have had a history of prior HSCT. Multiple studies have shown that overall outcomes are similar among patients with or without a history of prior HSCT.20,27 |
| DS | CAR T cells are a reasonable consideration for patients with relapsed DS-associated ALL, especially in light of inferior outcomes with standard-of-care therapies.82 | Individual CAR T-cell trials have reported small numbers of patients with DS-associated ALL. Pooled ELIANA/ENSIGN analysis: in a post hoc analysis of 16 patients with DS treated on 2 phase 2 trials and a phase 3b managed access protocol, 14 (88%) achieved a CR and 9 of 14 (64%) remained in remission with a median follow-up of 13.2 mo.37 There was no increased toxicity risk compared with patients without DS. |
| Infant B-ALL | CAR T cells are a reasonable consideration for patients with relapsed, infant B-ALL, especially in light of poor outcomes with standard-of-care therapies. Despite comparable relapse risks to other patients receiving CAR T cells, the risk of lineage switch is markedly higher with no long-term survivors reported after lineage switch. The role of post–CAR T-cell consolidative HSCT for these patients warrants further study as we do not know if it can prevent lineage switch. Further, avoidance of toxicities associated with total body radiation in young children make it challenging to deliver an optimal HSCT. | Several retrospective studies describe outcomes after CAR T cells for infant, KMT2A-rearranged B-ALL. CHOP clinical trials: in an analysis of 13 patients from CHOP, RFS was comparable to other patients with a 2-y RFS of 67% (HR 0.70; P = .704), but OS was worse (HR 3.6, P = .043) because of limited ability to salvage after post-CAR relapse.38 Notably, 3 patients experienced myeloid lineage switch and none survived. CAR-MA: of 29 patients with infant B-ALL, 25 (86%) achieved a CR, but 9 of 29 (31%) had a subsequent relapse; 6 relapses included myeloid lineage switch and none of those patients survived.23 In a PRWCC analysis, of 14 patients with infant B-ALL, 9 achieved an MRD− CR (64%), of which 7 remain in remission at a median follow-up of 290 d. Lineage switch was observed in 4 patients, 3 of which had a nonresponse to CAR T cells.39 European experience: 35 patients <3 y old at the time of screening for tisagenlecleucel, 31 (89%) achieved an MRD− CR, of which 21 (68%) remain in remission at a median follow-up of 14 mo.83 Lineage switch was not observed. |
| ALL with targetable mutations | Patients with BCR-ABL or other targetable mutations may benefit from use of these agents for disease control before CAR T-cell therapy. Careful consideration must be given to the effect of targeted therapy on collected apheresis products. Most targeted therapies have a clear anti–T-cell effect and should be avoided after CAR T-cell therapy, unless the patient has had loss of BCA. |
| Special population or unique scenario . | Summary and recommendations . | Available data . |
|---|---|---|
| Isolated CNS relapse of B-ALL | CAR T cells are effective in eradication of CNS disease in B-ALL. Consider CAR T cells in: Multiply relapsed isolated CNS disease. Early isolated CNS relapse (not currently an approved indication for tisagenlecleucel) Given favorable outcomes with standard of care therapy for late, isolated first relapse,80 CAR T cells would not be considered first line in this setting. | Several retrospective studies described outcomes after CD19 CAR T cells for B-ALL with CNS involvement using aggregate data sets. Importantly, severe neurotoxicity was not found to be increased in patients with CNS involvement.31,53,54, CHOP clinical trials: in a pooled analysis of 5 clinical trials at CHOP, the CR rate for patients treated with murine or humanized CD19 CAR T cells for isolated CNS disease (n = 43) was 98%.53 Of those, 38% experienced a subsequent relapse (7/16 with CNS involvement at post-CAR relapse); 2-y OS was 91%. PRWCC study: the CR rate for patients treated with tisagenlecleucel for isolated CNS disease (n = 23) was 96%.31 Of those, 32% experienced a subsequent relapse (4/7 with CNS involvement at post-CAR relapse); 2-y OS was 81%. International experience: in a multicenter study of 55 patients with CNS-positive disease treated with a variety of CD28 or 4-1BB CD19 CAR T cells, the CR rate was 94%.54 The 2-y EFS and OS were 40% and 75% for the full cohort, and 44% and 93% for those with isolated CNS disease (n = 15). Notably, among 8 patients who received tisagenlecleucel for isolated CNS disease, 6 subsequently relapsed (all in the CNS), but 2-y OS was 100%. |
| Primary refractory disease | High-risk patients with primary refractory disease should be considered for early referral to CAR T cells. The role for consolidative HSCT for patients who receive CAR T cells for primary refractory disease warrants prospective study. | As most clinical trials have enrolled patients with both r/r disease, isolating outcomes for those with primary refractory disease is challenging. Nonetheless, in patients with primary refractory disease across either early phase studies20 or pivotal trials,6 substantial benefit has been seen. An ongoing, multicenter, phase 2 clinical trial through the Children’s Oncology Group (NCT03876769) is evaluating long-term outcomes following CD19 CAR T cells in high-risk patients with detectable MRD by flow cytometry after 2 cycles of frontline chemotherapy. Given excellent outcomes with chemotherapy alone81 patients with NCI standard-risk B-ALL who are MRD+ after 2 cycles of chemotherapy, are presently excluded from the aforementioned study. The role of consolidative HSCT is ill defined; the COG study is testing use of CD19 CAR T cells in an earlier setting when consolidative HSCT may or may not be needed. |
| First relapse of ALL | Clinical trials evaluating the role for CD19 CAR T cells are urgently needed given the limited remission rates and toxicity associated with chemotherapy-based induction regimens for patients with first relapse. | Tisagenlecleucel is not currently approved for patients with first relapse. |
| History of previous HSCT | CAR T cells are an effective salvage treatment for patients with post-HSCT relapse of B-ALL. Given the risks associated with second HSCT,68 CAR T cells with curative potential should be preferentially considered to try to avoid the need for a consolidative second HSCT. | There are limited effective options for patients with post-HSCT relapsed B-ALL. A large proportion of patients treated with CAR T cells have had a history of prior HSCT. Multiple studies have shown that overall outcomes are similar among patients with or without a history of prior HSCT.20,27 |
| DS | CAR T cells are a reasonable consideration for patients with relapsed DS-associated ALL, especially in light of inferior outcomes with standard-of-care therapies.82 | Individual CAR T-cell trials have reported small numbers of patients with DS-associated ALL. Pooled ELIANA/ENSIGN analysis: in a post hoc analysis of 16 patients with DS treated on 2 phase 2 trials and a phase 3b managed access protocol, 14 (88%) achieved a CR and 9 of 14 (64%) remained in remission with a median follow-up of 13.2 mo.37 There was no increased toxicity risk compared with patients without DS. |
| Infant B-ALL | CAR T cells are a reasonable consideration for patients with relapsed, infant B-ALL, especially in light of poor outcomes with standard-of-care therapies. Despite comparable relapse risks to other patients receiving CAR T cells, the risk of lineage switch is markedly higher with no long-term survivors reported after lineage switch. The role of post–CAR T-cell consolidative HSCT for these patients warrants further study as we do not know if it can prevent lineage switch. Further, avoidance of toxicities associated with total body radiation in young children make it challenging to deliver an optimal HSCT. | Several retrospective studies describe outcomes after CAR T cells for infant, KMT2A-rearranged B-ALL. CHOP clinical trials: in an analysis of 13 patients from CHOP, RFS was comparable to other patients with a 2-y RFS of 67% (HR 0.70; P = .704), but OS was worse (HR 3.6, P = .043) because of limited ability to salvage after post-CAR relapse.38 Notably, 3 patients experienced myeloid lineage switch and none survived. CAR-MA: of 29 patients with infant B-ALL, 25 (86%) achieved a CR, but 9 of 29 (31%) had a subsequent relapse; 6 relapses included myeloid lineage switch and none of those patients survived.23 In a PRWCC analysis, of 14 patients with infant B-ALL, 9 achieved an MRD− CR (64%), of which 7 remain in remission at a median follow-up of 290 d. Lineage switch was observed in 4 patients, 3 of which had a nonresponse to CAR T cells.39 European experience: 35 patients <3 y old at the time of screening for tisagenlecleucel, 31 (89%) achieved an MRD− CR, of which 21 (68%) remain in remission at a median follow-up of 14 mo.83 Lineage switch was not observed. |
| ALL with targetable mutations | Patients with BCR-ABL or other targetable mutations may benefit from use of these agents for disease control before CAR T-cell therapy. Careful consideration must be given to the effect of targeted therapy on collected apheresis products. Most targeted therapies have a clear anti–T-cell effect and should be avoided after CAR T-cell therapy, unless the patient has had loss of BCA. |
CHOP, Children’s Hospital of Philadelphia; DS, Down syndrome.