Isolated CNS relapse

Systemic and intrathecal chemotherapy.

Cranial or craniospinal radiation.

HSCT.

CAR T-cell therapy for isolated CNS disease that is multiply relapsed.

In a Pediatric Oncology Group (POG) study using this strategy, children who had not previously received radiation therapy and whose initial remission was 18 months or longer had a 4-year EFS rate of approximately 80%, compared with EFS rates of approximately 45% for children with CNS relapse within 18 months of diagnosis.[216]

In a follow-up POG study, children who had not previously received radiation therapy and who had an initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only.[19]

In a follow-up POG study, children who had not previously received radiation therapy and who had an initial remission of 18 months or more were treated with intensive systemic and intrathecal chemotherapy for 1 year followed by 18 Gy of cranial radiation only.[19]

The 4-year EFS rate was 78%. Children with an initial remission of less than 18 months also received the same chemotherapy but had craniospinal radiation (24 Gy cranial/15 Gy spinal) as in the first POG study and achieved a 4-year EFS rate of 52%.

The Children’s Oncology Group AALL02P2 (NCT00096135) study enrolled 118 eligible children with B-ALL and late isolated CNS relapse. Patients received intensified systemic therapy, triple intrathecal chemotherapy, and 12 Gy of cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until 104 weeks postdiagnosis.[221]

The Children’s Oncology Group AALL02P2 (NCT00096135) study enrolled 118 eligible children with B-ALL and late isolated CNS relapse. Patients received intensified systemic therapy, triple intrathecal chemotherapy, and 12 Gy of cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until 104 weeks postdiagnosis.[221]

The 3-year EFS rate was 64.3% (± 4.5%), and the OS rate was 79.6% (± 3.8%).

The Children’s Oncology Group AALL02P2 (NCT00096135) study enrolled 118 eligible children with B-ALL and late isolated CNS relapse. Patients received intensified systemic therapy, triple intrathecal chemotherapy, and 12 Gy of cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until 104 weeks postdiagnosis.[221]

Second relapses that included the CNS occurred in 46.1% of patients (18 of 39).

The Children’s Oncology Group AALL02P2 (NCT00096135) study enrolled 118 eligible children with B-ALL and late isolated CNS relapse. Patients received intensified systemic therapy, triple intrathecal chemotherapy, and 12 Gy of cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until 104 weeks postdiagnosis.[221]

Of the 112 patients who completed therapy, 78 received protocol-specified radiation therapy.

The Children’s Oncology Group AALL02P2 (NCT00096135) study enrolled 118 eligible children with B-ALL and late isolated CNS relapse. Patients received intensified systemic therapy, triple intrathecal chemotherapy, and 12 Gy of cranial irradiation delivered at 12 months, with maintenance chemotherapy continuing until 104 weeks postdiagnosis.[221]

Study enrollment was closed after interim monitoring analysis showed inferior EFS compared with the POG 9412 study, in which patients received 18 Gy of cranial radiation. Thus, the lower dose of cranial radiation was deemed to be inadequate.

A retrospective, registry-based study compared the outcome of patients treated with either HLA-matched sibling transplants or chemoradiation therapy as in the POG studies above.[224][Level of evidence C2] This study included transplant of both early (<18 months from diagnosis) and late relapses.

A retrospective, registry-based study compared the outcome of patients treated with either HLA-matched sibling transplants or chemoradiation therapy as in the POG studies above.[224][Level of evidence C2] This study included transplant of both early (<18 months from diagnosis) and late relapses.

The 8-year probabilities of LFS adjusted for age (58%) and duration of first remission (66%) were similar.

A retrospective, registry-based study compared the outcome of patients treated with either HLA-matched sibling transplants or chemoradiation therapy as in the POG studies above.[224][Level of evidence C2] This study included transplant of both early (<18 months from diagnosis) and late relapses.

Because of the relatively good outcome of patients with isolated CNS relapse more than 18 months from diagnosis who were treated with chemoradiation therapy alone (>75%), transplant is generally not recommended by the COG for this group.

The MRC ALLR3 trial tested intensive induction with mitoxantrone versus idarubicin in relapsed ALL patients, defining a superior outcome when mitoxantrone was used. A subanalysis of 80 patients entering the trial with isolated CNS relapse included 13 patients with very early relapse (defined as <18 months from first diagnosis), 55 patients with early relapse (defined as >18 months from initial diagnosis but within 6 months of being off therapy), and 12 patients with late relapse.[17][Level of evidence B4]

The MRC ALLR3 trial tested intensive induction with mitoxantrone versus idarubicin in relapsed ALL patients, defining a superior outcome when mitoxantrone was used. A subanalysis of 80 patients entering the trial with isolated CNS relapse included 13 patients with very early relapse (defined as <18 months from first diagnosis), 55 patients with early relapse (defined as >18 months from initial diagnosis but within 6 months of being off therapy), and 12 patients with late relapse.[17][Level of evidence B4]

Patients with late relapse did very well with chemotherapy/cranial radiation therapy, with 11 of 12 patients surviving.

The MRC ALLR3 trial tested intensive induction with mitoxantrone versus idarubicin in relapsed ALL patients, defining a superior outcome when mitoxantrone was used. A subanalysis of 80 patients entering the trial with isolated CNS relapse included 13 patients with very early relapse (defined as <18 months from first diagnosis), 55 patients with early relapse (defined as >18 months from initial diagnosis but within 6 months of being off therapy), and 12 patients with late relapse.[17][Level of evidence B4]

Allogeneic HSCT was recommended for very early and early relapse. Sixty-six patients were alive and relapse free after the planned three induction courses. Fifty-four patients with early and very early isolated CNS relapse were eligible for protocol-recommended HSCT, and 39 patients (72%) received HSCT. Twenty-one percent of these patients relapsed, compared with a relapse rate of 71% in the group that did not receive HSCT.

The MRC ALLR3 trial tested intensive induction with mitoxantrone versus idarubicin in relapsed ALL patients, defining a superior outcome when mitoxantrone was used. A subanalysis of 80 patients entering the trial with isolated CNS relapse included 13 patients with very early relapse (defined as <18 months from first diagnosis), 55 patients with early relapse (defined as >18 months from initial diagnosis but within 6 months of being off therapy), and 12 patients with late relapse.[17][Level of evidence B4]

Of those eligible for transplant, treatment with mitoxantrone rather than idarubicin during reinduction was associated with a survival advantage (3-year progression-free survival rates, 61% vs. 21%; P = .027). As in the larger trial, the major advantage from the mitoxantrone arm occurred in those who received HSCT. Small patient numbers in the very early group prohibited detailed analysis of this cohort, and rates of failure within the early group treated with chemotherapy/cranial radiation therapy were inferior to other published experiences, calling into question this chemotherapy approach for early isolated CNS relapse patients.

A single-center study reported on 195 sequential patients treated with 4-1BB CD19-targeted CAR T cells, 66 of whom had CNS disease (43 with isolated CNS disease, 23 with combined BM/CNS disease).[186]

A single-center study reported on 195 sequential patients treated with 4-1BB CD19-targeted CAR T cells, 66 of whom had CNS disease (43 with isolated CNS disease, 23 with combined BM/CNS disease).[186]

Overall, there was no difference in remission rates and progression-free survival in patients with or without CNS disease.

A single-center study reported on 195 sequential patients treated with 4-1BB CD19-targeted CAR T cells, 66 of whom had CNS disease (43 with isolated CNS disease, 23 with combined BM/CNS disease).[186]

Of the patients with CNS disease, 79% were second or greater relapse.

A single-center study reported on 195 sequential patients treated with 4-1BB CD19-targeted CAR T cells, 66 of whom had CNS disease (43 with isolated CNS disease, 23 with combined BM/CNS disease).[186]

Patients with isolated CNS involvement had an RFS rate at 2 years of 66% (95% CI, 52%–82%), compared with 58% (95% CI, 50%–68%) for patients with bone marrow involvement (P = .15).