Childhood Acute Lymphoblastic Leukemia, part 3

In pilot clinical trials conducted at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania, 30 children and adults (25 of whom were aged 22 years or younger) with multiply relapsed or refractory CD19-positive ALL were given T cells transduced with CD19-directed 4-1BB CAR lentiviral vector.[171][Level of evidence C2]

Sources: 171 · Level of evidence C2

In pilot clinical trials conducted at the Children’s Hospital of Philadelphia (CHOP) and the Hospital of the University of Pennsylvania, 30 children and adults (25 of whom were aged 22 years or younger) with multiply relapsed or refractory CD19-positive ALL were given T cells transduced with CD19-directed 4-1BB CAR lentiviral vector.[171][Level of evidence C2]

CR was obtained in 90% of patients, including 15 of 18 patients (83%) who had previously received allogeneic HSCT.

The 6-month EFS rate was 67%, with most patients showing persistence of the CAR T cells and B-cell aplasia through 6 months.

All 30 patients experienced some degree of cytokine release syndrome. Eight patients (27%) had severe symptoms requiring vasopressors and/or respiratory support. Cytokine release syndrome was effectively treated with tocilizumab.

A report of a phase I trial of 45 children and young adults with relapsed/refractory CD19-positive B-ALL who received 4-1BB–based lentiviral vector expanded CAR T cells showed the following:[175]

Sources: 175

A report of a phase I trial of 45 children and young adults with relapsed/refractory CD19-positive B-ALL who received 4-1BB–based lentiviral vector expanded CAR T cells showed the following:[175]

An overall remission rate of 89% for all patients enrolled using an intent-to-treat analysis.

Improved long-term persistence of CAR T cells and B-cell aplasia in patients who: (1) received lymphodepleting strategies that contain fludarabine and cyclophosphamide, and (2) started the treatment with a higher percentage of cells expressing CD19, either on blasts or normal B cells.

A global phase II trial of the anti-CD19 4-1BB vector developed at the CHOP and the University of Pennsylvania led to U.S. Food and Drug Administration approval of tisagenlecleucel for children with multiply relapsed or refractory B-ALL.[148]

Sources: 148

A global phase II trial of the anti-CD19 4-1BB vector developed at the CHOP and the University of Pennsylvania led to U.S. Food and Drug Administration approval of tisagenlecleucel for children with multiply relapsed or refractory B-ALL.[148]

Of 92 patients enrolled, 75 were infused with successfully manufactured CAR T cells. Eighty-one percent of infused patients had two measures noting CR within the first 3 months of infusion, and 100% of the remissions were MRD negative.

The EFS rate of infused patients was 73% at 6 months and 50% at 12 months. The OS rate of infused patients was 90% at 6 months and 70% at 12 months.

The CIBMTR performed a real-world analysis of 255 patients with ALL that largely duplicated the outcomes shown in the pivotal trials, with an initial CR rate of 85.5%. The 12-month duration of response rate was 69.9%, the EFS rate was 52.4%, and the OS rate was 77.2%.[180]

Sources: 180

Children younger than 3 years were not included in the approval trial for tisagenlecleucel. A subgroup of patients, infants diagnosed at younger than 1 year with KMT2A-rearranged leukemia, often have disease that is highly refractory to intensive chemotherapy approaches. A multicenter retrospective study reported the outcomes of children younger than 3 years (originally diagnosed as high-risk infant ALL) with relapsed or refractory B-ALL who received commercial tisagenlecleucel.[181]

Sources: 181

Children younger than 3 years were not included in the approval trial for tisagenlecleucel. A subgroup of patients, infants diagnosed at younger than 1 year with KMT2A-rearranged leukemia, often have disease that is highly refractory to intensive chemotherapy approaches. A multicenter retrospective study reported the outcomes of children younger than 3 years (originally diagnosed as high-risk infant ALL) with relapsed or refractory B-ALL who received commercial tisagenlecleucel.[181]

Thirty-eight eligible patients were screened, 35 of whom (92%) were infused with tisagenlecleucel (2 patients did not receive an infusion because CAR T-cell manufacturing failed and 1 patient had disease progression).

Twenty-nine of 38 patients (76%) had KMT2A rearrangements, and 25 (66%) experienced relapse after previous HSCTs.

With a median follow-up of 14 months, the 12-month OS rate was 84%, the EFS rate was 69%, and the stringent EFS rate was 41%.

Feasibility, outcomes, and toxicity were comparable with those of older children.

A subsequent study from the University of Pennsylvania reported the 3-year updated results of the global phase II ELIANA (NCT02435849) trial that included 79 patients who were treated with tisagenlecleucel.[182][Level of evidence C2]

Sources: ELIANA (NCT02435849) · 182 · Level of evidence C2

A subsequent study from the University of Pennsylvania reported the 3-year updated results of the global phase II ELIANA (NCT02435849) trial that included 79 patients who were treated with tisagenlecleucel.[182][Level of evidence C2]

The overall remission rate was 82% at 3 months.

With a median follow-up of 38.8 months, the median duration of remission of the 66 patients with a complete response has not been reached. The estimated relapse-free survival (RFS) rate was 58% at 24 months and 52% at 36 months.

Of the 32 patients in CR who received no additional therapy, the estimated RFS rate was 81% at 24 months and 76% at 36 months.

A report from the Pediatric Oncology Branch at the NCI described the use of a different CD19-targeted CAR T-cell product with a CD28 costimulatory domain that used a retroviral vector for gene transduction.[178]

Sources: 178

A report from the Pediatric Oncology Branch at the NCI described the use of a different CD19-targeted CAR T-cell product with a CD28 costimulatory domain that used a retroviral vector for gene transduction.[178]

This CD19-CAR T-cell product induced complete responses in 70% of patients (14 of 20) (aged 1–30 years) with relapsed/refractory B-ALL.

Persistence of CAR T cells in this study was 1 to 2 months, with recovery of normal B-cell lymphopoiesis in patients who achieved CR.

In a subsequent follow-up study of 50 children and young adults who were treated with CD19-CAR T cells, 21 patients achieved an MRD-negative CR and received an allogeneic HSCT. In these 21 patients, the median OS was 70.2 months, and the 5-year EFS rate was 61.9%.[183][Level of evidence C2]

Sources: 183 · Level of evidence C2

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

Sources: 184 · Level of evidence A1

Another report described a multicenter trial of 25 children and young adults who were treated with anti-CD19, anti-CD28z CAR T cells. Investigators increased the dose of lymphodepleting cyclophosphamide during the trial and analyzed outcomes on the basis of low-dose and high-dose preconditioning, as well as the presence of MRD versus morphological evidence of disease before treatment.[184][Level of evidence A1]

All toxicities were reversible, including 16% of patients with severe cytokine release syndrome and 28% of patients with severe neurotoxicity.

The overall complete response rate was 75%, and 89% of patients in CR were MRD negative.

The response rate was superior in the high-dose cyclophosphamide cohort than in the low-dose cohort (94% vs. 38%); the response rate was higher in the MRD cohort than in the morphological disease cohort (93% vs. 50%).

Of 18 responding patients, 15 underwent consolidative HSCT.

Improvement in OS only occurred in patients who received the higher dose of cyclophosphamide conditioning.

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

Sources: 185

In an effort to overcome early loss of functional CD19-targeted CAR T cells, a humanized 4-1BB approach was tested in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma. Patients were treated in two cohorts: (1) patients without previous CAR T-cell exposure (CAR-naïve group) and (2) patients with previous CAR exposure who did not respond to more standard CARs, based on mouse-derived antibodies (re-treated group).[185]

CR was achieved in 98% of CAR-naïve patients and 64% of re-treated patients.

At 6 months, of those who responded, 27% of CAR-naïve patients and 48% of re-treated patients lost CAR persistence.

For CAR-naive patients, the RFS rate was 84% (95% CI, 72%–97%) at 12 months and 74% (95% CI, 60%–90%) at 24 months.

For the re-treatment cohort, the RFS rate was 74% (95% CI, 56%–97%) at 12 months and 58% (95% CI, 37%–90%) at 24 months.

While these results appear favorable, they were not directly compared to currently approved CAR T cells.

Active CNS disease at relapse and/or infusion.

Active CNS disease at relapse and/or infusion.

A single-center report analyzed 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 bone marrow/CNS disease).[186]

Sources: 186

Active CNS disease at relapse and/or infusion. › A single-center report analyzed 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 bone marrow/CNS disease).[186]

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

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).

Ninety-eight percent of patients were treated before their infusion for their CNS disease and reached CNS1 or CNS2 status at the time of CAR T-cell treatment. Patients with symptomatic/progressive CNS disease were not treated until the disease was controlled and stable.

Active CNS disease at relapse and/or infusion.

A retrospective report examined the outcomes of 184 patients who were treated with tisagenlecleucel at 15 U.S. institutions. In this series, patients were referred for CAR T-cell infusion for marrow-only disease (n = 129), CNS disease (n = 40; either isolated [n = 23] or combined marrow/CNS disease [n = 17]), and non-CNS EMD (n = 15; 6 patients with isolated EMD and 9 with marrow involvement). All but one patient with CNS disease received tisagenlecleucel after one or more relapses (none had previously underwent transplant), whereas 29 of the marrow-only patients (22%) received infusions in first CR, 10 of whom (7.8%) had previously underwent transplant.[187]

Sources: 187

Active CNS disease at relapse and/or infusion. › A retrospective report examined the outcomes of 184 patients who were treated with tisagenlecleucel at 15 U.S. institutions. In this series, patients were referred for CAR T-cell infusion for marrow-only disease (n = 129), CNS disease (n = 40; either isolated [n = 23] or combined marrow/CNS disease [n = 17]), and non-CNS EMD (n = 15; 6 patients with isolated EMD and 9 with marrow involvement). All but one patient with CNS disease received tisagenlecleucel after one or more relapses (none had previously underwent transplant), whereas 29 of the marrow-only patients (22%) received infusions in first CR, 10 of whom (7.8%) had previously underwent transplant.[187]

In patients referred to receive tisagenlecleucel for CNS disease (n = 40), 31 (78%) were already CNS-negative at the time of infusion, and 88% (35 of 40) were in CR at day 28 after infusion. For patients with non-CNS EMD, 10 of 15 (66%) were in CR at day 28.

The 12-month RFS rate was 59.4% for patients with marrow-only disease, 59.4% for patients with CNS disease (isolated or combined), and 50% for those with non-CNS EMD (isolated or combined) (P = .92).

In the CNS-disease cohort, there was no significant difference in 12-month RFS between patients with isolated CNS disease and those with combined CNS and marrow disease (P = .63).

Grade 3 or 4 neurotoxicity was observed in 3 of 40 patients (7.5%) in the CNS-disease cohort, compared with 9 of 129 patients (7%) with marrow-only disease. None of the patients with active CNS disease at the time of infusion experienced grade 3 or 4 neurotoxicity.

Active CNS disease at relapse and/or infusion.

A second multicenter report reviewed 55 patients with relapses involving the CNS (isolated or combined with bone marrow) who were treated with either a CD28-based institutional CAR (n = 12) or tisagenlecleucel (4-1BB vector, n = 43).[188]

Sources: 188

Active CNS disease at relapse and/or infusion. › A second multicenter report reviewed 55 patients with relapses involving the CNS (isolated or combined with bone marrow) who were treated with either a CD28-based institutional CAR (n = 12) or tisagenlecleucel (4-1BB vector, n = 43).[188]

Remission was achieved in 92% of children who received CD28-based CAR T cells and 93% of children who received 4-1BB–based CAR T cells.

Of 11 children who received CD28-based CAR T cells and achieved a CR, 9 underwent HSCT. Seven of these nine patients survived relapse free.

None of the 40 patients who were treated with the 4-1BB–based CAR T cells (tisagenlecleucel) and achieved a CR had a planned HSCT. Nineteen of these patients experienced relapses, 12 of whom had CNS relapses.

Patients who received tisagenlecleucel for an isolated CNS relapse had a high incidence of subsequent CNS relapse (6 of 8 patients).

For non-CNS EMD, available data are limited.

For non-CNS EMD, available data are limited.

The report of 195 patients above compared CNS EMD, non-CNS EMD, and bone marrow–only disease. No differences in OS and RFS were noted between the groups.[186]

Sources: 186

In contrast, a large retrospective analysis found that active EMD at infusion was independently associated with worse EFS (HR, 1.9; P = .01).[189]

Sources: 189

A separate analysis found that in 15 patients with non-CNS EMD, 10 achieved a CR, and 6 of the 10 patients subsequently relapsed. Consequently, only 4 of 15 patients remained event-free during the follow-up period.[187]

Sources: 187

A retrospective analysis from the NCI identified limitations in eradication of non-CNS EMD with CAR T cells, despite concurrent marrow responses, highlighting the important role of positron emission tomography scans for monitoring.[190]

Sources: 190

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]

Sources: 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%.

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

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.

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]

Sources: 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]

Sources: 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]

Sources: 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).

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.

Sources: 171

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]

Sources: 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.

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).

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

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%.

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]

Sources: 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.

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

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

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]

Sources: 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.

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

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.

A study looked at 166 relapses occurring after CAR T-cell therapy using either 4-1BB or CD28 costimulatory domains.[196]

Sources: 196

A study looked at 166 relapses occurring after CAR T-cell therapy using either 4-1BB or CD28 costimulatory domains.[196]

Eighty-three patients (50%) were CD19 positive, 68 (41%) were CD19 negative, and 12 (7.2%) had lineage switch relapses.

The median OS was 11.9 months (95% CI, 9–17 months), with no difference between CD19-positive and CD19-negative relapses.

Patients with lineage switch relapses had a dismal prognosis, with no long-term survivors.

CD19-positive relapses were associated with a greater prior treatment burden, shown by a greater number of previous remissions.

CD19-negative relapses were associated with a greater pre-CAR T-cell infusion disease burden, prior nonresponse to blinatumomab, older age, and a 4-1BB costimulatory domain.

Lineage switch relapses were associated with the presence of KMT2A rearrangements.

A second study reviewed 80 patients (27 nonresponders and 53 who relapsed) who received 4-1BB-based CD19-targeted CAR T-cell therapy that failed to produce remissions.[197]

Sources: 197

A second study reviewed 80 patients (27 nonresponders and 53 who relapsed) who received 4-1BB-based CD19-targeted CAR T-cell therapy that failed to produce remissions.[197]

Of the nonresponders, 95% had high disease burden (>5% blasts) before CAR T-cell infusion.

CD19-negative relapses were associated with a decreased OS rate at 1 year, compared with CD19-positive relapses (30% [95% CI, 14%–66%] vs. 68% [49%–92%]; P = .0068).

Only treatment followed by HSCT if remission was obtained was associated with long-term survival.

Second infusion of the first CAR T cells.

Second infusion of the first CAR T cells.

A retrospective study from the Children's Hospital of Philadelphia analyzed the outcomes of 81 repeat CAR T-cell infusions (CARTr) for three indications: (1) relapse prevention in at-risk patients (peripheral B-cell recovery [BCR] or emergence of CD19-positive hematogones), (2) CD19-positive MRD emergence or relapse, and (3) failure to go into remission after initial CAR T-cell infusion.[199]

Sources: 199

Second infusion of the first CAR T cells. › A retrospective study from the Children's Hospital of Philadelphia analyzed the outcomes of 81 repeat CAR T-cell infusions (CARTr) for three indications: (1) relapse prevention in at-risk patients (peripheral B-cell recovery [BCR] or emergence of CD19-positive hematogones), (2) CD19-positive MRD emergence or relapse, and (3) failure to go into remission after initial CAR T-cell infusion.[199]

Of 63 patients who received CARTr for relapse prevention, 52% achieved CR (BCR, 15 of 40 [38%]; hematogones, 18 of 23 [78%]).

Second infusion of the first CAR T cells. › A retrospective study from the Children's Hospital of Philadelphia analyzed the outcomes of 81 repeat CAR T-cell infusions (CARTr) for three indications: (1) relapse prevention in at-risk patients (peripheral B-cell recovery [BCR] or emergence of CD19-positive hematogones), (2) CD19-positive MRD emergence or relapse, and (3) failure to go into remission after initial CAR T-cell infusion.[199] › Of 63 patients who received CARTr for relapse prevention, 52% achieved CR (BCR, 15 of 40 [38%]; hematogones, 18 of 23 [78%]).

Lymphodepletion was associated with response to CARTr for BCR (odds ratio [OR], 33.57; P = .015) but not hematogones (OR, 0.30; P = .291).

The cumulative incidence of relapse was 29% at 24 months for CR, compared with 61% for nonresponse to CARTr (P = .259).

Second infusion of the first CAR T cells. › A retrospective study from the Children's Hospital of Philadelphia analyzed the outcomes of 81 repeat CAR T-cell infusions (CARTr) for three indications: (1) relapse prevention in at-risk patients (peripheral B-cell recovery [BCR] or emergence of CD19-positive hematogones), (2) CD19-positive MRD emergence or relapse, and (3) failure to go into remission after initial CAR T-cell infusion.[199]

For MRD/relapse, the CR rate after CARTr was 50% (5 of 10). However, no CRs were observed in the eight patients who had their initial CAR T-cell infusion fail.

CD28 CAR T-cell bridging approach.

CD28 CAR T-cell bridging approach.

A study examined 50 children and young adults who were treated with CD28-based CD19 CAR T-cell therapy.[183][Level of evidence C2]

Sources: 183 · Level of evidence C2

CD28 CAR T-cell bridging approach. › A study examined 50 children and young adults who were treated with CD28-based CD19 CAR T-cell therapy.[183][Level of evidence C2]

Twenty-one patients achieved an MRD-negative CR and underwent an allogeneic HSCT. In these 21 patients, the median OS was 70.2 months, and the 5-year EFS rate was 61.9%.

4-1BB CARs with varying approaches to HSCT.

4-1BB CARs with varying approaches to HSCT.

A study of 50 patients eligible for HSCT after 4-1BB-based CAR T-cell therapy reported the following results (PLAT-02 [NCT02028455] trial):[201]

Sources: PLAT-02 [NCT02028455] · 201

4-1BB CARs with varying approaches to HSCT. › A study of 50 patients eligible for HSCT after 4-1BB-based CAR T-cell therapy reported the following results (PLAT-02 [NCT02028455] trial):[201]

Patients who lost CAR T-cell function before 63 days after therapy had improved LFS if they underwent HSCT, compared with those who did not undergo HSCT (P = .01).

Patients with no prior history of HSCT had an improved LFS with a planned HSCT, with a trend toward significance (P = .09). This benefit was not evident in the 34 patients with a history of prior HSCT (P = .45).

4-1BB CARs followed by an intent to perform HSCT.

4-1BB CARs followed by an intent to perform HSCT.

In a study from China of 52 children who received either CD19- or CD22-targeted CAR T-cell therapy and underwent a planned HSCT at a median of 50 days after CAR T-cell infusion (range, 34–98 days; 48 MRD-negative and 4 MRD-positive patients at time of HSCT), the following results were reported:[202]

Sources: 202

4-1BB CARs followed by an intent to perform HSCT. › In a study from China of 52 children who received either CD19- or CD22-targeted CAR T-cell therapy and underwent a planned HSCT at a median of 50 days after CAR T-cell infusion (range, 34–98 days; 48 MRD-negative and 4 MRD-positive patients at time of HSCT), the following results were reported:[202]

The 1-year EFS rate was 73%, and the 1-year OS rate was 87.7%.

Although the survival rate of patients eligible to proceed to HSCT in remission was high, the analysis did not include patients who had a previous HSCT, patients who did not achieve remission with CAR T-cell infusions, and patients who were not eligible for HSCT after CAR T-cell therapy.

Investigators at the NCI reported a phase I/II trial of 58 children and young adults treated with a CD22-targeted CAR T-cell approach.[207][Level of evidence C2]

Sources: 207 · Level of evidence C2

Investigators at the NCI reported a phase I/II trial of 58 children and young adults treated with a CD22-targeted CAR T-cell approach.[207][Level of evidence C2]

Of the 55 patients with ALL who were infused, 40 achieved CRs (73%); 88% of those patients achieved MRD-negative remissions.

Although 86% of patients experienced cytokine release syndrome, 90% experienced grades 1 to 2 cytokine release syndrome.

Thirty-three percent of patients experienced neurotoxicity, all of which were grades 1 or 2, except in one patient who experienced an intracranial hemorrhage.

Thirty-eight percent of patients had an HLH/macrophage activation syndrome (MAS)–like syndrome that sometimes required management with anakinra.

Patients who received CD22-targeted therapy with inotuzumab or CD22 CAR T-cell therapy before this therapy had lower rates of CD22 expression, were less likely to achieve remission, and had shorter duration of remission.

Thirty of the 40 patients (75%) who achieved CRs relapsed; only patients who proceeded to HSCT had long-term remissions (14 patients proceeded to HSCT, 6 relapsed). The median RFS was 6 months for this group of patients who achieved CRs.

A Chinese group treated 34 patients who had failed previous CD19-targeted CAR T-cell therapy with CD22-targeted CAR T cells.[205]

Sources: 205

A Chinese group treated 34 patients who had failed previous CD19-targeted CAR T-cell therapy with CD22-targeted CAR T cells.[205]

CR occurred in 80% of the patients evaluable at day 30 (71% of all patients).

Seven patients received no further therapy, and three patients remained in remission at 5 to 13 months after therapy.

Eleven patients went on to HSCT, with a 1-year LFS rate of 72%.

This study demonstrated that long-term salvage of patients failing CD19-targeted CAR T cells can occur with CD22-targeted CAR T cells plus HSCT.

Use of two independently manufactured CAR T cells targeted at different antigens infused simultaneously or sequentially.

A single manufacturing process of CAR T cells that contain two populations of cells, each targeted at a different antigen.

A single manufacturing process where one CAR construct has binding domains to multiple antigens.

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]

Sources: 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]

Sources: 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]

Sources: AALL02P2 (NCT00096135) · 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%).

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

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

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.

Sources: 224 · Level of evidence C2

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.

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]

Sources: 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.

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.

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]

Sources: 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.

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

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).

Chemotherapy.

Radiation therapy.

The COG AALL02P2 (NCT00096135) trial tested whether radiation therapy could be eliminated for patients with late isolated testicular relapse (occurring more than 18 months from diagnosis).[227] On this trial, testicular size was reassessed after the initial month of reinduction chemotherapy, which included high-dose methotrexate. If the testicle remained enlarged, biopsy was performed, and if positive, patients were to be treated with local radiation therapy. Those with testes that normalized in size or who had negative biopsies were to be treated without radiation therapy. Postinduction chemotherapy for all patients (whether or not they were irradiated) included multiple courses of high-dose methotrexate.[228]

Sources: COG AALL02P2 (NCT00096135) · 227 · 228

The COG AALL02P2 (NCT00096135) trial tested whether radiation therapy could be eliminated for patients with late isolated testicular relapse (occurring more than 18 months from diagnosis).[227] On this trial, testicular size was reassessed after the initial month of reinduction chemotherapy, which included high-dose methotrexate. If the testicle remained enlarged, biopsy was performed, and if positive, patients were to be treated with local radiation therapy. Those with testes that normalized in size or who had negative biopsies were to be treated without radiation therapy. Postinduction chemotherapy for all patients (whether or not they were irradiated) included multiple courses of high-dose methotrexate.[228]

Of 40 patients enrolled, 26 had persistent testicular enlargement after reinduction. Testicular biopsy was positive in 12 of these 26 patients, 11 of whom received testicular radiation therapy; all other patients on the trial were treated without radiation.

Participants who received testicular radiation therapy achieved a 5-year EFS rate of 73% versus 61% for those who did not receive radiation (P = .6); the 5-year OS rate was 73% for those who received testicular radiation versus 71% (P = .9) for those who did not receive testicular radiation.

Thus, for patients with isolated testicular relapse achieving a favorable response after initial induction (documented by size reduction and/or biopsy), omission of testicular radiation therapy may be a feasible option.

Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate during induction (12 g/m2) and at regular intervals during the remainder of therapy (6 g/m2) without testicular radiation.[227]

Sources: 227

Dutch investigators treated five boys with a late testicular relapse with high-dose methotrexate during induction (12 g/m2) and at regular intervals during the remainder of therapy (6 g/m2) without testicular radiation.[227]

All five boys were long-term survivors.

In a small series of boys who had an isolated testicular relapse after an HSCT for a prior systemic relapse of ALL, five of seven boys had extended EFS without a second HSCT.[161][Level of evidence C1]

Sources: 161 · Level of evidence C1

pediatrician

Sources: pediatrician

hematologist

Sources: hematologist

medical oncologist

Sources: medical oncologist

pediatric surgeon

Sources: pediatric surgeon

radiation oncologist

Sources: radiation oncologist

pediatric intensivist

Sources: pediatric intensivist

neurologist

Sources: neurologist

neuroradiologist

Sources: neuroradiologist

pediatric nurse specialist

Sources: pediatric nurse specialist

social worker

Sources: social worker

rehabilitation specialist

Sources: rehabilitation specialist

psychologist

Sources: psychologist

child-life specialist

Sources: child-life specialist

fertility specialist

Sources: fertility specialist

Remission induction is the first phase of treatment. The goal is to kill the leukemia cells in the blood and bone marrow. This puts the leukemia into remission.

Sources: remission

Consolidation/intensification is the second phase of treatment. It begins once the leukemia is in remission. The goal of consolidation/intensification therapy is to kill any leukemia cells that remain in the body and may cause a relapse.

Sources: Consolidation/intensification · relapse

Maintenance is the third phase of treatment. The goal is to kill any remaining leukemia cells that may regrow and cause a relapse. Often the cancer treatments are given in lower doses than those used during the remission induction and consolidation/intensification phases. This is also called the continuation therapy phase.

Sources: Maintenance

whether the leukemia cells began from B lymphocytes or T lymphocytes

if your child has standard-risk, high-risk, or very high-risk ALL

your child's age at the time of diagnosis

whether there are certain changes in the chromosomes of lymphocytes, such as the Philadelphia chromosome

whether your child was treated with dexamethasone or prednisone before the start of remission induction therapy

how quickly and how low the leukemia cell count drops during treatment

if leukemia was found in the central nervous system

asparaginase

Sources: asparaginase

cyclophosphamide

Sources: cyclophosphamide

cytarabine

Sources: cytarabine

daunorubicin

Sources: daunorubicin

dexamethasone (steroid)

Sources: dexamethasone

doxorubicin

Sources: doxorubicin

etoposide

Sources: etoposide

mercaptopurine

Sources: mercaptopurine

methotrexate

Sources: methotrexate

nelarabine

Sources: nelarabine

prednisone (steroid)

Sources: prednisone

thioguanine

Sources: thioguanine

vincristine

Sources: vincristine

Blinatumomab: Blinatumomab works by bringing healthy T cells (immune cells that help kill cancer cells) and leukemia cells close together so the T cells can more effectively kill the leukemia. It does this by binding to a protein called CD3 on healthy T cells and a protein called CD19 on B cells (the immune cells that are cancerous in acute lymphoblastic leukemia). Blinatumomab is a type of targeted therapy drug called a bispecific T-cell engager (BiTE).

Sources: Blinatumomab

CAR T-cell therapy: This treatment changes the patient's T-cells (a type of immune system cell) so they will attack certain proteins on the surface of cancer cells. T cells are taken from the patient and special receptors are added to their surface in the laboratory. The changed cells are called chimeric antigen receptor (CAR) T cells. The CAR T cells are grown in the laboratory and given to the patient by infusion. The CAR T cells multiply in the patient's blood and attack cancer cells. CAR T-cell therapy is being studied in the treatment of childhood ALL that has relapsed (come back) a second time.

Sources: CAR T-cell therapy · receptors

Rituximab.

Sources: Rituximab

bortezomib

Sources: bortezomib

dasatinib

Sources: dasatinib

imatinib mesylate

Sources: imatinib mesylate

inotuzumab ozogamicin

Sources: inotuzumab ozogamicin

nivolumab

Sources: nivolumab

ruxolitinib

Sources: ruxolitinib

combination chemotherapy with or without immunotherapy (blinatumomab) and/or targeted therapy

Sources: combination chemotherapy · immunotherapy · targeted therapy

stem cell transplant, using stem cells from a donor

Sources: stem cell transplant · donor

targeted therapy (inotuzumab, imatinib, or dasatinib)

chimeric antigen receptor (CAR) T-cell therapy

Sources: chimeric antigen receptor (CAR) T-cell therapy

systemic chemotherapy and intrathecal chemotherapy with radiation therapy to the brain and/or spinal cord for cancer that comes back in the brain and spinal cord only

Sources: systemic chemotherapy · intrathecal chemotherapy · radiation therapy

stem cell transplant for cancer that has relapsed in the brain and/or spinal cord, especially if relapse occurs soon after initial diagnosis

combination chemotherapy and radiation therapy for cancer that comes back in the testicles only

Physical problems, including problems with the heart, blood vessels, liver, or bones, and fertility.

Sources: blood vessels · liver · fertility

Changes in mood, feelings, thinking, learning, or memory. Children younger than 4 years who have received radiation therapy to the brain have a higher risk of these effects.

Second cancers (new types of cancer) or other conditions, such as brain tumors, thyroid cancer, acute myeloid leukemia, and myelodysplastic syndrome.

Sources: conditions · brain tumors · thyroid cancer · acute myeloid leukemia · myelodysplastic syndrome