Clinical trialPhase 2Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403

Blood · 2019318 patients enrolled; 295 eligible and evaluable for response

Stock W, Luger SM, Advani AS, et al. Blood. 2019. 133:1548-1559

Study type: Clinical trial
Study name: CALGB 10403
Phase: Phase 2
Design: Prospective, single-arm, multicentre study (Alliance/CALGB), with doses and schedule identical to the COG AALL0232 study and delivered by adult treatment teams
Sample size: 318 patients enrolled; 295 eligible and evaluable for response
Source: Blood · 2019
Trial registration: NCT00558519

In plain words

In this study, teenagers and young adults aged 17 to 39 with acute lymphoblastic leukaemia were treated with the same programme used for children, but by doctors who treat adults. The treatment was safe, and the time patients stayed free of the disease was more than twice as long as in similar patients in the past; three years after starting, about 7 in every 10 patients were alive. Obesity and a type of genetic change called "Philadelphia-like" were linked with worse results.

Key results

78.1 months

Median event-free survival

95% CI: 41.8 to not reached; more than double the historical control of 30 months (22 to 38 months)

59%

3-year event-free survival

95% CI: 54% to 65%

73%

3-year overall survival

95% CI: 68% to 78%; median overall survival not reached

Treatment-related mortality

Only 2 deaths after achieving remission

Drugs in this study:Cyclophosphamide (Endoxan)Doxorubicin (Adriamycin)

Dose and schedule cards

Paediatric regimen in adolescents and young adults (CALGB 10403; identical to one arm of COG AALL0232)

Newly diagnosed Ph-negative ALL (B or T) in patients aged 17 to 39 years, ECOG 0–2On the page “Leukaemia” · Regimens and dosing in Philadelphia-negative ALL

Newly diagnosed Ph-negative ALL (B or T) in patients aged 17 to 39 years, ECOG 0–2

Drug	Dose	Route	Schedule
Induction (course I)
Prednisone	60 mg/m² per day in 2 divided doses	Oral or IV	Days 1–28
Vincristine	1.5 mg/m² (maximum 2 mg)	IV	Days 1, 8, 15 and 22
Daunorubicin	25 mg/m²	IV	Days 1, 8, 15 and 22
Pegaspargase	2500 units/m²	IM or IV	Day 4
Intrathecal cytarabine; intrathecal methotrexate	Cytarabine 70 mg; methotrexate 15 mg	Intrathecal	Cytarabine Day 1; methotrexate Days 8 and 29 (in CNS3, also Days 15 and 22)
Maintenance (12-week cycles)
Vincristine	1.5 mg/m² (maximum 2 mg)	IV	Days 1, 29 and 57
Maintenance
Dexamethasone	6 mg/m² per day in 2 divided doses	Oral or IV	Days 1–5, 29–33 and 57–61
Mercaptopurine	75 mg/m² per day	Oral	Days 1–84
Methotrexate	20 mg/m² weekly	Oral	Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71 and 78 (Day 29 is omitted in the first 4 cycles)
Methotrexate	15 mg	Intrathecal	Day 1 (in the first 4 cycles, also Day 29)

Cycle length: 28-day induction; maintenance in 12-week cycles
Duration: Induction → consolidation → interim maintenance → delayed intensification → maintenance until 3 years (men) or 2 years (women) from the start of interim maintenance

During induction, allopurinol 300 mg per day. Consolidation (course II): cyclophosphamide 1000 mg/m² Days 1 and 29; cytarabine 75 mg/m² IV or SC Days 1–4, 8–11, 29–32 and 36–39; mercaptopurine 60 mg/m² Days 1–14 and 29–42; vincristine Days 15, 22, 43 and 50; pegaspargase 2500 units/m² Days 15 and 43; intrathecal methotrexate Days 1, 8, 15 and 22. Interim maintenance (course III): IV methotrexate starting at 100 mg/m² and escalating by 50 mg/m² with each dose (Days 1, 11, 21, 31 and 41), pegaspargase Days 2 and 22, and intrathecal methotrexate Days 1 and 31. Delayed intensification (course IV): vincristine Days 1, 8, 43 and 50; dexamethasone 10 mg/m² per day on Days 1–7 and 15–21; pegaspargase Day 4 (or 5 or 6) and Day 43; cyclophosphamide 1000 mg/m² Day 29; cytarabine 75 mg/m² Days 29–32 and 36–39; thioguanine 60 mg/m² Days 29–42; intrathecal methotrexate Days 1, 29 and 36. In T-ALL, prophylactic cranial irradiation of 24 Gy during the first maintenance cycle, and 18 Gy for CNS involvement at diagnosis. The doses are taken from Figure 1 of the paper; use the full protocol for complete details (dose modifications and monitoring).

On the page “Leukaemia” · Regimens and dosing in Philadelphia-negative ALL

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Paediatric regimen (identical to COG AALL0232)

Courses in order (per ClinicalTrials.gov NCT00558519): Induction: intrathecal cytarabine on day 1; IV vincristine on days 1, 8, 15 and 22; oral or IV prednisone twice daily on days 1 to 28; IV daunorubicin on days 1, 8, 15 and 22; IV or IM pegaspargase on day 4, 5 or 6; intrathecal methotrexate on days 8 and 29 (also days 15 and 22 in CNS3); bone marrow on day 29 for response and MRD, with extended induction for an inadequate (M2) response. Consolidation: IV cyclophosphamide on days 1 and 29; IV or subcutaneous cytarabine on days 1 to 4, 8 to 11, 29 to 32 and 36 to 39; oral mercaptopurine on days 1 to 14 and 29 to 42; vincristine on days 15, 22, 43 and 50; pegaspargase on days 15 and 43; intrathecal methotrexate. Interim maintenance: vincristine and Capizzi IV methotrexate on days 1, 11, 21, 31 and 41; pegaspargase on days 2 and 22; intrathecal methotrexate on days 1 and 31. Delayed intensification: vincristine, dexamethasone, doxorubicin, pegaspargase, cyclophosphamide, cytarabine, thioguanine and intrathecal methotrexate. Maintenance (12-week courses): vincristine on days 1, 29 and 57; dexamethasone twice daily on days 1 to 5, 29 to 33 and 57 to 61; oral mercaptopurine on days 1 to 84; weekly oral methotrexate and intrathecal methotrexate; for 2 years (women) or 3 years (men) from the start of interim maintenance. Cranial radiotherapy for CNS3 involvement and in T-ALL, and testicular radiotherapy for testicular involvement, during the first maintenance course. Dose details in the full text of the paper.

Source of the regimen details: ClinicalTrials.gov NCT00558519 (course schedule, days and routes, without doses); doses in the full text of the paper

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Older adolescents and young adults with newly diagnosed B-‎ or T-precursor acute lymphoblastic leukaemia, enrolled from 2007 to 2012; median age 24 years (range 17 to 39 years). According to the ClinicalTrials.gov record: age 16 to 39 years, ECOG 0 to 2, no prior therapy except limited corticosteroids or hydroxyurea and a single dose of intrathecal cytarabine; Philadelphia-positive ALL, Burkitt-type leukaemia and Down syndrome were excluded.

Endpoints

According to ClinicalTrials.gov: complete response rate at the end of induction, event-free survival, disease-free survival, overall survival and the number of patients with at least one grade 3 or higher adverse event at least possibly related to treatment. Event-free survival was measured from registration to the first of these events: failure to achieve a bone marrow response by day 60, death, relapse at any site or a second malignancy.

Safety and side effects

Use of the paediatric regimen was safe: overall treatment-related mortality was 3%, and there were only 2 deaths after remission. Details of grade 3 or higher adverse events are in the full text of the paper.

Clinical significance and place in guidelines

This study showed that adult treatment teams can deliver the full paediatric regimen safely and effectively in patients up to 40 years of age; the authors considered it a new standard of care for adolescents and young adults with ALL, on which further research is being built.

Limitations

The study was single-arm, and its advantage was measured only against historical controls. Patients with Philadelphia-positive ALL and those with Down syndrome were not enrolled (ClinicalTrials.gov). Exact doses are not given in the abstract or the ClinicalTrials.gov record and must be taken from the full text of the paper and the protocol.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.