Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

N Engl J Med · 2017405 patients (271 in the blinatumomab group and 134 in the chemotherapy group); 376 patients received at least one dose

Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. N Engl J Med. 2017. 376:836-847

Study type: Clinical trial
Study name: TOWER
Phase: Phase 3
Design: Randomised multicentre phase 3 trial with 2:1 allocation
Sample size: 405 patients (271 in the blinatumomab group and 134 in the chemotherapy group); 376 patients received at least one dose
Source: N Engl J Med · 2017
Trial registration: NCT02013167

In plain words

In this study, adults with B-cell acute lymphoblastic leukaemia whose disease had come back or had not responded to earlier treatments received either blinatumomab or standard chemotherapy. Blinatumomab is a drug that helps the body's immune cells find and destroy leukaemia cells. Patients in the blinatumomab group lived longer on average (7.7 months versus 4.0 months), and more of them went into remission. Serious side effects were common in both groups.

Key results

7.7 months vs 4.0 months

Median overall survival

HR for death 0.71; 95% CI 0.55 to 0.93; P=0.01

34% vs 16%

Complete remission with full haematological recovery (within 12 weeks)

P<0.001

44% vs 25%

Complete remission with full, partial or incomplete haematological recovery (within 12 weeks)

P<0.001

31% vs 12%

Event-free survival (6-month estimate)

HR 0.55; 95% CI 0.43 to 0.71; P<0.001

7.3 months vs 4.6 months

Median duration of remission

24% in both groups

Allogeneic stem cell transplantation

Dose and schedule cards

Blinatumomab in ALL

CD19-positive B-ALL: Ph-negative consolidation (E1910) or relapsed/refractory (TOWER)On the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in leukaemias

CD19-positive B-ALL: Ph-negative consolidation (E1910) or relapsed/refractory (TOWER)

Drug	Dose	Route	Schedule
Consolidation (E1910)
Blinatumomab	45 kg or more: 28 mcg/day (less than 45 kg: 15 mcg/m²/day)	IV, continuous infusion	Days 1–28, then 14 days off
Relapsed/refractory, Cycle 1
Blinatumomab	9 mcg/day, then 28 mcg/day	IV, continuous infusion	Days 1–7, then Days 8–28
Relapsed/refractory, subsequent cycles
Blinatumomab	28 mcg/day	IV, continuous infusion	Days 1–28

Cycle length: Every 42 days (continued therapy cycles in relapse: every 84 days)
Duration: E1910: 4 cycles of blinatumomab interspersed with consolidation chemotherapy; relapse: up to 2 induction cycles, 3 consolidation cycles and 4 continued therapy cycles

Premedication with dexamethasone 20 mg before the first dose of each cycle, intrathecal prophylaxis, and hospitalisation during the first days (relapse: first 9 days of Cycle 1); boxed warning for cytokine release syndrome and neurological toxicity.

On the page “Blood cancers (leukaemia, lymphoma and myeloma)” · Treatment regimens and dosing in leukaemias

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

1Blinatumomab group

Blinatumomab by continuous IV infusion in 6-week cycles (4 weeks of treatment + 2 weeks off): 9 μg/day in week 1 of the first induction cycle, then 28 μg/day; 2 induction cycles, up to 3 consolidation cycles in responders, then maintenance with a 4-week infusion every 12 weeks for up to 12 months. Dose interruption or discontinuation was mandatory for neurological events and some other adverse events. 271 patients.

2Standard chemotherapy group

One of 4 prespecified regimens at the investigator's choice: FLAG ± anthracycline (for example idarubicin 10 mg/m² on days 1 and 3, fludarabine 30 mg/m² on days 1 to 5, cytarabine 2 g/m² on days 1 to 5; over 60 years: 5, 20 mg/m² and 1 g/m²), a high-dose cytarabine-based regimen (≥1 g/m² per day), a high-dose methotrexate-based regimen (500 mg/m² to 3 g/m² over up to 24 hours) or a clofarabine-based regimen (20 mg/m² per day for up to 5 days); 2 induction cycles, up to 3 consolidation cycles and continuation for up to 12 months. 134 patients.

Source of the regimen details: Full text of the paper in PMC (PMC5881572), Methods section, and ClinicalTrials.gov NCT02013167

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

Adults (18 years and older) with Philadelphia chromosome-negative B-precursor ALL in one of these situations: refractory to primary induction or to salvage with intensive combination chemotherapy, first relapse with a first remission lasting less than 12 months, second or later relapse, or relapse at any time after allogeneic transplantation; more than 5% bone marrow blasts and ECOG ≤2; at 101 centres in 21 countries.

Endpoints

Primary endpoint: overall survival. Other outcomes reported in the abstract: remission rate within the first 12 weeks, event-free survival, duration of response, allogeneic stem cell transplantation and adverse events.

Safety and side effects

Grade 3 or higher adverse events were reported in 87% of patients in the blinatumomab group and 92% of patients in the chemotherapy group.

Clinical significance and place in guidelines

This phase 3 trial showed that blinatumomab significantly improves overall survival compared with standard chemotherapy in adults with relapsed or refractory B-precursor ALL, providing randomised support for its use; the drug's earlier approval was based on single-arm trials. The exact status of clinical guidelines and drug approvals should be checked separately.

Limitations

According to the abstract, details of the chemotherapy doses and protocol are not specified. Patients in the chemotherapy group also received different standard-of-care regimens. Other limitations should be checked in the full text.

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.