Vincristine/corticosteroid pulses

A CCG randomized trial conducted in the 1980s demonstrated improved outcome in patients who received monthly vincristine/prednisone pulses.[119]

A meta-analysis combining data from six clinical trials from the same treatment era showed an EFS advantage for vincristine/prednisone pulses.[120,121] However, overall EFS from these trials was lower than is observed with more contemporary regimens.

A systematic review of the impact of vincristine plus steroid pulses from more recent clinical trials raised the question of whether such pulses are of value in current ALL treatment, which includes more intensive early therapy and risk stratification incorporating early response (MRD) and biological factors.[121]

In a multicenter randomized trial in children with intermediate-risk ALL being treated on a BFM regimen, there was no benefit associated with the addition of six pulses of vincristine/dexamethasone during the continuation phase, although the pulses were administered less frequently than in other trials in which a benefit had been demonstrated.[122]

A small multicenter trial of average-risk patients demonstrated superior EFS in patients receiving vincristine plus corticosteroid pulses. In this study, there was no difference in outcome based on type of steroid (prednisone vs. dexamethasone).[123][Level of evidence A1]

In the COG AALL0932 (NCT01190930) trial, standard-risk patients were randomly assigned during maintenance to receive vincristine/dexamethasone pulses every 4 weeks or every 12 weeks.[115][Level of evidence A1]

In the COG AALL0932 (NCT01190930) trial, standard-risk patients were randomly assigned during maintenance to receive vincristine/dexamethasone pulses every 4 weeks or every 12 weeks.[115][Level of evidence A1]

For the randomly assigned standard-risk patients, the 5-year DFS rate from the start of maintenance was 94.6%. There was no significant difference between the every-4-week group and the every-12-week group.

The Chinese Children’s Cancer Group conducted a randomized noninferiority trial to determine whether vincristine/dexamethasone pulses could be omitted during the second year of maintenance therapy. One year after the initiation of therapy, 5,054 patients with non-BCR::ABL1 fusion–positive ALL (B-ALL and T-ALL, aged 0–18 years) were randomly assigned to receive either vincristine/dexamethasone pulses every 8 weeks (seven pulses total) or no pulses during the second year of maintenance chemotherapy. Noninferiority was defined by calculating the one-sided 95% upper confidence bound of the difference in EFS probability between arms to ensure that an EFS decrement of 5% or more was ruled out.[124]

The Chinese Children’s Cancer Group conducted a randomized noninferiority trial to determine whether vincristine/dexamethasone pulses could be omitted during the second year of maintenance therapy. One year after the initiation of therapy, 5,054 patients with non-BCR::ABL1 fusion–positive ALL (B-ALL and T-ALL, aged 0–18 years) were randomly assigned to receive either vincristine/dexamethasone pulses every 8 weeks (seven pulses total) or no pulses during the second year of maintenance chemotherapy. Noninferiority was defined by calculating the one-sided 95% upper confidence bound of the difference in EFS probability between arms to ensure that an EFS decrement of 5% or more was ruled out.[124]

For low-risk patients (NCI standard-risk B-ALL with high hyperdiploidy or ETV6::RUNX1 and low end-induction MRD), the EFS difference between arms met the protocol definition of noninferiority, indicating that omission of vincristine/dexamethasone pulses during the second year of maintenance did not result in a decrement of EFS that was greater than 5%.

The Chinese Children’s Cancer Group conducted a randomized noninferiority trial to determine whether vincristine/dexamethasone pulses could be omitted during the second year of maintenance therapy. One year after the initiation of therapy, 5,054 patients with non-BCR::ABL1 fusion–positive ALL (B-ALL and T-ALL, aged 0–18 years) were randomly assigned to receive either vincristine/dexamethasone pulses every 8 weeks (seven pulses total) or no pulses during the second year of maintenance chemotherapy. Noninferiority was defined by calculating the one-sided 95% upper confidence bound of the difference in EFS probability between arms to ensure that an EFS decrement of 5% or more was ruled out.[124]

For intermediate-risk and high-risk patients, the difference in 5-year EFS between arms did not meet the protocol definition of noninferiority (the 95% upper confidence bound for the difference was 0.055, which exceeded the preset noninferiority margin of 0.05); therefore, it could not be concluded that vincristine/dexamethasone pulses could be omitted in these patients without resulting in an EFS decrement exceeding 5%.

The Japanese Childhood Cancer Group ALL-B12 trial included 1,107 patients with standard-risk B-ALL (i.e., NCI standard risk, good response to prednisone, day 15 marrow M1/2, end-of-induction marrow M1 without high-risk features [CNS3, KMT2A rearranged, TCF3::HLF fusion, TCF4::HLF fusion, hypodiploid]). Patients were randomly assigned to receive maintenance therapy, either with or without every 4-week vincristine/dexamethasone pulses.[125]

The Japanese Childhood Cancer Group ALL-B12 trial included 1,107 patients with standard-risk B-ALL (i.e., NCI standard risk, good response to prednisone, day 15 marrow M1/2, end-of-induction marrow M1 without high-risk features [CNS3, KMT2A rearranged, TCF3::HLF fusion, TCF4::HLF fusion, hypodiploid]). Patients were randomly assigned to receive maintenance therapy, either with or without every 4-week vincristine/dexamethasone pulses.[125]

There was no difference in EFS or adverse events between the two treatment groups.

A systematic review and meta-analysis evaluated the effect of reducing vincristine/steroid pulses on EFS, OS, and toxicity in patients with B-ALL. Twenty-five publications that included more than 12,000 patients were examined.[126]

A systematic review and meta-analysis evaluated the effect of reducing vincristine/steroid pulses on EFS, OS, and toxicity in patients with B-ALL. Twenty-five publications that included more than 12,000 patients were examined.[126]

This study demonstrated that the benefit of these pulses noted in historical trials was not seen in contemporary trials.

A systematic review and meta-analysis evaluated the effect of reducing vincristine/steroid pulses on EFS, OS, and toxicity in patients with B-ALL. Twenty-five publications that included more than 12,000 patients were examined.[126]

However, there was an increased risk of grade 3+ nonhepatic toxicity in the high-pulse frequency group.

A systematic review and meta-analysis evaluated the effect of reducing vincristine/steroid pulses on EFS, OS, and toxicity in patients with B-ALL. Twenty-five publications that included more than 12,000 patients were examined.[126]

The authors concluded that decreasing or removing pulses likely does not affect survival or risk of relapse, but it is associated with reduced toxicity.

In a CCG study, dexamethasone was compared with prednisone during the induction and maintenance phases for children aged 1 to younger than 10 years with lower-risk ALL.[6,71]

In a CCG study, dexamethasone was compared with prednisone during the induction and maintenance phases for children aged 1 to younger than 10 years with lower-risk ALL.[6,71]

Patients randomly assigned to receive dexamethasone had significantly fewer CNS relapses and a significantly better EFS rate.

In a MRC United Kingdom Acute Lymphoblastic Leukaemia (UKALL) trial, dexamethasone was compared with prednisolone during the induction and maintenance phases in both standard-risk and high-risk patients.[7]

In a MRC United Kingdom Acute Lymphoblastic Leukaemia (UKALL) trial, dexamethasone was compared with prednisolone during the induction and maintenance phases in both standard-risk and high-risk patients.[7]

The EFS and incidence of both CNS and non-CNS relapses improved with the use of dexamethasone.

In a MRC United Kingdom Acute Lymphoblastic Leukaemia (UKALL) trial, dexamethasone was compared with prednisolone during the induction and maintenance phases in both standard-risk and high-risk patients.[7]

Dexamethasone was associated with an increased risk of steroid-associated toxicities, including behavioral problems, myopathy, and osteopenia.

In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.[24]

In a DFCI ALL Consortium trial, patients were randomly assigned to receive either dexamethasone or prednisone during all postinduction treatment phases.[24]

Dexamethasone was associated with a superior EFS, but also with a higher frequency of infections (primarily episodes of bacteremia) and, in patients aged 10 years or older, an increased incidence of osteonecrosis and fracture.