Results from the COG AALL0331 trial in a low-risk subset of children with standard-risk B-ALL

For pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), a risk-adapted therapy intensification has led to survival improvements, with rates of 5-year survival exceeding 90%.

In 2004, the Children’s Oncology Group (COG) revised the ALL risk-based classification system, identifying a subset of patients with standard-risk (SR) B-ALL: SR-low. SR-low patients had no extramedullary disease, rapid early response to induction therapy, end-induction bone marrow (BM) minimal residual disease (MRD) <0.1%, and one of two favorable cytogenetic features (either ETV6-RUNX1 fusion or trisomies of chromosomes 4, 10, and 17).

Given the efficacy and tolerability of pegaspargase intensification in younger patients, the COG AALL0331 trial (NCT00103285) sought to investigate whether post-induction pegaspargase intensification on a low-intensity treatment backbone would improve the continuous complete remission (CCR) rate in a SR-low subset of patients with B-ALL.¹

Study design

The study schema is shown in Figure 1. Between 2005 and 2010, 5,377 patients with SR B-ALL aged 1─9 years and with an initial white blood cells (WBC) count <50,000/μL were enrolled in the study. Of these, 5,303 received a three-drug induction with dexamethasone, vincristine, and pegaspargase, plus intrathecal chemotherapy with cytarabine and methotrexate. Following the induction, risk assignment was refined into SR-low, SR-average, and SR-high, and 1,857 patients met the eligibility criteria for the inclusion in the SR-low cohort.

The low-risk criteria included:

• No corticosteroid pretreatment
• No central nervous system, testicular, or other extramedullary leukemia
• Favorable cytogenetics
• No high-risk features
• Rapid early response to induction therapy (<5% BM blasts by Day 15, and end-induction BM MRD <0.1%)

Patients in the SR-low cohort were then randomized 1:1 to receive standard consolidation and interim maintenance with (low-risk with intensified pegaspargase [LRA]; n = 928) or without (low-risk standard [LRS]; n = 929) four additional pegaspargase doses administered every 3 weeks.

After September 2008, during interim maintenance, all patients received the escalating dose of intravenous (IV) methotrexate without leucovorin rescue (LRS with IV methotrexate [LRS-IV]; LRA with IV methotrexate [LRA-IV]) instead of oral methotrexate. After June 2008, during delayed intensification, all patients received alternate-week dexamethasone instead of continuous dexamethasone. A summary of the treatment schedule is shown in Figure 2.

The primary endpoint of the study was CCR.

Figure 1. Study schema* 

IV, intravenous; LRA, low-risk with intensified pegaspargase; LRS, low-risk standard; SR, standard-risk.

*Data from Mattano et al.¹

Figure 2. Treatment summary*

IT, intrathecal; IV, intravenous; LRA, low-risk with intensified pegaspargase; LRA-IV, LRA with IV methotrexate; LRS, low-risk standard; LRS-IV, LRS with IV methotrexate; PO, oral.
*Adapted from Mattano et al.¹
†Dose escalated by 50 mg/m² every 10 days for a total of five doses, adjusted for toxicity.

 Patient characteristics

Characteristics of the patients in the SR-low cohort are reported in Table 1.

Table 1. Patient characteristics*

Outcomes

Outcomes are reported in Table 2. No significant differences in either CCR rates or OS were observed between LRA/LRA-IV and LRS/LRS-IV regimens, but a superior CCR was observed in the LRA arm when considering patients assigned to pre-amendment regimens (LRA and LRS). In addition, superior CCR and OS were observed in patients with triple trisomy compared with ETV6-RUNX1 fusion, and superior CCR was observed in patients with <5% BM blasts at Day 8 compared with those not achieving <5% BM blasts until Day 15.

Table 2. 6-year CCR and OS for the SR-low cohort*

In a comparative analysis with the SR-average cohort (n = 422; patients treated with therapy identical to LRS or LRS-IV, who met all the SR-low criteria but without favorable cytogenetics), SR‑low versus SR-average patients showed:

• Superior CCR, 94.0% ± 0.8% vs 88.6% ± 1.7% (HR, 1.95; 95% CI, 1.34─2.85; p = 0.0004)
• Superior OS, 99.2% ± 0.3% vs 96.1% ± 1.0% (HR, 5.42; 95% CI, 2.37─12.39; p = 0.0001)

Factors associated with inferior outcome in the SR-average vs SR-low cohort were:

• Age, ≥6 vs <6 years (HR, 1.821; 95% CI, 1.197─2.771; p = 0.0051)
• Risk group, SR-average vs SR-low (HR, 2.598; 95% CI, 1.448─4.662; p = 0.0014)
• Day 29 MRD, ≥0.01% vs <0.01% (HR, 2.706; 95% CI, 1.727─4.239; p < 0.0001)
• Cytogenetics, ETV6-RUNX1 fusion vs triple trisomies (HR, 1.807; 95% CI, 1.000─3.264; p = 0.0498).

Safety

A summary of the disease-free survival events and toxicities is reported in Table 3.

Table 3. Disease-free survival events and toxicities*

Conclusions

• Patients with SR-low B-ALL treated with low-intensity post-induction therapy with or without intensified pegaspargase had 6-year CCR 94.7% and OS 98.7%
• No significant differences in CCR and OS were observed between the two arms of the study
• Favorable cytogenetics was associated with superior CCR and OS, with triple trisomy associated with better CCR and OS compared with ETV6-RUNX1 fusion
• Remission deaths and the most common targeted toxicities, pancreatitis and osteonecrosis, were more frequent with intensified pegaspargase therapy

Altogether, results from this study show that, in selected settings, a reduction of treatment intensity that can limit toxicity without compromising the outcome may be successful. Also, the standard therapy without intensified pegaspargase could be easily delivered in an outpatient setting, which has important implications for ALL treatment.