ETV6::RUNX1 Acute Lymphoblastic Leukemia: how much therapy is needed for cure?

Abstract

Recent trials show 5-year survival rates >95% for ETV6::RUNX1 Acute Lymphoblastic Leukemia (ALL). Since treatment has many side effects, an overview of cumulative drug doses and intensities between eight international trials is presented to characterize therapy needed for cure. A meta-analysis was performed as a comprehensive summary of survival outcomes at 5 and 10 years. For drug dose comparison in non-high risk trial arms, risk group distribution was applied to split the trials into two groups: trial group A with ~70% (range: 63.5-75%) of patients in low risk (LR) (CCLSG ALL2004, CoALL 07-03, NOPHO ALL2008, UKALL2003) and trial group B with ~45% (range: 38.7-52.7%) in LR (AIEOP-BFM ALL 2000, ALL-IC BFM ALL 2002, DCOG ALL10, JACLS ALL-02). Meta-analysis did not show evidence of heterogeneity between studies in trial group A LR and medium risk (MR) despite differences in treatment intensity. Statistical heterogeneity was present in trial group B LR and MR. Trials using higher cumulative dose and intensity of asparaginase and pulses of glucocorticoids and vincristine showed better 5-year event-free survival but similar overall survival. Based on similar outcomes between trials despite differences in therapy intensity, future trials should investigate, to what extent de-escalation is feasible for ETV6::RUNX1 ALL.

Fig. 1. Meta-analysis of outcome of LR and MR arms of trials included in ETV6::RUNX1 therapy intensity study.

A 5-year event-free survival (%), B 5-year overall survival (%), C 5-year cumulative incidence of relapse (%), D 5-year cumulative incidence of death in remission (%). EFS event-free survival, OS overall survival, CIR clinical incidence of relapse, DCR death in complete remission, CCLSG Children’s Cancer and Leukemia Study Group, CoALL Childhood Acute Lymphoblastic Leukemia, NOPHO Nordic Society of Pediatric Hematology and Oncology, UKALL United Kingdom Acute Lymphoblastic Leukemia; AIEOP-BFM, Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin Frankfurt Münster; ALL IC-BFM Acute Lymphoblastic Leukemia Intercontinental-Berlin Frankfurt Münster, DCOG Dutch Childhood Oncology Group, JACLS Japan Childhood Leukemia Study Group.

Fig. 2. Outcome of trial group A LR.

A Visual summary of cumulative dose analysis. Colored squares represent cumulative dose relative to the largest trial. Green represents lower cumulative dose, yellow similar, and red higher cumulative dose. B Meta-analysis of 5-year event-free survival (%), C Meta-analysis of 5-year overall survival (%) CoALL 07-03 and CCLSG ALL2004 did not have any deaths, D Overview of cumulative drug doses proportionate to the largest clinical trial, E Relative dose intensity during day 0–90, day 0 till start maintenance and maintenance therapy. VCR vincristine, HD-MTX high-dose methotrexate, LD-MTX low-dose methotrexate, AraC cytarabine, SR standard risk, MT maintenance therapy.

Fig. 3. Outcome of trial group A MR.

A Visual summary of cumulative dose analysis. Colored squares represent cumulative dose relative to the largest trial. Green represents lower cumulative dose, yellow similar, and red higher cumulative dose. B Meta-analysis of 5-year event-free survival (%), C Meta-analysis of 5-year overall survival (%), D Overview of cumulative drug doses proportionate to the largest clinical trial, E Relative dose intensity during day 0–90, day 0 till start maintenance and maintenance therapy. VCR vincristine, HD-MTX high-dose methotrexate, LD-MTX low-dose methotrexate, AraC cytarabine, SR standard risk, MT maintenance therapy.

Fig. 4. Outcome of trial group B LR.

A Visual summary of cumulative dose analysis. Colored squares represent cumulative dose relative to the largest trial. Green represents lower cumulative dose, yellow similar, and red higher cumulative dose. B Meta-analysis of 5-year event-free survival (%), C Meta-analysis of 5-year overall survival (%), D Overview of cumulative drug doses proportionate to the largest clinical trial, E Relative dose intensity during day 0-90, day 0 till start maintenance and maintenance therapy. VCR vincristine, HD-MTX high-dose methotrexate, LD-MTX low-dose methotrexate, AraC cytarabine, SR standard risk, MT maintenance therapy.

Fig. 5. Outcome of trial group B MR.

A Visual summary of cumulative dose analysis. Colored squares represent cumulative dose relative to the largest trial. Green represents lower cumulative dose, yellow similar, and red higher cumulative dose. B Meta-analysis of 5-year event-free survival (%), C Meta-analysis of 5-year overall survival (%), D Overview of cumulative drug doses proportionate to the largest clinical trial, E Relative dose intensity during day 0–90, day 0 till start maintenance and maintenance therapy. VCR vincristine, HD-MTX high-dose methotrexate, LD-MTX low-dose methotrexate, AraC cytarabine, SR standard risk, MT maintenance therapy.