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ash2014-1

Children with T-lymphocytic leukemia have better outcomes than expected, regardless of the presence of an early thymic precursor protein signature

Data from the AALL0434 study, the largest study ever conducted in patients with T-lymphocytic leukemia (T-ALL), demonstrate that T-ALL patients have a better-than-expected outcome when they were treated with a tailored therapy. Moreover, the study revealed that an early thymic precursor (ETP) protein signature was not associated with a worse prognosis, as patients with an ETP signature were found to have an outcome identical to the outcome of non-ETP patients, despite having a higher incidence of residual disease early after therapy.

Relapse after therapy is a major challenge for children and young adults with T-ALL. Previous research has indicated that patients with a specific ETP protein signature of T-ALL have particularly poor outcomes. To better understand how the presence of this immunophenotype among pediatric T-ALL patients influences their response to therapy, the presented phase III study enrolled 1,144 T-ALL patients. As such, this is the largest ever clinical study conducted among patients with this leukemia subtype.

In the study at hand, all patients were treated with a standard 4-drug induction treatment (prednisone x 28 days, VCR weekly x 4, pegaspargase day 4, daunorubicin weekly x 4). After this induction phase, the investigators measured the levels of minimal residual disease (MRD) in each patient, dividing children into groups at low-, intermediate-, and high-risk of relapse (low risk <0.1% MRD; intermediate risk <1% MRD, and high risk >1% MRD). At that time, intermediate and high-risk patients were randomized to receive or not receive six 5-day courses of nelarabine during consolidation, delayed intensification and maintenance. All patients were also randomized to receive either the Capizzi regimen (methotrexate with asparaginase) or high-dose methotrexate during interim maintenance and all patients, except those who were at low-risk of relapse, received cranial irradiation (1200 cGY for CNS1 or 2 and 1800 cGy for CNS3). The trial included 130 children with the ETP immunophenotype (11.3%), 195 children with a nearly identical type of T-ALL depicted as “near-ETP” (ETP but with elevated CD5; 17%), and 819 children without the ETP immunophenotype (71.6%).

When researchers evaluated the overall responses of all T-ALL patients enrolled in the trial, they observed that children with the ETP and near-ETP immunophenotypic signatures of T-ALL had a higher incidence of residual disease after initial treatment and most commonly fitted into the higher-risk groups. Despite significantly higher (P<0.0001) rates of induction failure (>25% blasts by morphology at end induction) for ETP (7.8%) and near-ETP (6.7%) patients as compared to not-ETP patients (1.1%), all 3 immunophenotypic groups showed excellent 5-year event-free (EFS) and overall survival (OS) rates that were not statistically different: ETP (EFS: 87.0% and OS: 93.0%), near-ETP (EFS: 84.4% and OS: 91.6%), and non-ETP (EFS: 86.9% and OS: 92.0%). Of note, in all 3 groups, most events occurred within 12 months from diagnosis and plateaued after 2 years, although events generally occurred earlier for ETP and near-ETP patients than for non-ETP subjects. There were no relapses in ETP patients later than 12 months post diagnosis.

An initial white blood cell count greater than 200,000/microliter was seen in 9.6% of the ETP patients and in 30% of the non-ETP and near-ETP population (p< 0.0001). This was associated with inferior EFS and OS for near-ETP (EFS p=0.0003) and non-ETP patients (EFS p= 0.012), but not for patients with an ETP signature. In addition, day 29 MRD >0.01% was associated with inferior EFS (76.3% vs. 89.0%; p= 0.0001) and OS (86.6% vs. 93.8%; p= 0.0008) for the total cohort and was detected in 81.4%, 64.8%, and 30.5% of ETP, near-ETP and non-ETP patients, respectively. Interestingly, there was no difference in EFS or OS for day 29 MRD <0.01% vs. 0.01%-1.0%, suggesting significance largely for MRD >1.0%. Day 29 MRD >0.01% was also associated with inferior EFS (76.6% vs. 90.8%; p= 0.0001) and OS (84.3% vs. 94.0%; p= 0.0064) in non-ETP patients and with inferior EFS (80.2% vs. 94.0%; p= 0.0073) in the near-ETP patients. However, no difference was seen for EFS or OS in patients with an ETP signature.

In summary, AALL0434 is the largest study of T-ALL ever conducted and shows excellent outcomes for T-ALL patients. Interestingly, patients with an ETP protein signature were found to have an outcome identical to that of non-ETP patients. In addition to this, the study indicated that a white blood cell count above 200,000/microliter is associated with inferior outcome in non-ETP T-ALL patients. Bone marrow MRD > 1% at day 29 was able to identify a subset of non-ETP T-ALL patients having inferior outcomes.

Reference

Wood B, Winter S, Dunsmore K, et al. T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype and Validation of the Prognostic Value of End-Induction Minimal Residual Disease (MRD) in Children’s Oncology Group (COG) Study AALL0434. Presented at ASH 2014; Abstract #1.

Speaker Brent Wood

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Brent L. Wood, MD, PhD,
SCCA Laboratories, University of Washington, Seattle, USA

 

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