The Hematologist

September-October 2017, Volume 14, Issue 5

Abrogating Early Treatment Resistance in Early T-cell Precursor Acute Lymphoblastic Leukemia

Elizabeth Raetz, MD Professor in the Division of Pediatric Hematology-Oncology; Director of High-Risk Leukemia and Lymphoma Program
University of Utah, Salt Lake City, Utah

Published on: August 14, 2017

Bond J, Graux C, Lhermitte L, et al. Early response-based therapy stratification improves survival in adult early thymic precursor acute lymphoblastic leukemia: a Group for Research on Adult Acute Lymphoblastic Leukemia study. J Clin Oncol. 2017;35:2683-2691.

Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a clinically and biologically unique subtype of T-lineage ALL (T-ALL) arising from early thymic progenitor cells and comprising 12 to 16 percent of T-ALL in children.1-4 While historically ETP ALL was associated with a poor prognosis, several pediatric studies have demonstrated that outcomes are not inferior with response-based contemporary T-ALL therapy.1,3,4 Comparative data in adults have been lacking, prompting a comprehensive analysis of adult patients with ETP ALL treated with pediatric-inspired therapy on the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) –2003 and –2005 studies.

Dr. Jonathan Bond and colleagues analyzed 213 patients with newly diagnosed T-ALL who were treated on the GRAALL-2003 phase II (n=49) and GRAALL-2005 (n=164) trials and met the inclusion criteria of having available diagnostic material for categorization as ETP-ALL. ETP-ALL was defined immunophenotypically using criteria of Coustan-Smith as reduced or absent expression of CD1a, CD5, and CD8, with expression of stem cell or myeloid markers.2 Forty-seven patients (22.1%) met criteria for ETP-ALL. Forty-one patients with T-ALL were profiled by RNA-sequencing (6 ETP-ALL, 35 non–ETP-ALL), and they were found to have distinctive patterns of gene expression that mirrored those observed in pediatric patients with ETP-ALL. The adult ETP-ALL cohort also had distinct clinical differences that included a lower proportion of male patients, older age, and lower presenting white blood cell counts when compared with the non–ETP-ALL cohort. Patients with ETP-ALL were also more likely to have incomplete rearrangement of T-cell receptor genes and markedly elevated rates of absence of biallelic deletion of the TRG locus, which was not unexpected given the immature phenotype.

The authors also performed targeted next-generation sequencing in 172 patient samples (37 ETP, 135 non-ETP) using a panel comprising genes known to be mutated in pediatric ETP-ALL.5 Mutations were observed in 89.2 percent of the ETP patients versus 63.7 percent in the non-ETP cohort. Adult ETP-ALL was distinct from non–ETP-ALL and was characterized by a genotype very similar to that of pediatric ETP-ALL, with alterations in cytokine receptor and RAS signaling; hematopoiesis; and histone modifications. The only exception was that significant rates of mutations in genes involved in DNA methylation were uniquely observed in adult ETP-ALL and not pediatric cases. Similar to pediatric ETP-ALL, alterations in the JAK-STAT pathway were common, occurring in approximately one-third of ETP cases.

Outcomes of ETP-ALL patients were also assessed. Despite similar remission rates of 87.2 percent (ETP) and 92.2 percent (non-ETP), the ETP patients showed significantly higher rates of end-induction minimal residual disease (MRD) positivity (≥ 10-4), a response pattern also observed in children. Despite early chemotherapy resistance, however, five-year event-free survival (EFS) and overall survival (OS) rates for ETP patients were not inferior to those in the non-ETP cohort (5-year EFS, 51.1% vs. 58.1%, and 5-year OS, 59.6% vs. 66.5%, for the ETP and non-ETP cohorts, respectively). However, a significantly greater proportion of patients with ETP-ALL met protocol-specified criteria for transplantation in first complete remission (CR1) due largely to poor induction treatment responses (48.9% vs. 28.3%). The authors separately analyzed the impact of allogeneic stem cell transplantation (allo-SCT) on outcomes in ETP-ALL. Among the 124 patients who met criteria for allo-SCT in CR1, there was a trend for better OS in the ETP group who underwent transplantation (hazard ratio, 0.36; p=0.07) but not in the non-ETP group, suggesting that intensification with allo-SCT abrogated the negative prognostic impact of early chemotherapy resistance in the ETP subgroup.

This is the largest report of uniformly diagnosed and treated adults with ETP-ALL, a phenotypically defined subset with unique genomic features. This report demonstrated that adult ETP-ALL is very similar to its pediatric counterpart both clinically and biologically. One main genetic distinction is a higher frequency of mutations in genes involved in DNA methylation among adults, perhaps suggesting greater similarities to myeloid disease. This study demonstrated that while patients with ETP-ALL are more likely to have a higher end-induction tumor burden, this is effectively overcome by intensified, response-based therapy in both children and adults. In children, this has been largely achieved by intensified chemotherapy, with transplantation in CR1 generally reserved for persistent MRD at the end of consolidation (or day 78) or for frank induction failures. The indications for transplantation in CR1 were broader in this adult study and were based on early patterns of treatment resistance during induction rather than the later time point of MRD assessment, and therefore, a greater proportion of patients were allocated to transplantation. Regardless of the approach, response-based therapy in both chidden and adults with ETP-ALL has been shown to be effective, yielding comparable outcomes to non–ETP-ALL. In addition to further assessing the role of transplantation in CR1 when using MRD-based stratification, therapeutic targeting of the JAK-STAT pathway may be another approach to investigate in this unique disease subset.

References

  1. Conter V, Valsecchi MG, Buldini B, et al. Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis. Lancet Haematol. 2016;3:e80-e86.
  2. Coustan-Smith E, Mullighan CG, Onciu M, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10:147-156.
  3. Patrick K, Wade R, Goulden N, et al. Outcome fro children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol. 2014;166:421-424.
  4. Wood BL, Winter SS, Dunsmore KP, 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. Blood. 2014;124:1.
  5. Zhang J, Ding L, Holmfeldt L, et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 2012;481:157-163.

Conflict of Interests

Dr. Raetz indicated no relevant conflicts of interest. back to top