“How I Treat”: Case studies on treatment approaches in children with ETP-ALL

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a novel subtype of immature T-cell ALL, representing 10−15% of cases, and is characterized by a lack of expression of CD1a and CD8, negative or weak expression of CD5, and expression of one or more myeloid and/or stem cell markers.¹

Here, we summarize a “How I Treat” article, published by Summers et al.¹ in Blood, discussing the treatment approaches and common clinical questions for children, adolescents, and young adults with ETP-ALL in three patient cases (Figure 1). The case studies cover the role of end-of-induction (EOI) minimal residual disease (MRD), choice of post-induction therapy, and the role of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first complete remission.

ETP-ALL, early T-precursor acute lymphoblastic leukemia.
*Data from Summers, et al.¹

Case 1: Newly diagnosed ETP-ALL with induction failure and MRD negativity at the end of consolidation¹

Treatment and outcome

• Patient received the following treatment:
  • prednisone-based induction as per arm B of COG AALL0434 trial (NCT00408005);
  • an augmented Berlin-Frankfurt-Münster (BFM) consolidation with nelarabine;
  • a single interim maintenance phase with escalating doses of methotrexate plus pegaspargase; and
  • 1,200 centigray of cranial radiotherapy (CRT).
• At the EOI, bone marrow showed induction failure, with 62% T-lymphoblasts.
• By mid-consolidation, bone marrow was MRD negative (<0.01%).
• Patient remains in remission at 5 years posttreatment.

Recommendations

• Preclinical data has shown that ETP-ALL is more intrinsically glucocorticoid-resistant than mature T-ALL; therefore, dexamethasone-based induction is recommended for patients with newly diagnosed ETP-ALL

• In AALL0434, nelarabine led to a significant reduction in central nervous system (CNS) relapse and was well tolerated; therefore, it is recommended for the treatment of ETP-ALL (Figure 2).
• Comparable survival outcomes were reported in patients treated with vs without CRT and by CNS status in AAALL0434 and AALL1231, respectively.
  • CRT is only recommended for patients with CNS3 and omission should be considered for patients aged <5 years or those with additional risk factors.

Case 2: Refractory ETP-ALL¹

Treatment and outcome

• Received dexamethasone-based induction, after which EOI MRD was 4.3%
• Augmented BFM consolidation incorporating nelarabine, after which MRD was 0.5%
• Received one high-risk block of BFM, and then became MRD negative
• Patient underwent allo-HSCT and remains disease-free 4 years later

Recommendations

• Immunophenotyping alone is not adequate to identify patients with immature, treatment-resistant T-ALL
• Specific genomic factors could be used alongside MRD for risk stratification
• HSCT is recommended in patients with end of consolidation flow-based MRD 0.01−0.1% who do not achieve MRD (Figure 2).

Case 3: Relapsed ETP-ALL¹

Treatment approach and outcome

• Received daratumumab plus vincristine, prednisone, and calaspargase to achieve CR with an MRD of 1.2%
• Subsequently, received consolidation therapy with daratumumab plus methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine to achieve MRD negativity.
• Experienced isolated bone marrow relapse 6 months post-HSCT
• Enrolled in a phase I trial of allogeneic CD7-directed chimeric antigen receptor T-cell therapy and remains in remission 9 months after treatment

Recommendations

• Based on the survival rate post relapse of <35%, allo-HSCT is recommended in patients with relapsed ETP-ALL after achieving second complete remission (Figure 2).
• Comprehensive genomic profiling to identify biomarkers and enrollment in clinical trials are encouraged for patients with relapsed ETP-ALL (Figure 2).

aBFM, augmented Berlin-Frankfurt-Münster; ETP-ALL, early T-cell precursor acute lymphoblastic leukemia; CMTX, Capizzi methotrexate; CR2, second complete remission; HSCT, hematopoietic stem cell transplant; MRD, minimal residual disease.
*Data from Summers, et al.^1
†Continued chemotherapy or HSCT is a feasible option for these patients.

 

Key learnings

Treatment approaches for patients with ETP-ALL and near-ETP ALL should be same as patients with non-ETP ALL. Dexamethasone is the recommended treatment for induction and post-induction therapy, with the incorporation of nelarabine. CRT should only be used for patients with CNS3 disease and omitted in those with high-risk features and aged <5 years. HSCT is recommended for patients with poor end of consolidation MRD response (0.01−0.1%). Novel therapies or clinical trial enrollment should be encouraged in children with relapsed/refractory T-cell ALL.