ABSTRACT
PURPOSE: To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL. PATIENTS AND METHODS: Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients. RESULTS: AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS (P = .412) and OS (P = .600). CONCLUSION: Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.
Subject(s)
Lymphoma , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bortezomib/adverse effects , Child , Disease-Free Survival , Humans , Infant , Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , T-Lymphocytes , Young AdultABSTRACT
As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.
Subject(s)
ADP-ribosyl Cyclase 1/antagonists & inhibitors , Antibodies, Monoclonal/pharmacology , Membrane Glycoproteins/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , ADP-ribosyl Cyclase 1/metabolism , Adolescent , Adult , Animals , Antibodies, Monoclonal/adverse effects , Child , Child, Preschool , Female , Gene Expression Regulation, Leukemic/drug effects , Humans , Male , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Proteins/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Xenograft Model Antitumor AssaysABSTRACT
Transient myeloproliferative disorder (TMD) occurs in 10% of infants with Down syndrome (DS). Down syndrome infants with resolved TMD may later develop acute megakaryocytic leukemia (AMKL). In these patients, AMKL is associated with somatic mutations in the X-linked transcription factor gene, GATA1. AMKL also has been described after TMD in children without DS. We report on a non-DS child identified with trisomy 21 mosaicism and a GATA1 mutation in the original blast cells who has been followed for 2 years without exhibiting AMKL. Currently, the risk for such infants developing acute leukemia is uncertain. We recommend that nondysmorphic infants with TMD undergo chromosome analysis for trisomy 21 and testing for GATA1 mutations to aid surveillance for leukemic transformation.