First Report of Clinical Response to Venetoclax in Early T-Cell Precursor Acute Lymphoblastic Leukemia

Abstract

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently recognized, high-risk subgroup of ALL characterized by early differentiation arrest and distinct genetic and transcriptional features. ETP-ALL represents 10-30% of TALL cases in adults and 10-15% of cases in children, exhibits inferior response rates to chemotherapy, and is characterized by high relapse rates with dismal outcomes in the relapsed/refractory setting. 1 Recent insights into the biology of ETP-ALL using "BH3-profiling" have revealed BCL-2 dependence 2 with exquisite in vitro sensitivity to the BCL-2-selective antagonist, venetoclax. 3 Herein, we report a patient with refractory ETP-ALL and another with TALL and some features suggestive of the ETP subtype who had excellent responses to venetoclax, given in combination with cytotoxic chemotherapy. Both patients received venetoclax off-label and provided written informed consent after receiving counselling about the unapproved nature of this treatment, the rationale for its use and possible adverse effects from the medication. Patient 1: A 71-year-old woman was diagnosed with ETP-ALL in April 2017 with 80% bone marrow blasts. She received 2 cycles of hyper-fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (HyperCVAD), alternating with high-dose methotrexate and cytarabine and was refractory to treatment. Subsequently, she failed to respond to 2 nd line treatment with nelarabine and 3 rd line therapy with liposomal vincristine (Figure 1). At presentation to our center, she had 90% bone marrow blasts. Flow cytometry was positive for cytoplasmic CD3, CD4 (partial), CD5 (dim, small subset, 6.8%), CD7 (bright), CD10 (dim, small subset, 2%), CD13, CD33, CD34, CD38, CD45 (dim), CD56 (dim, small subset, 9%), CD117, CD123 (partial), and HLA-DR. Negative markers included CD1a, CD2, surface CD3, CD8, CD14, CD15, CD19, CD22, CD25, CD36, CD41, myeloperoxidase, and TdT. Immunohistochemical staining revealed uniformly strong BCL-2 expression on the blasts (Figure 2, panel D). Targeted next-generation sequencing (NGS) revealed mutations in ASXL1 and PTPN11. Cytogenetics revealed add(1)(p13) and t(7;13) (q36;q12). She was enrolled on a phase I clinical trial of palbocicib and dexamethasone and