nelarabine and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

This article reviews the recent advances in the pathophysiology and management of acute lymphoblastic leukemia (ALL) in adults.. Addition of rituximab to standard chemotherapy improves survival in the frontline treatment of B cell ALL, and measurable residual disease (MRD) is the most important prognostic factor. Tyrosine kinase inhibitors (TKI), particularly ponatinib, in combination with Hyper-CVAD significantly improve outcomes in Ph + ALL challenging the benefit of allogeneic stem cell transplant in first line for these patients. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T cells are better options than chemotherapy alone for the treatment of relapsed or refractory ALL. Combination of these agents with chemotherapy and their incorporation in the frontline setting show promises to improve cure rates of ALL. Development of monoclonal antibodies, CAR T, and potent TKI has improved the outcome of ALL. Advances in our understanding of ALL biology are expected to bring new therapeutic strategies in the upcoming years.

Topics: Adult; Antibodies, Bispecific; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Humans; Immunotherapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Rituximab; Stem Cell Transplantation

The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine.

Topics: Antineoplastic Agents; Arabinonucleosides; Biomarkers, Tumor; Cell Line, Tumor; DNA Methylation; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; SAM Domain and HD Domain-Containing Protein 1

The long-term prognosis of adult patients with relapsed Philadelphia chromosome-negative acute lymphoblastic lymphoma (ALL) is poor. Allogeneic stem cell transplant in second remission is the only curative approach and is the goal when feasible. There is no standard chemotherapy regimen for relapsed disease, although a few agents are approved for use in this setting. The bispecific CD19-directed CD3 T-cell engager, blinatumomab, has recently been granted accelerated approval by the US Food and Drug Administration for relapsed or refractory disease of B-cell lineage. For patients with relapsed T-cell ALL, nelarabine is available. Liposomal vincristine is also approved for relapsed disease. When selecting combination chemotherapy salvage options, evaluation of the prior treatment and timing of relapse informs treatment decisions. Monoclonal and cellular investigational therapies are quite promising and should be explored in the appropriate patient.

Topics: Antibodies, Bispecific; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleosides; Drug Resistance, Neoplasm; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Molecular Targeted Therapy; Philadelphia Chromosome; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Salvage Therapy; Transplantation, Homologous; Young Adult