Hyper-CVAD: a regimen for all seasons

The major therapeutic advances in acute lymphoblastic leukaemia in adults have occurred in discrete stages over the past three decades. First, the application of intensive, prolonged, multiagent systemic and CNS-directed therapy that was pioneered in children was shown to benefit older patients with acute lymphoblastic leukaemia, especially adolescents and young adults. 1 Stock W Luger SM Advani AS et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019; 133: 1548-1559 Crossref PubMed Scopus (195) Google Scholar Second was the use of allogeneic haematopoietic stem-cell transplantation (HSCT) for selected patients with acute lymphoblastic leukaemia in complete remission. 2 DeFilipp Z Advani AS Bachanova V et al. Hematopoietic cell transplantation in the treatment of adult acute lymphoblastic leukemia: updated 2019 evidence-based review from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019; 25: 2113-2123 Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar Third was the addition of tyrosine kinase inhibitors to conventional chemotherapy in patients with the Philadelphia chromosome (Ph) rearrangement (BCR-ABL1 fusion gene). 3 Fielding AK Rowe JM Buck G et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014; 123: 843-850 Crossref PubMed Scopus (253) Google Scholar Fourth was the introduction of monoclonal antibodies and antibody–chemotherapy conjugates directed against antigens expressed by malignant acute lymphoblastic leukaemia cells, especially in the B-cell subtype. The prime monoclonal antibody example is rituximab. Researchers at the MD Anderson Cancer Center (Houston, TX, USA) introduced rituximab as an addition to their already well established hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) chemotherapy regimen. 4 Thomas DA O'Brien S Faderl S et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010; 28: 3880-3889 Crossref PubMed Scopus (308) Google Scholar In a subsequent randomised controlled trial 5 Maury S Chevret S Thomas X et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016; 375: 1044-1053 Crossref PubMed Scopus (201) Google Scholar in Europe, the addition of rituximab to an intensive multiagent systemic chemotherapy regimen resulted in significant improvement in event-free survival in adults with CD20-positive B-cell acute lymphoblastic leukaemia. Newer-generation monoclonal antibodies and antibody conjugates include ofatumumab, directed against CD20, and inotuzumab ozogamicin, directed against CD22. Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trialThe combination of hyper-CVAD plus ofatumumab is safe and active in adults with Ph-negative CD20-positive B-cell acute lymphoblastic leukaemia. Modifications of this regimen with the addition of novel monoclonal and bispecific antibody constructs targeting CD19 and CD22 might further improve outcomes and allow reduction in the intensity and duration of chemotherapy. Full-Text PDF