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Promising targets for MRD therapies in AML
trols.91 Additionally, the dendritic cell vaccine elicited WT1-specific CD8+ T-cell responses resulting in expression that correlated with long-term survival.91 Another prospective study of a vaccine composed of patient- derived AML cells fused with autologous dendritic cells in patients in CR after induction chemotherapy not eligible for allogeneic SCT led to sustained remission in 12 of 17 patients receiving at least one dose of vaccine and a 4-year progression-free survival rate of 71%: the median progres- sion-free and overall survival had not been reached.92 The vaccine was well tolerated with the most common adverse events being erythema, pruritis and/or induration at the vaccine site.92 The dendritic cell/AML fusion also induced CD8+ T-cell specific responses and an increased circulating leukemia-reactive T-cell population that per- sisted for more than 6 months.92
Antibody drug conjugates and bispecific T-cell engaging therapy
Cluster of differentiation 33 (CD33)
The development of an antibody-based therapy targeting antigens expressed on leukemic blasts to eradicate MRD is supported by the efficacy of the CD19/CD3 bispecific anti- body, blinatumomab in B-cell acute lymphoblastic leukemia.73 CD33 is a transmembrane sialic acid-binding immunoglobulin-like lectin (SIGLEC) family protein that is expressed by cells of the myeloid lineage but not hematopoietic stem cells.93-95 CD33 is expressed on leukemic blasts as well as CD34+/CD38- leukemic stem cells.96 CD33 levels are highest in acute promyelocytic leukemia and AML with NPM1, FLT3-ITD and KMT2A mutations and lower in those with core-binding factor translocations or complex cytogenetics.97 Gemtuzumab ozogamicin (GO) is a human antibody conjugated to a
DNA-damaging calicheamicin derivative by an acid-labile linker.98 Based on promising results from three single-arm phase II studies at a dose of 9 mg/m2 given every 2 weeks, GO was initially granted FDA approval for patients >60 years of age with CD33+ AML who were not candidates for aggressive chemotherapy.99 However, GO was later with- drawn from the commercial market in October 2010 after the confirmatory phase III SWOG S0106 study showed no survival benefit and increased treatment-related mortality in patients treated with GO compared to those given stan- dard induction.100 Subsequent studies have evaluated reduced and fractionated dosing of GO to decrease treat- ment-related toxicity.100-103 A large meta-analysis from five randomized controlled trials of patients with newly diag- nosed AML receiving GO with induction chemotherapy revealed that the addition of GO was associated with a reduced risk of relapse (odds ratio 0.81, P=0.0001) and improved overall survival at 5 years (odds ratio 0.9, P=0.01), especially in patients with favorable and intermediate-risk cytogenetics.104 Additionally, the NCRI AML17 trial demon- strated a lower rate of veno-occlusive disease and early mortality but no difference in relapse or survival at 4 years between patients given GO at a dose of 3 mg/m2 or a dose of 6 mg/m2.105 As a result GO received FDA approval for adults with newly diagnosed AML, whose tumor expresses the CD33 antigen. Retrospective analysis of adult patients with NPM1-mutated AML enrolled in the ALFA-0701 trial revealed that GO in combination with induction chemotherapy increased the proportion of patients with MRD-negative disease at the end of treatment, as deter- mined by NPM1 gene transcript levels, when compared to those treated with chemotherapy alone (91% vs. 61%, P=0.028).106 This has led to a phase II trial of fractionated GO on days 1, 4, and 7 in patients with MRD after at least one cycle of induction chemotherapy. (NCT03737955)
Figure 1. Active clinical trials evaluating minimal residual disease-directed therapies arranged by trial design. Trials with induction and consolidation-based com- binations are shown on the left, non-chemotherapy post-remission therapies are shown on the right. Studies evaluating post-allogeneic transplant minimal residual disease therapies are not included.
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