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B. Ball and E.M. Stein et al.
reduce the potential for recurrence by eliminating leukemia regenerating cells. AML is a heterogeneous dis- ease that includes populations of bulk leukemic blasts and leukemic stem cells that are thought to be more refractory to treatment than others.10 Leukemic stem cells were ini- tially defined phenotypically by specific cell surface mark- ers CD34+ CD38- and functionally by an ability to initiate leukemia in animal transplant models.11 Cellular tracking of leukemic cell populations demonstrated the persistence of either leukemic stem cell subclones or more committed leukemia cells that retained stemness transcriptional pro- grams from disease initiation to relapse.12 Therefore, cen- tral to the development of MRD targeting is the ability of the novel therapies to eradicate leukemic stem cells.
In this review, we discuss MRD targets of therapeutic potential. We focus on the therapies that have been devel- oped for each target and, if available, evidence of efficacy in reducing MRD prior to allogeneic SCT.
Targeting oncogenic driver mutations
Fms-like tyrosine kinase 3 (FLT3)
Fms-like tyrosine kinase 3 (FLT3) is the most commonly
mutated gene in AML with FLT3 internal tandem duplica- tions (ITD) and FLT3 tyrosine kinase domain (TKD) muta- tions occurring in 22-32% and 8% of newly diagnosed cases, respectively.13,14 In a large population-based study the incidence of FLT3-ITD mutations was lower at 18.9% and decreased with age.15 FLT3-ITD mutations are associ- ated with worse prognosis and increased risk of relapse with allogeneic transplantation.13,14,16-18 As monotherapy, FLT3 inhibitors are capable of inducing molecular remis- sions and gilteritinib (Xospata) is approved for relapsed or refractory FLT3-mutated AML.19,20 Quizartinib has also demonstrated efficacy as monotherapy in patients with relapsed or refractory FLT3-ITD-mutated AML.21 The combination of FLT3 inhibitors with chemotherapy has the potential to induce deeper remissions than induction chemotherapy alone. Midostaurin (Rydapt) is a first-gen- eration FLT3 inhibitor that was originally developed as a protein kinase C inhibitor and found to have inhibitory activity against multiple tyrosine kinases including FLT3.22 The phase III RATIFY trial randomized younger patients with newly diagnosed FLT3-TKD or FLT3-ITD mutated AML to midostaurin in combination with induction and consolidation chemotherapy or placebo with standard chemotherapy. Patients in the midostaurin arm had a sig- nificantly longer median overall survival (74.7 vs. 25.6 months, P=0.009) leading to approval of the regimen. In this study, MRD was not assessed; however, among patients undergoing allogeneic SCT, midostaurin in com- bination with chemotherapy led to a near significant increase in overall survival (P=0.07) and a significant decrease in cumulative incidence of relapse [hazard ratio (HR) 0.47, P=0.02].23,24
Next-generation FLT3 inhibitors have greater specificity and higher potency. Type I inhibitors such as gilteritinib and crenolanib are active against FLT3-TKD or FLT3-ITD mutations. In contrast, FLT3-TKD mutations in the activa- tion loop and gatekeeper domain confer resistance to type 2 inhibitors such as quizartinib.25 Active clinical trials eval- uating next-generation FLT3 inhibitors in combination with induction and consolidation include NCT02283177 for crenolanib, NCT02236013 for gilteritinib, and
NCT02668653 for quizartinib. In a single-arm, phase II study (NCT02283177) of crenolanib in combination with standard induction and consolidation chemotherapy fol- lowed by crenolanib maintenance for 1 year, 24 out of 29 (83%) patients achieved CR and 20 out of 25 evaluable patients (80%) achieved MRD-negative disease, as deter- mined by multiparameter flow cytometry.26,27 Similarly, in a phase I study in patients with newly diagnosed FLT3- mutated AML, gilteritinib in combination with induction and consolidation led to a high CR rate of 77% (n=23/30).28 A phase I study of quizartinib in combination with induction and consolidation in newly diagnosed AML led to CR in six of nine (67%) patients and a mor- phological leukemia-free state in two of nine (22%) patients with FLT3-ITD mutations.29 The high response rates of next-generation FLT3 inhibitors in combination with chemotherapy in early phase studies led to the devel- opment of randomized studies comparing gilteritinib (NCT03836209) and crenolanib (NCT02283177) to midostaurin in combination with induction and consoli- dation chemotherapy.
Isocitrate dehydrogenases (IDH1 and IDH2)
Mutations involving the isocitrate dehydrogenase-1 (IDH1) and -2 (IDH2) genes occur in about 6-10% and 9- 13% of newly diagnosed cases of AML, respectively.30-35 Mutant IDH has neomorphic enzyme activity leading to aberrant production of the oncometabolite 2-hydroxyglu- tarate.33,36 Accumulation of 2-hydroxyglutarate competi- tively inhibits α-ketoglutarate-dependent enzymes includ- ing TET2, a DNA hydroxymethylase resulting in global hypermethylation, a block in cellular differentiation, an increase in self-renewal and enhancement of leukemic transformation.36-38 Ivosidenib (Tibsovo) and enasidenib (Idhifa) are oral inhibitors of mutant IDH1 and IDH2, respectively and are approved for relapsed or refractory IDH1- and IDH2-mutant AML.39,40 In relapsed or refractory AML, ivosidenib led to clearance of IDH1 mutations in seven out of 25 (28%) patients who achieved either CR or CR with incomplete count recovery (CRi).39 Similarly, treatment with enasidenib in relapsed or refractory AML led to IDH2 mutation clearance in nine out of 29 (31%) patients achieving a CR.41 Preliminary results from a phase I study of ivosidenib or enasidenib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed IDH-mutated AML demonstrated that the combination was well tolerated. Among patients treated with ivosidinib, responses [CR, CRi or CR with imcomplete platelet recovery (CRp)] occurred in 26 out of 28 (93%) and 33 out of 45 (73%) patients with de novo and secondary IDH1-mutated AML, respectively. In the enasidenib group responses occurred in 33 out of 45 (73%) and 20 out of 32 (63%) patients with de novo and secondary IDH2-mutated AML, respectively. Furthermore, IDH-mutation clearance was observed in nine out of 22 (41%) of the patients with IDH1 mutations and in 11 out of 31 (30%) of those with IDH2 mutations. MRD negativity by multiparameter flow cytometry was observed in eight out of nine (89%) patients with IDH1 mutations and seven out of 12 (58%) of those with IDH2 mutations.42 Although IDH inhibitors and chemotherapy may increase MRD-negative rates, further studies are needed to determine the impact of the combination on survival after allogeneic SCT. A phase III, randomized study of ivosidenib or enasidenib in combination with
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haematologica | 2019; 104(8)