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B. Ball and E.M. Stein et al.
Table 1. Outcomes of clinical trials targeting minimal residual disease with induction chemotherapy or as post-remission therapy.
MRD target
FLT3 TKD FLT3 ITD
FLT3 TKD FLT3 ITD
FLT3 ITD
IDH1 IDH2
BCL-2
DNMT1
PD1
Drug name
Gilteritinib (ASP 2215)
Crenolanib
Quizartinib
Ivosidenib Enasidenib
Venetoclax
Azacitidine
Nivolumab
Trial
NCT02236013
NCT02283177
NCT01892371
NCT02632708
NCT03214562
NCT01462578
NCT02464657
Combination
Gilteritinib
with induction and consolidation chemotherapy
Crenolanib with induction and consolidation chemotherapy
Quizartinib with induction and consolidation chemotherapy
Ivosidenib or enasidenib in combination with induction and consolidation chemotherapy
Venetoclax in combination with FLAG-IDA
None
Nivolumab in combination with standard induction and consolidation chemotherapy
Population Clinical phase
Newly I diagnosed
AML
Newly II diagnosed FLT3-mutated
AML
Newly I diagnosed
AML
Newly I diagnosed AML
with an IDH1
and/or IDH2 mutation
Relapsed or I refractory AML
Advanced MDS I/II or AML in CR,
MRD+ after
induction or
allo-SCT
High-MDS II or AML, chemotherapy
naïve
Efficacy
Among FLT3 mutated patients: CR 23/30 (77%) CRc (CR/CRp/ CRi) 27/30 (90%) CRc
100% at 120 mg dose
CR 24/ 29 (83%)
2 patients relapsed with a median follow-up of 14 months
Among FLT3-ITD mutated patients CR 6/9 (67%) MLFS 2/9 (22%)
Ivosidenib
De novo AML
CRc (CR, CRi, CRp) 26/28 (93%) Secondary AML CRc 6/13 (46%)
Enasidenib De novo AML CRc 33/45 (73%) Secondary AML
CRc 20/32 (63%)
CR+CRi 8/11 (73%)
Primary endpoint: relapse-free at
6 months
post- treatment 31/53 (58%)
CR+CRi 34/44 (77%)
MRD negative rate
Not reported
20/25 (80%) by MPFC
Not reported
IDH1 MC: 9/22 (41%) of responding patients by NGS
IDH2 MC: 11/37 (30%) of responding patients by NGS
Not reported
19/53 (36%) by NPM1 or fusion gene transcript levels
18/34 (53%) by MPFC after induction
Ref.
(28)
(26, 27)
(29)
(42)
(54)
(81)
(86)
AMG 330 is a bispecific T-cell engager (BiTE) antibody construct that binds CD33 on leukemic blasts and CD3 on T cells.107 Preliminary results from a phase I study (NCT02520427) of AMG330, revealed serious adverse events in 23 out of 35 patients (66%) including cytokine release syndrome in 11 patients. The cytokine release syn- drome was mitigated with step-up dosing, corticosteroid pretreatment, intravenous fluids, tocilizumab, and drug interruption. Two patients had a CR and two had a CRi during dose escalation.108
Cluster of differentiation 123 (CD123)
CD123 is the alpha chain of the interleukin-3 receptor heterodimer and is expressed at higher levels in leukemic stem cells than on normal hematopoietic bone marrow stem cells.109,110 CD123+CD34+CD38- leukemic cells are capable of initiating and maintaining leukemia in NOD/SCID mice.110 IMGN632 is a CD123-targeting anti- body-drug conjugate consisting of a CD123 antibody linked to a DNA alkylating indolino-benzodiazepine dimer (IGN) via a protease cleavable linker.111 In a phase I
trial of IMGN632 (NCT03386513) in patients with relapsed or refractory CD123+ hematologic malignancies, four out of 12 (33%) patients with AML achieved a CR or CRi.112 Elzonris (tagraxofusp or SL-401) is a recombinant fusion protein consisting of human interleukin-3 fused via a Met-His linker to a truncated diptheria toxin that is cur- rently FDA-approved for the treatment of blastic plasma- cytoid dendritic-cell neoplasm.113,114 The interleukin-3 domain binds to the interleukin-3 receptor leading to translocation of the diphtheria A fragment and thus to inactivation of protein synthesis and cell death. A phase I/II study of SL-401 as consolidation therapy for patients in first or second CR is ongoing. (NCT02270463)
C-type lectin-like molecule-1 (CLL1 or CLEC12A)
C-type lectin-like molecule-1 (CLL1 or CLEC12A) is a transmembrane glycoprotein that functions as an inhibito- ry receptor. CLL-1 is expressed on leukemic blasts in the majority of cases and selectively expressed in leukemic CD34+CD38- cells but not normal hematopoietic stem cells. Moreover, CLL1+ CD34+ cells are serially trans-
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