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Promising targets for MRD therapies in AML
induction and consolidation chemotherapy followed by maintenance therapy in newly diagnosed AML or myelodysplastic syndrome (MDS) with excess blasts-2 with an IDH1 or IDH2 mutation (NCT03839771) will soon begin enrollment.
The observation that cancer stem cells are resistant to therapies targeting BCR-ABL in chronic myeloid leukemia and JAK2 V617F in myeloproliferative neoplasms raises concern regarding the ability of targeted therapies to erad- icate leukemic stem cells.21,22 If indeed FLT3 and IDH1/2 inhibitors are unable to eradicate leukemic stem cells, then targeted therapy may reduce or maintain low levels of bulk disease but will likely not be curative unless com- bined with allogeneic SCT or other therapies targeting leukemic stem cell. A leukemic stem cell population that is refractory to targeted therapy may also contribute to clon- al evolution and the acquisition of secondary resistance mutations. Clinical studies evaluating FLT3 and IDH inhibitors as maintenance therapy after induction and consolidation and allogeneic SCT are also essential to determine the optimal duration of treatment. In the phase II AMLSG 16-10 trial, treatment with midostaurin in com- bination with induction and consolidation chemotherapy followed by maintenance midostaurin for 1 year after allo- geneic SCT was associated with improved 1-year event- free survival when compared to that of historical controls with FLT3-ITD-mutated AML [HR 0.58; 95% confidence interval (95% CI): 0.48-0.7; P<0.001].43
Targets of apoptosis evasion
B-cell lymphoma 2 (BCL2)
Evasion of apoptosis is a hallmark of malignant tumor progression, allowing for tumor survival and resistance to cancer treatments.37 The anti-apoptotic protein B-cell lym- phoma 2 (BCL2) is overexpressed in AML and associated with resistance to chemotherapy and poor outcomes.44 The prosurvival BCL2 family of proteins such as BCL2 and MCL1 sequester the apoptosis initiator protein BIM to prevent initiation of apoptosis.45 Aberrant BCL2 expres- sion is also essential for maintaining oxidative phosphory- lation in quiescent leukemic stem cells. BCL2 inhibition reduces oxidative phosphorylation and preferentially induces cell death in leukemic stem cells.46,47
Venetoclax is an oral, BH3 mimetic that selectively binds BCL2, displacing pro-apoptotic proteins leading to apoptosis.48 Monotherapy with venetoclax demonstrated clinical activity in early phase studies but was associated with modest response rates and a short duration of response.49 Combinations of venetoclax with both low- dose cytarabine and hypomethylating agents in previous- ly untreated, newly diagnosed elderly patients not eligible for chemotherapy resulted in high response rates and durable remissions leading, to Food and Drug Administration (FDA) approval of these regimens.50,51 Venetoclax and hypomethylating agents led to a CR or CRi with MRD-negative disease by multiparameter flow cytometry in 45% of patients.52 Similarly, treatment with venetoclax and low-dose cytarabine led to MRD-negative disease in 32% of patients in CR or CRi.53 This spurred the development of trials evaluating venetoclax in combina- tion with 7+3 (NCT03709758), CPX-351 (NCT03629171), or FLAG-IDA (NCT03214562) based induction regimens in newly diagnosed patients eligible for chemotherapy. In
a phase I study of venetoclax in combination with FLAG- IDA in relapsed or refractory AML, treatment was well tolerated and eight of 11 patients achieved a CR or CRi.54 The high MRD-negative rates associated with venetoclax combinations are encouraging; however, additional phase III studies are needed to determine if there is a survival benefit, in particular among patients who undergo allo- geneic SCT.
Tumor protein 53 (TP53)
p53 is a transcription factor that is activated by cellular
stress and promotes cell cycle arrest, senescence and apop- tosis.55 Loss of p53 induces oncogenic self-renewal in mouse hematopoietic progenitor cells.56 In AML, inactivat- ing mutations in the TP53 gene occur in 7-18% of patients with newly diagnosed AML and are enriched in patients with other poor prognostic features including complex karyotype and therapy-related disease.57,58 The co-occur- rence of TP53 mutations and a complex karyotype is asso- ciated with an especially dismal prognosis and a high rate of relapse after allogeneic SCT.59 In AML, p53 inactivation more commonly results from overexpression of negative regulators.60,61 MDMX and MDM2 inhibit p53 transactiva- tion and induce its ubiquitination with subsequent degra- dation.62 Idasanutlin is an oral selective MDM2 inhibitor capable of activating apoptosis in a p53-dependent man- ner.63 Current trials evaluating the combination of this MDM2 inhibitor with chemotherapy include a phase I/II study (NCT03850535) of idasanutlin in combination with standard induction chemotherapy in newly diagnosed AML and a phase III study (NCT02545283) of idasanutlin with or without cytarabine in relapsed or refractory AML.
Despite many patients achieving deep and durable remissions with apoptosis inhibitors, primary and second- ary resistance is known to occur. In particular, RAS path- way mutations and TP53 mutations are associated with decreased responses to venetoclax.47,51,64,65 MCL-1 also serves as a redundant pro-survival pathway that mediates resistance to venetoclax.48,49 In cell lines resistant to BCL2 inhibition, idasanutlin led to induction of apoptosis through p53 activation and MCL1 degradation.52 MCL1 mimetics currently in active trials as monotherapy and in combination with venetoclax include S64315 (Servier) (NCT02979366, NCT03672695), AMG 176 (Amgen) (NCT02675452, NCT03797261), and AMG 397 (Amgen) (NCT03465540). Additionally, TP53-mutant AML are resistant to MDM2 inhibitors and prolonged exposure to idasanutlin in cancer cell lines has been associated with the development of TP53 mutations. APR-246 is a prodrug that is converted to the Michael acceptor methylene quin- uclidinone, which covalently binds mutated p53 cysteine residues 124 and 277, leading to refolding and restoration of p53 function.66,67 In a phase Ib study of APR-246 in com- bination with azacitidine in patients with TP53-mutant MDS and AML, all 11 evaluable patients responded with nine patients achieving CR (82%) and eight having clear- ance of p53 mutations (73%).68
Methylation
The hypomethylating agents 2’deoxy-5-azacitidine (decitabine) and 5-azacitidine (azacitidine) are approved for the treatment of MDS and newly diagnosed AML patients unfit for chemotherapy.69-71 Azacitidine and
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