Future directions

Combinations of HMA and IDHmut inhibitors are being evaluated in several clinical trials because this combination increases hemoglobinization and the expression of erythroid differentiation markers, reduces leukemic stem cell populations, and potentiates apoptosis.54,55 The addition of azacitidine had no impact on FT-2102 pharmacokinetics.

At data cutoff (April 7, 2018), 26 patients had beentreated with FT-2102 (150 mg/24 hrs or 150 mg/12 hrs) plus azacitidine (75 mg/m2 for 7 days) for a median of 3 months (range 0.2–12 months), 20 of them with R/R AML56 (Table 1). Preliminary end points reported were CR rate of 0%, CRi + MLFS of 32%, and OR of 32%. AEs with a grade ≥3 occurring in >5% of patients of the entire cohort are summarized in Table 1. IDH-DS developed in 3 patients, all of which remitted after temporary interruption and treatment (glucocorticoids, hydroxyurea, and supportive care). No deaths related to FT-2102 were reported.

Untreated AML patients were also included in a Phase I/II clinical trial, with scarce reported data [NCT02719574] (Table 2): 3 patients were treated with FT-2102 monotherapy53 and 4 patients had it in combination with azacytidine.56 At the first cutoff, these schemes had obtained CR of 0% and 50%, CRi/MLFS of 33% and 25%, and OR of 33% and 75%, respectively. Safety profiles were analyzed together with the subsets of R/R AML and MDS.

FT-2102 monotherapy at 150 mg/12 hrs will be analyzed in an ongoing Phase II study with three cohorts [NCT02719574]: R/R AML, AML/MDS with CR/CRi (ie, with MRD), and R/R MDS/AML with a prior exposure to an IDH1m inhibitor. Moreover, three Phase 2 combination-therapy (FT-2102 150 mg/12 hrs plus azacitidine 75 mg/m2 7 days) cohorts are currently open [NCT02719574]: patients <60 years with R/R AML or MDS naïve to HMA and IDH1m inhibitors; R/R AML or MDS with inadequate response/PD on HMA; and R/R AML or MDS who have progressed on a prior IDH1m inhibitor.

Other IDH1mut inhibitors

IDH305

IDH305 is an oral small-molecule IDH1mut inhibitor active against the IDH1R132 mutation and assayed in a Phase I dose-finding clinical trial [NCT02381886] in AML/MDS (including R/R AML; Table 1), gliomas, and other/noncentral nervous system (CNS) solid tumors. Preliminary results in 21 AML patients were reported at cutoff on March 30, 2016, showing promising antitumoral activity:57 a CR of 9.5%, a CRi of 4.8%, and partial remission (PR) of 19%. Hepatotoxicity was detected in the 3 malignancies (Table 1), although in AML/MDS the incidence was lower. Unfortunately, 3 subsequent clinical trials [NCT02987010, NCT02977689, NCT02826642] were withdrawn before enrolling the first participant, and no new clinical data about this drug have been reported.

Vorasidenib (AG881)

Vorasidenib (AG-881) is an oral inhibitor of IDH1mut and IDH2mut which is being evaluated in a Phase I trial in solid tumors, including gliomas, as it penetrates the blood–brain barrier [NCT02481154], with the first report of the safety profile in 93 of the patients.58 Furthermore, AG-881 is being tested in advanced hematologic malignancies after progression with a prior IDHmut-inhibitor treatment [NCT02492737].

BAY1436032

BAY1436032 is an oral pan-mutant IDH1 inhibitor, active against IDH1R132HIDH1R132CIDH1R132GIDH1R132L, and IDH1R132S, which has demonstrated, in preclinical in vitro and in vivo studies strong antileukemic activity in IDH1mut patient-derived xenograft (PDX) models.59 BAY1436032 is being tested in Phase I trials as a single agent in R/R AML [NCT03127735] and advanced solid tumors [NCT02746081], but the clinical reports have not been presented yet. Also, synergistic activity has been detected in PDX IDH1mut models with a combination of BAY-1436032 and azacitidine through inhibition of the cell cycle by dysregulating EGR, GFI1, and NFkB signaling.60

DS-1001

DS-1001 is a new oral IDH1mut inhibitor being studied in patients with recurring or progressing gliomas [NCT03030066]. Potentially, DS-1001 could be active in R/R AML IDH1mut patients.

Non-targeted therapies tested in IDH1mut AML

Venetoclax

Venetoclax is an oral selective inhibitor of the antiapoptotic B-cell lymphoma-2 (BCL-2) that is being tested in R/R AML. Preclinical studies have obtained activity against IDHmut cells mediated by the intracellular accumulation of the oncometabolite D2HG.61 This finding was reproduced in clinical trials of venetoclax monotherapy in R/R or untreated AML62 and combined with HMA or low-dose cytarabine in R/R myeloid malignancies,63 achieving a CR/CRi of 33% and a 27% response rate in IDHmutpatients, respectively. This study revealed that venetoclax could be an alternative treatment after IDH-inhibitor failure (7 of 11 patients were pretreated with IDHmut inhibitors).63 In elderly untreated AML patients who are unfit for intensive therapies, combinations of HMA and venetoclax obtained in an IDHmut subgroup a CR/CRi rate of 71% and a median OS of 24.4 months.64 Combinations of venetoclax and ivosidenib will be tested in this subset of patients in a Phase I/II trial [NCT03471260].

CB839

CB-839 is an oral glutaminase inhibitor under investigation. Glutaminase is an enzyme which generates glutamine, the main source of α-KG in IDH1mut cells. Preclinical and in vivo studies demonstrated that CB839 reduced the growth of IDH1/2mut AML cells.65–67 In R/R AML IDHmutpatients, CB-839 is being tested in monotherapy and in combinations with azacitidine [NCT02071927].68

PARP inhibitors: olaparib and talazoparib

The D2HG produced by IDH1/2mut enzymes is associated with increased DNA damage and improved responses to poly (ADP-ribose) polymerases (PARP) inhibitors in solid tumor cells. In an in vitro study, AML IDH1/2mut cells were sensitive to monotherapy with PARP inhibitors (olaparib and talazoparib). This activity was potentiated in combination with daunorubicin, a DNA-damaging agent. However, the combination of PARP and IDH1/2mut inhibitors decreased and antagonized their efficacy.69 Monotherapy with olaparib is being studied in glioma, cholangiocarcinoma, and other solid tumors with IDH1mut or IDH2mut [NCT03212274], and BGB-290 (PARP inhibitor) combined with temozolomide in glioma, but these agents have not been tested in R/R AML yet.

IDH1-PEPTIDE VACCINE

The mutation-specific vaccination of IDH1 (R132H) has been tested as a novel target for immunotherapy in glioma, as this neoantigen shows high uniform expression and penetrance in glioma cells. Preclinical studies in mice with IDH1-peptide vaccination obtained an effective mutation-specific antitumour immune response against IDH1R132H-expressing tumor cells and reduced the growth of gliomas.70,71 Three different clinical trials are evaluating the safety and efficacy of IDH1-peptide vaccine in different grades of glioma alone [NCT02454634, NCT02771301] or combined with temozolamide [NCT02193347].

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