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2023-03-07T14:05:28.000Z

ASH 2022 roundup: IDH inhibitors

Mar 7, 2023
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Learning objective: After reading this article, learners will be able to cite a new development in the treatment of IDH-mutated AML.

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Approximately 20% of patients with acute myeloid leukemia (AML) are found to have somatic mutations in genes encoding the isocitrate dehydrogenase (IDH) enzyme, with ~5–10% of patients having an IDH1 mutation and ~15% of patients having an IDH2 mutation.1,2 Previous reports have suggested that patients with IDH-mutated AML have a higher 1-year relapse rate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) compared with patients without IDH mutations.1 Here, we discuss four presentations from the 64th American Society of Hematology (ASH) Annual Meeting and Exposition; the speakers discussed relapse rates in patients with IDH mutations and the use of enasidenib and ivosidenib treatment in this patient population.

Prognostic value of MRD in IDH mutated-AML3

Among patients in complete remission (CR), measurable residual disease (MRD) prior to allo-HSCT has been shown to increase posttransplant relapse risk. In a study presented by Ravindra,3 which included 56 patients with IDH-mutated AML who received an allo-HSCT at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, US, between 2015 and 2020, pre- and posttransplant bone marrow samples were sequenced using droplet digital polymerase chain reaction or next generation sequencing (NGS); of these patients, 28, 26, and 2 patients had IDH1, IDH2, or both mutations.

Key findings

Pretransplant droplet digital polymerase chain reaction/NGS analysis (n = 50) showed 56% of patients with an IDH mutation were also MRD-positive. Posttransplant (n = 48), 10% of patients were MRD positive; two of these patients subsequently experienced disease progression and died, whereas three remained in remission. The original IDH mutation was present at relapse (n = 10) in 90% of patients, with additional mutations also found in several samples. Overall survival (OS) was similar between patients with persistent mutations in IDH1 or IDH2 and those without. In addition, CR rates were comparable between patients with MRD-positivity and MRD-negativity, irrespective of IDH-mutation status.

In this study, the presence of pre- or posttransplant MRD in patients with IDH mutations was not found to be prognostic of relapse.

Enasidenib

Posttransplant enasidenib maintenance1

Salhotra discussed a multicenter, pilot phase II trial (NCT03728335) in 15 adult patients with IDH2-mutated AML who received enasidenib as post-HSCT maintenance therapy. The primary objective was safety and tolerability, with secondary objectives including OS, leukemia-free survival, non-relapse mortality, and 1-year chronic graft-versus-host disease-free and relapse-free survival. Baseline patient characteristics are shown in Table 1.

Table 1. Baseline patient characteristics*

Characteristic, % (unless otherwise stated)

N = 15

Median age (range), years

58 (27–77)

Gender ratio, male:female

6:9

Median time to start enasidenib post-HSCT (range), days

104 (54–131)

Disease status at transplant

 

               First CR

66

               Second CR

26

               MRD positivity

7

Cytogenetics

 

               Favorable

13.3

               Intermediate

60

               Adverse

26

Conditioning treatment

 

               NMA/RIC

53

               MAC

47

CR, complete remission; HSCT, hematopoietic stem cell transplant; MAC, myeloablative conditioning; MRD, measurable residual disease; NMA, non-myeloablative; RIC, reduced-intensity conditioning.
*Adapted from Salhotra.1

The most common Grade 1–3 adverse events in Cycle 1 and 2 of maintenance therapy were anemia, nausea, hyperbilirubinemia, and lymphopenia.1 The incidence of adverse events was similar from Cycle 3 onwards, with the most common Grade 1–3 adverse events being anemia, diarrhea, hyperbilirubinemia, and neutropenia. At data cut-off (June 2022), 33% of patients had completed treatment; the median number of completed cycles was 20 cycles (range, 1–24 cycles). In this trial, enasidenib was well tolerated and effectively prevented relapse in patients with IDH2 mutations. The Kaplan-Meier estimate for leukemia-free survival was 1.0 at both 12 and 24 months, with an estimate of 0.8 for chronic graft-versus-host disease-free relapse-free survival at 12 and 24 months.

Achievement of complete remission with enasidenib4

The updated results and 3-year follow-up of the Beat AML Master Study phase II/Ib sub-study (NCT03013998) were presented by Cai.4 The design of the sub-study, which included patients ≥60 years of age with R140/R172 mutations in IDH2, is shown in Figure 1.

Figure 1. Beat AML Master Study phase II/Ib sub-study design* 

AZA, azacitidine; CR, complete remission; CRi, CR with incomplete hematologic recovery; ENA, enasidenib; IDH2, isocitrate dehydrogenase 2.
*Adapted from Cai.4 

The primary endpoint of the sub-study was CR or CR with incomplete hematologic recovery in patients treated with enasidenib. The baseline patient characteristics are shown in Table 2.

Table 2. Baseline characteristics of patients in the Beat AML Master Study phase II/Ib sub-study*

Characteristic, % (unless
otherwise stated)

Phase II (enasidenib
monotherapy
(n = 60)

Phase Ib (enasidenib + azacitidine)
(n = 17)

Median age (range), years

75 (60–89)

75 (60–86)

Gender

 

 

               Male

48

59

               Female

52

41

ECOG Performance Status

 

 

               0

27

41

               1

53

35

               2

20

24

ELN risk

 

 

               Adverse

53

47

               Intermediate

28

29

               Favorable

18

24

Mutated IDH2

 

 

               Median (range), n

40.5 (6–58)

36 (14–51)

               R140

73

47

               R172

27

53

ECOG, Eastern Cooperative Oncology Group; ELN, European Leukemia Net; IDH2, isocitrate dehydrogenase 2.
*Adapted from Cai.4

Median duration of response was 11.1 months and 14.6 months for phase II and phase Ib, respectively, with a median OS of 17.1 months and 12.5 months, respectively.4 Nine patients harbored TP53 mutations (usually patients with TP53 mutations are assigned to other Beat AML sub-studies) and TP53 mutations did not appear to impact CR or CR with incomplete hematologic recovery response. Response rates and the incidence of disease progression in both study phases are shown in Figure 2.

Figure 2. Response and progression rates* 

CR, complete remission; CRi, CR with incomplete hematologic recovery.
*Adapted from Cai.4

The most common adverse events were,

  • in phase II: nausea (58.3%), anemia (56.7%), hypokalemia (56.7%), diarrhea (43.3%), musculoskeletal pain (43.3%), and decreased appetite (40%); and
  • in phase Ib: anemia (41.2%), nausea (35.3%), vomiting (35.3%), hypoalbuminemia (35.3%), hyponatremia (35.3%), and hypophosphatemia (35.3%).

Differentiation syndrome was also common in both the phase II (23.3%) and Ib (17.6%), with tumor lysis syndrome occurring in 3.3% of patients in phase II and no patients in phase Ib.

This study demonstrated that enasidenib can be used safely and effectively in patients with IDH2-mutated AML. However, addition of azacitidine may reduce toxicities whilst retaining the efficacy of enasidenib monotherapy.

Mutational clearance with ivosidenib2

Ivosidenib, a selective IDH1 enzyme inhibitor, was approved in 2022 by the U.S. Food and Drug Administration (FDA) for the treatment of patients with relapsed/refractory IDH1-mutated AML in combination with azacitidine. Dohner presented an update from the AGILE study (NCT03173248), which compared outcomes of ivosidenib plus azacitidine versus placebo plus azacitidine in patients with newly diagnosed IDH1-mutated AML and discussed the clearance of co-mutations and the emergence of mutations leading to relapse.

Of the 146 patients with newly diagnosed AML (ivosidenib plus azacitidine, n = 76; placebo plus azacitidine, n = 74), 46 who received ivosidenib plus azacitidine had molecular data available; of these, eight had NGS data and seven had single-cell DNA sequencing data available at the time of relapse.

Key findings

An association was found between achievement of CR and clearance of baseline mutations, with 73% of patients who achieved CR after treatment with ivosidenib plus azacitidine (n = 30) also clearing all baseline mutations at ≥1 on-study timepoint. In total, 30 of 33 patients who achieved CR/CRi and harbored an IDH1 mutation demonstrated mutational clearance, this was not found to be associated with baseline variant allele frequency.

Mutations emerging whilst on treatment were identified in 22 of 46 patients, including seven patients who had achieved CR and cleared all baseline mutations. However, no second-site IDH1 mutations were noted, although an emerging IDH2 mutation was found in two patients. Relapse occurred in six of eight patients, with mutations found in the following genes:

  • Patient 1: PHF6, RUNX1, TET2
  • Patient 2: EZH2, JAK2, ZRSR2
  • Patient 3: ASXL1, FLT3-ITD, KRAS
  • Patient 4: ASXL1, TET2
  • Patient 5: TP53
  • Patient 6: CREBBP, FLT3-TKD, RUNX1

This study demonstrated that use of ivosidenib and azacitidine led to durable responses and clearance of baseline IDH1 mutations. Mutated IDH1 was not detected at relapse in six of eight patients who experienced disease progression.

Conclusion

In the study presented by Ravindra,3 NGS revealed similar OS between patients with persistent IDH1 or IDH2 mutations and those without and the presence of pre- or posttransplant MRD in patients with IDH mutations was not found to be prognostic of relapse. However, this study was limited by the small cohort size.3

In both studies, enasidenib was found to be well tolerated; the most common adverse events were anemia and gastrointestinal events.1,4 The Beat AML study also demonstrated similar efficacy with enasidenib in combination with azacitidine compared with enasidenib monotherapy, and there were also fewer toxicities.4 Treatment with ivosidenib in combination with azacitidine achieved higher CR rates and cleared baseline IDH mutations.2 Future studies of enasidenib and ivosidenib with larger cohort sizes are warranted to provide further data on the efficacy of these treatments in patients with IDH-mutated AML.

  1. Salhotra A. Multicenter pilot clinical trial of enasidenib as maintenance therapy after allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia (AML) carrying IDH2 mutations. Oral abstract #779. 64th American Society of Hematology Annual Meeting and Exposition, Dec 12, 2022, New Orleans, US.
  2. Döhner H. Molecular characterization of clinical response and relapse in patients with IDH1m ND-AML treated with Ivo + AZA in the AGILE study. Oral abstract #223. 64th American Society of Hematology Annual Meeting and Exposition, Dec 10, 2022, New Orleans, US.
  3. Ravindra N, Dillon LW, Gui G, et al. Pre- and post-transplant measurable residual IDH mutations are not associated with relapse in patients with IDH-mutated AML. Abstract #1470. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, Dec 10, 2022, New Orleans, US.
  4. Cai SF. A risk-adapted study to assess the efficacy of enasidenib and subsequent response-driven addition of azacitidine for newly diagnosed IDH2-mutant AML patients: 3-year follow-up. Oral abstract #834. 64th American Society of Hematology Annual Meeting and Exposition, Dec 12, 2022, New Orleans, US.

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