SOHO State of the Art Updates and Next Questions: IDH inhibition

Matteo Dragani1, Stéphane de Botton1*

1Hematology Department, Gustave Roussy Cancer Centre, Villejuif, France

*Corresponding author: Dr. Stéphane de Botton Email: [email protected] Telephone: +33 01 42 11 63 17
Hematology Department, Gustave Roussy Cancer Centre, 114 Rue Edouard Vaillant, 94805 Villejuif, France

Abstract:

There have been extraordinary progress in the field of targeted therapy for myeloid malignancies in the last few years, especially due to the approval of various agents that can be used as monotherapy or in combination, as first line treatment or facing a refractory/relapsed disease: many successful trials have been conducted recently and a consistent body of work about the efficacy of novel molecules is nowadays available. In this review, we sought to explain how Enasidenib and Ivosidenib have changed the face of myeloid neoplasms’ treatment through IDH inhibition and to summarize the trials results that have led to the current commercial indications for the two molecules.

Keywords: targeted therapy; enasidenib; ivosidenib; AML; MDS

Introduction

Isocitrate dehydrogenase 1 and 2 (IDH 1/2) mutations are common alteration in myeloid disorders. These mutations were both identified in 2008 and 2009 thanks to genome sequencing projects conducted independently on various cancers, and found in glioblastoma multiforme and acute myeloid leukemia, with the peculiarity of being mutually exclusive and present in hemizygous state [1–3]. In IDH1, the disease-associated mutations are all missense and involve a single arginine residue, R132, in the enzyme active site, and the R132H substitution represents the majority of mutational cases. In IDH2, the mutations which predominate are R172K and at another arginine site R140Q [4]. These mutations confer a gain-of-function in cancer cells, resulting in the accumulation of a vast excess of D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis through enhanced proliferation and impaired differentiation of immature hematopoietic cells [5, 6].
It has been verified in vitro that mutated IDH2-R172 enzyme leads to greater accumulation of D- 2HG than mutated IDH2-R140; however, mutant IDH1 R132, whose localization is cytoplasmatic and not mitochondrial like the two IDH2 isoforms, demonstrated a lesser accumulation of D-2HG than cells expressing IDH2 R172 though being structurally similar, but greater than mutant IDH2 R140 [7].
IDH1/2 mutations occur in about 20% of acute myeloid leukemias (AML), with mIDH1 being present in 6-16% of cases and IDH2 in about 8-19%. For the latter, the R140 isoform represents the 80% of all IDH2 mutations occurring in AML [8]. Clinical features that are associated with IDH mutations are the frequent incidence in older patients, the increased percentage of blasts at diagnosis both in peripheral blood and bone marrow, the prevalence among cytogenetically normal AML and cytogenetically intermediate risk disease [8–10]. The pattern of co-mutations varies between different isoforms: mIDH1 and mIDH2-R140 are mostly associated with mutations in NPM1, DNMT3A and FLT3-ITD, whereas mIDH2-R172 is associated with DNMT3A mutations and is mutually exclusive with other class defining lesions as showed in the genomic characterization of AMLs proposed by Papaemmanuil et al [11, 12]. Prognostic significance of IDH mutations in AML has been controversial across studies: some of these have shown an improved overall survival (OS) and/or complete remission rate in IDH-mutated patients, particularly in association with the NPM1 mutation and especially in absence of mutated DNMT3A [13–17]. On the contrary, other reported the lack of a prognostic impact of the IDH mutation or even a negative prognostic for the IDH2 R172 isoform, and in IDH-mutated patients in association with normal karyotype and NPM1 mutation without FLT3-ITD [12, 18–23].
In myelodysplastic syndromes (MDS), mIDH1/2 occur in 4 to 12% with mIDH2 being more frequent than the others [24]; these mutations are associated to lower absolute neutrophil counts, higher bone marrow blast percentage, a trend for higher platelet cell count and are rather enriched in high risk than in low risk MDS, playing a role in clinical progression to more aggressive malignancies [25].
The role of mutated IDH1 and IDH2 in the acquisition of a more aggressive phenotype has been confirmed also in the case of myeloproliferative neoplasms (MPN). Several studies on large cohorts of patients revealed the presence of mIDH1/2 in about 4% of chronic phase MPNs, with a marked increase of their incidence, up to 21%, in blastic phase [26, 27].
As briefly discussed above, IDH mutations are recurrent in several myeloid malignancies and are involved in leukemogenesis through the production of an oncogenic metabolite; it is intuitive that mutant IDH can be a therapeutic target and in vitro and in vivo preclinical studies have demonstrated that inhibition of IDH 1/2-mutant enzymes decrease intracellular D-2HG levels, reverse epigenetic dysregulation and release the differentiation block.
At this writing, there are two approved selective mIDH inhibitor drugs, Ivosidenib for mutant IDH1 and Enasidenib for mutant IDH2, not only effective in relapsed or refractory (R/R) AML patients but also in newly diagnosed AML who are 75 years or older or who have comorbidities that preclude the use of intensive induction chemotherapy. Various combinations with intensive chemotherapy, hypomethylating agents and other targeted therapies are ongoing.

Monotherapy Enasidenib monotherapy

The phase 1-2 study which led to the accelerated approval for Enasidenib for IDH2 mutated relapsed-refractory AML was conducted on 345 patients with a median age of 69 years (19-100). Of them, 214 patients received the 100 mg daily dose currently approved which was the one chosen for the study expansion on the basis of drug concentration and plasma inhibition of D-2HG.
The overall response rate (ORR), defined as the sum of complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial response (PR) and morphologic leukemia-free state (MLFS) was 38.8% (95% CI: 32.2%-45.7%), with 42 patients achieving CR. Median time to best response was 3.7 months (0.6-14.7).
Median overall survival (OS) was 8.8 months, with an estimated OS of 22.9 months in 42 R/R AML patients who achieved CR, 10.6 months for patients who achieved a non-CR response, and 5.6 months for non-responders. No significant difference in ORR or OS was found between patients with R140 and R172 mutated IDH2. 19 patients discontinued Enasidenib treatment to proceed to allogenic bone transplant.
Interestingly, the study showed that mutated IDH2 VAF reductions were greatest in patients who achieved CR compared with non-responders, with the decrease being more consistent in IDH2- R140 carriers. Twelve patients (11.9%), all R140 mutated, achieved also IDH2 molecular remission which was associated with a survival advantage if compared with those who did not, but between patients who achieved morphologic remission there was no significant difference in survival based on IDH2 residual positivity. D-2HG decrease was particularly observed in R140 mutants, and its reduction correlated with the possibility of achieving CR. Other factors mostly associated with resistance to Enasidenib were baseline co-mutations, especially FLT3 -ITD/TKD and NRAS, paving the way to the realization of combination therapies with other available inhibitors [28, 29].
In the pivotal phase study aforementioned, 39 patients with newly diagnosed AML unfit to receive standard induction therapy were enrolled and received Enasidenib as first line treatment. Median age was 77 years (58-87). Globally, the ORR as previously defined was 30.8%, not significantly different between R140 and R172 mutated patients, with median time to best response of 3.7 months. Seven patients (18%) achieved CR. In this context, the likelihood of response was positively influenced by the presence of a concomitant DNMT3A mutation whereas no detrimental impact was associated with RAS signaling pathway mutation [30].
In the context of myelodysplasia, 17 patients with MDS were treated in the phase 1 protocol after receiving other lines of therapy such as hypomethylating agents and/or allotransplant. The median age of the cohort was 67 years (60.5 – 73), with an ORR of 53% and a median duration of response of 9.2 months, which has led to a median OS of 16.9 months, underlying the interest of testing MDS for IDH mutations [31].
Recently, the experience of three hematological centers in the United States was reported about Enasidenib use as maintenance therapy following hematopoietic stem cell transplant for IDH2- mutated myeloid malignancies: 16 patients with AML or MDS and various types of transplant (in terms of donor and intensity of conditioning therapy) were treated with 50 mg or 100 mg of Enasidenib starting between day 30 and 90 after transplantation. In terms of toxicity profile, 6 patients required dose interruptions for a median of 19 days, 4 patients had a dose reduction from 100 mg to 50 mg and 1 patient interrupted the treatment due to hyperbilirubinemia. After a median follow up of 11.7 months, 2 patients (13%) experienced relapse while on therapy [32].
In mIDH2 R/R AML treated with Enasidenib, primary resistance was due to the concomitant presence of receptor tyrosine kinase (RTK) mutations with lesser CR obtained. It has been showed that secondary resistance after an initial clinical response to the drug may be the result of clonal evolution or selection with acquisition of mutations typically AML-related; it may involve mutations of cytokine receptors’ genes like CSF3R, CBL and FLT3, mutations of hematopoietic transcription factors like RUNX1, BCORL1, GATA2, BCL11A (all of them not detected before Enasidenib therapy), deletion of the entire or part of chromosome 7 (selected at relapse or already present pre-therapy), detection of genes variants not well studied in AML (i.e. NFKB1 M216I, DHX15 R222G, DEAF1 N372K, DDX41 G699A, MTUS1 Q781H). Moreover, relapse can be associated to the occurrence of second-site IDH2 mutations interfering with Enasidenib inhibition, or with the emergence of IDH1 mutations, both mechanisms leading to a rise of D-2HG levels [29, 33–35].

Ivosidenib monotherapy

In the phase 1 study, 125 patients with a median age of 68 years with a R/R AML received Ivosidenib 500 mg daily, the dose selected for the expansion phase. ORR, CR and CR+ CRi (complete remission with incomplete hematological recovery) were respectively 41.6%, 21.6% and 30.4%. Median time to CR was 2.8 months; the median OS after a median follow up of 14.8 months was 8.8 months. The achievement of CR+CRi was significantly associated with a lower co-mutational burden although no particular mutation (not even of the RAS signaling pathway) was linked to clinical response or resistance to Ivosidenib. Clearance of IDH1 mutational burden, although not observed in all patients who obtained CR or CRi suggests a longer duration of remission and longer OS. D- 2HG level was normalized in almost all cases, consequently being unreliable as a surrogate marker of efficacy [36]. An update about 17 patients included into this protocol and who underwent allogenic stem cell transplant was recently published: median age was 62 years old (36-68) and just before transplantation 10 patients were in CR, 4 patients obtained a CRi and 3 patients were in morphologic leukemic-free state (MLFS). Median OS post transplantation was 7.7 months, with a survival rate of 76.5% at 6 months and 47.1% at 1 year after the procedure. Median relapse-free survival (RFS) post transplantation was 7.3 months with a relapse-free survival rate of 58.8% and 47.1% at 6 and 12 months respectively. Interestingly, for all those patients who achieved CR as overall best response (n = 11) pre-transplantation, median OS was not estimable. Moreover, only one patient out of 17 achieved an IDH1 clearance in digital PCR before the procedure, showing that the persistence of an IDH-related minimal residual disease is not an imperative prerequisite in order to benefit from the allogenic transplantation [37].
Frontline treatment with Ivosidenib monotherapy has been also assessed in 34 elderly newly diagnosed AML patients’ ineligible for standard induction chemotherapy. Median age in this cohort was 76.5 years, most of them diagnosed with secondary AML (77%) vs 24% of de novo AML. ORR, CR and CR+CRi were 54.5%, 30.3% and 42.4% respectively. With a median follow up of 23.5 months, median OS was 12.6 months with an estimated 1-year OS rate of 51.1%. Again, no single gene mutation was significantly associated with CR and CRi [38].
Molecular mechanisms behind Ivosidenib resistance have been thoroughly examined on 174 R/R AML patients enrolled in the phase 1 study, showing that mutations involving tyrosine kinase receptors, such as NRAS or PTPN11, may influence the initial response and be associated with relapse and that there is a statistically significant difference between responders and non-responders in terms of number of co-occurring mutations (1.8 for CR+CRh vs 2.6 for all others, p=0.017). Furthermore, secondary resistance to Ivosidenib can be associated to the emergence of D-2HG restoring-mutations, like a mutated IDH2 not detectable at baseline or the occurrence of a second- site IDH1 mutation [39].
Recently, the efficacy of Ivosidenib monotherapy in R/R AML or as first line therapy in unfit older patients (the current EMA approval for the drug) has been underlined through a matched comparison to an historical cohort, composed by patients of different registries (AML Study Group, Germany, France, UK and Spain) having the same characteristics of those for whom Ivosidenib is currently commercialized: 109 patients received Ivosidenib and 60 patients were treated with other regimens (subjects underwent intensive chemotherapy as the most recent therapy were excluded), resulting in higher rates of CR and median OS for those treated with the IDH1 inhibitor (CR 18.3% vs 7%; 8.1 vs 2.9 months) [40].
As was done for Enasidenib, a phase 1 study assessing Ivosidenib role as post-transplant maintenance therapy is currently recruiting in the US, searching for the maximum tolerated dose, the Ivosidenib-related adverse events and rates of graft versus host disease (clinical trial NCT03564821).

Clinical efficacy in combination Enasidenib plus intensive treatment

In an open label multicenter phase 1 study, eligible patients with newly diagnosed mutated-IDH2 AML were treated with intensive induction therapy consisting in the classical 3+7 regimen (cytarabine 200 mg/m2/day for seven days plus either daunorubicine 60 mg/m2/daily for three days or idarubicine 12mg/m2/daily for three days) in combination with Enasidenib 100 mg once daily.
Ninety-three patients with a median age of 63 years old were treated with this regimen; 62% of patients had de novo AML. Complete remission and composite remission (CR + CRi + CRp – complete remission with incomplete platelets recovery) rates were 47% and 63% respectively at the end of induction, and 55% and 74% at any time on study, with better outcomes for those with de novo AML than secondary AML (s-AML) and a lower probability to achieve a remission in presence of comutations like ASXL1, NRAS, U2AF1 and TP53. Median OS was 25.6 months with a 1-year OS probability of 76% after a median follow up of 14.5 months.
Notably, the use of Enasidenib in combination with standard induction chemotherapy did not preclude the recovery of neutrophils and platelets within the expected timeframe [41].

Ivosidenib plus intensive treatment

In the phase 1 study, eligible patients with newly diagnosed mutant IDH1 received induction therapy based on 7-days cytarabine plus an anthracycline (either daunorubicine or idarubicine) in combination with Ivosidenib 500 mg daily. Sixty patients were enrolled and treated, with a median age of 62.5 years; 70% of the cohort was classified as having de novo AML. Rates of CR and CR + CRi + CRp were respectively 55% and 72% at the end of induction and 68% and 77% at any time. As already showed with Enasidenib, de novo AML fared better than s-AML in terms of response. Median OS was not reached for the IDH1 cohort after a median FU of 9.3 months. One-year survival probability was 78%. No co-mutations were found to have an impact on the probability to achieve a response. As happened with the IDH2 inhibitor, the addiction of Ivosidenib did not have an impact on hematological recovery after chemotherapy [41].
A phase 3, multicenter, double-blind, randomized, placebo-controlled study named HOVON150 of Ivosidenib or Enasidenib in combination with induction therapy and consolidation therapy followed by maintenance therapy in patients with newly diagnosed AML or myelodysplastic syndrome with excess blasts-2, with an IDH1 or IDH2 mutation, respectively, eligible for intensive chemotherapy is currently ongoing and recruiting patients.

Enasidenib plus hypomethylating agent

Patients with mIDH2 newly diagnosed AML not eligible for intensive chemotherapy were recently enrolled in a phase 1b study which tested the combination of Enasidenib 100 mg or 200 mg daily with sub-cutaneous azacitidine. The interest of adding a targeted therapy to azacitidine alone derives from the results obtained from some retrospective cohorts of mutated IDH patients treated with hypomethylating agents (93 patients in the French study, 11 patients in the American study), which showed the lack of a substantial impact of these drugs in terms of response and survival, regardless of the IDH isoform [42, 43].
The combination was judged safe and has led to a randomized phase II study which compared the combination of Enasidenib plus azacitidine versus azacitidine monotherapy whose interim results were presented at the European Hematology Congress in 2020. Sixty-eight patients received Enasidenib plus azacitidine and 33 azacitidine only; median age was 75 years old for the entire cohort. Though median OS was 22 months in both arms and EFS was not significantly different (17.2 months vs 10.8 months respectively, p=0.13), ORR and CR rates favored the combination of Enasidenib plus azacitidine rather that azacitidine monotherapy (71% vs 42% for the ORR, p < 0.01; 53% vs 12% for the CR, p < 0.001). Interestingly, in this context no baseline co-mutation was associated with primary resistance [44].

Ivosidenib plus hypomethylating agent

An open label phase 1b dose finding and dose expansion study has recently reported the efficacy and safety of Ivosidenib in combination with azacitidine for mIDH1 AML ineligible for intensive treatment. Twenty-three patients have been enrolled in the study with a median age of 76 years old and were treated with Ivosidenib 500 mg daily plus subcutaneous azacitidine in 28-days cycles. The ORR and CR rates were 78.3% and 60.9%. After a median follow up of 16 months, the median OS was not reached with an estimated 1-year overall survival of 82%. Notably, three out of five patients with comutations which predicted resistance to single agent Ivosidenib like NRAS, KRAS and PTPN11, achieved remission with the combination of IDH1 inhibitor and azacitidine [45]. These promising results led to the current enrolling AGILE phase III trial, a randomized study of azacitidine with or without Ivosidenib in patient with newly diagnosed mIDH1 AML not eligible for intensive chemotherapy, which will give an accurate confirmation of the clinical benefit in this difficult to treat population [46]. Recently, the results of the phase 1b/II study of Ivosidenib in combination with the Bcl-2 inhibitor Venetoclax +/- azacitidine have been presented at ASCO; the study design is based on three cohorts: the first cohort tested Ivosidenib 500 mg with Venetoclax 400 mg, the second Ivosidenib 500 mg with Venetoclax 800 mg and the third a triplet of Ivosidenib 500 mg, Venetoclax 400 mg and azacitidine. Seventeen AML patients and two high risk MDS were included; the composite complete remission rates (i.e. including incomplete or partial hematologic recovery) were 78% overall (100% for the 5 treatment naïve patients, 75% among the ones with a R/R disease) and 67%, 100% and 67% by cohort: despite the short follow up of 3.5 months, these combinations appear to be very promising in terms of tolerance and survival, which was not reached in treatment naïve patients and was 9.7 months in R/R patients [47]. A summary of protocols’ main results is shown in Table 1.

Study N Age OS (median) ORR/CR/CR+CRi Median FU
Roboz GJ [38]
Ivosidenib 1st line unfit 34 76.5 yrs
(64-87) 12.6 months 54.5%/30.3%/42.4% 23.5 months
Pollyea DA [30]
Enasidenib 1st line unfit 39 77 yrs
(58-87) 11.3 months 30.8%/18%/21% 8.4 months
DiNardo CD [36]
Ivosidenib AML R/R 258 68 yrs
(18-89) 8.8 months 41.6%/21.6%/30.4% 14.8 months
Stein EM [28]
Enasidenib AML R/R 176 67 yrs
(19-100) 9.3 months 40.3%/19.3%/26.1% 7.7 months
DiNardo CD [45] AZA+Ivo 1st line unfit 23 76 yrs
(61-88yrs) NR
(82% at 12 mo) 78.3%/60.9%/69.6% 16 months
DiNardo CD [44]
AZA + Ena vs AZA only 68 75 yrs
(57-85) 22 months Aza+Ena 71%/53%/63% NA
33 Aza only 42%/12%/24%
Stein EM [41]
3+7+Enasidenib 93 63 yrs
(27-77) 25.6 months 86.8%/55%/74% * 14.5 months
Stein EM [41] 3+7+Ivosidenib 60 62.5 yrs (24-76) NR
(78% at 12 mo) 86.7%/68%/77% * 9.3 months
Lachowiez CA [47] Ivo + Venetoclax 
AZA 19 68 yrs NR (1st line pts) 9.7mo (R/R pts) 89%/39%/78% 3.5 months

Table 1. Results of principal studies about IDH inhibitors; ORR = overall response rate; CR = complete remission; CRi = complete remission with incomplete hematologic recovery; FU = follow up; yrs = years; mo = months; pts = patients; NR = not reached; NA= not available. *results at any time after treatment

Tolerability of IDH inhibitors

Due to their mechanism of action, Ivosidenib and Enasidenib are particularly associated with differentiation syndrome (DS). This clinical entity was first described in patients receiving ATRA (all-trans retinoic acid) for acute promyelocytic leukemia (APL) who showed symptoms like fever, dyspnea, hyperleukocytosis, weight gain, acute renal failure, hypotension, pulmonary infiltrates and pleuro-pericardial effusions: patients who have at least two or three signs are classified as having moderate DS and those with at least four signs as having severe DS [48, 49]. In the context of IDH mutated patients receiving an IDH inhibitor the prevalence of this syndrome is still a matter of debate: in the trials about R/R AML who led to the approval of Ivosidenib and Enasidenib, the incidence of DS ranged from 11% to 14%, whereas in a systematic review conducted by FDA it was 19% for both drugs [28, 36, 50, 51]. Under recognition of the syndrome may happen as leukocytosis is not always present and a differential diagnosis with a systemic infection, a common adverse event in the context of AML, can be hard to establish. Pulmonary symptoms like dyspnea of pulmonary infiltrates or pleuro-pericardial effusions predominate the clinical picture of DS for IDH inhibitors: these features are similar to those seen in APL, but their onset is more likely to happen 20 days (range 1-78) after treatment with Ivosidenib and 19 days (range 1-86) for Enasidenib, and not in the first days like in APL. The management of DS relies on corticosteroid administration, hydroxyurea to control hyperleukocytosis if present, diuretics and drug discontinuation if needed [52].
Some factors associated with a potential increased risk of DS have been identified: baseline bone marrow blast percentage  48% and peripheral blood blasts  25% and 15% for Ivosidenib and Enasidenib respectively, co-mutations in TET2 for Ivosidenib-treated patients and co-mutations in SRSF2 for Enasidenib-treated patients [51]. Interestingly, Norsworthy et al. showed in their retrospective analysis that the occurrence of DS is associated with an inferior outcome in terms of survival and response rate, whereas in the phase 1/ 2 trial of Enasidenib in R/R AML patients who experienced a DS fared slightly better than the others in terms of overall response rate [50, 51]. For now, given the uncertainties on diagnosis, incidence and the fact that a worse response rate may be due to a reduced dose intensity of Ivosidenib/Enasidenib in case of DS, it is impossible to establish a connection between the syndrome and remission/survival based on the available data. As expected, the frequency of differentiation syndrome is reported being sensibly less frequent when Ivosidenib and Enasidenib are associated to intensive chemotherapy: in the phase 1 study about Ivosidenib or Enasidenib combined to 3+7 regimen in patients with newly diagnosed AML only 2 patients in the Ivosidenib cohort (3.3%) and 2 patients in the Enasidenib cohort (2.2%) were reported experiencing symptoms of DS [41]. Differentiation syndrome can also manifest itself in an atypical way, as reported by some off-protocol experiences, in the form of thyroiditis or skin rash along with or without the other classical signs and symptoms of DS, and which respond to the aforementioned therapeutic measures [52–54].
There were few other side effects collected in the studies worth mentioning; with Ivosidenib, prolongation of QT interval (requiring careful monitoring especially in concomitance with other drugs known to prolong the QT like azoles), febrile neutropenia, thrombocytopenia, anemia and fatigue were the most reported. As for Enasidenib, indirect hyperbilirubinemia consistent with inhibition of UGT1A1 enzyme in the liver, generally non clinically significant and which resolves with continuous treatment was the most reported along with nausea, fatigue, decreased appetite, thrombocytopenia. Notably, the use of IDH inhibitors with intensive therapy did not impair neutrophil and platelet count recovery, overcoming the initial concerns regarding an increased and prolonged hematological toxicity in the context of combination therapy [41].

Conclusion

The availability of IDH inhibitors, along with the development of other targeted drugs, such as FLT3 inhibitors, CPX-351, Venetoclax and others, represent a revolution in the context of AML where the therapeutic options have been very limited for a long time, especially for older unfit patients not eligible to intensive chemotherapy and/or transplantation. Ivosidenib and Enasidenib, given the not negligible frequency of mutated IDH1 and IDH2 in myeloid malignancies, are currently being investigated in different combinations that will potentially overcome the limits of monotherapy in terms of primary resistance and relapse. Several studies are ongoing, including some based on combination with other drugs like Venetoclax and Vyxeos, and their results are eagerly awaited.

Conflicts of Interest:
The authors declare no potential conflict of interest.

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