What the Future Holds in Targeting Cancer Metabolism

IDH Mutations as a Target in AMLIsocitrate dehydrogenase (IDH) mutations perturb the normal metabolic pathway in the cell; the normal function of IDH is to convert isocitrate to α-ketoglutarate to produce energy for the cellMutations in IDH, whether IDH1 or IDH2, result in a neomorphic enzyme; the mutated enzyme causes α-ketoglutarate to be transformed into beta-hydroxyglutarateBeta-hydroxyglutarate accumulates in cells, and that accumulation causes a block in myeloid differentiation; this is the clinical phenotype of acute myeloid leukemia (AML)IDH inhibitors inhibit cell proliferation and cause cells to differentiate, reverting cellular pathways to normal

Targeting Specific Tumor Types[3]Older patients have a greater likelihood of developing a mutation in IDH1 or IDH2; these mutations are rarely seen in pediatric populationsIn general, IDH mutations are enriched in patients who are in the intermediate risk group of patients with AML who have a normal karyotypePatients with mutations in R140Q have more co-occurring mutations than patients with R172 mutations

IDH Mutation as a Prognostic Indicator[4]It is controversial whether IDH1 or IDH2 in isolation confer a good prognosisPatients with mutations in IDH2 and nucleophosmin 1 (NPM1), without mutations in receptor-type tyrosine protein kinase 3 (FLT3), a FLT3/internal tandem duplication (ITD), appeared to have an excellent prognosis with induction and standard consolidation chemotherapy

Should Patients With AML Be Tested for IDH Mutations?[4]Dr Stein: I think patients with AML should be tested for IDH mutations for 2 reasons:We are learning more about what the prognostic impact of these mutations isThere are ongoing clinical trials in combining IDH inhibitors with standard of care chemotherapy, offering the possibility that we may be able to increase the overall survival rate in patients with AMLDr Stein: I think many academic centers are now routinely testing for IDH1 and IDH2 mutationsIn other locations, which may not have access to next generation sequencing or even standard polymerase chain reaction (PCR) testing, doctors have been sending samples to commercial testing companiesDr Tallman: What are the implications if an IDH mutation is found? Does that change the initial therapy? Does it change post-remission therapy?Dr Stein: At this point, in terms of standard of care therapy, it would not change what we do for induction and post-remission therapyDr Tallman: I would agree; I think it does not change initial therapy or post-remission therapy unless there is a clinical trial that might incorporate an IDH1 or IDH2 mutation inhibitor, either in induction or post-remission therapy

Additional Mutation Testing[5]Dr Stein: The literature on and the criteria for newly diagnosed AML suggest that patients be tested for NPM1 and CEBPα, in addition to IDH mutationsHaving a biallelic CEBPα mutation confers a better prognosis and may avoid an allogeneic bone marrow transplant as post-remission therapyTesting for an FLT3-ITD, and to some extent a tyrosine kinase domain mutation, would be standard of care, even in the absence of a clinical trial that might target any of those specific mutationsDr Tallman: An IDH mutation may not change initial or post-remission therapy unless there is a clinical trial; it sounds like the other mutations you mentioned really could alter post-remission therapy

Ongoing Clinical Trials[6-16]There are a wide variety of clinical trials now availableStudies showed substantial clinical activity with IDH inhibition, with overal change what we do for induction and post-remission therapy

Dr Tallman: I would agree; I think it does not change initial therapy or post-remission therapy unless there is a clinical trial that might incorporate an IDH1 or IDH2 mutation inhibitor, either in induction or post-remission therapy

Additional Mutation Testing[5]Dr Stein: The literature on and the criteria for newly diagnosed AML suggest that patients be tested for NPM1 and CEBPα, in addition to IDH mutationsHaving a biallelic CEBPα mutation confers a better prognosis and may avoid an allogeneic bone marrow transplant as post-remission therapyTesting for an FLT3-ITD, and to some extent a tyrosine kinase domain mutation, would be standard of care, even in the absence of a clinical trial that might target any of those specific mutations

Dr Tallman: An IDH mutation may not change initial or post-remission therapy unless there is a clinical trial; it sounds like the other mutations you mentioned really could alter post-remission therapy

Ongoing Clinical Trials[6-16]There are a wide variety of clinical trials now availableStudies showed substantial clinical activity with IDH inhibition, with overal response rates of approximately 30% to 53%; both agents were well tolerated, and the maximum tolerated dose was not reached for either agentThere was no dose-response association with the response rate observedDr. Stein: Now that we have had experience with IDH1 and IDH2 inhibitors in relapsed and refractory AML, these agents are being pushed into the first-line setting, in combination with standard of care chemotherapy

Differentiation Syndrome in Patients Treated With IDH Inhibitors[17]What is observed with the response in the population of patients with relapsed and refractory AML who receive single agent IDH inhibitors is reminiscent of what was seen in the initial stages of treating acute promyelocytic leukemia with all trans retinoic acid (ATRA)Morphologically, what is seen is the maturation of blasts from the myeloblast stage up to the mature neutrophil stage; and what is really interesting is that the IDH mutation from myeloblasts into neutrophils can actually be tracked, suggesting that these neutrophils are derived from the abnormal clone, even though they act normally and work well

Similarly, as seen with acute promyelocytic leukemia, a differentiation syndrome occurs in patients who receive differentiation therapy with IDH inhibitorsThis can manifest as noncardiogenic pulmonary edema, sometimes fevers, pericardial effusions, and pleural effusionsThese symptoms are responsive to steroid therapy (eg, dexamethasone 10 mg twice a day)In the initial data from phase 1/2 trials, differentiation syndrome occurs in approximately 5% to 10% of patients; it is still uncertain which patients are more likely to develop differentiation syndrome in this population

Dr. Stein: Historically, in the treatment of AML, hematologists/oncologists spent a lot of time intensifying the amount of chemotherapy given to patients, whether with additional agents like fludarabine, or higher doses of daunorubicinI think we are getting away from that now; it is time to move towards combining that intensified chemotherapy, like higher doses of daunorubicin, with targeted agentsThere are mutations in other genes that we are now able to target in AML; the field is moving to standard of care therapy in combination with inhibitors of specific mutationsThis is a targeted and personalized approach to the treatment of leukemia, for e.g., there is a drug called midostaurin that has been combined with standard of care induction chemotherapy and has showed an overall survival benefit in patients who have a FLT3 internal tandem duplicationWe hope that other targeted agents, like IDH inhibitors and inhibitors of other mutant proteins, will provide similar benefits to this patient population

Concluding RemarksThis presents a new era in the treatment of AML; a move away from more conventional cytotoxic chemotherapy and toward targeted therapy specifically targeted to a specific genetic or immunophenotypic antigenDr Stein: As you know, for a long time in the treatment of AML, we spent time intensifying the amount of chemotherapy we gave to patients; whether that was with additional agents added on, such as fludarabine; or whether it was with giving higher doses of drugs like daunorubicinAs you say, I think we are moving away from that a now. I think the feeling is in the field, that we have intensified a great deal to chemotherapy and gotten good mileage out of that, but it is time to move towards combining that intensified chemotherapy with targeted agents