Importance of NGS and Targetable Mutations Stressed in AML

Suman Kambhampati, MD

There are many molecular subgroups in acute myeloid leukemia (AML) that reflect the evolution of the disease and aid in prognostication, according to Suman Kambhampati, MD. In recent years, certain mutations have provided clues as to how to optimally treat patients.

The prevalence of common mutations such as FLT3-ITD, BCL-2, and TP53 often indicate a poor prognosis. But, there are some exceptions, such as core-binding factor AML without c-KIT mutations, and the presence of a NPM1 mutation, which both indicate a better or neutral prognosis.

Impact of NGS

In a presentation during the 2018 OncLive^® State of the Science Summit™ on A Summer of Progress: Updates From ASCO 2018, Kambhampati, co-medical director of the Blood Cancer Program at Sarah Cannon Research Institute, discussed the impact of next-generation sequencing (NGS) on treatment selection, updates in the inhibition of BCL-2, IDH1/2, and FLT3-ITD, and new agents on the horizon for the treatment of patients with AML.One of the most discussed AML abstracts at the 2018 ASCO Annual Meeting, according to Kambhampati, investigated the impact of NGS on treatment selection for patients with AML.¹ This retrospective analysis looked at NGS of more than 1400 patients who were treated over a decade, beginning with a 53-gene panel, and followed by a 28-gene panel.

Investigators evaluated the impact of NGS in detecting actionable mutations and shed light on how this type of NGS research could aid in clinical trial selection, Kambhampati said. The 17 genes identified to be actionable were ALK, CSF1R, FGFR1, FGFR2, FGFR3, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, NPM1, NRAS, PDGFRA, PTPN11, RET, and TP53. An actionable mutation was defined as any gene that is potentially targetable directly or through a nearby pathway.

Results showed that 66% of patients with AML had 1 to 5 actionable mutations, with a median of 2. Investigators determined that about 65% of those patients enrolled on clinical trials.

“Those patients who were offered targeted therapy had a better relapse-free survival in both the newly diagnosed and relapsed/refractory settings. Thus, suggesting that NGS, the detection of actionable mutations, and offering targeted therapies could make a difference in the prospective treatment of these patients with AML,” Kambhampati said.

BCL-2 Inhibitors

If performing a wide-platform NGS test is not possible, then Kambhampati said that some of the important mutations to look for are IDH2 in relapsed/refractory disease, FLT3-ITD, NPM1, and TP53, as they have associated targeted therapies.AML cells have a high expression of BCL-2, said Kambhampati. Investigators are looking at combining venetoclax (Venclexta) with either decitabine or azacitidine in elderly patients with AML (NCT02203773).

Inclusion criteria for this study include an age of 65 years or older, ineligibility for standard induction therapy with cytarabine and anthracycline, and an ECOG performance status of 0 to 2. Key exclusion criteria include prior hypomethylating agents or chemotherapy for antecedent hematologic disorder, chimeric antigen receptor T-cell therapy, active central nervous system involvement, white blood count >25 x 10⁹ per liter, and infection with HIV, or hepatitis B or C.

Overall, venetoclax plus either decitabine or azacitidine demonstrated a tolerable safety profile. Investigators confirmed preliminary data which suggested that 400 mg of venetoclax is the optimal dose in this combination. Kambhampati said that early responses were promising across high-risk subgroups, such as those with poor cytogenetics, secondary AML, and aged 75 years and older.²

Kambhampati said that treating patients who have poor cytogenetics has traditionally been challenging as they struggle with chemotherapy. Best supportive care for these patients is the last resort after failure on demethylating therapies.

“With a median 15.6 months of follow up, the observed median overall survival (OS) was 17.5 months, with approximately 50% survival at 1 year,” said Kambhampati. “Pretty remarkable results compared with what we are used to with best supportive care and/or demethylating therapies.”

Additionally, minimal residual disease was achieved in more than 45% of patients treated with the 400 mg dose of venetoclax plus azacitidine.

IDH1 Inhibitors

“This abstract further adds to the body of literature showing that venetoclax plus a hypomethylating agent can achieve deeper responses and durable outcomes,” concluded Kambhampati.Approximately 20% of patients with AML harbor mutations in IDH1 and IDH2, although IDH2 mutations are more common, noted Kambhampati. These mutations tend to occur in patients who are older, have increased blasts, thrombocytopenia, diploid cytogenetics or trisomy 8, and those with NPM1 or FLT3-ITD mutations. IDH mutations are mutually exclusive with TET2 and WT1.

“[These factors] lead to a gain of function-mutant IDH, which leads to accumulation of 2-hydroxyglutarate. That leads to the inhibition of the TET2 enzyme, leading to a block of differentiation and proliferation of leukemia cells,” Kambhampati explained.

In August 2017, the FDA approved enasidenib (Idhifa) as a treatment for patients with relapsed/refractory IDH2-mutated AML, based on findings from the phase I/II AG221-C-001 study.³ Enasidenib showed a complete remission (CR) rate of 19.3% (95% CI, 13.8%-25.9%), and a median duration of CR of 8.2 months.

The FDA approved ivosidenib (Tibsovo) for the treatment of adult patients with relapsed/refractory IDH1-mutant AML in July 2018. The findings that led to this approval were from a single-arm phase I study of 174 patients with IDH1-positive relapsed/refractory AML.⁴ This study showed a CR rate of 24.7% (n = 43; 95% CI, 18.5%-31.8%) and the CR with partial hematologic improvement (CRh) rate was 8% (n = 14; 95% CI, 4.5%-13.1%). Additionally, the median duration of CR plus CRh was 8.2 months (range, 5.6-12).

“This is a breakthrough in the treatment of AML, given that IDH1 and IDH2 mutations are present in approximately 20% of patients with AML,” Kambhampati said.

FLT3 Inhibitors

Currently, the IDH1 inhibitor FT-2102 is being evaluated in a phase I dose-escalation study in patients with AML or myelodysplastic syndrome (MDS; NCT02719574).Targeting FLT3 mutations is another difficult task in AML given their frequency, said Kambhampati. About 25% to 30% of patients with AML present with a FLT3-ITD mutation at diagnosis. This proportion increases in patients with relapsed/refractory AML, he said.

Agents that are currently being used, either on clinical trial or in the clinic, are lestaurtinib, midostaurin (Rydapt), sorafenib (Nexavar), quizartinib, crenolanib, and gilteritinib.

In April 2017, the FDA approved midostaurin for the treatment of adult patients with newly diagnosed FLT3-positive AML in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

Most recently, the phase III QuANTUM-R study showed that the FLT3 inhibitor quizartinib reduced the risk of disease progression or death by 24% compared with salvage chemotherapy in patients with FLT3-ITD—positive relapsed/ refractory AML.⁵ Findings presented at the 2018 European Hematology Association Congress showed a median OS of 6.2 months with quizartinib (95% CI, 5.2-7.2) compared with 4.7 months with salvage chemotherapy (95% CI, 4.0-5.5) at a median follow-up of 23.5 months (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).

Novel Agents

“The QuANTUM-R trial is the first study to demonstrate that a FLT3 inhibitor significantly prolongs OS in relapsed/refractory FLT3-ITD AML patients compared with salvage chemotherapy,” Kambhampati said.Kambhampati shared information on 2 novel agents in the AML space.

The first, mivebresib (ABBV-075), is an oral pan-BET inhibitor that is currently being evaluated in a phase I, open-label, doseescalation study with monotherapy or combination dosing schedules (NCT02391480). To date, 23 patients with AML have been treated—12 with single-agent mivebresib and 11 in combination with venetoclax.

No dose-limiting toxicities have been reported so far, and the most common treatment-related adverse events (AEs) of any grade are fatigue (61%), anemia (52%), and dysgeusia (48%).6 Grade 3/4 AEs reported were anemia (52%), thrombocytopenia (44%), and febrile neutropenia (26%). Of those evaluable for efficacy (3/17), the overall response rate was 17.6%.

The second novel agent is bemcentinib (BGB324). This first-in-class, selective, orally bioavailable AXL inhibitor is currently being evaluated in a phase I/II trial in patients with relapsed/ refractory AML and MDS who have completed dose escalation and expansion.⁷

Thus far, investigators have established a maximum tolerated dose of 200 mg per day. Three patients have achieved a CR, and 3 have achieved a partial response of the 32 patients that have been treated.

References

1. Assi R, Alfonso A, Devendra KC, et al. Impact of next-generation sequencing (NGS) on treatment selection in acute myeloid leukemia (AML). J Clin Oncol. 2018;36(suppl 15; abstr 103). doi: 10.1200/JCO.2018.36.15_suppl.103.
2. Dinardo CD, Pratz KW, Potluri J, et al. Durable response with venetoclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia (AML). J Clin Oncol. 2018;36(15 suppl; abstr 7010).
3. Stein EM, Dinardo CD, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): results of a phase I dose-escalation and expansion study. J Clin Oncol. 2017;35(15 suppl; abstr 7004). doi: 10.1200/JCO.2017.35.15_suppl.7004.
4. FDA grants approval of TIBSOVO®, the first oral, targeted therapy for adult patients with relapsed/refractory acute myeloid leukemia and an IDH1 mutation. Published July 20, 2018. bit.ly/2mwqScv. Accessed July 24, 2018.
5. Cortes J, Khaled S, Martinelli G, et al. Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication—mutated (MUT) relapsed/refractory AML in the phase 3, randomized, controlled QuANTUM-R trial. Presented at: 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract LB2600.
6. Borthakur G, Wolff JE, Aldoss I, et al. First-in-human study of ABBV-075 (mivebresib), a pan-inhibitor of bromodomain and extra terminal (BET) proteins, in patients (pts) with relapsed/refractory (RR) acute myeloid leukemia (AML): preliminary data. J Clin Oncol. 2018;36(suppl; abstr 7019).
7. Gjertsen BT, Hellesøy M, Reikvam H, et al. Analysis of anti-leukemic activity, predictive biomarker candidates, immune activation and pharmakodynamics in R/R AML and MDS in response to treatment with bemcentinib (BGB324), a firstin- class selective AXL inhibitor, in a phase II open-label, multi-centre study. J Clin Oncol. 2018;36(suppl; abstr 7020).