Treatment of Acute Myeloid Leukemia

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1		Maximilian Fleischmann	+ 1399 word(s)	1399	2021-11-23 09:42:18	\|
2	format corrected.	Beatrix Zheng	Meta information modification	1399	2021-12-02 02:32:51	\|

This entry is adapted from the peer-reviewed paper 10.3390/cancers13225722

Acute myeloid leukemia (AML) is a heterogenous disease with a broad spectrum of cytogenetic and molecular aberrations contributing to the definition of distinct AML subgroups. Treatment options for patients suffering from AML are continuously expanding and targeted therapies are available for distinct molecularly defined subgroups. Nevertheless, AML treatment remains challenging; in particular, patients with high-risk AML not eligible for intensive treatment or allogeneic hematopoietic stem cell transplantation (alloHSCT) are characterized by an unfavorable outcome.

AML targeted therapy clinical trial resistance

1. Introduction

The occurrence of AML relapse is attributed to the persistence and clonal evolution of leukemic stem cells (LSCs). To date, the approval of AML-targeted therapy is mostly restricted to elderly AML patients or relapsed or refractory AML (r/r AML), while only a minority of patients who are refractory to chemotherapy subsequently undergo potential curative alloHSCT. Thus, current strategies of AML precision medicine aim to target the LSC compartment, to allow longer remission and to provide the chance of further consolidation treatment.

2. Epigenetic Treatment of AML

As an important mechanism in different types of cancer, aberrant hypermethylation of specific promotor regions contributes to elementary alterations in gene function, and cell regulation ^[1]. Today, HMAs, such as 5-azacitidine (AZA) or decitabine (DEC), are acting as inhibitors of DNA methyltransferases (DNMT), and are widely implemented in standard care of older and fragile AML patients. Introduction of HMAs has significantly improved OS compared to conventional regimens, such as low dose cytarabine (LDAC) or more intensive chemotherapy. Due to its well tolerability and efficacy compared with conventional palliative chemotherapy, HMAs became the backbone as well as in first line treatment in elderly patients not eligible for intensive treatment and as a treatment option in r/r AML ^[2]^[3]^[4]. Nevertheless, survival rates are not satisfying and efforts in increasing HMA efficacy are ongoing.

Currently, due to the pharmacological profile of AZA or DEC, respectively, treatment with HMAs requires subcutaneous or intravenous application over 5 to 7 days in 28-day cycles. In the phase III, multicenter and placebo-controlled QUAZAR AML-001 trial (median age 68 years, range 55–86) a novel oral formulation of AZA (CC-486) as maintenance therapy for patients with de novo AML in first remission after induction chemotherapy which are ineligible for subsequent alloHSCT has been investigated. In detail, a significant prolongation of OS (24.7 vs. 14.8 months for CC-486 and placebo, respectively) and PFS (10.2 vs. 4.8 months for CC-486 and placebo, respectively) with comparable adverse event profiles to injectable AZA could be demonstrated. AML relapse was observed in 60% of patients in the AZA group and in 77% in the placebo cohort, respectively ^[5].

For oral AZA, a more sustained epigenetic activity over the treatment course by a prolonged exposure time over 14 days is hypothesized. Notably, pharmacokinetic analysis demonstrated significant differences compared to parenteral AZA in terms of metabolization, while CC-486 is not considered as bioequivalent ^[6]. In the QUAZAR AML-001 trial, CC-486 compared to the placebo was also associated with a significantly reduced length and risk of hospitalization, which increases the patient’s quality of life and substantially safes costs ^[7]. FDA and EMA approvals were granted in September 2020 and June 2021, respectively, for treatment of AML in first remission as maintenance therapy following intensive induction chemotherapy who are not able to finish curative intended chemotherapy or undergo consolidation with alloHSCT.

De Lima and co-workers investigated CC-486 in a phase II trial as maintenance treatment in the situation of CR following alloHSCT ^[8]. They could demonstrate low relapse rates, low disease progression, and low GvHD rates as well as a good tolerance to drug exposure.

Furthermore, HMA in combination with donor lymphocyte infusions (DLI), in case of molecular relapse following alloHSCT, is a therapeutic option, which was investigated in the phase II RELAZA trial ^[9]. Another prospective phase II trial is investigating a potential additive effect of the immunomodulator lenalidomide as addition to AZA + DLI in setting of relapse of myelodysplastic syndrome (MDS) and AML with MDS related changes following alloHSCT. An interim analysis demonstrated a promising ORR of 68% and a median molecular relapse-free survival (RFS) of 183 days (range, 113–513) ^[10].

The Role of Venetoclax in HMA-Based Treatment

Recently, the BCL-2 inhibitor venetoclax has received FDA and EMA approvals for previously untreated elderly and unfit patients in combination with HMA or LDAC representing a remarkable improvement in a hard-to-treat patient cohort ^[11]^[12]. The underlying data result from the open labeled, multicenter VIALE-A trial including 431 previously untreated AML patients (median age of 76 years) randomized in a 2:1 fashion into AZA/venetoclax and AZA/placebo, respectively. With a median follow-up of 20.5 months (range, 0.1 to 30.7 months), a significantly improved OS of 14.7 months for AZA/venetoclax compared to 9.6 months for AZA alone was achieved. Moreover, a higher CR rate (17.9% vs. 36.7%) to favor of the HMA plus venetoclax group could be shown ^[13]. An improvement was also seen presented in phase III VIALE-C trial when venetoclax was combined LDAC ^[14]. Both trials set a new standard in treatment of elderly AML patients, while the search for response predicting molecular signatures and subgroups is ongoing. In detail, NPM1-mutations are associated with excellent survival and response rates while TP53 or FLT3-ITD mutations are predictors for resistance towards HMA plus venetoclax ^[15].

The use of venetoclax in various treatment scenarios is under intensive investigation. Application of HMA plus venetoclax in the situation of r/r AML has not been analyzed systematically in clinical trials so far. In a phase II study, including 32 patients with r/r AML who received monotherapy venetoclax, only a moderate ORR with 19% was seen ^[16]. However, published retrospective data for HMA combination with venetoclax are providing promising results in treatment of patients with r/r AML where suitable treatment options are rare ^[17]^[18]^[19]^[20]^[21].

HMA plus venetoclax is also considered in relapsed AML following alloHSCT. A retrospective analysis of 32 patients demonstrated satisfying response rates when HMA/venetoclax is applied as salvage treatment or early at molecular relapse ^[22]^[23]. Using prior to alloHSCT HMA/venetoclax has shown an excellent ORR of 68.8% in a small cohort of 32 patients (including 19 with r/r AML and 13 with de novo AML), providing a feasible strategy of remission induction ^[24].

Improvement of response by adding venetoclax to intensive induction chemotherapy regimens is subject of current research. Results of phase I and II trials for the combination of FLAG-IDA (fludarabine, cytarabine, idarubicin and G-CSF) with venetoclax show convincing results regarding efficacy (ORR 70–97%), deep response (96% of de novo AML achieved MRD negative CR) accompanied by an acceptable safety profile ^[25]. Additionally, phase I trials combining venetoclax with frontline 7 + 3 daunorubicin/cytarabine based induction treatment (NCT03709758) or a phase II trial evaluating venetoclax, cladribine, AZA and LDAC combination for previously untreated AML patients in frontline (NCT03586609) will further yield evidence.

Preclinical studies indicate synergistic effects between FLT3 inhibitors plus venetoclax, which mainly seems to be caused by downregulation of MCL-1 und BCL(x)L ^[26]^[27]^[28]. Early clinical studies subsequently show positive effects and an acceptable safety profile for the combinations of FLT3 inhibitor plus HMA and FLT3 inhibitor plus venetoclax with ORRs of 65–80% and 85%, respectively ^[29]^[30]. Several studies investigating FLT3 inhibitors plus venetoclax combinations are ongoing: a phase I trial testing a combination of venetoclax and the second-generation TKI gilteritinib (NCT03625505) or a phase Ib/II trial for venetoclax and quizartinib, both in patients with FLT3 mutated r/r AML (NCT03735875). A Phase Ib study is combining gemtuzumab ozogamicin with venetoclax in patients with CD33 positive r/r AML (NCT04070768).

3. Conclusions

Cytogenetic, especially molecular genetic analysis of AML cells, at diagnosis and at relapse, is indispensable for risk stratification with respect to alloHSCT consolidation treatment, and to implement target therapies up-front.

Treatment algorithms for elderly AML patients not eligible for intensive chemotherapy have been changed and the addition of venetoclax to epigenetic therapy has improved survival of elderly AML patients tremendously. Understanding the molecular mechanisms of primary or acquired resistance to venetoclax-based regimens in AML is of importance to improve second-line strategies for those patients not responding adequately to this treatment. Several candidates that are responsible for resistance to venetoclax were identified and molecularly defined strategies (e.g., inhibition of MCL-1) have the potential to overcome resistance in this clinical setting.

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