Molecular Analysis Should Guide Treatment Individualization in AML

Stefan Faderl, MD

Cytogenetic and molecular data are becoming increasingly important in the individualization of treatment for patients of acute myeloid leukemia (AML), according to a presentation by Stefan Faderl, MD, at the 2015 International Congress on Hematologic Malignancies.

In his talk, Faderl, from the John Theurer Cancer Center at the Hackensack University Medical Center in New Jersey, examined potential treatments and investigational approaches for patients with a variety of risk factors and molecular aberrations. Each example characterized the importance of cytogenetic information and proper risk stratification.

Intermediate Risk Younger Patients With AML

"Cytogenetic-molecular data are becoming increasingly crucial, not only at the initial point of making a diagnosis, or prognosticating, but also in the identification of treatment targets," Faderl said. "There are exciting new treatments in clinical studies, which hopefully at some point will make it into clinical practice."Risk stratification is generally conducted early in the treatment process for patients with AML, based on karyotype. This process has been refined over time to further classify the intermediate-risk population, in an attempt to better define outcomes.

"Traditionally, karyotyping has been one of the most important pretreatment factors to determine posttreatment outcomes, as far as it relates to relapse and survival," Faderl explained. "FLT3 mutations, NPM1, and CEBPA have formed the basis for revised risk stratification models, which have allowed for the some intermediate risk patients to be reassigned to other risk groups."

This redefinition of risk created favorable, intermediate-1, intermediate-2, and adverse subgroups. The favorable group is defined by core binding factor (CBF) AML while those with KIT mutations were moved to an intermediate-1 group. Adverse risk is characterized by TP53 mutations, monosomal karyotype, and other complex cytogenetic abnormalities.

The intermediate-2 risk group is classified by having no discernable favorable or adverse karyotype features. Treatment for these patients includes standard induction chemotherapy with 7 days of cytarabine and 3 days of daunorubicin (7+3). With this treatment, the projected 4-year overall survival (OS) rate is approximately 20% to 40% for this group of patients, Faderl explained.

Clinical studies have attempted to improve the standard 7+3 regimen with some success, in limited subgroups. High-dose daunorubicin (90 mg/m²) has been explored but has been found to elicit similar outcomes to the standard dose of the drug (60 mg/m²).

Additionally, studies have explored high-dose cytarabine (3 g/m²), with some improvements in efficacy along with a significant increase in mortality and side effects. In younger patients with adverse risk AML, there were some benefits with high-dose cytarabine.

"For younger patients, high-dose cytarabine seemed to particularly improve remissions in poor-risk AML, such as secondary or AML associated with poor-risk cytogenetics, indicating that higher-dose cytarabine might be able to overcome resistance associated with these particular clinical situations," Faderl said.

Clinical studies have sought to add novel agents onto the standard 7+3 regimen, Faderl notes. The SAL-SORAML trial examined standard therapy plus sorafenib (n = 134) or placebo (n = 133) in younger patients with newly diagnosed AML.¹ In the study, sorafenib at 800 mg was given regardless of FLT3-ITD status, which was present in 17% of patients.

The complete remission (CR) was the same in both arms, at approximately 60%. The median event-free survival (EFS) was 20.5 months in the sorafenib arm versus 9.2 months with placebo. Additionally, the 3-year EFS rate was 40% with sorafenib versus 22% with placebo (P = .013).

The median relapse-free survival (RFS) was not yet reached in the sorafenib arm versus 23 months with placebo. The 3-year RFS rate was 56% versus 38% and the 3-year OS rate was 63% versus 56%, for sorafenib and placebo, respectively.

Common post-remission treatments for younger patients with intermediate-2 risk AML include allogeneic stem cell transplant (SCT), autologous SCT, or chemotherapy. In most situations, transplant induces better long-term outcomes than chemotherapy, Faderl noted.

Elderly or Unfit Patients With AML

"A number of factors contribute to the outcomes of chemotherapy or stem cell transplant," Faderl noted. "These factors are presenting white cell count in combination with a particular cytogenetic abnormality, time to response, MRD status, and inclusion of comorbidity scores."Before making a treatment decision in older patients with AML, Faderl stressed the importance of assessing the fitness status of the patient. A global geriatric assessment status should be used that goes beyond performance status and age. This assessment should look at social, emotional, functional, and psychosocial issues, Faderl noted.

"Treatment approaches in older patients with AML are typically dominated by the few treatments that patients can tolerate," Faderl said. "These patients have a different biological profile of blasts that makes AML in older patients more difficult to approach with the same combination therapy used in younger patients."

In a fit patient, cytogenetic-molecular features can be utilized to help make a treatment decision. During this assessment, two of the more important features include CBF and NPM1 mutation status, in the absence of a FLT3 mutation.

"For patients with these factors, use of intensive chemotherapy, meaning along the 3+7 line, makes sense," Faderl said. "This comes with the caveat that what is favorable in younger patients is not quite as favorable in older patients."

In the intermediate and high-risk group of patients, the treatment selection is not quite as straight forward for older patients with AML, Faderl said. In these patients, the goal is to preserve as much quality of life as possible, which generally results in the utilization of treatment with low-dose cytarabine (LDAC) or a hypomethylating agent.

To assess the role of hypomethylating agents, a retrospective study looked at the impact of intermediate-risk (n = 228) and high-risk (n = 74) cytogenetics on outcomes for patients with AML treated with azacitidine.² The median age in this study was 75 years.

This study did not find a statistical difference between responses seen in the intermediate- and high-risk groups. The median OS was significantly longer at 9.8 months in the intermediate group versus 5.4 months in the high-risk patients (P = .046). In patients who responded to azacitidine, the median OS was similar between the two groups (19.9 versus 19.3 months, intermediate- and high-risk, respectively).

"In clinical studies it has become a very popular approach and strategy to combine low-dose cytarabine or a hypomethylating agent with a number of established or newer drugs as a partner regimen," Faderl said.

In a randomized phase II trial, patients with AML who were not suited for induction therapy received LDAC (n = 45) or LDAC plus the polo-like kinase 1(PLK1) inhibitor volasertib (n = 42).³ The median age of patients in this trial was 75 years.

The CR rate with volasertib was 14% versus 7% with LDAC alone. The CR with incomplete blood count recovery rate was 17% with volasertib versus 7% with LDAC alone. The median EFS rate was 5.6 versus 2.3 months and the median OS was 8 versus 5.2 months, with volasertib plus LDAC and LDAC monotherapy, respectively.

"The combination group had significantly better complete remission and incomplete remission rates, including in 5 out of 14 patients with high-risk cytogenetics," Faderl explained. "This improvement in outcome came at some price of increase in toxicity, mainly myelosuppression."

KIT Mutated CBF-AML

In September 2013, volasertib in combination with LDAC received a breakthrough therapy designation from the FDA for its potential as a treatment for patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive remission induction therapy.In general, KIT mutations are present in approximately 20% to 30% of patients with CBF-AML, with a complete remission rate of nearly 90% with standard therapy. Although CBF-AML is generally considered a favorable subtype, the presence of a KIT mutation has been associated with an increased risk of relapse and shorter survival compared with the KIT wild type for CBF-AML.

To address the higher rate of relapsed in KIT-mutated patients with CBF-AML, a phase II study explored the addition of the KIT inhibitor dasatinib to standard 7+3 chemotherapy.⁴ Patients in the study represented a broad range of ages, with some up to 85 years old, Faderl noted.

Overall, the addition of dasatinib was effective across all molecular subtypes with a tolerable safety profile. The CR rate was nearly 90% across all arms of the study, including patients with KIT-mutations and those with wild-type KIT. Additionally, the 2-year disease-free survival rate was similar between patients with KIT mutations and those with wild-type tumors (70% versus 72%, respectively). The 2-year OS rate was 90% in KIT-mutated versus 86% in KIT wild type.

"Whenever you have this combination of CBF-AML with a KIT-mutation, one question that always comes to mind is should this patient now go to transplant or not," Faderl said. "I don't think there is any conclusive answer for this. Maybe this question is not the right one to start with, maybe it isn't as important that there is a KIT mutation, but rather how well the patients responds to treatment."

MLL Rearranged AML

In general, Faderl explained, the type of therapy and mutation status did not impact the rate of CR or relapse-free survival. However, whether the patient achieved minimal residual disease (MRD) negativity did have an impact on long-term outcome. Those with MRD-negative disease did far better than those with MRD-positive disease, suggesting the response to therapy should guide future therapy more than mutational status, in some situations.MLL rearrangements are associated with a poor outcome that is similar to those with a poor cytogenetic profile. In many situations, molecular aberrations are used for predicting prognosis; however, in many situations molecular testing is beginning to guide therapy, Faderl suggested.

"An MLL rearrangement essentially creates a fusion protein that involves the histone methyltransferase activity of the MLL protein," Faderl explained. "This leads to the recruitment of another histone methyltransferase, which is the DOT1L protein, forming a multiprotein complex. This leads to the methylation of particular histone residue and genes, which leads to the expression of 'wrong genes' that push the cell towards a leukemic cell."

One study to address this mechanism looked at the DOT1L inhibitor EPZ-5676 in patients with relapsed or refractory MLL-rearranged leukemia.⁵ The 37-patient study, the median age of patients was 53 and 14 had undergone a prior stem cell transplant. Overall, the agent was well tolerated and exhibited activity. Treatment with EPZ-5676 demonstrated inhibition of H3K79 methylation in 52% of patients. Additionally, CRs were observed in some patients.

More research continues to assess novel agents in AML, including FLT3 inhibition. In a phase II study the combination of the FLT3 inhibitor quizartinib with azacitidine or LDAC demonstrated a high-level of activity in patients with AML.⁶ Responses were seen in 18 of 26 patients (69%) across both arms of the study. The response rate was 63% with LDAC and was 72% with azacitidine.

In closing, Faderl noted that the collection of studies highlighted during his talk demonstrated where the field of AML was heading. The emphasis in the future will be closely focused on targeted therapies along with molecular and cytogenetic aberrations.

References:

1. Röllig C, Müller‐Tidow C, Hüttmann A, et al. Sorafenib versus placebo in addition to standard therapy in adult patients ≤60 years with newly diagnosed acute myeloid leukemia: results from the randomized‐controlled SORAML trial. Presented at: 2014 American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, California.
2. Pleyer L, Burgstaller S, Stauder R, et al. Azacitidine in Patients with Acute Myeloid Leukemia: Impact of Intermediate-Risk Vs High-Risk Cytogenetics on Patient Outcomes. Presented at: 2014 American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, California.
3. Döhner H, Lübbert M, Fiedler W, et al. Randomized Phase 2 Trial of LDAC ± Volasertib in AML Patients not Suitable for Induction Therapy. Blood. 2014;124(9):1426-1433.
4. Marcucci G, Geyer S, Zhao W, et al. Adding KIT Inhibitor Dasatinib (DAS) to Chemotherapy Overcomes the Negative Impact of KIT Mutation/over-Expression in Core Binding Factor (CBF) Acute Myeloid Leukemia (AML): Results from CALGB 10801 (Alliance). Presented at: 2014 American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, California.
5. Stein EM, Garcia-Manero G, Rizzieri DA, et al. The DOT1L Inhibitor EPZ-5676: Safety and Activity in Relapsed/Refractory Patients with MLL-Rearranged Leukemia. Presented at: 2014 American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, California.
6. Borthakur G, Kantarjian HM, O'Brien S, et al. The Combination of Quizartinib with Azacitidine or Low Dose Cytarabine Is Highly Active in Patients (Pts) with FLT3-ITD Mutated Myeloid Leukemias: Interim Report of a Phase I/II Trial. Presented at: 2014 American Society of Hematology Annual Meeting; December 6-9, 2014; San Francisco, California.

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