Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia

Highlights

• Relapsed and refractory AML remains an area of unmet clinical need.

• Cytogenetics and duration of first CR remain the most important prognostic factors.

• Treatment decisions should be based on patient characteristics and performance status.

• Intensive chemotherapy can induce second remission in up to 76% of younger adults.

• Novel agents need further randomised studies to confirm clinical benefit.

Abstract

Despite advances in understanding the complexities of acute myeloid leukaemia (AML), the treatment of refractory or relapsed AML (rrAML) remains a daunting clinical challenge. Numerous clinical trials have failed to identify new treatments or combinations of existing therapies that substantially improve outcomes and survival. This may be due, at least in part, to heterogeneity among study patients with respect to multiple inter-related factors that have been shown to affect treatment outcomes for patients with rrAML; such factors include age, cytogenetics, immunophenotypic changes, and (in the case of relapsed AML) duration of first complete remission, or if the patient has had a previous blood and marrow transplant (BMT). A clear understanding of disease characteristics and patient-related factors that influence treatment response, as well as expected outcomes with existing and emerging therapies, can aid clinicians in helping their patients navigate through this complex disease state.

Introduction

Acute myeloid leukaemia (AML) is the most common of the acute leukaemias among adults [1], with approximately 20,000 new cases expected in the US in 2015 [2] and an estimated incidence of 18,000 new cases annually in the European Union [3]. AML is primarily a disease of older adults; the median age at diagnosis is approximately 67 years [2]. Although survival has generally improved since the 1980s and 1990s, the 5-year relative survival rate still is only about 25% in the US [2] and is 15% to 20% in Europe [3], [4], [5], [6], [7].

Induction therapy with intensive chemotherapy regimens can produce a complete remission (CR) in about 50% to ≥80% of adult patients with newly diagnosed AML [8], [9]. However, this leaves many patients who do not respond to induction treatment. Also, even among patients who achieve CR, the majority eventually relapse despite receiving post-remission therapy; relapses can occur several months to years after the initial remission, but the risk is highest within the first 3 years after initial treatment [10], [11], [12]. Thus, refractory or relapsed AML (rrAML) is a relatively common clinical scenario, but one that is difficult to manage, as effective therapies are limited. Also, rrAML is a very heterogeneous disease in which patient and disease characteristics need to be carefully considered when managing treatment over time.

Overall, patients with rrAML have a poor prognosis and few treatment options, as there currently is no standard of care [8], [13]. Challenges in treating patients with rrAML include accurately assessing the disease prognosis and likelihood of achieving CR, selecting the salvage therapy that is most likely to succeed and that can be tolerated, and identifying patients for whom haematopoietic cell transplantation (HCT) is a viable option [14].

The purpose of this manuscript is to discuss the clinical considerations that present challenges in trying to achieve effective treatment of rrAML. In the context of these considerations, current treatment guidelines and emerging treatment options for rrAML in late-stage development are also reviewed. References for this review were identified through searches of PubMed with the search terms “(‘acute myeloid leukemia’ OR “acute myeloid leukaemia” OR “acute myelogenous leukemia” OR “acute myelogenous leukaemia”) AND (relaps*[ti] OR refractory [ti]) NOT child*” and were limited to those published in the last 10 years. Articles were also identified through reviews of reference lists from the retrieved articles and treatment guidelines. Only papers published in English were reviewed. The final reference list was generated on the basis of relevance to the scope of this review.