Fast Facts: Acute Myeloid Leukemia

New Modular Targets - First New Treatment for decades

W. Blum, V. Mathews, William Blum, Vikram Mathews

• Publisher: S. Karger
• Year: 2018
• Print ISBN: 9781910797594
• eBook ISBN: 9781910797600
• Topic: Medicine
• Subtopic: Oncology

This last year has seen the approval of the first targeted treatments for acute myeloid leukemia (AML) - following decades with no new developments and a poor prognosis for most patients with the disease. The new drugs reflect the remarkable progress that has been made in our understanding of the pathophysiology of AML and its underlying cytogenetic and molecular abnormalities - which differ not only between patients but also within a patient over time and with treatment. 'Fast Facts: Acute Myeloid Leukemia' provides a comprehensive yet concise foundation for understanding AML: from basic epidemiology, diagnosis, classification and the current 'standard' treatment, through to recent advances in our understanding of the cytogenetic and molecular underpinnings of the disease, such as the IDH2 mutation, and the future for tailored therapy. It will be useful to primary care providers, medical students, specialist nurses, junior doctors and allied healthcare professionals who want to develop a thorough grounding in our evolving understanding of AML and its treatment.

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Treatment

Until relatively recently, a ‘one way fits all’ approach was used in the treatment of acute myeloid leukemia (AML). This chapter provides an overview of this standard therapeutic approach and illustrates the complexity of treatment decisions in weighing benefit versus risk in patients with different risk status. It also discusses novel approaches, including new targeted therapies that are emerging as our understanding of the genetic pathology of AML improves and the heterogeneity of the disease is recognized. Outcomes remain poor, highlighting the reality for AML patients that, when feasible, treatment on clinical trials remains the best option. The unique treatment of acute promyelocytic leukemia (APL) is considered separately at the end of this chapter.

Standard treatment

The standard treatment course for patients with newly diagnosed AML is:

• induction chemotherapy to remove the majority of malignant cells and restore normal hematopoiesis, followed, once remission is achieved, by

• consolidation therapy with either high-dose non-myeloablative chemotherapy or allogeneic hematopoietic cell transplantation (alloHCT) to effectively eliminate residual disease.

Standard induction chemotherapy

The regimen for standard induction chemotherapy was established from a series of studies conducted by the Cancer and Leukemia Group B in the 1970s and 1980s. It consists of daunorubicin for 3 days and cytosine arabinoside (cytarabine; AraC), 100–200 mg/m² per day, administered as a continuous infusion for 7 days, commonly known as the 3 + 7 schedule.¹ It is recognized today that previously used doses of daunorubicin 45 mg/m²/day were suboptimal; a dose intensity of daunorubicin 60–90 mg/m² is now the norm.

The aim of induction chemotherapy is complete remission (CR), defined morphologically as fewer than 5% blasts on a bone marrow aspirate, with recovery of blood counts to normal (hemoglobin > 110 g/L, absolute neutrophil count > 1000/mm³ and platelet count > 100 000/mm³). CR is achieved 4–5 weeks after initiating induction chemotherapy in 60–70% of patients. However, all patients require some form of consolidation therapy following achievement of CR to prevent disease recurrence. The definition of CR is further defined based on the detection of residual disease by cytogenetic or molecular testing. Treatment for patients who do not achieve CR after at least two cycles of induction chemotherapy (refractory or relapsed disease) is discussed on page 45.

Mortality due to complications after induction chemotherapy – largely due to infection – varies from 3% to 15% and is related to performance status (PS), age, leukemic complications at presentation and medical comorbidities.² PS refers to the general medical condition of the patient and is scored from 0 to 5, where PS 0 denotes a fully active patient and PS 4 denotes a completely disabled patient who is confined to bed/chair (PS 5 is dead). Assessment of organ function, medical comorbidities, PS and other disease- or patient-specific factors helps to determine patient ‘fitness’ for intensive therapy, but the final decision on eligibility remains largely subjective.

Use of alternative anthracyclines. While daunorubicin has been the most commonly used anthracycline in the management of AML, alternatives have been considered. Idarubicin has a potentially superior pharmacokinetic profile to daunorubicin. Comparisons of these two agents in four large trials showed a significant improvement in CR rates with idarubicin, but disease-free survival (DFS) improved in only one trial. Another large trial conducted by the French GOELAM group found no benefit with idarubicin in terms of inducing remission or long-term survival. Successive Eastern Cooperative Oncology Group studies demonstrated that daunorubicin 60 mg/m² and idarubicin 12 mg/m² had equivalent response rates (reviewed in Cassileth et al.¹). There was some suggestion that increasing the dose of daunorubicin to 90 mg/m² would improve outcomes;³ however, current opinion is that daunorubicin 60 mg/m²/day for 3 days is optimal, based on the balance between efficacy and toxicity.^4,5

High-dose AraC for induction. Several studies have explored the use of high-dose AraC (six doses of AraC 2–3 g/m² at 12-hour intervals) in induction chemotherapy. While a few earlier studies suggested a benefit,^6,7 more recent data, including the SWOG S1203 randomized controlled trial, showed no benefit of high-dose AraC (with or without vorinostat) over a conventional-dose 3 + 7 induction regimen.⁸

Newly approved drugs

After more than three decades with virtually no new agents, four new treatments were recently approved (Table 3.1). Midostaurin and enasidenib in particular highlight the value and potential for genetic testing in AML. Below are summarized new agents for initial therapy: midostaurin, CPX-351, and gemtuzumab ozogamicin. Enasidenib is discussed under the treatment of relapsed disease on page 47.

TABLE 3.1 New drugs approved for the treatment of AML in 2017
Drug (brand name; manu-facturer)	Mechanism of action	Date of FDA approval	Indication
Midostaurin (Rydapt; Novartis)	Inhibits FLT3 (plus PDGFR, KIT and other tyrosine kinases)	April 2017^*	Newly diagnosed FLT3-positive AML,^‡ in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation
Enasidenib (Idhifa; Celgene)	Oral inhibitor of IDH2, which catalyzes the conversion of isocitrate to alpha-ketoglutarate in the Krebs cycle	August 2017	Relapsed or refractory AML with IDH2 mutation^‡
CPX-351 (Vyxeos; Jazz Pharmaceuticals)	Cytarabine plus daunorubicin in a liposomal formulation for injection	August 2017	Newly diagnosed therapy-related AML or AML with myelodysplasia-related changes
Gemtuzumab ozogamicin (Mylotarg; Pfizer)	Anti-CD33 monoclonal antibody drug conjugate (antibody–calicheamicin)	Sept 2017^†	Adults with newly diagnosed CD33-positive AML Patients aged ≥ 2 years with relapsed or refractory CD33-positive AML
^* Approved by the European Medicines Agency (EMA), September 2017. †Positive opinion from the EMA Committee for Human Medicinal Products received February 2018. ‡As detected by an FDA-approved test. AML, acute myeloid leukemia; FDA, Food and Drug Administration; IDH, isocitrate dehydrogenase; PDGFR platelet-derived growth factor receptor.

Midostaurin is an oral multiple tyrosine kinase inhibitor (TKI) that mainly inhibits FLT3 but also PDGFR, KIT and other tyrosine kinases. Midostaurin was approved by the US Food and Drug Administration (FDA) in April 2017 for use in combination with standard intensive chemotherapy in the first-line treatment of adults with FLT3-mutated AML; the US label specifies use of the LeukoStrat CDx FLT3 Mutation Assay to detect the FLT3 mutation. Early clinical trials with midostaurin as monotherapy showed only modest clinical benefit, but this...

Table of contents

• Cover
• Title Page
• Copyright
• Contents
• List of abbreviations
• Introduction
• Epidemiology, pathophysiology and etiology
• Diagnosis
• Treatment
• Supportive care
• Prognosis and monitoring
• Research directions
• Useful resources
• Index