Resources for Hematology Fellows

Case Study: New Therapies for Acute Myeloid Leukemia

A 76-year-old woman presents to the emergency department following two weeks of progressive dyspnea and fatigue, and a new rash. Her medical history is significant for stage 2 chronic kidney disease, coronary artery disease, and diabetes.

Physical examination results are within normal limits, except for skin pallor and a petechial rash on the lower extremities bilaterally. She has an Eastern Cooperative Oncology Group (ECOG) performance status score of 1. Complete blood count with differential is significant for a white blood cell count of 18 × 109/L with 40 percent circulating blasts, hemoglobin 6.7 g/dL, and platelet count of 20 × 109/L. A bone marrow biopsy reveals a hypercellular marrow with 22 percent blasts, consistent with a diagnosis of acute myeloid leukemia (AML). Flow cytometry demonstrates CD33 negativity, and classic cytogenetic analysis revealed a normal karyotype. Molecular markers are pending for FLT3, IDH1, IDH2, and NPM1.

A pre-treatment echocardiogram is performed and is notable for mild global systolic dysfunction and a left-ventricular ejection fraction of 45 percent.

Which of the following is the most appropriate therapy?

  1. Gilternitinib
  2. Azacitidine and venetoclax
  3. Ivosidenib
  4. Liposomal daunorubicin and cytarabine
  5. Gemtuzumab ozogamicin

Answer

  1. Azacitidine and venetoclax

Explanation

The best treatment option for this patient is azacitidine and venetoclax. Recently, the U.S. Food and Drug Administration (FDA) approved the BCL-2 inhibitor venetoclax in combination with a hypomethylating agent for patients with newly diagnosed AML who are 75 years or older, or those with comorbidities that preclude the use of intensive induction chemotherapy.1 Approval was based on preliminary data published in February 2018 from a phase Ib study of 57 patients to evaluate the safety and efficacy of either azacitidine or decitabine in combination with venetoclax.2

Eligibility criteria included previously untreated patients aged 65 years and older with AML who were ineligible for standard induction therapy, ECOG performance status of 0 to 2, and intermediate-risk or poor-risk cytogenetics. During dose escalation, oral venetoclax was administered daily in combination with either decitabine (days 1-5) or azacitidine (days 1-7). Results from this study population showed a complete remission (CR) or CR with incomplete marrow recovery (CRi) in 61 percent of patients.2 A follow-up of the same clinical trial was recently published in January 2019 evaluating 145 patients.3 This study demonstrated a CR + CRi rate at all doses of 67 percent, with notable responses in those with poor-risk cytogenetics and those who were at least 75 years old. The median duration of CR + CRi was 11.3 months, with a median overall survival of 17.5 months.3

While this patient has newly diagnosed AML, her age and comorbidities, including CKD, borderline heart function, and diabetes, likely preclude her from being able to tolerate a standard induction chemotherapy regimen.4 Gilteritinib (answer A) is an oral kinase inhibitor that was recently approved for treatment of relapsed or refractory AML, with a FLT3 mutation based on interim analysis of 138 patients in the ADMIRAL trial, showing CR or CRh in 21 percent of patients.5 Answer D is incorrect because the liposomal form of daunorubicin and cytarabine is approved for indications of newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes,6 which is not the case with this patient. Additionally, the left ventricular dysfunction is a relative contraindication to the danunorubicin. Ivosidenib is an IDH-1 inhibitor approved for patients with relapsed or refractory AML with a mutation in the IDH-1 gene.7 While gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody, is well tolerated in older patients with newly diagnosed or relapsed AML, its approval is for treatment of CD33+ disease.8 It would be an inappropriate choice for this patient because her flow cytometry demonstrated CD33 negativity. It is also not used as a single agent for initial induction therapy.

In summary, for older patients with newly diagnosed AML, a hypomethylating agent in combination with venetoclax should be considered when comorbidities preclude the use of standard induction chemotherapy.

Case study submitted by Nicole Held, DO, and Talha Badar, MD, of Medical College of Wisconsin, Milwaukee, WI.

Resources 

  1. U.S. Food and Drug Administration FDA approves venetoclax in combination for AML in adults.. 2018.
  2. DiNardo CD, Pratz KW, Letai A, et al Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid luekaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 19:216-228.
  3. DiNardo CD, Pratz K, Pullarkat V, et al Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019 133:7-17.
  4. Kantarjian H, O’brien S, Cortes J, et al Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006 106:1090-1098.
  5. U.S. Food and Drug Administration FDA approves gilteritinib for relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation. 2018.
  6. Vyxeos (daunorubicin and cytarabine) package insert. Jazz Pharmaceuticals. 2017.
  7. U.S. Food and Drug Administration FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation. 2018.
  8. Sievers EL, Larson RA, Stadtmauer EA, et al Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001 19:3244-3254.
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