Treating Newly-Diagnosed AML:
Hypothetical Patient Case Studies

Two case studies presented by
Dr Amer Zeidan, MBBS, MHS


This promotional feature has been funded by Pfizer who has had an influence on the content. This feature is intended for use by healthcare professionals.
PP-GDG-GBR-0062 | October 2020

Click here to view the prescribing information for DAURISMO®(glasdegib) | Click here to view the prescribing information for Cytarabine
DAURISMO is indicated, in combination with low-dose cytarabine, for the treatment of newly diagnosed de novo or secondary acute myeloid leukaemia (AML) in adult patients who are not candidates for standard induction chemotherapy.1

DAURISMO can cause embryo-fetal death or severe birth defects when administered to a pregnant woman.1 DAURISMO present in semen may cause harm or death to an unborn child.1 Male patients prescribed DAURISMO must be provided with a patient alert card by healthcare providers (HCPs).

Click here for more information on the DAURISMO therapy management guide | Click here for the DAURISMO risk management plan summary

The standard of care treatment option for younger, and suitably fit, patients with AML is intensive induction chemotherapy.2,3 However, for many elderly patients with AML, this treatment pathway is not an option due to pre-existing co-morbidities.2,3 Historically, the prognosis is poor for these patients and treatment options have been limited to clinical trials or palliative care.3,4 However, the treatment landscape is rapidly evolving in AML, with a number of targeted therapies approved in the last couple of years.5

In 2020, the European Medicines Agency (EMA) approved the use of glasdegib in combination with low-dose cytarabine (LDAC) for the treatment of adult patients with newly diagnosed de novo or secondary AML who are not eligible for standard induction chemotherapy.1,6

This approval was supported by data from the Phase II BRIGHT AML 1003 study in which 116 adult patients with de novo or secondary AML who were not suitable for intensive chemotherapy were randomized 2:1 to receive glasdegib + LDAC or LDAC alone.*1,7

After a median follow-up of 20 months, glasdegib + LDAC resulted in superior, extended overall survival, with a median of 8.3 months (95% CI, 4.72-12.2) vs 4.3 months (95% CI, 1.9-5.7) with LDAC alone (HR 0.463; P = 0.0002).1

The goal of therapy for patients with newly diagnosed AML who are not candidates for intensive chemotherapy, is to achieve clinical benefit, extend survival, and maintain or improve quality of life.2
Below, Dr Amer Zeidan, a leading hematologist, discusses two typical cases he sees in his clinic, and the factors he considers when making treatment decisions for these patients.

 

*The full study population (N = 132) included 116 patients with AML.7 The efficacy results presented here are from the AML population only, this sub-population analyses show numerical benefit for patients but are not powered for statistical significance1

Case Study 1: An 80-year-old female patient with newly diagnosed secondary AML

So how would I treat this patient? I would first discuss the goals of care with her. In many older patients with acute myeloid leukemia, the treatment goal is palliative and not curative; taking into consideration the patient’s quality of life and aiming to reduce transfusions and infection, keep the patient out of the hospital, and ideally prolong survival

Case Study 2: A 78-year-old male patient with de novo AML

‘Glasdegib plus low-dose cytarabine also offers the potential for treatment at home, minimizing the frequency of visits to the clinic’

‘Glasdegib plus low-dose cytarabine had a median overall survival of 8.3 months versus 4.3 months with low-dose cytarabine alone’1

Glasdegib mechanism of action

Glasdegib is a selective inhibitor of SMO, a key component of the Hh signaling pathway in LSCs.1,8

Preclinical research suggests that the Hedgehog pathway plays a role in regulating the self-renewal and dormancy of LSCs in some hematologic malignancies.8-10

 

The Hh pathway: Active state8,10-12

1. Extracellular Hh ligand binds to PTCH on the stem cell surface
2. PTCH releases suppression of SMO
3. SMO activation leads to accumulation of GLI transcription factors in the nucleus
4. GLI activates transcription of target genes involved in stem cell renewal
5. This results in LSC self-renewal

 

 

Glasdegib inhibits the SMO receptor, a key mediator of Hh pathway signaling in leukemic stem cells1,8

1. Glasdegib binds to and inhibits SMO1,8
2. Inhibition of SMO results in decreased GLI transcription factor activity and                      downstream pathway signaling1

 

 

 

Based on preclinical evidence, glasdegib and LDAC are thought to work synergistically, with glasdegib sensitizing LSCs to the chemotherapeutic effects of LDAC1,8

1. Glasdegib chemosensitizes LSCs and limits LSC self-renewal1,8
2. Chemotherapy targets both the bulk leukemic blast cells and the                        sensitized LSCs8,13
3. This results in cell death8,13

The mechanism of action of the combination is based on preclinical research and is not fully understood

 

GLI = glioma-associated oncoprotein; Hh = hedgehog; LDAC = low-dose cytarabine; LSC = leukemic stem cell; PTCH = patched; SMO = smoothened. 

Glasdegib safety profile

  • Glasdegib is indicated, in combination with LDAC, for the treatment of newly diagnosed de novo or secondary AML in adult patients who are not candidates for standard induction chemotherapy1
  • The tolerability and safety profile of glasdegib + LDAC is consistent with toxicities reported for elderly patients receiving chemotherapy and toxicities for other marketed smoothened inhibitors*7
  • For patients with mild, moderate, or severe hepatic or renal impairment, no dose adjustments are required when taking glasdegib (no data are available in patients requiring hemodialysis)
  • The most frequently reported adverse reactions (ARs) (≥ 20%) in patients receiving glasdegib were anemia (45.2%), hemorrhages (45.2%), febrile neutropenia (35.7%), nausea (35.7%), decreased appetite (33.3%), fatigue (30.9%), muscle spasms (30.9%), thrombocytopenia (30.9%), pyrexia (29.7%), diarrhea (28.5%), pneumonia (28.5%), dysgeusia (26.1%), edema peripheral (26.1%), constipation (25.0%), abdominal pain (25.0%), rash (25.0%), dyspnea (25.0%), vomiting (21.4%) and weight decreased (20.2%)1
  • The most frequent and significant Grade ≥ 3 ARs in patients receiving glasdegib included anemia (41.6%), febrile neutropenia (35.7%), thrombocytopenia (30.9%), pneumonia (23.8%), platelet count decreased (16.6%), neutrophil count decreased (13.0%), white blood cell count decreased (13.0%), hemorrhages (11.9%), neutropenia (11.9%), sepsis (5.9%), electrocardiogram QT prolonged (3.5%) and atrial fibrillation (2.3%)1


*The safety profile of glasdegib is based on data from clinical studies, including the BRIGHT AML 1003 study in 84 patients (AML, n = 75; high-risk MDS, n = 9)1 

Glasdegib method of administration

  • Glasdegib is a once-daily oral treatment regimen1
  • Glasdegib + LDAC may be administered as an outpatient or at-home treatment1,14
  • Glasdegib may be taken with or without food1
  • Patients should be encouraged to take their dose at approximately the same time each day1


Glasdegib special warnings and precautions for use: Embryo-fetal toxicity1

Glasdegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman, and may be present in semen. Therefore, glasdegib should not be used during pregnancy and in females of child-bearing age who are not using contraception. Male patients taking glasdegib must always use a condom (with spermicide, if available) when having sex with a female partner during treatment and for 30 days after the last dose. Male patients prescribed glasdegib must be provided with a patient alert card by HCPs.

Click here for more information on managing adverse reactions in the therapy management guide
Click here for the male patient alert card

▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected ARs.

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Adverse events should also be reported to Pfizer Medical Information on 0044 (0)1304 616161.

References

1. DAURISMO [summary of product characteristics]. Brussels, Belgium: Pfizer; 2020

2. Stein EM, DiNardo CD, Pollyea DA et al. Response kinetics and clinical benefits of nonintensive AML therapies in the absence of morphologic response. Clin Lymphoma Myeloma Leuk. 2020;20(2):e66-e75. doi: 10.1016/j.clml.2019.11.017

3. Palmieri R, Paterno G, De Bellis E, et al. Therapeutic choice in older patients with acute myeloid leukemia: A matter of fitness. Cancers (Basel). 2020;12(1). doi:10.3390/cancers12010120

4. Kantar Health CancerMPact® Treatment architecture: Western Europe; Acute myeloid leukemia. 2017

5. Fiorentini A, Capelli D, Saraceni F, et al. The time has come for targeted therapies for AML: Lights and shadows. Oncol Ther. 2020;8(1):13-32. doi:10.1007/s40487-019-00108-x

6. European Medicines Agency (EMA). Date of issue of marketing authorization. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/daurismo. Accessed: September 2020, Last update: July 2020

7. Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33(2):379-389. doi:10.1038/s41375-018-0312-9

8. Fukushima N, Minami Y, Kakiuchi S, et al. Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Sci. 2016;107(10):1422-1429. doi:10.1111/cas.13019

9. Justilien V, Fields AP. Molecular pathways: Novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res. 2015;21(3):505-513. doi: 10.1158/1078-0432.CCR-14-0507

10. Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med. 2013;19(11):1410-1422. doi:10.1038/nm.3389

11. Rimkus TK, Carpenter RL, Qasem S, et al. Targeting the sonic hedgehog signaling pathway: Review of smoothened and GLI inhibitors. Cancers (Basel). 2016;8(2):22. doi:10.3390/cancers8020022

12. Cochrane CR, Szczepny, A, Watkins DN, et al. Hedgehog signaling in the maintenance of cancer stem cells. Cancers (Basel). 2015;7(3):1554-1585. doi.org/10.3390/cancers7030851

13. Siveen KS, Uddin S, Mohammad RM. Targeting acute myeloid leukemia stem cell signaling by natural products. Mol Cancer. 2017;16(1):13. doi:10.1186/s12943-016-0571-x

14. Heuser M, Ofran Y, Boissel N, et al. Acute myeloid leukemia in adult patients: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(6):697-712. doi: 10.1016/j.annonc.2020.02.018

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