Hypomethylating agents for the treatment of acute myeloid leukemia in the elderly

Abstract Introduction Risk-stratification of patients with acute myeloid leukemia (AML) can not only improve treatment response, but also reduce side effects of the treatment, especially in the elderly. A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with AML. However, comprehensive studies regarding the impact of genetic alterations in this group of patients are limited. Methods and Materials A total of 500 adult patients with newly diagnosed de novo AML who had enough bone marrow cryopreserved cells for analysis at the National Taiwan University Hospital were enrolled consecutively. We compared the clinico-biological features, cytogenetics and molecular gene mutations between patients aged 60 years or older (n=185) and those younger (<60 years, n=315). Result Among older patients, those received standard intensive chemotherapy had a longer overall survival (OS) than those treated with palliative care. Compared with younger patients, the elderly had a higher incidence of poor-risk cytogenetic changes, but a lower frequency of favorable-risk cytogenetics. The median number of molecular gene mutations at diagnosis was higher in the elderly than the younger. Older patients had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A, and P53 mutations but a lower frequency of WT1 mutations. In multivariate analysis for OS among the elderly who received standard intensive chemotherapy, high WBC >50,000/μL at diagnosis, RUNX1 mutations, DNMT3A mutations, and P53 mutations were independent worse prognostic factors, while the presence of NPM1 mutations in the abcence of FLT3/ITD mutations was an independent good prognostic factor. The frequency of acquiring one or more adverse genetic alterations was much higher in older patients than younger ones. Further, the pattern of gene mutations could divide older patients with intermediate cytogenetics into three groups with significantly different complete remission rates, OS, and disease-free survival. Conclusion Older AML patients frequently harbored high-risk cytogenetics and gene mutations, and had poorer prognosis. Integration of cytogenetics and molecular alterations could risk-stratify older patients into groups with significant different outcomes. For those patients with poor prognosis under current chemotherapy, novel therapies, such as demethylating agents or other targeted therapies may be indicated. Disclosures Tang: Novartis: Consultancy, Honoraria.

Download Full-text

Acute Myeloid Leukemia: Advanced Practice Management From Presentation to Cure

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2020.11.8.4 ◽

2020 ◽

Vol 11 (8) ◽

Author(s):

Meredith Beaton, RN, MSN, AG-ACNP ◽

Glen J. Peterson, RN, DNP, ACNP ◽

Kelly O'Brien, RN, MSN, ANP-C, ACNP-BC

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Performance Status ◽

Treatment Options ◽

Signs And Symptoms ◽

The Elderly ◽

Poor Performance Status ◽

Curative Therapy ◽

Initial Symptoms ◽

Acute Myeloid

Acute myeloid leukemia (AML) is the most common acute leukemia in adults, diagnosed in approximately 21,450 individuals annually in the US with nearly 11,000 deaths attributable to this disease (National Cancer Institute, 2020). Acute myeloid leukemia is a disease of the elderly, with the average age of diagnosis being 68 years old (Kouchkovsky & Abdul-Hay, 2016). It is a heterogeneous disease with widely varying presentations but universally carries a poor prognosis in the majority of those affected. Unfortunately, the 5-year overall survival rate remains poor, at less than 5% in patients over 65 years of age (Thein, Ershler, Jemal, Yates, & Baer, 2013). The landscape of AML is beginning to change, however, as new and improved treatments are emerging. Advanced practitioners (APs) are often involved in the care of these complex patients from the time of initial symptoms through diagnosis, treatment, and potentially curative therapy. It is vitally important for APs to understand and be aware of the various presentations, initial management strategies, diagnostic workup, and treatment options for patients with AML, especially in the elderly population, which until recently had few treatment options. This Grand Rounds article highlights the common presenting signs and symptoms of patients with AML in the hospital, including a discussion of the upfront clinical stability issues, oncologic emergencies, diagnostic evaluation, and current treatment options for elderly patients and those with poor performance status.

Download Full-text

Allogeneic Stem Cell Transplantation (Allo-Sct) in the Elderly Patients (Age > 65 Years) with Acute Myeloid Leukemia (AML) Is Safe and Effective

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2011.12.512 ◽

2012 ◽

Vol 18 (2) ◽

pp. S292

Author(s):

D. Jagadeesh ◽

J. Cerny ◽

M. Ramanathan ◽

G.D. Raffel ◽

L. Petrillo-Deluca ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Elderly Patients ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

The Elderly ◽

Acute Myeloid

Download Full-text

Phase 3 VERONA study of venetoclax with azacitidine to assess change in complete remission and overall survival in treatment-naïve higher-risk myelodysplastic syndromes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps7054 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS7054-TPS7054

Author(s):

Amer Methqal Zeidan ◽

Jacqueline Suen Garcia ◽

Pierre Fenaux ◽

Uwe Platzbecker ◽

Yasushi Miyazaki ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Hypomethylating Agents ◽

Newly Diagnosed ◽

Phase 3 ◽

Transfusion Independence ◽

Treatment Naïve ◽

The U.S ◽

Acute Myeloid

TPS7054 Background: Patients with higher-risk myelodysplastic syndromes (HR-MDS) experience peripheral cytopenias, disease progression to acute myeloid leukemia, and high mortality with expected median overall survival of less than 2 years. Allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative treatment. Patients ineligible for transplantation are treated with hypomethylating agents such as azacitidine (Aza), which is not curative and provides limited improvement in clinical benefit. Venetoclax (Ven) is a selective, potent, oral B-cell lymphoma-2 (BCL-2) inhibitor that is approved in the U.S. in combination with hypomethylating agents for treating older or co-morbid patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Ven is approved in the U.S. as first-line treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. For patients with treatment-naïve HR-MDS, Ven + Aza demonstrated manageable safety and a combined complete remission (CR)/marrow CR (mCR) rate of 79% in a single arm phase 1b study (NCT02942290). To confirm these benefits, the VERONA study, a randomized, double-blind, phase 3 study (NCT04401748) of patients with treatment-naïve HR-MDS, will assess the safety and efficacy of Ven combined with Aza including CR rate and overall survival. Methods: Patients (≥18 years) with newly diagnosed HR-MDS per WHO 2016 classification with = 20% bone marrow blasts per marrow biopsy/aspirate at screening will be enrolled at ̃200 sites globally (̃500 patients). Patients must have intermediate risk or higher IPSS-R (score > 3), ECOG ≤2, and be hematopoietic stem cell transplant (HSCT) eligible without any pre-arranged donor, or HSCT ineligible without a plan for HSCT at Study Day 1. De novo patients without prior hypomethylating agents, chemotherapy for MDS, or allogenic stem cell transplantation are eligible. Patients will be randomized 1:1 to receive placebo or Ven 400 mg oral tablet once daily on Days 1-14, both in combination with Aza 75 mg/m2 (intravenous or subcutaneous) on Days 7-0-0 or Days 5-2-2 per 28-days. Patients will receive study treatment until disease progression, unacceptable toxicity, HCT, withdrawal of consent, or discontinuation. The primary endpoints are CR rate (as adjudicated by investigator) per IWG 2006 criteria and overall survival. Secondary outcomes are red blood cell transfusion independence, platelet transfusion independence, change in fatigue as measured by Patient-Reported Outcomes Measurement Information System (PROMIS)-fatigue SF 7a scale score, time to deterioration in physical functioning domain of EORTC QLC-C30 scale, overall response (CR + partial response), and modified overall response (CR + mCR + partial response). Exploratory objectives are predictive biomarkers and pharmacokinetics. Clinical trial information: NCT04401748.

Download Full-text