Treatment considerations in older patients with AML


As part of the Blood 2021 Annual Scientific Meeting from 20–23 September 2021, the limbic attended a virtual AbbVie-sponsored presentation given by Professor Andrew Wei, a clinical acute myeloid leukaemia (AML) researcher at the Alfred Hospital in Melbourne, Australia. Here are some highlights from his talk on the treatment of older patients with AML.

What are the challenges faced when managing older patients with AML?

According to Prof. Wei, managing older patients is “one of the most difficult areas” of treating AML, particularly in those aged 70 years and older. He presented data provided to him by Gunnar Juliisson on behalf of the Swedish registry, that showed that the early death rate increased to ≥10% when intensive chemotherapy was delivered to AML patients aged 70 years and older. The success of treatment was also reduced in older AML patients.

Prof. Wei explained that the proportion of patients receiving intensive chemotherapy declines as patients get older due to “less confidence in the safety and efficacy of intensive chemotherapy.” Accordingly, data from the Swedish registry indicated that 2-year survival for patients aged 70 years and older was under 30%.1

What are the key considerations when choosing an appropriate treatment for older patients with AML?

Prof. Wei explained that the decision of whether to use non-intensive or intensive treatments in older patients with AML can be very challenging. “Initially, we often compare different treatments with respect to the impact on overall survival, the complete remission rate and the risk of early death,” said Prof. Wei. “However, you can see that the situation is far more complex than this,” he added.

Treatment considerations need to take into account age, performance score, frailty, functional capacity, prognosis, the patient’s acceptance of time spent in hospital, quality of life and potential complications from treatment.2

 What does the evidence say?

Current treatments for older patients with AML include hypomethylating agents, such as azacitidine, or low-dose cytarabine (LDAC). However, these treatments do not offer a significantly better alternative than intensive chemotherapy,” said Prof. Wei. Studies have reported a low rate of response (azacitidine – 28%3; LDAC – 18%4) and low overall survival (OS) (azacitidine – median OS – 10.4 months4; LDAC – ~4 months5) with these treatments in older AML patients (median age 74–75).3,4

Venetoclax is a selective small molecule BCL2 inhibitor and represents a new treatment option for adult patients with newly diagnosed AML ineligible for intensive chemotherapy.5,6 “There’s been a major shift in the management of older AML patients with the development of venetoclax,” said Prof. Wei. Venetoclax demonstrated improved benefits over azacitidine or LDAC monotherapy in two phase 3, multicentre, randomised, double-blind trials.5,7

 VIALE-A

Studied azacitidine plus venetoclax (n=286) vs azacitidine plus placebo (n=145) in AML patients ineligible for intensive chemotherapy due to age (≥75 years) or comorbidities. Unlike VIALE-C, this study excluded patients who had prior receipt of hypomethylating agents or favourable risk cytogenetics:5

  • Median follow-up: 20.5 months
  • Median OS (primary endpoint): 14.7 months vs 9.6 months (HR 0.66; 95% CI 0.52–0.85; p<0.001)
  • CR/CRi : 66.4% vs 28.3% (p<0.001)

VIALE-C

A study that ran alongside VIALE-A and evaluated LDAC plus venetoclax (n=143) vs LDAC plus placebo (n=68) in AML patients ineligible for intensive chemotherapy due to age (≥75 years) or comorbidities:7

  • At 12 months, the primary endpoint of overall survival was not statistically different between the two groups (7.2 versus 4.1 months; HR 0.75; 95% CI 0.52–1.07; P=0.11)
    • CR was 27% versus 7% (p<0.001)
    • CR/CRi was 48% versus 13%
  • Post-hoc analysis with additional 6 months of follow-up showed:
    • Median OS (primary endpoint): 8.4 months vs 4.1 months (HR 0.70; 95% CI 0.50-0.99) p=0.04)

Who can be treated with venetoclax?

At this stage, the clinical trial data would suggest that patients under 75 should only be treated [with venetoclax] if they have a comorbidity or low performance status, which would render them high risk for treatment-related mortality with intensive chemotherapy,” explained Prof. Wei. “If the patient is considered suitable for intensive chemotherapy, that still remains the standard of care,” he said.

Venetoclax

In the Viale-A clinical trial, patients were considered to be ineligible for standard induction chemotherapy if they were6:

  • ≥ 75 years of age

OR

  • ≥ 18 to 74 years and ≥1 of:
    • ECOG performance status of 2 or 3
    • Ejection fraction ≤ 50%
    • Chronic stable angina
    • DLCO ≤ 65% or FEV1 ≤ 65%
    • Creatinine clearance ≥30 mL/min to < 45 mL/min
    • Bilirubin > 1.5 to ≤0 × ULN
    • Other comorbidity

How do you manage adverse events with venetoclax?

One of the most important aspects of initial therapy with venetoclax-based therapies is to prevent tumour lysis syndrome (TLS). And this is because these treatments work very rapidly”, explained Prof. Wei. Clinical trials of venetoclax in AML have reported low rates of biochemical TLS (0–6%).5,7,9,10 There are a number of preventative measures for TLS; however, some patients will have a high risk of developing it. “I would almost always hospitalise these patients [at high risk of TLS], at least until the end of the dose ramp-up of venetoclax before considering management as an outpatient”, explained Prof. Wei.

Prof. Wei presented what he considers as the potential risk factors for TLS and preventative measures he takes to mitigate against it:

Potential risk factors for TLS Preventative measures for TLS
High WCC

NPM1 mutation

IDH mutation

High LDH

High marrow blasts

 

Reduce WCC to <25 x 109/L with hydroxyurea

Admit patients for IV hydration

Normalise electrolytes

Provide allopurinol +/- rasburicase (if risk factors present)

Omit CYP3A4 inhibitors for ≥5 half-lives

Commence venetoclax with a dose ramp up from 100 mg on day 1 to 200 mg on
day 2 to 400 mg on day 3 (and to 600 mg on day 4 if with LDAC) in the absence of CYP3A4 inhibitors.

Monitor TLS 4–6h after each ramp-up dose

 

* Venetoclax dose increase occurs incrementally over 3 days (in combination with AZA) or 4 days (in combination with LDAC)

There is an increased risk of neutropenia and febrile neutropenia, which can cause cycle delays and also require venetoclax dose duration reductions”, said Professor Wei, based on data from VIALE-A.6 Reduction in the dose of azacitidine–venetoclax or azacitidine–placebo owing to adverse events occurred in 3% and 4% of the patients. Discontinuations due to adverse events were similar in the two groups (24% in the azacitidine–venetoclax group and 20% in the control group).8

Refer to the venetoclax product information for full safety information including prophylaxis and monitoring recommendations for identified risks with treatment.

Concluding remarks

 “Venetoclax, in combination with low intensity therapies, represents a major breakthrough for patients with AML considered unfit for intensive chemotherapy”, summarised Prof. Wei. “Venetoclax gives patients and their physicians an important and effective alternative to previous therapies, that hopefully will deliver major improvements in this older patient population for many years to come.”

 AZA: azacitidine. AML: acute myeloid leukaemia. CI: confidence interval. CR: complete remission. CRi: complete remission with incomplete count recovery. DCLO: diffusion lung capacity for carbon monoxide. ECOG: Eastern Cooperative Oncology Group. FEV1: forced expiratory volume. HR: hazard ratio. IV=intravenous. LDAC: low-dose cytarabine. OS: overall survival. ULN: upper limit of normal. WCC: white cell count.

Disclosure

This article was commissioned and sponsored by AbbVie Pty Ltd. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing Venclexta (venetoclax), please review the full product information (link) or available from request from AbbVie. Treatment decisions based on these data are the responsibility of the prescribing physician.

Date of preparation: November 2021

References

  1. Juliusson G, et al. Blood 2019;134(18):1558–61.
  2. Wei AH. Blood 2021;138(5):356–58.
  3. Dombret H, et al. Blood 2015;126(3):291–99.
  4. Burnett A, et al. Cancer 2007;109(6):1114–24.
  5. DiNardo CD, et al. N Engl J Med 2020;383:617–29
  6. Tallman M et al. NCCN Guidelines Version 3.2021.
  7. Wei AH, et al. Blood 2020;135(24):2137–45.
  8. Venclexta (venetoclax) Product Information.
  9. DiNardo CD, et al. Blood 2019;133(1):7–17.
  10. Wei AH, et al. J Clin Oncol 2019;37(15):1277–84.
PBS Information: VENCLEXTA (venetoclax) in combination with rituximab is PBS listed for relapsed or refractory chronic lymphocytic leukaemia (CLL). VENCLEXTA in combination with obinutuzumab is PBS listed for first line treatment of CLL or small lymphocytic lymphoma (SLL). General Schedule listing. Authority required (telephone). Refer to PBS schedule for full authority information. VENCLEXTA monotherapy is not listed on the PBS. VENCLEXTA is not listed on the PBS for treatment of acute myeloid leukaemia (AML).

AbbVie Pty Ltd, Mascot, NSW 2020

AU-VENA-210059

 

 

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