24/77 Treatment attenuation in acute myeloid leukaemia commissioning brief

Introduction

The aim of the HTA Programme is to ensure that high quality research information on the clinical effectiveness, cost-effectiveness and broader impact of healthcare treatments and tests are produced in the most efficient way for those who plan, provide or receive care from NHS and social care services. The commissioned workstream invites applications in response to calls for research on specific questions which have been identified and prioritised for their importance to the NHS, patients and social care.

Research Question

Is it feasible to conduct a randomised trial investigating the clinical and cost effectiveness of venetoclax treatment attenuation in acute myeloid leukaemia?

1. Patient group: Patients with newly diagnosed acute myeloid leukaemia (AML) who are deemed unfit for intensive chemotherapy on the grounds of age or co-morbidity. Applications are encouraged which include recruitment from geographic populations with high disease burden which have been historically underserved by research activity in this field.
2. Interventions: Attenuated dosing schedule of venetoclax. Applicants to define and justify. Applicants to consider treatment discontinuation/deintensification in patients who have achieved an elite response (no measurable residual disease, MRD). Applicants to define and justify. 
3. Control: Standard dose schedule as per NICE guidance.
4. Important outcomes and outputs: Number of patients potentially eligible for recruitment; potential recruitment rates; feasibility of trial delivery; acceptability of randomisation to patients and clinicians; determination of important outcomes for use in a future trial, to include health-related quality of life; need and feasibility for international recruitment.
   Applicants are encouraged to report recruitment and findings disaggregated by sex (and other demographic factors where relevant).  
5. Setting: Oncology centres.
6. Study design: A feasibility study to assess whether a substantive trial is possible and to establish key elements of the potential future trial design, including whether international recruitment is required. 

A decision on whether to advertise for a randomised trial will be made at a later date, once the results of the feasibility report are known. 

Rationale

Acute myeloid leukaemia (AML) is an aggressive and fast-growing cancer of the blood and bone marrow. AML is the most common acute leukaemia in adults, and the UK has the highest prevalence in Europe. AML occurs when genetic abnormalities cause immature white blood cells to accumulate. This accumulation of cancerous cells and reduction of normal functioning blood cells causes anaemia, bleeding problems and serious infections. This can result in a number of debilitating symptoms such as fatigue, weight loss, bone pain and enlarged organs.

Older adults with AML represent a particularly vulnerable population. They tend to have worse disease, are often not eligible for intense treatment and have higher rates of treatment mortality. The goal of treatment in AML is control and, where possible, eradication of disease.

Standard-of-care first line treatment for patients with AML is often intensive chemotherapy, however many patients in older age groups are not eligible for intensive chemotherapy. They are instead commonly treated with less intensive regimens, including low dose cytarabine (LDAC), a newer drug called venetoclax, and hypomethylating agents (HMA) – such as azacitidine or decitabine.

Although venetoclax combinations are now frontline treatment for elderly patients unfit for intensive chemotherapy, there are still significant side effects, and approximately 50% of patients require dose reduction. This often results in hospital or day unit admission.

Currently, there are no randomised trials comparing different doses or dosing schedules of venetoclax in AML, and the results of this study have the potential to impact treatment practice worldwide. Due to the significant toxicity often observed with venetoclax, it is very likely that patient quality of life would be substantially improved in patients treated with a de-escalated protocol. Older patients account for nearly half of those with AML, and because they are unfit or unlikely to benefit from conventional chemotherapy, they represent an important unmet need.

There is a need to evaluate the clinical and cost effectiveness of venetoclax treatment attenuation in patients with AML who are unfit for intensive chemotherapy. However, scoping and feasibility work is required prior to full evaluation. Therefore, the HTA programme wishes to commission research in this area to inform the development of a potential future trial.

Additional background information

A background document is available that provides further information to support applicants for this call. It is intended to summarise what prompted the call and the existing evidence base, including relevant work from the HTA and wider NIHR research portfolio. It was researched and written on the basis of information from a search of relevant sources and databases, and in consultation with a number of experts in the field. If you would like a copy please email htaresearchers@nihr.ac.uk.

Making an application

If you would like to apply for this funding opportunity, you can begin your application via the funding opportunity page.

Your application must be submitted online no later than 1pm on the 29th January 2025. Applications will be considered by the HTA Funding Committee at its meeting in March 2025.

Guidance notes and supporting information for HTA Programme applications are available

Shortlisted Stage 1 applicants will be given eight weeks to submit a Stage 2 application. The Stage 2 application will be considered at the Funding Committee in July 2025.

For commissioned topics, the Programme strongly discourages the practice of the same co-applicant joining more than one competing team, other than in unusual circumstances (for example, a lead from a named charity or a unique national expert in a condition).

For such exceptions, each application needs to state the case as to why the same person is included. The shared co-applicant should not divulge application details between teams, and both teams should acknowledge in their application that they are aware of the situation, and that study details have not been shared.

Should you have any queries please contact htagb@nihr.ac.uk